2-(methylamino)-1-phenylpropan-1-ol [(Pseudo)Eph] by Asch

Query Query

Results

Date

592 reactions in Reaxys

2016-09-08 16h:45m:01s (EST)

OH H N

1. Query

Search as: As drawn, No mixtures, No charges, No radicals

1/209

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HN -1

H 2O5Si2

racemate

Rx-ID: 26305700 View in Reaxys 1/592 Yield

Conditions & References in neat (no solvent), excess of guest compd., room temp. or 65°C, 24 h; powder X-ray diffraction Beneke, Klaus; Thiesen, Peter; Lagaly, Gerhard; Inorganic Chemistry; vol. 34; (1995); p. 900 - 907 ; (from Gmelin) View in Reaxys

H H 311C

H 11 C 3

H 2N

H N

Rx-ID: 9773826 View in Reaxys 2/592 Yield

Conditions & References Ding, Y.-S.; Mueller, M.; Schwaegler, M.; Alexoff, D.; Roesch, F.; Fowler, J. S.; Volkow, N. D.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 46; (2003); p. S373 - S373 View in Reaxys

H H 311C

NH 2

H 11 C 3

H N

Rx-ID: 9773827 View in Reaxys 3/592 Yield

OH O

H 2N H

11C

H 11 3 C

H N

Rx-ID: 41229547 View in Reaxys 4/592 Yield

Conditions & References With phenylsilane, zinc(II) chloride, C{N(2,6-iPr2C6H3)CH}2 in diethylene glycol dimethyl ether, Time= 0.333333h, T= 150 °C , chemoselective reaction Liger, Franois; Eijsbouts, Ture; Cadarossanesaib, Florence; Tourvieille, Christian; Le Bars, Didier; Billard, Thierry; European Journal of Organic Chemistry; vol. 2015; nb. 29; (2015); p. 6434 - 6438 View in Reaxys

H N

H 2N H

Rx-ID: 97350 View in Reaxys 5/592

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Yield

Conditions & References With aluminium Patent; Temmler-Werke; DE871155; (1938) View in Reaxys

O HO

H N

racemate

Rx-ID: 204887 View in Reaxys 6/592 Yield

Conditions & References Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys Kanao; Chem. Zentralbl.; vol. 98; nb. I; (1927); p. 2539 View in Reaxys Nagai; Kanao; Justus Liebigs Annalen der Chemie; vol. 470; (1929); p. 174; Chem. Zentralbl.; vol. 99; nb. II; (1928); p. 2553 View in Reaxys

O OH

H HN

racemate

Rx-ID: 204914 View in Reaxys 7/592 Yield

H N

NH racemate

Rx-ID: 333840 View in Reaxys 8/592 Yield

Conditions & References With diethyl ether Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys

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H N

OH –O

Na +

racemate

Rx-ID: 333844 View in Reaxys 9/592 Yield

Conditions & References Patent; C.H. Boehringer Sohn; DE673486; (1937); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 25; p. 339 View in Reaxys

H N

Rx-ID: 333847 View in Reaxys 10/592 Yield

Conditions & References With hydrogenchloride Chou; Journal of Biological Chemistry; vol. 70; (1926); p. 110,111 View in Reaxys With sulfuric acid, acetic anhydride, anschliessend Erhitzen des Reaktionsprodukts mit wss. Schwefelsaeure Welsh; Journal of the American Chemical Society; vol. 69; (1947); p. 128,130, 134 View in Reaxys Patent; Legerlotz; DE585164; (1932); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 20; p. 962 View in Reaxys

H N

OH H

racemate

Rx-ID: 333851 View in Reaxys 11/592 Yield

Conditions & References With sodium methylate, decalin, Trennung der Stereoisomeren mit Hilfe von Oxalsaeure Patent; C.H. Boehringer Sohn; DE673486; (1937); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 25; p. 339 View in Reaxys

H N

NH racemate

Rx-ID: 333852 View in Reaxys 12/592 Yield

Conditions & References With sodium ethanolate Patent; C.H. Boehringer Sohn; DE673486; (1937); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 25; p. 339 View in Reaxys

4/209

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O N

NH racemate

Rx-ID: 353589 View in Reaxys 13/592 Yield

Conditions & References With hydrogenchloride, palladium, Hydrogenation Patent; I.G. Farbenind.; DE524717; (1927); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 17; p. 2515 View in Reaxys With ethanol, nickel, Hydrogenation Patent; I.G. Farbenind.; DE526087; (1928); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 17; p. 463 View in Reaxys With ethanol, nickel, Hydrogenation Patent; I.G. Farbenind.; DE526087; (1928); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 17; p. 463 View in Reaxys With hydrogenchloride, nickel, Hydrogenation Patent; I.G. Farbenind.; DE526087; (1928); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 17; p. 463 View in Reaxys

H N

H HN

OH H

H racemate

Rx-ID: 356229 View in Reaxys 14/592 Yield

Conditions & References With diethyl ether Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys

–O

H HN

Na +

H HN

H racemate

racemate

Rx-ID: 356230 View in Reaxys 15/592 Yield

Conditions & References Patent; C.H. Boehringer Sohn; DE673486; (1937); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 25; p. 339 View in Reaxys

5/209

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H N

Rx-ID: 356232 View in Reaxys 16/592 Yield

Conditions & References With sulfuric acid, acetic anhydride, anschliessend Erhitzen des Reaktionsprodukts mit wss. Schwefelsaeure Patent; Legerlotz; DE585164; (1932); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 20; p. 962 View in Reaxys With hydrogenchloride Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys With hydrogenchloride, Gleichgewicht dieser Reaktion Emde; Helvetica Chimica Acta; vol. 12; (1929); p. 393 View in Reaxys

H racemate

Rx-ID: 356235 View in Reaxys 17/592 Yield

Conditions & References With sodium ethanolate Patent; C.H. Boehringer Sohn; DE673486; (1937); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 25; p. 339 View in Reaxys Reaction Steps: 2 1: hydrochloric acid 2: diethyl ether With hydrogenchloride, diethyl ether Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys

H N

Rx-ID: 356238 View in Reaxys 18/592 Yield

Conditions & References With hydrogenchloride Kanao; Yakugaku Zasshi; 1027,Nr.540,S.17; Chem. Zentralbl.; vol. 98; nb. I; (1927); p. 2539 View in Reaxys Acidic conditions

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Salouros, Helen; Sutton, Gordon J.; Howes, Joanna; Hibbert, D. Brynn; Collins, Michael; Analytical Chemistry; vol. 85; nb. 19; (2013); p. 9400 - 9408 View in Reaxys

NH racemate

Rx-ID: 356240 View in Reaxys 19/592 Yield

Conditions & References With sodium amide, decalin Patent; Abbott Labor.; US2214034; (1939) View in Reaxys With sodium hydride, decalin Patent; Abbott Labor.; US2214034; (1939) View in Reaxys

H N

H HN

racemate

Rx-ID: 393870 View in Reaxys 20/592 Yield

Conditions & References With sodium amalgam Fourneau; Kanao; Bulletin de la Societe Chimique de France; vol. <4> 35; (1924); p. 620 View in Reaxys Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 89 View in Reaxys Kanao; Chem. Zentralbl.; vol. 98; nb. I; (1927); p. 2538 View in Reaxys

0.098 g

With zinc(II) tetrahydroborate in diethyl ether, Time= 1h, T= -78 °C Fraser, David S.; Park, Sheldon B.; Chong, J. Michael; Canadian Journal of Chemistry; vol. 82; nb. 2; (2004); p. 87 - 101 View in Reaxys

H N

NH racemate

Rx-ID: 393871 View in Reaxys 21/592 Yield

Conditions & References With palladium, Hydrogenation Patent; Merck,E.; DE472466; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 16; p. 2835 View in Reaxys With aluminum isopropoxide, isopropyl alcohol

7/209

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Pfanz; Mueller; Archiv der Pharmazie (Weinheim, Germany); vol. 288; (1955); p. 11,20 View in Reaxys

H N

Rx-ID: 394193 View in Reaxys 22/592 Yield

Conditions & References With hydrogenchloride, T= 100 °C Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys

H N

Rx-ID: 437423 View in Reaxys 23/592 Yield

Conditions & References With lithium aluminium tetrahydride Takamatsu; Yakugaku Zasshi; vol. 76; (1956); p. 1227; ; (1957); p. 4304 View in Reaxys With sodium tetrahydroborate Takamatsu; Yakugaku Zasshi; vol. 76; (1956); p. 1227; ; (1957); p. 4304 View in Reaxys

H 2N

racemate

NH racemate

Rx-ID: 437468 View in Reaxys 24/592 Yield

Conditions & References durch Metylierung Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 258; (1920); p. 104 View in Reaxys

H 2N HO

H N

Rx-ID: 437481 View in Reaxys 25/592 Yield

Conditions & References With nickel, acetone, Hydrogenation Patent; I.G. Farbenind.; DE599433; (1930); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 21; p. 691 View in Reaxys

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H HN

NH racemate

racemate

Rx-ID: 438156 View in Reaxys 26/592 Yield

H HN

racemate

Rx-ID: 438157 View in Reaxys 27/592 Yield

Conditions & References With chromic acid, nachfolgende Hydrierung in Gegenwart von Nickel Patent; Merck,E.; DE495534; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 16; p. 2467 View in Reaxys

H N

racemate

Rx-ID: 438164 View in Reaxys 28/592 Yield

Conditions & References With L-(+)-tartaric acid Patent; I.G. Farbenind.; DE549970; (1929); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 19; p. 1446,1447 View in Reaxys Patent; I.G. Farbenind.; DE551778; (1929) View in Reaxys With lactase, Petroleum ether, benzene Lecoq; Bulletin de la Societe Royale des Sciences de Liege; vol. 12; (1943); p. 316 View in Reaxys With (2S,3S)-2,3-dihydroxybutanedioic acid Patent; I.G. Farbenind.; DE553788; (1927); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 18; p. 3032 View in Reaxys With hydrogenchloride, (S)-(+)-2-methyl-2-phenylbutanedioic acid, 1.) CHCl3, reflux, 30 min, 2.) Et2O, room temp., 30 min, Yield given. Multistep reaction Gharpure, Milind M.; Rao, A. S.; Synthesis; nb. 5; (1988); p. 410 - 411 View in Reaxys

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racemate

Rx-ID: 438165 View in Reaxys 29/592 Yield

Conditions & References With Petroleum ether, β-D-lactose, benzene, durch Chromathographie Lecoq; Bulletin de la Societe Royale des Sciences de Liege; vol. 12; (1943); p. 316 View in Reaxys

N H

racemate

Rx-ID: 441137 View in Reaxys 30/592 Yield

Conditions & References With sodium hydroxide Tanaka; Yakugaku Zasshi; vol. 70; (1950); p. 212,215; ; (1950); p. 7273 View in Reaxys With hydrogenchloride Pfanz; Wieduwilt; Archiv der Pharmazie (Weinheim, Germany); vol. 288; (1955); p. 563,578 View in Reaxys

H N

H HN

OH H

Rx-ID: 441934 View in Reaxys 31/592 Yield

Conditions & References With palladium on activated charcoal, perchloric acid, acetic acid, Hydrogenation Takamatsu; Yakugaku Zasshi; vol. 76; (1956); p. 1227; ; (1957); p. 4304 View in Reaxys

O O

N N O

H HN

OH H

Rx-ID: 448003 View in Reaxys 32/592 Yield

Conditions & References With hydrogenchloride Kanao; Yakugaku Zasshi; nb. 540; (1927); p. 18; Chem. Zentralbl.; vol. 98; nb. I; (1927); p. 2539 View in Reaxys

10/209

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O H

racemate

Rx-ID: 460248 View in Reaxys 33/592 Yield

Conditions & References With hydrogen bromide, T= 100 °C Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys

H N

H HN

NH 2

NH racemate

racemate

Rx-ID: 462842 View in Reaxys 34/592 Yield

Conditions & References With hydrogenchloride, Diazotization.die Diazoverbindung durch Behandlung mit unterphosphoriger Saeure und mit Kupferpulver oder durch Reduktion mit Zinn(II)-chlorid-Loesung und Salzsaeure und Erwaermen des entstandenen Hydrazins mit Kupfersulfat-Loesung Patent; I.G.Farbenind.; DE481436; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 16; p. 2833 View in Reaxys With hydrogenchloride, sodium nitrite, Diazotization.Versetzen der Diazoloesung mit Kupferpulver Patent; I.G.Farbenind; DE481436; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 16; p. 2833 View in Reaxys Patent; I.G.Farbenind.; DE481436; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 16; p. 2833 View in Reaxys With hydrogenchloride, Diazotization.die Diazoverbindung durch Reduktion mit Zinn(II)-chlorid-Loesung und Salzsaeure und Erwaermen des entstandenen Hydrazins mit Kupfersulfat-Loesung Patent; I.G.Farbenind; DE481436; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 16; p. 2833 View in Reaxys With hydrogenchloride, Diazotization.die Diazoverbindung durch Behandlung mit unterphosphoriger Saeure und mit Kupferpulver Patent; I.G.Farbenind; DE481436; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 16; p. 2833 View in Reaxys Ersetzen der Diazogruppe durch Wasserstoff.Diazotization Patent; I.G.Farbenind.; DE481436; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 16; p. 2833 View in Reaxys

HO N O

H HN

racemate

Rx-ID: 463103 View in Reaxys 35/592

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Yield

Conditions & References With coppered zinc, acetic acid Nagai; Kanao; Justus Liebigs Annalen der Chemie; vol. 470; (1929); p. 174; Chem. Zentralbl.; vol. 99; nb. II; (1928); p. 2553 View in Reaxys Kanao; Yakugaku Zasshi; vol. 49; (1929); p. 26; ; Chem. Zentralbl.; vol. 100; nb. I; (1929); p. 2411 View in Reaxys

–

N H H

Na +

H N

Rx-ID: 534697 View in Reaxys 36/592 Yield

Conditions & References T= 100 °C Emde; Helvetica Chimica Acta; vol. 12; (1929); p. 393 View in Reaxys

racemate

OH H

racemate

Rx-ID: 588059 View in Reaxys 37/592 Yield

Conditions & References With chloroform, phosphorus pentachloride, anschliessend Erhitzen des Reaktionsprodukts mit Wasser auf 100-110grad Skita; Keil; Meiner; Chemische Berichte; vol. 66; (1933); p. 974,979 View in Reaxys

H N

H OH

NH racemate

racemate

Rx-ID: 597821 View in Reaxys 38/592 Yield

Conditions & References Takagi; Yakugaku Zasshi; vol. 71; (1951); p. 655; ; (1952); p. 8046 View in Reaxys

H 2N

racemate

H N

racemate

OH H

racemate

Rx-ID: 770929 View in Reaxys 39/592 Yield

Conditions & References T= 20 - 25 °C , Lichtausschluss

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Stevens; Journal of the American Chemical Society; vol. 60; (1938); p. 3089 View in Reaxys Stevens; Allenby; DuBois; Journal of the American Chemical Society; vol. 62; (1940); p. 1424,1427 View in Reaxys

H 2N

H N

racemate

OH H

racemate

Rx-ID: 772211 View in Reaxys 40/592 Yield

Conditions & References With methanol, beim 4-woechigen Behandeln unter Lichtausschluss Stevens; Allenby; DuBois; Journal of the American Chemical Society; vol. 62; (1940); p. 1424,1427 View in Reaxys

H N

H 2N HO

Rx-ID: 772212 View in Reaxys 41/592 Yield

Conditions & References

64 %

With platinum(IV) oxide, hydrogen in methanol, acetic acid n-butyl ester, Time= 1h, p= 2250.2Torr Cervinka, Otakar; Struzka, Vladimir; Collection of Czechoslovak Chemical Communications; vol. 55; nb. 11; (1990); p. 2685 - 2691 View in Reaxys With ethanol, palladium, Hydrogenation Freudenberg; Schoeffel; Braun; Journal of the American Chemical Society; vol. 54; (1932); p. 234 View in Reaxys With diethyl ether, water, platinum, Hydrogenation Patent; Knoll A.G.; DE548459; (1930); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 18; p. 3032 View in Reaxys With diethyl ether, aluminium amalgam, water Patent; Knoll A.G.; DE548459; (1930); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 18; p. 3032 View in Reaxys With zinc(II) tetrahydroborate, 1.) ether, 0 deg C, 2.) -76 deg C, 1 h, Multistep reaction Jackson, W. Roy; Jacobs, Howard A.; Jayatilake, Gamini S.; Matthews, Barry R.; Watson, Keith G.; Australian Journal of Chemistry; vol. 43; nb. 12; (1990); p. 2045 - 2062 View in Reaxys

H 2N HO O

NH racemate

Rx-ID: 772213 View in Reaxys 42/592

13/209

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Yield

Conditions & References With ethanol, nickel, Hydrogenation Patent; I.G. Farbenind.; DE588880; (1930); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 20; p. 964 View in Reaxys With water, nickel, Hydrogenation Patent; I.G. Farbenind.; DE588880; (1930); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 20; p. 964 View in Reaxys

H 2N HO

racemate

Rx-ID: 772214 View in Reaxys 43/592 Yield

Conditions & References With methanol, platinum, p= 36775.4Torr , Hydrogenation Murahashi; Hagihara; Memoirs of the Institute of Scientific and Industrial Research, Osaka University; vol. 6; (1948); p. 96,98 View in Reaxys With diethyl ether, aluminium amalgam, water, p= 36775.4Torr , Hydrogenation Patent; Knoll A.G.; DE525837; (1929); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 18; p. 3035 View in Reaxys

H 2N

H HN

racemate

Rx-ID: 772699 View in Reaxys 44/592 Yield

Conditions & References With platinum(IV) oxide, ethanol Manske; Johnson; Journal of the American Chemical Society; vol. 51; (1929); p. 282 View in Reaxys With hydrogenchloride, Pt/Al2O3, colloid Skita; Keil; Chemische Berichte; vol. 62; (1929); p. 1145; Angewandte Chemie; vol. 42; (1929); p. 502 View in Reaxys With platinum(IV) oxide, ethanol, Hydrogenation Manske; Johnson; Journal of the American Chemical Society; vol. 51; (1929); p. 282 View in Reaxys With hydrogenchloride, Pt/Al2O3, colloid, water, Hydrogenation Skita; Keil; Chemische Berichte; vol. 62; (1929); p. 1145; Angewandte Chemie; vol. 42; (1929); p. 502 View in Reaxys

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H 2N

NH racemate

Rx-ID: 772700 View in Reaxys 45/592 Yield

Conditions & References With diethyl ether, aluminium amalgam, water Patent; Knoll A.G.; DE524806; (1929); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 18; p. 3034 View in Reaxys With methanol, sulfur dioxide, zinc Patent; Knoll A.G.; DE524806; (1929); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 18; p. 3034 View in Reaxys

OH H

H 2N

N H

Rx-ID: 806751 View in Reaxys 46/592 Yield

Conditions & References With benzene Foltz; Witkop; Journal of the American Chemical Society; vol. 79; (1957); p. 201,203 View in Reaxys Belzecki; Lange; Roczniki Chemii; vol. 28; (1954); p. 561,563, 567, 568; ; (1955); p. 6871 View in Reaxys Belzecki; Lange; Roczniki Chemii; vol. 33; (1959); p. 703,704, 709; ; (1960); p. 2236 View in Reaxys Fourneau; Benoit; Bulletin de la Societe Chimique de France; vol. <5> 12; (1945); p. 985,988 View in Reaxys

OH O

I H HN

OH H

Rx-ID: 842721 View in Reaxys 47/592 Yield

Conditions & References T= 100 °C Schmidt; Calliess; Archiv der Pharmazie (Weinheim, Germany); vol. 250; (1912); p. 163,169; Chem. Zentralbl.; vol. 82; nb. II; (1911); p. 33 View in Reaxys

H N

HN O O

Rx-ID: 1703267 View in Reaxys 48/592

15/209

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Yield

Conditions & References With lithium aluminium tetrahydride in tetrahydrofuran, Time= 14h, Heating, Yield given Jephcote, Vincent J.; Pratt, Andrew J.; Thomas, Eric J.; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); (1989); p. 1529 - 1535 View in Reaxys

H N

racemate

Rx-ID: 2198865 View in Reaxys 49/592 Yield

Conditions & References Brown; Moudachirou; Tetrahedron; vol. 50; nb. 34; (1994); p. 10309 - 10320 View in Reaxys Schmid; Wirnsberger; Guebitz; Pharmazie; vol. 51; nb. 11; (1996); p. 852 - 854 View in Reaxys OH

OH H N erythro erythro

Rx-ID: 2217358 View in Reaxys 50/592 Yield

Conditions & References With zinc(II) tetrahydroborate in diethyl ether, T= -76 °C Jackson, W. Roy; Jacobs, Howard A.; Matthews, Barry R.; Jayatilake, Gamini S.; Watson, Keith G.; Tetrahedron Letters; vol. 31; nb. 10; (1990); p. 1447 - 1450 View in Reaxys

H N

H O

H H

Rx-ID: 2555802 View in Reaxys 51/592 Yield

Conditions & References With water Abdallah, Hassan; Gree, Rene; Carrie, Robert; Tetrahedron Letters; vol. 23; nb. 5; (1982); p. 503 - 506 View in Reaxys

H N

H HN

OH H

Rx-ID: 2659629 View in Reaxys 52/592 Yield

Conditions & References With sodium tetrahydroborate, lithium aluminium tetrahydride, ozone, Multistep reaction. Title compound not separated from byproducts Kashima, Choji; Maruyama, Tatsuya; Fujioka, Yoko; Harada, Kazuo; Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999); (1989); p. 1041 - 1046

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View in Reaxys

H N

H HN

OH H

Rx-ID: 3041990 View in Reaxys 53/592 Yield

Conditions & References With sodium tetrahydroborate, lithium aluminium tetrahydride, other reagents, Product distribution Buckley, Thomas F.; Rapoport, Henry; Journal of the American Chemical Society; vol. 103; nb. 20; (1981); p. 6157 - 6163 View in Reaxys

H N

H HN

OH H

Rx-ID: 3043728 View in Reaxys 54/592 Yield

Conditions & References With lithium aluminium tetrahydride in tetrahydrofuran, Time= 2h, T= 60 °C , Yield given. Yields of byproduct given Buckley, Thomas F.; Rapoport, Henry; Journal of the American Chemical Society; vol. 103; nb. 20; (1981); p. 6157 - 6163 View in Reaxys

H N

Rx-ID: 3043731 View in Reaxys 55/592 Yield

Conditions & References

80 %

With lithium aluminium tetrahydride in tetrahydrofuran, Time= 1.5h, T= 60 °C Fujita, Makoto; Hiyama, Tamejiro; Journal of Organic Chemistry; vol. 53; nb. 23; (1988); p. 5415 - 5421 View in Reaxys

O H HO

H HN

OH H

Rx-ID: 3091694 View in Reaxys 56/592 Yield 90 %

Conditions & References With lithium aluminium tetrahydride in diethyl ether, Time= 2h, T= 55 °C Koehl, M; Spreitzer, H.; Fleischhacker, W.; Monatshefte fuer Chemie; vol. 123; nb. 10; (1992); p. 911 - 918 View in Reaxys

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OH H N erythro erythro

HO erythro N

erythro

N H

Rx-ID: 3192248 View in Reaxys 57/592 Yield

Conditions & References

91 %, 90 %, 91 %, 6.4 %, 0.5 %

With water, T= 25 °C , anodic oxidation, carbonate buffer, pH 10; effect of substituents investigated with different types of β-alkanolamines, Product distribution, Mechanism Masui, Masaichiro; Kamada, Yoshiyuki; Sasaki, Etuko; Ozaki, Shigeko; Chemical and Pharmaceutical Bulletin; vol. 30; nb. 4; (1982); p. 1234 - 1243 View in Reaxys OH H N erythro erythro

O erythro N

erythro

N H

Rx-ID: 3192464 View in Reaxys 58/592 Yield

Conditions & References

76 %, 79 With water, T= 25 °C , anodic oxidation, pH 10, carbonate buffer, Further byproducts given %, 56 %, 8 Masui, Masaichiro; Kamada, Yoshiyuki; Sasaki, Etuko; Ozaki, Shigeko; Chemical and Pharmaceutical Bulletin; % vol. 30; nb. 4; (1982); p. 1234 - 1243 View in Reaxys OH H N erythro erythro

O erythro N

erythro

N H

H 2N

Rx-ID: 3192465 View in Reaxys 59/592 Yield

Conditions & References

79 %, 56 With water, T= 25 °C , anodic oxidation, carbonate buffer, pH 10; effect of substituents investigated with different %, 76 %, types of β-alkanolamines, Product distribution, Mechanism 60 %, 8 %, Masui, Masaichiro; Kamada, Yoshiyuki; Sasaki, Etuko; Ozaki, Shigeko; Chemical and Pharmaceutical Bulletin; 7% vol. 30; nb. 4; (1982); p. 1234 - 1243 View in Reaxys

OH N H

H N

N H

H 2N

Rx-ID: 3198554 View in Reaxys 60/592 Yield

Conditions & References With hydrogenchloride, hydrogen, palladium on activated charcoal in ethanol, Time= 12h, T= 45 °C , p= 4045.3Torr , Yield given. Yields of byproduct given Takahashi; Tomita; Noguchi; Chemical and Pharmaceutical Bulletin; vol. 29; nb. 11; (1981); p. 3387 - 3391 View in Reaxys

OH N H

H N

H 2N

Rx-ID: 3198555 View in Reaxys 61/592

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Yield

Conditions & References With hydrogenchloride, hydrogen, palladium on activated charcoal in ethanol, Time= 8h, T= 50 - 60 °C , p= 4413.05Torr , Yield given. Yields of byproduct given Takahashi; Tomita; Noguchi; Chemical and Pharmaceutical Bulletin; vol. 29; nb. 11; (1981); p. 3387 - 3391 View in Reaxys

H N

OH H

H O

Rx-ID: 3210531 View in Reaxys 62/592 Yield

Conditions & References in dimethyl sulfoxide, T= 25 °C , Equilibrium constant Zingg, S. P.; Arnett, Edward M.; McPhail, Andrew T.; Bothner-By, Aksel A.; Gilkerson, W. R.; Journal of the American Chemical Society; vol. 110; nb. 5; (1988); p. 1565 - 1580 View in Reaxys

O HO

N H HO

H HO

Rx-ID: 3210532 View in Reaxys 63/592 Yield

H N

OH H

H N

H HO

H O

Rx-ID: 3210533 View in Reaxys 64/592 Yield

H N

H O

Rx-ID: 3210534 View in Reaxys 65/592 Yield

Conditions & References in dimethyl sulfoxide, T= 25 °C , Equilibrium constant

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Zingg, S. P.; Arnett, Edward M.; McPhail, Andrew T.; Bothner-By, Aksel A.; Gilkerson, W. R.; Journal of the American Chemical Society; vol. 110; nb. 5; (1988); p. 1565 - 1580 View in Reaxys

OH H

Rx-ID: 3210535 View in Reaxys 66/592 Yield

H N

OH OH

HO O

Rx-ID: 3210536 View in Reaxys 67/592 Yield

H H

N H OH

H N

OH OH

Rx-ID: 3210537 View in Reaxys 68/592 Yield

OH OH

OH HO H

H N

Rx-ID: 3210538 View in Reaxys 69/592 Yield

Conditions & References in dimethyl sulfoxide, T= 25 °C , Equilibrium constant

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Zingg, S. P.; Arnett, Edward M.; McPhail, Andrew T.; Bothner-By, Aksel A.; Gilkerson, W. R.; Journal of the American Chemical Society; vol. 110; nb. 5; (1988); p. 1565 - 1580 View in Reaxys OH

H N

H racemate

Rx-ID: 3498941 View in Reaxys 70/592 Yield

Conditions & References

80 %

With lithium aluminium tetrahydride in tetrahydrofuran, T= 60 °C Fujita, Makoto; Hiyama, Tamejiro; Journal of the American Chemical Society; vol. 106; nb. 16; (1984); p. 4629 4630 View in Reaxys

H N

OH erythro erythro

Rx-ID: 3605591 View in Reaxys 71/592 Yield

Conditions & References Prelog, Vladimir; Mutak, Stjepan; Helvetica Chimica Acta; vol. 66; nb. 7; (1983); p. 2274 - 2278 View in Reaxys Prelog, Vladimir; Mutak, Stjepan; Kovacevic, Krunoslav; Helvetica Chimica Acta; vol. 66; nb. 7; (1983); p. 2279 2284 View in Reaxys

H N

OH threo threo

H N

Rx-ID: 3605592 View in Reaxys 72/592 Yield

OH O

H N

Rx-ID: 3648539 View in Reaxys 73/592 Yield 100 %

Conditions & References With diethylamine, palladium diacetate, triphenylphosphine-3,3',3''-trisulfonic acid trisodium salt in water, acetonitrile, Time= 0.25h, Ambient temperature Genet, Jean Pierre; Blart, Errol; Savignac, Monique; Lemeune, Stephane; Lemaire-Audoire, Sandrine; Paris, Jean-Marc; Bernard, Jean-Marie; Tetrahedron; vol. 50; nb. 2; (1991); p. 497 - 503 View in Reaxys

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H N

H 2N HO

OH H N

Rx-ID: 3731677 View in Reaxys 74/592 Yield

Conditions & References With sodium tetrahydroborate, 1.) ether, 0 deg C, 30 min, 2.) from 10 deg C to RT, Yield given. Multistep reaction. Yields of byproduct given. Title compound not separated from byproducts Jackson, W. Roy; Jacobs, Howard A.; Jayatilake, Gamini S.; Matthews, Barry R.; Watson, Keith G.; Australian Journal of Chemistry; vol. 43; nb. 12; (1990); p. 2045 - 2062 View in Reaxys

HN O

Rx-ID: 3825544 View in Reaxys 75/592 Yield

Conditions & References

65 %

With lithium aluminium tetrahydride in tetrahydrofuran, Ambient temperature Kano, Shinzo; Yokomatsu, Tsutomu; Iwasawa, Haruo; Shibuya, Shiroshi; Tetrahedron Letters; vol. 28; nb. 50; (1987); p. 6331 - 6334 View in Reaxys

HN O O racemate

NH racemate

Rx-ID: 3825545 View in Reaxys 76/592 Yield

Conditions & References

93 %

With lithium aluminium tetrahydride in tetrahydrofuran, Time= 12h, Heating Heathcock, Clayton H.; Buse, Charles T.; Kleschick, William A.; Pirrung, Michael C.; Sohn, John E.; Lampe, John; Journal of Organic Chemistry; vol. 45; nb. 6; (1980); p. 1066 - 1081 View in Reaxys

N O O racemate

NH racemate

Rx-ID: 3826845 View in Reaxys 77/592 Yield 95 %

Conditions & References With potassium hydroxide Shono,Tatsuya; Matsumura, Yoshihiro; Kanazawa, Takenobu; Tetrahedron Letters; vol. 24; nb. 42; (1983); p. 4577 - 4580 View in Reaxys

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77 %

With potassium hydroxide, water in ethanol, Time= 2h, Heating, Hydrolysis Bach; Schroder; Journal of Organic Chemistry; vol. 64; nb. 4; (1999); p. 1265 - 1273 View in Reaxys

OH O

OH H

Rx-ID: 4002407 View in Reaxys 78/592 Yield

Conditions & References

100 %

With diethylamine, Pd(0) (in situ from Pd(OAc)2 and m.sulfonated triphenylphosphine) in water, acetonitrile, Time= 0.25h, 5 molpercent catalyst Lemaire-Audoire; Lemaire-Audoire, Sandrine; Savignac; Savignac, Monique; Blart; Blart, Errol; Pourcelot; Pourcelot, Guy; Genet; Genet, Jean Pierre; Bernard; Bernard, Jean-Marie; Tetrahedron Letters; vol. 35; nb. 47; (1994); p. 8783 - 8786 View in Reaxys

H N N

Rx-ID: 4292507 View in Reaxys 79/592 Yield

Conditions & References

263 mg

With hydrogen, palladium dihydroxide in methanol, Time= 0.75h, p= 760Torr , Ambient temperature Marco, Jose L.; Journal of Chemical Research, Miniprint; nb. 2; (1988); p. 684 - 690 View in Reaxys

OH H

Rx-ID: 4292508 View in Reaxys 80/592 Yield 263 mg

Conditions & References With hydrogen, palladium dihydroxide in methanol, Time= 0.75h, p= 760Torr , Ambient temperature Marco, Jose L.; Journal of Chemical Research, Miniprint; nb. 2; (1988); p. 684 - 690 View in Reaxys

H 2N

H HN

OH H

H 2N

H NH 2

Rx-ID: 4343210 View in Reaxys 81/592 Yield

Conditions & References With water, lithium chloride, lithium diisopropyl amide, Yield given. Multistep reaction. Yields of byproduct given

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Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys With water, lithium chloride, lithium diisopropyl amide, Yield given. Multistep reaction. Yields of byproduct given. Title compound not separated from byproducts Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

NH 2

OH N

NH 2

Rx-ID: 4366208 View in Reaxys 82/592 Yield

Conditions & References

86 %

With water, Time= 10h, Heating Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

NH 2

N H

NH 2

Rx-ID: 4376097 View in Reaxys 83/592 Yield

Conditions & References

88 %

With water, Time= 10h, Heating Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

NH 2

OH N

O H

OH NH 2

OH H

Rx-ID: 4376245 View in Reaxys 84/592 Yield 87 %

Conditions & References With water, Time= 10h, Heating Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

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NH 2

OH N

H O

NH 2

OH H

Rx-ID: 4376639 View in Reaxys 85/592 Yield

Conditions & References

77 %

With water, Time= 18h, Heating Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

OH N

Rx-ID: 4441084 View in Reaxys 86/592 Yield

Conditions & References

100 %

With 2-mercapto benzoic acid, 1,4-di(diphenylphosphino)-butane, bis(dibenzylideneacetone)-palladium(0) in tetrahydrofuran, Time= 0.25h, T= 20 °C Lemarie-Audoire, Sandrine; Savignac, Monique; Dupuis, Christophe; Genet, Jean Pierre; Bulletin de la Societe Chimique de France; vol. 132; (1995); p. 1157 - 1166 View in Reaxys

Rx-ID: 4619567 View in Reaxys 87/592 Yield

Conditions & References

90 %

With ammonium formate, palladium on activated charcoal, Time= 1h, Heating Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys

H N

Rx-ID: 4677217 View in Reaxys 88/592 Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether, Time= 2h, T= -10 - 20 °C , Yield given Effenberger, Franz; Gutterer, Beate; Jaeger, Juergen; Tetrahedron Asymmetry; vol. 8; nb. 3; (1997); p. 459 - 467 View in Reaxys

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H 2N

H N

H N H

Si O

Rx-ID: 4693934 View in Reaxys 89/592 Yield

Conditions & References With sodium tetrahydroborate, Yield given. Multistep reaction Effenberger, Franz; Gutterer, Beate; Jaeger, Juergen; Tetrahedron Asymmetry; vol. 8; nb. 3; (1997); p. 459 - 467 View in Reaxys

O racemate

racemate

Rx-ID: 4696687 View in Reaxys 90/592 Yield

Conditions & References

86 %

With lithium aluminium tetrahydride in tetrahydrofuran, T= 25 °C Bach, Thorsten; Schroeder, Juergen; Tetrahedron Letters; vol. 38; nb. 21; (1997); p. 3707 - 3710 View in Reaxys

86 %

With lithium aluminium tetrahydride in tetrahydrofuran, Time= 15h, T= 0 - 20 °C , Reduction Bach; Schroder; Journal of Organic Chemistry; vol. 64; nb. 4; (1999); p. 1265 - 1273 View in Reaxys

H N

Rx-ID: 4698041 View in Reaxys 91/592 Yield

Conditions & References With lithium aluminium tetrahydride in diethyl ether, Time= 1h, Heating, Yield given Effenberger, Franz; Gutterer, Beate; Jaeger, Juergen; Tetrahedron Asymmetry; vol. 8; nb. 3; (1997); p. 459 - 467 View in Reaxys

H N

OH H N H

Rx-ID: 4698768 View in Reaxys 92/592 Yield

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O O

S O

N O

racemate

Rx-ID: 4703660 View in Reaxys 93/592 Yield

Conditions & References With potassium hydroxide, sodium tetrahydroborate, 1.) DMSO, 150 deg C, 1 h; 2.) aq. EtOH, reflux, 2 h, Yield given. Multistep reaction Bach, Thorsten; Schroeder, Juergen; Tetrahedron Letters; vol. 38; nb. 21; (1997); p. 3707 - 3710 View in Reaxys Reaction Steps: 2 1: 72 percent / sodium borohydride / dimethylsulfoxide / 2 h / 150 °C 2: 77 percent / KOH; water / ethanol / 2 h / Heating With potassium hydroxide, sodium tetrahydroborate, water in ethanol, dimethyl sulfoxide, 1: Reduction / 2: Hydrolysis Bach; Schroder; Journal of Organic Chemistry; vol. 64; nb. 4; (1999); p. 1265 - 1273 View in Reaxys

P HO

O HN

Rx-ID: 4739131 View in Reaxys 94/592 Yield

Conditions & References With hydrogenchloride, Time= 48h, T= 80 °C , Yield given Schrader, Thomas; Chemistry - A European Journal; vol. 3; nb. 8; (1997); p. 1273 - 1282 View in Reaxys

O O

N H HN

racemate

Rx-ID: 5252467 View in Reaxys 95/592 Yield

Conditions & References With potassium hydroxide, nickel monoaluminide in methanol, Time= 24h, T= 25 °C , Reduction, denitrosation, Title compound not separated from byproducts Saavedra, Joseph E.; Farnsworth, David W.; Organic Preparations and Procedures International; vol. 23; nb. 2; (1991); p. 139 - 146 View in Reaxys With potassium hydroxide, aluminum-copper alloy in methanol, Time= 24h, T= 25 °C , Reduction, denitrosation, Title compound not separated from byproducts Saavedra, Joseph E.; Farnsworth, David W.; Organic Preparations and Procedures International; vol. 23; nb. 2; (1991); p. 139 - 146 View in Reaxys

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H 2N

H N

(1S,2R)-1-methylamino-1-phenyl-propan-2-ol (C10H15NO)

Rx-ID: 5497352 View in Reaxys 96/592 Yield

Conditions & References Foltz; Witkop; Journal of the American Chemical Society; vol. 79; (1957); p. 201,203 View in Reaxys Belzecki; Lange; Roczniki Chemii; vol. 28; (1954); p. 561,563, 567, 568; ; (1955); p. 6871 View in Reaxys Belzecki; Lange; Roczniki Chemii; vol. 33; (1959); p. 703,704, 709; ; (1960); p. 2236 View in Reaxys Fourneau; Benoit; Bulletin de la Societe Chimique de France; vol. <5> 12; (1945); p. 985,988 View in Reaxys

H 2N

(1R,2S)-1-methylamino-1-phenyl-propan-2-ol H

Rx-ID: 5508938 View in Reaxys 97/592 Yield

O OH

H 2N

H HN

racemate

OH H

(1RS,2RS)-1-methylamino-1-phenyl-propan-2ol ('(+-)-pseudoisoephedrine')

racemate

Rx-ID: 5554072 View in Reaxys 98/592 Yield

Conditions & References T= 100 °C Belzecki; Lange; Roczniki Chemii; vol. 33; (1959); p. 703,704, 709; ; (1960); p. 2236 View in Reaxys

H N

H O

Rx-ID: 5673531 View in Reaxys 99/592

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Yield

Conditions & References O.N-benzyliden-ephedrine Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 99; Chem. Zentralbl.; vol. 84; nb. II; (1913); p. 1310 View in Reaxys

H O

Rx-ID: 5673534 View in Reaxys 100/592 Yield

Conditions & References O.N-benzylidene-pseudoephedrine Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 99; Chem. Zentralbl.; vol. 84; nb. II; (1913); p. 1310 View in Reaxys

colloid/al platinum

NH racemate

Rx-ID: 5815390 View in Reaxys 101/592 Yield

Conditions & References T= 20 °C , p= 2280Torr , Kinetics Skita; Keil; Chemische Berichte; vol. 62; (1929); p. 1145; Angewandte Chemie; vol. 42; (1929); p. 502 View in Reaxys

H 2N

platinum

2-methylamino-1-phenyl-propanone-(1)

racemate

Rx-ID: 5815391 View in Reaxys 102/592 Yield

Conditions & References Hydrogenation Skita; Keil; Baesler; Chemische Berichte; vol. 66; (1933); p. 865 View in Reaxys

O OH

H 2N

platinum oxide

H HN

racemate

Rx-ID: 5815392 View in Reaxys 103/592 Yield

Conditions & References Hydrogenation

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Manske; Johnson; Journal of the American Chemical Society; vol. 51; (1929); p. 582 View in Reaxys

H N

Rx-ID: 6714150 View in Reaxys 104/592 Yield

Conditions & References Komponenten Patent; UCB; NL6605816; (1966); ; vol. 67; nb. 64437 View in Reaxys entspr. Stammverb., Nitrosierung Vilvala; Halmekoski; Farmaseuttinen Aikakauslehti; vol. 84; (1975); p. 115,118-120, 122, 124 View in Reaxys trans/cis-Epoxid, alkohol. H2NMe Mathew et al.; Current Science; vol. 42; (1973); p. 17 View in Reaxys Aus 2-Benzylmethylaminopropiophenon, kat. Red. Sekiya; Kawarabata; Chemical and Pharmaceutical Bulletin; vol. 18; (1970); p. 2081,2085 View in Reaxys (+-)-1-Phenyl-propan-1-ol-2-on, wss. Methylamin, NaBH4, Isolierung als Hydrochlorid, (neben (+-)-Ephedrin) Weichet,J. et al.; Collection of Czechoslovak Chemical Communications; vol. 26; (1961); p. 2040 - 2044 View in Reaxys <1-Methylamino-aethyl>-phenyl-keten-hydrochlorid, aethanol. Alkali, H2, Raney-Ni Fel'dman et al.; J. Appl. Chem. USSR (Engl. Transl.); vol. 35; (1962); p. 1364,1309; ; vol. 57; nb. 11064; (1962) View in Reaxys (+-)-1-Phenyl-propan-1-ol-2-on, wss. Methylamin, NaBH4, Isolierung als Hydrochlorid, (neben (+-)-Pseudoephedrin) Weichet,J. et al.; Collection of Czechoslovak Chemical Communications; vol. 26; (1961); p. 2040 - 2044 View in Reaxys Aus d. Keton, NaBCl4 Patent; Mueller; Baborowski; DD39123; (1965); ; vol. 63; nb. 17969b; (1965) View in Reaxys Keton, NaBCl4 Patent; Mueller; Baborowski; DD39123; (1965); ; vol. 63; nb. 17969b; (1965) View in Reaxys (+-)-ψ-Ephedrin, 1) K2Cr2O7/wss. H2SO4, 2) LiAlH4/Ae. Pierre; Baret; Handel; Annales pharmaceutiques francaises; vol. 34; nb. 3-4; (1976); p. 151 - 152 View in Reaxys

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H N

H HN

OH H

racemate

Rx-ID: 7051584 View in Reaxys 105/592 Yield

Conditions & References anschliessend Erwaermen mit Propenylbenzol und Kochen des Reaktionsprodukts mit 3n-HCl Foeldi; Chemische Berichte; vol. 63; (1930); p. 2262 View in Reaxys

H N

Rx-ID: 7364047 View in Reaxys 106/592 Yield 84%

Conditions & References II. Splitting with ephedrine 35.46 mmoles of racemic acid in solution in 50 ml of ether are placed in a flask. 17.73 mmols of (+) ephedrine in solution in 60 ml of ether are added with continuous stirring. It is left to crystallize at room temperature without stirring. The salt is filtered, washed with ether and dried under vacuum. The salt of the acid is obtained at a yield of 84percent MP=102°-116° C. [α]D 25 =+7.7° (c=1.2, MeOH). Patent; Societe Civile Bioprojet; US5599951; (1997); (A1) English View in Reaxys Mathew et al.; Current Science; vol. 42; (1973); p. 17 View in Reaxys Each of the following compounds exhibited a significant dose- and time-effect, with an interaction of dose and time (all Fs>2.7; all p values <0.01): (+)-amphetamine, (-)-ephedrine, (+)-ephedrine, (-)-norpseudoephedrine, (+)-norpseudoephedrine and mephentermine. Patent; Booth, Anthony; Caffrey, James L.; US2003/105332; (2003); (A1) English View in Reaxys More specifically, for example the following compounds can be given as said optically active aminoalcohols. Norephedrine Ephedrine 2-Amino-1-(2-methylphenyl)-1-propanol 2-Amino-1-(2-ethylphenyl)-1-propanol 2-Amino-1-(2-methoxyphenyl)-1-propanol 2-Amino-1-(2-ethoxyphenyl)-1-propanol 2-Amino-1-(2,5-dimethylphenyl)-1-pronanol 2-Amino-1-(2,5-diethylphenyl)-1-propanol 2-Amino-1-(2,5-dimethoxyphenyl)-1-propanol ... Patent; Sumitomo Chemical Company, Limited; US5145998; (1992); (A1) English View in Reaxys

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(3) Aryl- and heteroaryl ethanolamine derivative, including catecholamine, such as ... etilefrine octopamine synephrine phenylephrine ephedrine orciprenaline isoprenaline dichloroisoprenaline ... Patent; Speiser; Peter; Vaizoglu; M. Orhan; US4810697; (1989); (A1) English View in Reaxys Each of the esters of Examples 1 through 7 is converted to the following illustrative di-amine salts by the procedure of the invention. ammonia ... 2-amino-2-methyl-1-propanol N-methylglucamine ephedrine tetramethylammonium Patent; The Upjohn Company; US3962308; (1976); (A1) English View in Reaxys The optically active amine includes, for example, optically active compounds such as 1-phenyl-2-(p-tolyl)ethylamine, α-(1-naphthyl)-ethylamine, ... erythro- α,β-diphenyl-β-hydroxyethylamine, N-methylephedrine, N-(2,2,2-trichloro-1-formamideethyl)piperidine, 2-benzylamino-1-butanol, ephedrine, cis-N-benzyl-2-(hydroxymethyl)cyclohexylamine, N-(p-hydroxybenzyl)-1-phenylethylamine, N-(p-hydroxybenzyl)-1-(p-tolyl)ethylamine, ... Patent; Sumitomo Chemical Company, Limited; EP933349; (1999); (A1) English View in Reaxys XVIII : Resolution of chlocyphos with (-)-ephedrine and (+)-phencyphos EXAMPLE XVIII Resolution of chlocyphos with (-)-ephedrine and (+)-phencyphos To a solution of (-)-ephedrine (2,4 g) in 2-propanol (50 ml) was added (+)-phencyphos (1,75 g) and rac. chlocyphos (1,85 g). The mixture was heated to reflux and allowed to cool to RT. The salt (3,31 g) was treated with 10percent KOH/ toluene. The organic layer was acidified and the solid analyzed with HPLC (6). Both (+)-phencyphos and (+)-chlocyphos were enantiomerically pure (>98percent). Patent; DSM N.V.; US6235927; (2001); (B1) English View in Reaxys The optically active amine includes, for example, optically active compounds such as 1-phenyl-2-(p-tolyl)ethylamine, α-(1-naphthyl)-ethylamine, α-(2-naphthyl)-ethylamine, 1-phenylethylamine, erythro-α,β-diphenyl-β-hydroxyethylamine, N-methylephedrine, N-(2,2,2-trichloro-1-formamideethyl)piperidine, 2-benzylamino-1-butanol, ephedrine, cis-N-benzyl-2-(hydroxymethyl)cyclohexylamine, N-(p-hydroxybenzyl)-1-phenylethylamine,

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N-(p-hydroxybenzyl)-1-(p-tolyl)ethylamine, N-(p-hydroxybenzyl)-1-(p-isopropylphenyl)ethylamine, N-(p-hydroxybenzyl)-1-(p-nitrophenyl)ethylamine, N-(p-hydroxybenzyl)-1-(p-bromophenyl)ethylamine, ... Patent; Sumitomo Chemical Company, Limited; US6268525; (2001); (B1) English View in Reaxys

H N

(1R:2S)-2-<methyl-benzyl-amino>-1-phenyl-propanol-(1)-hydrochloride

Rx-ID: 7364048 View in Reaxys 107/592 Yield

Conditions & References With ethanol, palladium, Hydrogenation Patent; I.G. Farbenind.; DE538455; (1930); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 18; p. 3046 View in Reaxys With ethanol, water, Hydrogenation Patent; I.G. Farbenind.; DE538455; (1930); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 18; p. 3046 View in Reaxys

d-pseudoephedrine hydrochloride

H N

Rx-ID: 7364049 View in Reaxys 108/592 Yield

Conditions & References With barium dihydroxide, water, T= 170 - 180 °C , im Einschlussrohr Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys Schmidt; Calliess; Archiv der Pharmazie (Weinheim, Germany); vol. 250; (1912); p. 156; Chem. Zentralbl.; vol. 82; nb. II; (1911); p. 33 View in Reaxys With hydrogenchloride Schmidt,E.; Archiv der Pharmazie (Weinheim, Germany); vol. 246; (1908); p. 217 View in Reaxys

N-methyl-<l-ephedrine>-hydroxy methylate

H N

Rx-ID: 7364050 View in Reaxys 109/592 Yield

Conditions & References bei der Destillation einer waessr. Loesung Schmidt; Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 64,66 View in Reaxys

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H N

N-methyl-<l-ephedrine>-iodo methylate

Rx-ID: 7364051 View in Reaxys 110/592 Yield

Conditions & References With sodium amalgam, water Schmidt; Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 64,66 View in Reaxys

H N

(S)-2-methylamino-1-phenyl-propanone-(1)

Rx-ID: 7364052 View in Reaxys 111/592 Yield

Conditions & References With water, palladium, Hydrogenation Patent; I.G. Farbenind.; DE639126; (1935); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 23; p. 481 View in Reaxys

H N

H HN

OH H

Rx-ID: 7432161 View in Reaxys 112/592 Yield

Conditions & References T= 100 °C , Gleichgewicht dieser Reaktion Emde; Helvetica Chimica Acta; vol. 12; (1929); p. 393 View in Reaxys Erhitzen Flaecher; Archiv der Pharmazie (Weinheim, Germany); vol. 242; (1904); p. 380 View in Reaxys Schmidt,E.; Archiv der Pharmazie (Weinheim, Germany); vol. 244; (1906); p. 239 View in Reaxys Nagai; Chemiker-Zeitung, Chemische Apparatur; vol. 14; (1890); p. 441; Chem. Zentralbl.; vol. 59; (1888); p. 130 View in Reaxys Emde; Archiv der Pharmazie (Weinheim, Germany); vol. 244; (1906); p. 247,250 View in Reaxys

H N

H HN

OH H

Rx-ID: 7432162 View in Reaxys 113/592 Yield

Conditions & References T= 100 °C , teils ersatz von OH durch Br Emde; Helvetica Chimica Acta; vol. 12; (1929); p. 393 View in Reaxys

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H N

salt of (+)-ephedrine

racemate

Rx-ID: 7457746 View in Reaxys 114/592 Yield

Conditions & References With dextrorotatory α-lt;4-arsono-anilinogt;-propionic acid amide, ergibt das Salz des (-)-Ephedrins Fourneau; Nicolitch; Bulletin de la Societe Chimique de France; vol. <4> 43; (1928); p. 1239 View in Reaxys

H N

H H

Rx-ID: 7545185 View in Reaxys 115/592 Yield

Conditions & References Schmidt,E.; Archiv der Pharmazie (Weinheim, Germany); vol. 246; (1908); p. 217 View in Reaxys Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 248; (1908); p. 210 View in Reaxys T= 100 °C , Gleichgewicht Emde; Helvetica Chimica Acta; vol. 12; (1929); p. 393 View in Reaxys

Br H HN

H N

OH H

Rx-ID: 7545186 View in Reaxys 116/592 Yield

Conditions & References T= 100 °C , wobei das Gleichgewicht nach ca. 280 Stdn. erreicht wird,teils Ersatz von OH durch Br Emde; Helvetica Chimica Acta; vol. 12; (1929); p. 393 View in Reaxys

H HN

OH H

Rx-ID: 7584297 View in Reaxys 117/592 Yield

Conditions & References Mathew et al.; Current Science; vol. 42; (1973); p. 17 View in Reaxys Cleavage of Pseudoephedrine Auxiliary 21k (R9=n-propyl, R9b=H, m=1)

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Cleavage of Pseudoephedrine Auxiliary 21k (R9=n-propyl, R9b=H, m=1) To a solution of amide 21j (R9=n-propyl, R9b=H, m=1) (3.42 g, 8.22 mmol, 1 equiv) in MeOH (170 mL) at 23° C. was added 1.0 M aqueous NaOH (41.1 mL, 41.1 mmol, 5 equiv). The reaction was refluxed for 24 h (oil-bath temperature at 100° C.), then cooled to 23° C. and concentrated via rotary evaporation to remove most of the MeOH. The resulting aqueous solution was transferred to a separatory funnel, diluted with H2O (100 mL) and extracted with Et2O (100 mL). The ether extract was washed with 0.5 M aqueous NaOH (70 mL) then discarded. The combined basic aqueous layers were acidified to pH 2 with 1.0 N HCl, extracted with EtOAc (2*200 mL). The organic extracts were dried (MgSO4), filtered and concentrated to give the desired Boc-protected amino acid 21k (2.46 g) (R9=n-propyl, R9b=H, m=1). NMR (300 MHz, CDCl3) (Spectrum shows rotamers) 5.36 (d, J=22.8 Hz, 1H), 5.09 (d, J=4.8 Hz, 0.5H), 4.90 (br s,

0.5H), 4.14-3.97 (m, 1H), 3.83-3.67 (m, 1H), 2.57-2.37 (m, 2H), 1.98 (t, J=7.2 Hz, 2H), 1.48 (s, 6H), 1.47-1.35 (m, 2H), 1.46 (s, 3H), 0.86 (t, J=7.2 Hz, 3H); MS (ESPOS): 292.1 [M+Na]+; MS (ESNEG): 268.2 [M-H]-. Patent; Lewis, Jason G.; Anandan, Sampath K.; O'Dowd, Hardwin; Gordeev, Mikhail F.; US2005/215488; (2005); (A1) English View in Reaxys

(1S:2S)-1-chloro-2-methylamino-1phenyl-propane hydrochloride

H HN

OH H

Rx-ID: 7584298 View in Reaxys 118/592 Yield

Conditions & References With water, T= 100 - 110 °C Skita; Keil; Meiner; Chemische Berichte; vol. 66; (1933); p. 974,979 View in Reaxys

l-ephedrine hydrochloride

H HN

OH H

Rx-ID: 7584299 View in Reaxys 119/592 Yield

Conditions & References With sulfuric acid Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 121; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 52 View in Reaxys Emde; Helvetica Chimica Acta; vol. 12; (1929); p. 393 View in Reaxys Schmidt; Chem. Zentralbl.; vol. 82; nb. II; (1911); p. 33 View in Reaxys Schmidt; Calliess; Archiv der Pharmazie (Weinheim, Germany); vol. 250; (1912); p. 156; Chem. Zentralbl.; vol. 82; nb. II; (1911); p. 33 View in Reaxys With hydrogenchloride Flaecher; Archiv der Pharmazie (Weinheim, Germany); vol. 242; (1904); p. 380 View in Reaxys Schmidt,E.; Archiv der Pharmazie (Weinheim, Germany); vol. 244; (1906); p. 239 View in Reaxys

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Nagai; Chemiker-Zeitung, Chemische Apparatur; vol. 14; (1890); p. 441; Chem. Zentralbl.; vol. 59; (1888); p. 130 View in Reaxys Emde; Archiv der Pharmazie (Weinheim, Germany); vol. 244; (1906); p. 247,250 View in Reaxys

levorotatory α-bromo-β-methylamino-α-phenyl-propane hydrobromide

H HN

OH H

Rx-ID: 7584300 View in Reaxys 120/592 Yield

Conditions & References beim Aufbewahren der waessr. Loesung Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 121; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 52 View in Reaxys beim Erwaermen mit Silbernitrat-Loesung auf dem Wasserbad Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 121; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 52 View in Reaxys

N-acetyl-l-ephedrine

Rx-ID: 7584301 View in Reaxys 121/592 Yield

Conditions & References With hydrogenchloride Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 121; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 52 View in Reaxys Calliess; Chem. Zentralbl.; vol. 81; nb. II; (1910); p. 1480 View in Reaxys Schmidt; Calliess; Archiv der Pharmazie (Weinheim, Germany); vol. 250; (1912); p. 163,169; Chem. Zentralbl.; vol. 82; nb. II; (1911); p. 33 View in Reaxys

N-nitroso-l-ephedrine

H HN

OH H

Rx-ID: 7584302 View in Reaxys 122/592 Yield

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Schmidt; Calliess; Archiv der Pharmazie (Weinheim, Germany); vol. 250; (1912); p. 163,169; Chem. Zentralbl.; vol. 82; nb. II; (1911); p. 33 View in Reaxys

O-sulfuric acid ester of pseudoephedrine

H HN

OH H

Rx-ID: 7584303 View in Reaxys 123/592 Yield

Rx-ID: 7584304 View in Reaxys 124/592 Yield

Conditions & References Stork et al.; Tetrahedron Letters; (1979); p. 771,773 View in Reaxys Each of the following compounds exhibited a significant dose- and time-effect, with an interaction of dose and time (all Fs>2.7; all p values <0.01): (+)-amphetamine, (-)-ephedrine, (+)-ephedrine, (-)-norpseudoephedrine, (+)-norpseudoephedrine and mephentermine. Patent; Booth, Anthony; Caffrey, James L.; US2003/105332; (2003); (A1) English View in Reaxys 2 : Fluorodehydroxylation of D-Ephedrine EXAMPLE 2 Fluorodehydroxylation of D-Ephedrine D-Ephedrine, subjected to the same conditions as in Example 1, resulted a mixture of erythro-fluorodehydroxy-Dephedrine and threo-fluorodeoxy-D-ephedrine, in the form of hydrochloride salt. Patent; Merck and Co., Inc.; US4096180; (1978); (A1) English View in Reaxys

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(1S:2R)-2-<methyl-benzyl-amino>-1-phenyl-propanol-(1)-hydrochloride

Rx-ID: 7584305 View in Reaxys 125/592 Yield

Conditions & References With ethanol, palladium, Hydrogenation Patent; I.G. Farbenind.; DE538455; (1930); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 18; p. 3046 View in Reaxys With water, palladium, Hydrogenation Patent; I.G. Farbenind.; DE538455; (1930); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 18; p. 3046 View in Reaxys

(R)-2-methylamino-1-phenyl-propanone-(1) H

Rx-ID: 7584306 View in Reaxys 126/592 Yield

Conditions & References With water, palladium, Hydrogenation Patent; I.G. Farbenind.; DE639126; (1935); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 23; p. 481 View in Reaxys

H N

(+)-ephedrine hydrochloride

Rx-ID: 7789078 View in Reaxys 127/592 Yield

O N

nickel-cobalt-copper catalyst

NH racemate

Rx-ID: 7912716 View in Reaxys 128/592 Yield

Conditions & References T= 100 °C , p= 29420.3Torr , Hydrogenation Patent; I.G. Farbenind.; DE526087; (1928); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 17; p. 463 View in Reaxys

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nickel

NH racemate

Rx-ID: 7912717 View in Reaxys 129/592 Yield

Conditions & References T= 80 - 100 °C , p= 29420.3Torr , Hydrogenation Patent; I.G. Farbenind.; DE526087; (1928); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 17; p. 463 View in Reaxys Patent; Winthrop Chem. Co.; US1913520; (1928) View in Reaxys

O OH

nickel

NH racemate

Rx-ID: 7912718 View in Reaxys 130/592 Yield

H N

nickel

NH racemate

Rx-ID: 7912719 View in Reaxys 131/592 Yield

Conditions & References Hydrogenation Patent; Merck; DE469782; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 16; p. 2908 View in Reaxys

H N

O H

palladium/charcoal

NH racemate

Rx-ID: 7912720 View in Reaxys 132/592 Yield

Conditions & References unter geringem Ueberdruck.Hydrogenation Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 258; (1920); p. 104 View in Reaxys Patent; Merck; DE472466

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View in Reaxys

palladium

NH racemate

Rx-ID: 7912721 View in Reaxys 133/592 Yield

Conditions & References Hydrogenation Patent; I.G. Farbenind.; DE524717; (1927); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 17; p. 2515 View in Reaxys Patent; Winthrop Chem. Co.; US1913520; (1928) View in Reaxys

O OH

palladium

NH racemate

Rx-ID: 7912722 View in Reaxys 134/592 Yield

H N

platinum oxide

NH racemate

Rx-ID: 7912723 View in Reaxys 135/592 Yield

Conditions & References p= 1520 - 2280Torr , Hydrogenation Hyde; Browning; Adams; Journal of the American Chemical Society; vol. 50; (1928); p. 2290 View in Reaxys

H N

sodium amalgam

H HN

racemate

Rx-ID: 7912724 View in Reaxys 136/592 Yield

Conditions & References T= 0 - 5 °C Fourneau; Kanao; Bulletin de la Societe Chimique de France; vol. <4> 35; (1924); p. 620

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View in Reaxys Kanao; Yakugaku Zasshi; nb. 540; (1927); p. 18; Chem. Zentralbl.; vol. 98; nb. I; (1927); p. 2539 View in Reaxys Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 89 View in Reaxys

salt of (-)-ephedrine H

racemate

Rx-ID: 7925132 View in Reaxys 137/592 Yield

Conditions & References With dextrorotatory α-lt;4-arsono-anilinogt;-propionic acid amide, ergibt das Salz des (+)-Ephedrins Fourneau; Nicolitch; Bulletin de la Societe Chimique de France; vol. <4> 43; (1928); p. 1239 View in Reaxys

H N

aq.-ethanolic NaOH-solution

Rx-ID: 7989587 View in Reaxys 138/592 Yield

Conditions & References Welsh; Journal of the American Chemical Society; vol. 69; (1947); p. 128,130, 134 View in Reaxys

amalgamated aluminium HO

aqueous ether

H N

Rx-ID: 7989588 View in Reaxys 139/592 Yield

Conditions & References eines Gemisches.Hydrogenation Patent; Bilhuber Inc.; US1956950; (1931) View in Reaxys Patent; Knoll A. G.; GB360334; (1931) View in Reaxys

H 2N HO

H N

palladium

Rx-ID: 7989589 View in Reaxys 140/592 Yield

Conditions & References eines Gemisches.Hydrogenation Freudenberg; Schoeffel; Braun; Journal of the American Chemical Society; vol. 54; (1932); p. 234

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View in Reaxys

O HO

H N

platinum

H 2N

Rx-ID: 7989590 View in Reaxys 141/592 Yield

Conditions & References eines Gemisches.Hydrogenation Patent; Bilhuber Inc.; US1956950; (1931) View in Reaxys Patent; Knoll A. G.; GB360334; (1931) View in Reaxys

Cl H HN

barium hydroxide

water

H N

Rx-ID: 7989591 View in Reaxys 142/592 Yield

Conditions & References T= 170 - 180 °C , im Einschlussrohr Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys Schmidt; Calliess; Archiv der Pharmazie (Weinheim, Germany); vol. 250; (1912); p. 156; Chem. Zentralbl.; vol. 82; nb. II; (1911); p. 33 View in Reaxys

O O

N N

H O

H HN

OH H

Rx-ID: 7991366 View in Reaxys 143/592 Yield

Conditions & References bei der Siedetemperatur Kanao; Yakugaku Zasshi; nb. 540; (1927); p. 17; Chem. Zentralbl.; 1927I,2539 View in Reaxys

H N

H HO

H HN

OH H

Rx-ID: 7991367 View in Reaxys 144/592 Yield

Conditions & References Welsh; Journal of the American Chemical Society; vol. 69; (1947); p. 128,130, 134 View in Reaxys

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H N

O H

S OO

Rx-ID: 7991368 View in Reaxys 145/592 Yield

Conditions & References Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 121; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 52 View in Reaxys

O H HN

H N

S OO

H HN

OH H

Rx-ID: 7991369 View in Reaxys 146/592 Yield

Conditions & References Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 121; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 52 View in Reaxys

H N

Rx-ID: 7993964 View in Reaxys 147/592 Yield

Conditions & References Kanao; Yakugaku Zasshi; nb. 540; (1927); p. 18; Chem. Zentralbl.; vol. 98; nb. I; (1927); p. 2539 View in Reaxys

(1RS,2RS)-2-<benzyl-methyl-amino>-1phenyl-propan-1-ol hydrochloride

H HN

OH H

racemate

Rx-ID: 8096605 View in Reaxys 148/592 Yield

Conditions & References With water, nickel, Hydrogenation Pfanz; Mueller; Archiv der Pharmazie (Weinheim, Germany); vol. 288; (1955); p. 11,20 View in Reaxys

O HN

H HN

OH H

racemate

Rx-ID: 8096606 View in Reaxys 149/592

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Yield

Conditions & References T= 100 °C Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys

dl-ephedrine hydrochloride

H HN

OH H

racemate

Rx-ID: 8096607 View in Reaxys 150/592 Yield

Conditions & References With hydrogenchloride Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 258; (1920); p. 104 View in Reaxys

d-pseudoephedrine hydrochloride

l-pseudoephedrine hydrochloride

H HN

OH H

racemate

Rx-ID: 8096608 View in Reaxys 151/592 Yield

Conditions & References With water Spaeth; Chemische Berichte; vol. 58; (1925); p. 199 View in Reaxys

optically inactive 2-methylamino-1-ethoxy-1-phenyl-propane

H HN

OH H

racemate

Rx-ID: 8096609 View in Reaxys 152/592 Yield

Conditions & References With hydrogen bromide Bossert; Brode; Journal of the American Chemical Society; vol. 56; (1934); p. 165 View in Reaxys

H 2N

(+-)-cis-2-methyl-3-phenyl-oxirane

H N

racemate

OH H

racemate

Rx-ID: 8096610 View in Reaxys 153/592 Yield

Conditions & References Belzecki; Lange; Roczniki Chemii; vol. 33; (1959); p. 703,704, 709; ; (1960); p. 2236 View in Reaxys

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α-methylamino-propiophenone hydrochloride

NH racemate

Rx-ID: 8096611 View in Reaxys 154/592 Yield

Conditions & References With platinum(IV) oxide, ethanol, p= 1520 - 2280Torr , Hydrogenation Hyde; Browning; Adams; Journal of the American Chemical Society; vol. 50; (1928); p. 2290 View in Reaxys With ethanol, nickel, Hydrogenation Patent; Merck,E.; DE469782; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 16; p. 2908 View in Reaxys With hydrogenchloride, sodium amalgam, T= 0 - 5 °C Schmidt; Chem. Zentralbl.; vol. 82; nb. II; (1911); p. 33 View in Reaxys Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 89 View in Reaxys With palladium on activated charcoal, water, p= 956.2Torr , Hydrogenation Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 258; (1920); p. 104 View in Reaxys

H N

OH Cl

(+)-ephedrine hydrochloride

NH racemate

Rx-ID: 8096612 View in Reaxys 155/592 Yield

Conditions & References With ethanol Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys

alkali

racemate racemate

Rx-ID: 8096613 View in Reaxys 156/592 Yield

Conditions & References Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 258; (1920); p. 104 View in Reaxys

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H 2N HO

nickel catalyst

racemate

Rx-ID: 8096614 View in Reaxys 157/592 Yield

Conditions & References Hydrierung eines Gemisches.Hydrogenation Patent; I.G. Farbenind.; DE588880; (1930); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 20; p. 964 View in Reaxys

H 2N HO

palladium

racemate

Rx-ID: 8096615 View in Reaxys 158/592 Yield

Conditions & References Hydrierung eines Gemisches.Hydrogenation Freudenberg; Schoeffel; Braun; Journal of the American Chemical Society; vol. 54; (1932); p. 234 View in Reaxys

H N

H 2N

(+-)-1-acetoxy-1-phenyl-acetone

NH racemate

Rx-ID: 8096616 View in Reaxys 159/592 Yield

Conditions & References With diethyl ether, ethanol, platinum, Hydrogenation Patent; Temmler,Th. H.; DE767193; (1938); View in Reaxys

H 2N

(+-)-trans-2-methyl-3-phenyl-oxirane

N H OH

racemate

NH racemate

Rx-ID: 8096617 View in Reaxys 160/592 Yield

Conditions & References Belzecki; Lange; Roczniki Chemii; vol. 28; (1954); p. 561,563, 567, 568; ; (1955); p. 6871 View in Reaxys

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coppered zinc

H HN

racemate

Rx-ID: 8096618 View in Reaxys 161/592 Yield

Conditions & References Kanao; Yakugaku Zasshi; nb. 540; (1927); p. 18; Chem. Zentralbl.; vol. 98; nb. I; (1927); p. 2539 View in Reaxys Nagai; Kanao; Justus Liebigs Annalen der Chemie; vol. 470; (1929); p. 174; Chem. Zentralbl.; vol. 99; nb. II; (1928); p. 2553 View in Reaxys Kanao; Yakugaku Zasshi; vol. 49; (1929); p. 26; ; Chem. Zentralbl.; vol. 100; nb. I; (1929); p. 2411 View in Reaxys

formaldoxim-N-<β-oxy-β-phenyl>-isopropyl ether

H HN

racemate

Rx-ID: 8096619 View in Reaxys 162/592 Yield

H N

OH Cl

concentrated sulfuric acid

H 2N

H HN

OH H

Rx-ID: 8261601 View in Reaxys 163/592 Yield

Conditions & References bei langerer Einw. Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 121; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 52 View in Reaxys Emde; Helvetica Chimica Acta; vol. 12; (1929); p. 393 View in Reaxys Schmidt; Chem. Zentralbl.; vol. 82; nb. II; (1911); p. 33 View in Reaxys Schmidt; Calliess; Archiv der Pharmazie (Weinheim, Germany); vol. 250; (1912); p. 156; Chem. Zentralbl.; vol. 82; nb. II; (1911); p. 33 View in Reaxys

H 2N

optically-inactive 1.2-epoxy-3-phenyl-propane

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ephedrine, (1RS:2SR)-1-methylamino-1-phenyl-propanol-(2)

racemate

Rx-ID: 8275789 View in Reaxys 164/592 Yield

Conditions & References With ethanol Ettel; Weichet; Collection of Czechoslovak Chemical Communications; vol. 13; (1948); p. 316,323 View in Reaxys

optically inactive 2-amino-1-methoxy-1-phenyl-propane

H HN

ephedrine

racemate

Rx-ID: 8275791 View in Reaxys 165/592 Yield

Conditions & References With potassium hydroxide, p-toluenesulfonyl chloride, anschliessend Behandeln mit Dimethylsulfat und Erhitzen des Reaktionsprodukts mit wss. Salzsaeure auf 130grad Patent; Hoffmann-La Roche; DE554553; (1929); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 17; p. 2511 View in Reaxys

H H

H N

I–

water

N-methyl-<l-ephedrine>

methyl-<β-oxy-α-phenyl-propyl>-<βoxy-β-phenyl-isopropyl>-amine Rx-ID: 8427393 View in Reaxys 166/592

Yield

Conditions & References bei der Destillation Schmidt; Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 64,66 View in Reaxys

H N

H HN

α-bromo-β-methylamino-α-phenyl-propane hydrobromide

silver nitrate

OH H

Rx-ID: 8470029 View in Reaxys 167/592

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Yield

Conditions & References Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 121; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 52 View in Reaxys

H N

water

Rx-ID: 8470030 View in Reaxys 168/592 Yield

Conditions & References Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 121; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 52 View in Reaxys

H N

water

Rx-ID: 8470031 View in Reaxys 169/592 Yield

Conditions & References Emde; Helvetica Chimica Acta; vol. 12; (1929); p. 393 View in Reaxys

N H H

water

H N

H HN

OH H

Rx-ID: 8470032 View in Reaxys 170/592 Yield

Conditions & References T= 100 °C Emde; Helvetica Chimica Acta; vol. 12; (1929); p. 393 View in Reaxys

H N+

Cl – H H

H N

water

OH N

N-methyl-<l-ephedrine>

methyl-<β-oxy-α-phenyl-propyl>-<βoxy-β-phenyl-isopropyl>-amine Rx-ID: 8493234 View in Reaxys 171/592

Yield

Conditions & References bei der Destillation Schmidt; Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 64,66 View in Reaxys

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OH HO

Rx-ID: 8582706 View in Reaxys 172/592 Yield

Conditions & References

93 %

With sulfuric acid in 1,4-dioxane, Time= 2h, Heating, Hydrolysis Vicario, Jose L.; Badia, Dolores; Dominguez, Esther; Rodriguez, Monica; Carrillo, Luisa; Journal of Organic Chemistry; vol. 65; nb. 12; (2000); p. 3754 - 3759 View in Reaxys

N OH

Rx-ID: 8582720 View in Reaxys 173/592 Yield

Conditions & References

85 %

OH N OH

Rx-ID: 8582725 View in Reaxys 174/592 Yield

Conditions & References

98 %

OH HO

Rx-ID: 8582739 View in Reaxys 175/592 Yield 96 %

Conditions & References With sulfuric acid in 1,4-dioxane, Time= 2h, Heating, Hydrolysis Vicario, Jose L.; Badia, Dolores; Dominguez, Esther; Rodriguez, Monica; Carrillo, Luisa; Journal of Organic Chemistry; vol. 65; nb. 12; (2000); p. 3754 - 3759 View in Reaxys

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heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, complex with (+)-ephedrine

H 2N

heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, complex with n-propylamine

Rx-ID: 8741186 View in Reaxys 176/592 Yield

Conditions & References in methanol, water, Kinetics Grigorean; Lebrilla; Analytical Chemistry; vol. 73; nb. 8; (2001); p. 1684 - 1691 View in Reaxys

H H 2N

heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, complex with (+)-ephedrine

heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, complex with (R)-1-amino-2-propanol

Rx-ID: 8747021 View in Reaxys 177/592 Yield

Conditions & References in methanol, water, Kinetics Grigorean; Lebrilla; Analytical Chemistry; vol. 73; nb. 8; (2001); p. 1684 - 1691 View in Reaxys

H H 2N

permethylated maltoheptaose, complex with (+)-ephedrine

permethylated maltoheptaose, complex with (R)-1-amino-2-propanol

Rx-ID: 8747022 View in Reaxys 178/592 Yield

Conditions & References in methanol, water, Kinetics Grigorean; Lebrilla; Analytical Chemistry; vol. 73; nb. 8; (2001); p. 1684 - 1691 View in Reaxys

H H 2N

H N

heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, complex with (-)-ephedrine

heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, complex with (R)-1-amino-2-propanol Rx-ID: 8747023 View in Reaxys 179/592

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Yield

Conditions & References in methanol, water, Kinetics Grigorean; Lebrilla; Analytical Chemistry; vol. 73; nb. 8; (2001); p. 1684 - 1691 View in Reaxys

H H 2N

H N

permethylated maltoheptaose, complex with (-)-ephedrine

permethylated maltoheptaose, complex with (R)-1-amino-2-propanol

Rx-ID: 8747024 View in Reaxys 180/592 Yield

Conditions & References in methanol, water, Kinetics Grigorean; Lebrilla; Analytical Chemistry; vol. 73; nb. 8; (2001); p. 1684 - 1691 View in Reaxys

S I

H H

OH NH 2

NH 2

Rx-ID: 8808263 View in Reaxys 181/592 Yield

Conditions & References Stage 1: With tetrabutylammomium bromide, sodium ethanolate in tetrahydrofuran, Time= 0.75h, T= 20 °C Stage 2: With hydrogenchloride in tetrahydrofuran, T= 20 °C Stage 3: in water, T= 100 °C , Title compound not separated from byproducts Guillena, Gabriela; Najera, Carmen; Tetrahedron Asymmetry; vol. 12; nb. 2; (2001); p. 181 - 183 View in Reaxys

NH 2

N O

H 2N

H HN

OH H

Rx-ID: 8820017 View in Reaxys 182/592 Yield

Conditions & References Stage 1: With tetrabutylammomium bromide, lithium tert-butylate in tetrahydrofuran, Time= 0.5h, T= 20 °C Stage 2: With hydrogenchloride in tetrahydrofuran, T= 20 °C Stage 3: in water, T= 100 °C , Title compound not separated from byproducts Guillena, Gabriela; Najera, Carmen; Tetrahedron Asymmetry; vol. 12; nb. 2; (2001); p. 181 - 183 View in Reaxys

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S S

NH 2

Rx-ID: 8824496 View in Reaxys 183/592 Yield

Conditions & References Stage 1: With tetrabutylammomium bromide, lithium tert-butylate in tetrahydrofuran, Time= 3h, T= 20 °C Stage 2: With hydrogenchloride in tetrahydrofuran, T= 20 °C Stage 3: in water, T= 100 °C , Title compound not separated from byproducts Guillena, Gabriela; Najera, Carmen; Tetrahedron Asymmetry; vol. 12; nb. 2; (2001); p. 181 - 183 View in Reaxys

S S

H NH 2

NH 2 O

H HN

OH H

Rx-ID: 8859234 View in Reaxys 184/592 Yield

Conditions & References Stage 1: With tetrabutylammomium bromide, lithium tert-butylate in tetrahydrofuran, Time= 5h, T= 20 °C Stage 2: With hydrogenchloride in tetrahydrofuran, T= 20 °C Stage 3: in water, T= 100 °C , Title compound not separated from byproducts Guillena, Gabriela; Najera, Carmen; Tetrahedron Asymmetry; vol. 12; nb. 2; (2001); p. 181 - 183 View in Reaxys

H N

N O O

Rx-ID: 8902068 View in Reaxys 185/592 Yield

Conditions & References

88 %

With potassium hydroxide in ethanol, Time= 2h, Heating Testa, Ma Luisa; Hajji, Chakib; Zaballos-Garcia, Elena; Belen Garcia-Segovia, Ana; Sepulveda-Arques, Jose; Tetrahedron Asymmetry; vol. 12; nb. 9; (2001); p. 1369 - 1372 View in Reaxys

OH O

N H

O racemate

OH H

racemate

Rx-ID: 9994814 View in Reaxys 186/592 Yield 63 %

Conditions & References With trifluoroacetic acid in dichloromethane, Time= 0.75h Fraser, David S.; Park, Sheldon B.; Chong, J. Michael; Canadian Journal of Chemistry; vol. 82; nb. 2; (2004); p. 87 - 101 View in Reaxys

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H N

Rx-ID: 10040209 View in Reaxys 187/592 Yield

Conditions & References With hydrogen Kurashima, Naoki; Makino, Yukiko; Sekita, Setsuko; Urano, Yasuteru; Nagano, Tetsuo; Analytical Chemistry; vol. 76; nb. 14; (2004); p. 4233 - 4236 View in Reaxys

H N

H 2N HO

Rx-ID: 10064858 View in Reaxys 188/592 Yield

Conditions & References With nickel Kurashima, Naoki; Makino, Yukiko; Sekita, Setsuko; Urano, Yasuteru; Nagano, Tetsuo; Analytical Chemistry; vol. 76; nb. 14; (2004); p. 4233 - 4236 View in Reaxys

NH 2

H N

Rx-ID: 10151339 View in Reaxys 189/592 Yield

Conditions & References With sodium hydroxide, Time= 2h, Heating Ryan, Shannon J.; Zhang, Yongda; Kennan, Alan J.; Organic Letters; vol. 7; nb. 21; (2005); p. 4765 - 4767 View in Reaxys

H N

Rx-ID: 10512480 View in Reaxys 190/592 Yield 28 %

Conditions & References With sodium hydroxide in ethanol, water, Time= 12h, Heating Arai, Noriyoshi; Ooka, Hirohito; Azuma, Keita; Yabuuchi, Toshio; Kurono, Nobuhito; Inoue, Tsutomu; Ohkuma, Takeshi; Organic Letters; vol. 9; nb. 5; (2007); p. 939 - 941 View in Reaxys

28 %

With sodium hydroxide, water in ethanol, Time= 12h, Reflux Ooka, Hirohito; Arai, Noriyoshi; Azuma, Keita; Kurono, Nobuhito; Ohkuma, Takeshi; Journal of Organic Chemistry; vol. 73; nb. 22; (2008); p. 9084 - 9093 View in Reaxys With sodium hydroxide, water in ethanol, Reflux Chiwara, Vinia Ipai; Haraguchi, Naoki; Itsuno, Shinichi; Journal of Organic Chemistry; vol. 74; nb. 3; (2009); p. 1391 - 1393

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View in Reaxys

H N

Rx-ID: 11915435 View in Reaxys 191/592 Yield

Conditions & References Reaction Steps: 2 1: 90 percent / H2; t-BuOK / RuCl2[(S)-tolbinap][(R)-dmapen] / propan-2-ol / 9 h / 30 °C / 6080 Torr 2: 28 percent / NaOH / H2O; ethanol / 12 h / Heating With sodium hydroxide, potassium tert-butylate, hydrogen, RuCl2[(S)-tolbinap][(R)-dmapen] in ethanol, water, isopropyl alcohol Arai, Noriyoshi; Ooka, Hirohito; Azuma, Keita; Yabuuchi, Toshio; Kurono, Nobuhito; Inoue, Tsutomu; Ohkuma, Takeshi; Organic Letters; vol. 9; nb. 5; (2007); p. 939 - 941 View in Reaxys

H N

H 2N

Rx-ID: 12616176 View in Reaxys 192/592 Yield

Conditions & References Reaction Steps: 2 1.1: LHMDS; LiCl / tetrahydrofuran / 0.67 h / 0 °C 1.2: 61 percent / tetrahydrofuran / 1 h / 0 °C 2.1: aq. NaOH / 2 h / Heating With sodium hydroxide, lithium chloride, lithium hexamethyldisilazane in tetrahydrofuran Ryan, Shannon J.; Zhang, Yongda; Kennan, Alan J.; Organic Letters; vol. 7; nb. 21; (2005); p. 4765 - 4767 View in Reaxys

O O

N O

H HN

OH H

racemate

Rx-ID: 12805477 View in Reaxys 193/592 Yield

Conditions & References Reaction Steps: 2 1: 98 percent / Super-hydride(R) / tetrahydrofuran / 0.25 h / -78 °C 2: 63 percent / TFA / CH2Cl2 / 0.75 h With lithium triethylborohydride, trifluoroacetic acid in tetrahydrofuran, dichloromethane Fraser, David S.; Park, Sheldon B.; Chong, J. Michael; Canadian Journal of Chemistry; vol. 82; nb. 2; (2004); p. 87 - 101 View in Reaxys Reaction Steps: 2 1: anisole; TFA / CH2Cl2 / 0.75 h 2: Zn(BH4)2 / diethyl ether / 1 h / -78 °C With zinc(II) tetrahydroborate, methoxybenzene, trifluoroacetic acid in diethyl ether, dichloromethane Fraser, David S.; Park, Sheldon B.; Chong, J. Michael; Canadian Journal of Chemistry; vol. 82; nb. 2; (2004); p. 87 - 101

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View in Reaxys

O O

N O

NH racemate

Rx-ID: 12805478 View in Reaxys 194/592 Yield

Conditions & References Reaction Steps: 2 1: anisole; TFA / CH2Cl2 / 0.75 h 2: 0.098 g / Zn(BH4)2 / diethyl ether / 1 h / -78 °C With zinc(II) tetrahydroborate, methoxybenzene, trifluoroacetic acid in diethyl ether, dichloromethane Fraser, David S.; Park, Sheldon B.; Chong, J. Michael; Canadian Journal of Chemistry; vol. 82; nb. 2; (2004); p. 87 - 101 View in Reaxys

OH O

N O

H HN

OH H

racemate

Rx-ID: 12805481 View in Reaxys 195/592 Yield

Conditions & References Reaction Steps: 3 1: 92 percent / N-methylmorpholine-N-oxide; 4 Angstroem molecular sieves; tetrapropylammonium perruthenate / CH2Cl2 / 1 h 2: 98 percent / Super-hydride(R) / tetrahydrofuran / 0.25 h / -78 °C 3: 63 percent / TFA / CH2Cl2 / 0.75 h With tetrapropylammonium perruthennate, 4 A molecular sieve, lithium triethylborohydride, 4-methylmorpholine Noxide, trifluoroacetic acid in tetrahydrofuran, dichloromethane Fraser, David S.; Park, Sheldon B.; Chong, J. Michael; Canadian Journal of Chemistry; vol. 82; nb. 2; (2004); p. 87 - 101 View in Reaxys Reaction Steps: 3 1: 92 percent / N-methylmorpholine-N-oxide; 4 Angstroem molecular sieves; tetrapropylammonium perruthenate / CH2Cl2 / 1 h 2: anisole; TFA / CH2Cl2 / 0.75 h 3: Zn(BH4)2 / diethyl ether / 1 h / -78 °C With tetrapropylammonium perruthennate, zinc(II) tetrahydroborate, 4 A molecular sieve, methoxybenzene, 4-methylmorpholine N-oxide, trifluoroacetic acid in diethyl ether, dichloromethane Fraser, David S.; Park, Sheldon B.; Chong, J. Michael; Canadian Journal of Chemistry; vol. 82; nb. 2; (2004); p. 87 - 101 View in Reaxys

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OH O

N O

NH racemate

Rx-ID: 12805482 View in Reaxys 196/592 Yield

Conditions & References Reaction Steps: 3 1: 92 percent / N-methylmorpholine-N-oxide; 4 Angstroem molecular sieves; tetrapropylammonium perruthenate / CH2Cl2 / 1 h 2: anisole; TFA / CH2Cl2 / 0.75 h 3: 0.098 g / Zn(BH4)2 / diethyl ether / 1 h / -78 °C With tetrapropylammonium perruthennate, zinc(II) tetrahydroborate, 4 A molecular sieve, methoxybenzene, 4-methylmorpholine N-oxide, trifluoroacetic acid in diethyl ether, dichloromethane Fraser, David S.; Park, Sheldon B.; Chong, J. Michael; Canadian Journal of Chemistry; vol. 82; nb. 2; (2004); p. 87 - 101 View in Reaxys

SASRIN-maleidobenzoic acid resin O

H HN

OH H

racemate

Rx-ID: 12832366 View in Reaxys 197/592 Yield

Conditions & References Reaction Steps: 4 1.1: BuLi / tetrahydrofuran; hexane / 0.25 h / -78 °C 1.2: 91 percent / tetrahydrofuran; hexane / 0.25 h / -78 °C 2.1: 92 percent / N-methylmorpholine-N-oxide; 4 Angstroem molecular sieves; tetrapropylammonium perruthenate / CH2Cl2 / 1 h 3.1: 98 percent / Super-hydride(R) / tetrahydrofuran / 0.25 h / -78 °C 4.1: 63 percent / TFA / CH2Cl2 / 0.75 h With n-butyllithium, tetrapropylammonium perruthennate, 4 A molecular sieve, lithium triethylborohydride, 4-methylmorpholine N-oxide, trifluoroacetic acid in tetrahydrofuran, hexane, dichloromethane Fraser, David S.; Park, Sheldon B.; Chong, J. Michael; Canadian Journal of Chemistry; vol. 82; nb. 2; (2004); p. 87 - 101 View in Reaxys Reaction Steps: 4 1.1: BuLi / tetrahydrofuran; hexane / 0.25 h / -78 °C 1.2: 91 percent / tetrahydrofuran; hexane / 0.25 h / -78 °C 2.1: 92 percent / N-methylmorpholine-N-oxide; 4 Angstroem molecular sieves; tetrapropylammonium perruthenate / CH2Cl2 / 1 h 3.1: anisole; TFA / CH2Cl2 / 0.75 h 4.1: Zn(BH4)2 / diethyl ether / 1 h / -78 °C With n-butyllithium, tetrapropylammonium perruthennate, zinc(II) tetrahydroborate, 4 A molecular sieve, methoxybenzene, 4-methylmorpholine N-oxide, trifluoroacetic acid in tetrahydrofuran, diethyl ether, hexane, dichloromethane Fraser, David S.; Park, Sheldon B.; Chong, J. Michael; Canadian Journal of Chemistry; vol. 82; nb. 2; (2004); p. 87 - 101 View in Reaxys

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SASRIN-maleidobenzoic acid resin O

NH racemate

Rx-ID: 12832367 View in Reaxys 198/592 Yield

H N

[(bipy)Ni(C2H4COO)]

Rx-ID: 12877169 View in Reaxys 199/592 Yield

Conditions & References Reaction Steps: 2 1: H2 With hydrogen Kurashima, Naoki; Makino, Yukiko; Sekita, Setsuko; Urano, Yasuteru; Nagano, Tetsuo; Analytical Chemistry; vol. 76; nb. 14; (2004); p. 4233 - 4236 View in Reaxys

H N

bis<chloro(η3-1,3-diphenylallyl)palladium> Rx-ID: 12878683 View in Reaxys 200/592 Yield

Conditions & References Reaction Steps: 3 1: Br2 2: H2 With hydrogen, bromine Kurashima, Naoki; Makino, Yukiko; Sekita, Setsuko; Urano, Yasuteru; Nagano, Tetsuo; Analytical Chemistry; vol. 76; nb. 14; (2004); p. 4233 - 4236 View in Reaxys

H N

H HO

Rx-ID: 15273733 View in Reaxys 201/592

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Yield

Conditions & References Reaction Steps: 7 1: 81 percent / imidazole / CH2Cl2 / 1.5 h / 20 °C 2: Ph3P; di-iso-propyl azodicarboxylate / diethyl ether / 24 h / 20 °C 3: 1.35 g / NaI / acetone / 4 h / Heating 4: 83 percent / KF / methanol / 3 h / Heating 5: 72 percent / pyridine / 15 h 6: 76 percent / NaBH4 / dimethylsulfoxide / 2 h / 150 °C 7: 88 percent / aq. KOH / ethanol / 2 h / Heating With pyridine, 1H-imidazole, potassium fluoride, potassium hydroxide, sodium tetrahydroborate, di-isopropyl azodicarboxylate, triphenylphosphine, sodium iodide in methanol, diethyl ether, ethanol, dichloromethane, dimethyl sulfoxide, acetone Testa, Ma Luisa; Hajji, Chakib; Zaballos-Garcia, Elena; Belen Garcia-Segovia, Ana; Sepulveda-Arques, Jose; Tetrahedron Asymmetry; vol. 12; nb. 9; (2001); p. 1369 - 1372 View in Reaxys

H N

N O O

Rx-ID: 15275827 View in Reaxys 202/592 Yield

Conditions & References Reaction Steps: 3 1: 72 percent / pyridine / 15 h 2: 76 percent / NaBH4 / dimethylsulfoxide / 2 h / 150 °C 3: 88 percent / aq. KOH / ethanol / 2 h / Heating With pyridine, potassium hydroxide, sodium tetrahydroborate in ethanol, dimethyl sulfoxide Testa, Ma Luisa; Hajji, Chakib; Zaballos-Garcia, Elena; Belen Garcia-Segovia, Ana; Sepulveda-Arques, Jose; Tetrahedron Asymmetry; vol. 12; nb. 9; (2001); p. 1369 - 1372 View in Reaxys

N Si

H N

Rx-ID: 15277804 View in Reaxys 203/592 Yield

Conditions & References Reaction Steps: 5 1: 1.35 g / NaI / acetone / 4 h / Heating 2: 83 percent / KF / methanol / 3 h / Heating 3: 72 percent / pyridine / 15 h 4: 76 percent / NaBH4 / dimethylsulfoxide / 2 h / 150 °C 5: 88 percent / aq. KOH / ethanol / 2 h / Heating With pyridine, potassium fluoride, potassium hydroxide, sodium tetrahydroborate, sodium iodide in methanol, ethanol, dimethyl sulfoxide, acetone Testa, Ma Luisa; Hajji, Chakib; Zaballos-Garcia, Elena; Belen Garcia-Segovia, Ana; Sepulveda-Arques, Jose; Tetrahedron Asymmetry; vol. 12; nb. 9; (2001); p. 1369 - 1372 View in Reaxys

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HN Si

H N

Rx-ID: 15279188 View in Reaxys 204/592 Yield

Conditions & References Reaction Steps: 6 1: Ph3P; di-iso-propyl azodicarboxylate / diethyl ether / 24 h / 20 °C 2: 1.35 g / NaI / acetone / 4 h / Heating 3: 83 percent / KF / methanol / 3 h / Heating 4: 72 percent / pyridine / 15 h 5: 76 percent / NaBH4 / dimethylsulfoxide / 2 h / 150 °C 6: 88 percent / aq. KOH / ethanol / 2 h / Heating With pyridine, potassium fluoride, potassium hydroxide, sodium tetrahydroborate, di-isopropyl azodicarboxylate, triphenylphosphine, sodium iodide in methanol, diethyl ether, ethanol, dimethyl sulfoxide, acetone Testa, Ma Luisa; Hajji, Chakib; Zaballos-Garcia, Elena; Belen Garcia-Segovia, Ana; Sepulveda-Arques, Jose; Tetrahedron Asymmetry; vol. 12; nb. 9; (2001); p. 1369 - 1372 View in Reaxys

H N

O N

H O Si

Rx-ID: 15280197 View in Reaxys 205/592 Yield

Conditions & References Reaction Steps: 4 1: 83 percent / KF / methanol / 3 h / Heating 2: 72 percent / pyridine / 15 h 3: 76 percent / NaBH4 / dimethylsulfoxide / 2 h / 150 °C 4: 88 percent / aq. KOH / ethanol / 2 h / Heating With pyridine, potassium fluoride, potassium hydroxide, sodium tetrahydroborate in methanol, ethanol, dimethyl sulfoxide Testa, Ma Luisa; Hajji, Chakib; Zaballos-Garcia, Elena; Belen Garcia-Segovia, Ana; Sepulveda-Arques, Jose; Tetrahedron Asymmetry; vol. 12; nb. 9; (2001); p. 1369 - 1372 View in Reaxys

O O

H N

S O

H N

Rx-ID: 15281391 View in Reaxys 206/592 Yield

Conditions & References Reaction Steps: 2 1: 76 percent / NaBH4 / dimethylsulfoxide / 2 h / 150 °C 2: 88 percent / aq. KOH / ethanol / 2 h / Heating With potassium hydroxide, sodium tetrahydroborate in ethanol, dimethyl sulfoxide

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Testa, Ma Luisa; Hajji, Chakib; Zaballos-Garcia, Elena; Belen Garcia-Segovia, Ana; Sepulveda-Arques, Jose; Tetrahedron Asymmetry; vol. 12; nb. 9; (2001); p. 1369 - 1372 View in Reaxys

OH N O

H HN

OH H

Rx-ID: 15925530 View in Reaxys 207/592 Yield

Conditions & References Reaction Steps: 2 1.1: LDA / tetrahydrofuran / -78 - 20 °C 1.2: bis(cyclopentadienyl)zirconium dichloride / tetrahydrofuran / 1 h / -78 °C 1.3: 94 percent / tetrahydrofuran / 2.33 h / -105 °C 2.1: aq. H2SO4 / dioxane / 2 h / Heating With sulfuric acid, lithium diisopropyl amide in tetrahydrofuran, 1,4-dioxane, 1.1: deprotonation / 1.2: transmetallation / 1.3: aldol reaction / 2.1: Hydrolysis Vicario, Jose L.; Badia, Dolores; Dominguez, Esther; Rodriguez, Monica; Carrillo, Luisa; Journal of Organic Chemistry; vol. 65; nb. 12; (2000); p. 3754 - 3759 View in Reaxys Reaction Steps: 2 1.1: LDA / tetrahydrofuran / -78 - 20 °C 1.2: bis(cyclopentadienyl)zirconium dichloride / tetrahydrofuran / 1 h / -78 °C 1.3: 94 percent / tetrahydrofuran / 2.33 h / -105 °C 2.1: aq. H2SO4 / dioxane / 2 h / Heating With sulfuric acid, lithium diisopropyl amide in tetrahydrofuran, 1,4-dioxane, 1.1: deprotonation / 1.2: transmetallation / 1.3: aldol reaction / 2.1: Hydrolysis Vicario, Jose L.; Badia, Dolores; Dominguez, Esther; Rodriguez, Monica; Carrillo, Luisa; Journal of Organic Chemistry; vol. 65; nb. 12; (2000); p. 3754 - 3759 View in Reaxys Reaction Steps: 2 1.1: LDA / tetrahydrofuran / -78 - 20 °C 1.2: ZnCl2 / tetrahydrofuran 1.3: tetrahydrofuran / 0 °C 2.1: 80 percent / aq. H2SO4 / dioxane / 2 h / Heating With sulfuric acid, lithium diisopropyl amide in tetrahydrofuran, 1,4-dioxane, 1.1: deprotonation / 1.2: transmetallation / 1.3: aldol reaction / 2.1: Hydrolysis Vicario, Jose L.; Badia, Dolores; Dominguez, Esther; Rodriguez, Monica; Carrillo, Luisa; Journal of Organic Chemistry; vol. 65; nb. 12; (2000); p. 3754 - 3759 View in Reaxys Reaction Steps: 2 1.1: LDA / tetrahydrofuran / -78 - 20 °C 1.2: bis(cyclopentadienyl)zirconium dichloride / tetrahydrofuran / 1 h / -78 °C 1.3: 88 percent / tetrahydrofuran / 2.33 h / -105 °C 2.1: aq. H2SO4 / dioxane / 2 h / Heating With sulfuric acid, lithium diisopropyl amide in tetrahydrofuran, 1,4-dioxane, 1.1: deprotonation / 1.2: transmetallation / 1.3: aldol reaction / 2.1: Hydrolysis Vicario, Jose L.; Badia, Dolores; Dominguez, Esther; Rodriguez, Monica; Carrillo, Luisa; Journal of Organic Chemistry; vol. 65; nb. 12; (2000); p. 3754 - 3759 View in Reaxys Reaction Steps: 2 1.1: LDA / tetrahydrofuran / -78 - 20 °C

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1.2: bis(cyclopentadienyl)zirconium dichloride / tetrahydrofuran / 1 h / -78 °C 1.3: 90 percent / tetrahydrofuran / 2.33 h / -105 °C 2.1: aq. H2SO4 / dioxane / 2 h / Heating With sulfuric acid, lithium diisopropyl amide in tetrahydrofuran, 1,4-dioxane, 1.1: deprotonation / 1.2: transmetallation / 1.3: aldol reaction / 2.1: Hydrolysis Vicario, Jose L.; Badia, Dolores; Dominguez, Esther; Rodriguez, Monica; Carrillo, Luisa; Journal of Organic Chemistry; vol. 65; nb. 12; (2000); p. 3754 - 3759 View in Reaxys

H N

H HN

OH H

racemate

Rx-ID: 16166918 View in Reaxys 208/592 Yield

Conditions & References Reaction Steps: 3 1.1: CrO3; aq. H2SO4 / 2 h / 40 °C 1.2: 62 percent / NaNO2 / CH2Cl2 / 20 °C 2.1: 84 percent / NaOH; Na2CO3 / dimethylformamide / 1.25 h / 25 °C 3.1: aluminum-copper alloy; aq. KOH / methanol / 24 h / 25 °C With chromium(VI) oxide, potassium hydroxide, sodium hydroxide, aluminum-copper alloy, sulfuric acid, sodium carbonate in methanol, N,N-dimethyl-formamide, 1.1: Oxidation / 1.2: Nitrosation / 2.1: Methylation / 3.1: Reduction Saavedra, Joseph E.; Farnsworth, David W.; Organic Preparations and Procedures International; vol. 23; nb. 2; (1991); p. 139 - 146 View in Reaxys

H N

NH racemate

Rx-ID: 16166919 View in Reaxys 209/592 Yield

O O

N H HN

OH H

racemate

Rx-ID: 16171572 View in Reaxys 210/592

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Yield

Conditions & References Reaction Steps: 2 1: 84 percent / NaOH; Na2CO3 / dimethylformamide / 1.25 h / 25 °C 2: aluminum-copper alloy; aq. KOH / methanol / 24 h / 25 °C With potassium hydroxide, sodium hydroxide, aluminum-copper alloy, sodium carbonate in methanol, N,N-dimethylformamide, 1: Methylation / 2: Reduction Saavedra, Joseph E.; Farnsworth, David W.; Organic Preparations and Procedures International; vol. 23; nb. 2; (1991); p. 139 - 146 View in Reaxys

O O

NH racemate

Rx-ID: 16171573 View in Reaxys 211/592 Yield

HI, I2

H HN

OH H

racemate

Rx-ID: 16523760 View in Reaxys 212/592 Yield

Conditions & References Reaction Steps: 2 1: acetonitrile / 18 h / Irradiation 2: 86 percent / LiAlH4 / tetrahydrofuran / 15 h / 0 - 20 °C With lithium aluminium tetrahydride in tetrahydrofuran, acetonitrile, 1: Cycloaddition / 2: Reduction Bach; Schroder; Journal of Organic Chemistry; vol. 64; nb. 4; (1999); p. 1265 - 1273 View in Reaxys

N O O racemate

NH racemate

Rx-ID: 16530732 View in Reaxys 213/592 Yield

Conditions & References Reaction Steps: 3 1: 98 percent / pyridine / 15 h / 5 °C 2: 72 percent / sodium borohydride / dimethylsulfoxide / 2 h / 150 °C 3: 77 percent / KOH; water / ethanol / 2 h / Heating

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With pyridine, potassium hydroxide, sodium tetrahydroborate, water in ethanol, dimethyl sulfoxide, 1: Tosylation / 2: Reduction / 3: Hydrolysis Bach; Schroder; Journal of Organic Chemistry; vol. 64; nb. 4; (1999); p. 1265 - 1273 View in Reaxys Reaction Steps: 2 1: 86 percent / pyridine / 15 h 2: 1.) NaBH4; 2.) KOH / 1.) DMSO, 150 deg C, 1 h; 2.) aq. EtOH, reflux, 2 h With pyridine, potassium hydroxide, sodium tetrahydroborate Bach, Thorsten; Schroeder, Juergen; Tetrahedron Letters; vol. 38; nb. 21; (1997); p. 3707 - 3710 View in Reaxys

O N O O

racemate

Rx-ID: 16530755 View in Reaxys 214/592 Yield

Conditions & References Reaction Steps: 4 1: 58 percent / trifluoroacetic acid / CH2Cl2 / -78 - 20 °C 2: 98 percent / pyridine / 15 h / 5 °C 3: 72 percent / sodium borohydride / dimethylsulfoxide / 2 h / 150 °C 4: 77 percent / KOH; water / ethanol / 2 h / Heating With pyridine, potassium hydroxide, sodium tetrahydroborate, water, trifluoroacetic acid in ethanol, dichloromethane, dimethyl sulfoxide, 1: Isomerization / 2: Tosylation / 3: Reduction / 4: Hydrolysis Bach; Schroder; Journal of Organic Chemistry; vol. 64; nb. 4; (1999); p. 1265 - 1273 View in Reaxys Reaction Steps: 3 1: 58 percent / trifluoroacetic acid / CH2Cl2 / 2 h / -78 °C 2: 86 percent / pyridine / 15 h 3: 1.) NaBH4; 2.) KOH / 1.) DMSO, 150 deg C, 1 h; 2.) aq. EtOH, reflux, 2 h With pyridine, potassium hydroxide, sodium tetrahydroborate, trifluoroacetic acid in dichloromethane Bach, Thorsten; Schroeder, Juergen; Tetrahedron Letters; vol. 38; nb. 21; (1997); p. 3707 - 3710 View in Reaxys

H N

H 2N H

Rx-ID: 17289430 View in Reaxys 215/592 Yield

Conditions & References Reaction Steps: 2 1: diethyl ether / 1 h / -30 °C 2: LiAlH4 / diethyl ether / 2 h / -10 - 20 °C With lithium aluminium tetrahydride in diethyl ether Effenberger, Franz; Gutterer, Beate; Jaeger, Juergen; Tetrahedron Asymmetry; vol. 8; nb. 3; (1997); p. 459 - 467 View in Reaxys

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OH H

H N

Rx-ID: 17291089 View in Reaxys 216/592 Yield

Conditions & References Reaction Steps: 2 1: pyridine / diethyl ether 2: 3.) NaBH4 With pyridine, sodium tetrahydroborate in diethyl ether Effenberger, Franz; Gutterer, Beate; Jaeger, Juergen; Tetrahedron Asymmetry; vol. 8; nb. 3; (1997); p. 459 - 467 View in Reaxys Reaction Steps: 4 1: pyridine / diethyl ether 2: 2.) NaBH4, 3.) H2O, H+ / 1.) Et2O 3: diethyl ether / 1 h / -30 °C 4: LiAlH4 / diethyl ether / 2 h / -10 - 20 °C With pyridine, sodium tetrahydroborate, lithium aluminium tetrahydride, water, hydrogen cation in diethyl ether Effenberger, Franz; Gutterer, Beate; Jaeger, Juergen; Tetrahedron Asymmetry; vol. 8; nb. 3; (1997); p. 459 - 467 View in Reaxys Reaction Steps: 3 1: 100 percent / imidazole, DMAP / diethyl ether 2: 2.) 2 M HCl / 1.) ether, reflux, 2 h 3: 2.) NaBH4 / 1.) ether, 0 deg C, 30 min, 2.) from 10 deg C to RT With 1H-imidazole, hydrogenchloride, 4-(N,N-dimethlyamino)pyridine, sodium tetrahydroborate in diethyl ether Jackson, W. Roy; Jacobs, Howard A.; Jayatilake, Gamini S.; Matthews, Barry R.; Watson, Keith G.; Australian Journal of Chemistry; vol. 43; nb. 12; (1990); p. 2045 - 2062 View in Reaxys Reaction Steps: 3 1: 100 percent / imidazole, DMAP / diethyl ether 2: 2.) 2 M HCl / 1.) ether, reflux, 2 h 3: 2.) Zn(BH4)2 / 1.) ether, 0 deg C, 2.) -76 deg C, 1 h With 1H-imidazole, hydrogenchloride, 4-(N,N-dimethlyamino)pyridine, zinc(II) tetrahydroborate in diethyl ether Jackson, W. Roy; Jacobs, Howard A.; Jayatilake, Gamini S.; Matthews, Barry R.; Watson, Keith G.; Australian Journal of Chemistry; vol. 43; nb. 12; (1990); p. 2045 - 2062 View in Reaxys

OH H

H N

Rx-ID: 17291090 View in Reaxys 217/592 Yield

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3: 2.) NaBH4 / 1.) ether, 0 deg C, 30 min, 2.) from 10 deg C to RT With 1H-imidazole, hydrogenchloride, 4-(N,N-dimethlyamino)pyridine, sodium tetrahydroborate in diethyl ether Jackson, W. Roy; Jacobs, Howard A.; Jayatilake, Gamini S.; Matthews, Barry R.; Watson, Keith G.; Australian Journal of Chemistry; vol. 43; nb. 12; (1990); p. 2045 - 2062 View in Reaxys

H N

Rx-ID: 17293024 View in Reaxys 218/592 Yield

Conditions & References Reaction Steps: 2 1: 3.) NaBH4 2: LiAlH4 / diethyl ether / 1 h / Heating With sodium tetrahydroborate, lithium aluminium tetrahydride in diethyl ether Effenberger, Franz; Gutterer, Beate; Jaeger, Juergen; Tetrahedron Asymmetry; vol. 8; nb. 3; (1997); p. 459 - 467 View in Reaxys

H N

Rx-ID: 17293025 View in Reaxys 219/592 Yield

H N Si O

Rx-ID: 17294587 View in Reaxys 220/592 Yield

Conditions & References Reaction Steps: 3 1: 2.) NaBH4, 3.) H2O, H+ / 1.) Et2O 2: diethyl ether / 1 h / -30 °C 3: LiAlH4 / diethyl ether / 2 h / -10 - 20 °C With sodium tetrahydroborate, lithium aluminium tetrahydride, water, hydrogen cation in diethyl ether Effenberger, Franz; Gutterer, Beate; Jaeger, Juergen; Tetrahedron Asymmetry; vol. 8; nb. 3; (1997); p. 459 - 467 View in Reaxys Reaction Steps: 2 1: 2.) 2 M HCl / 1.) ether, reflux, 2 h 2: 2.) NaBH4 / 1.) ether, 0 deg C, 30 min, 2.) from 10 deg C to RT With hydrogenchloride, sodium tetrahydroborate

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Jackson, W. Roy; Jacobs, Howard A.; Jayatilake, Gamini S.; Matthews, Barry R.; Watson, Keith G.; Australian Journal of Chemistry; vol. 43; nb. 12; (1990); p. 2045 - 2062 View in Reaxys Reaction Steps: 2 1: 2.) 2 M HCl / 1.) ether, reflux, 2 h 2: 2.) Zn(BH4)2 / 1.) ether, 0 deg C, 2.) -76 deg C, 1 h With hydrogenchloride, zinc(II) tetrahydroborate Jackson, W. Roy; Jacobs, Howard A.; Jayatilake, Gamini S.; Matthews, Barry R.; Watson, Keith G.; Australian Journal of Chemistry; vol. 43; nb. 12; (1990); p. 2045 - 2062 View in Reaxys

H N

Rx-ID: 17308073 View in Reaxys 221/592 Yield

H N

Rx-ID: 17308074 View in Reaxys 222/592 Yield

H O

C-phenyl-C-<2-methoxy-naphthyl-(1)>-methylamine

NH racemate

Rx-ID: 17381555 View in Reaxys 223/592 Yield

Conditions & References Reaction Steps: 4 1: 56 percent / acetonitrile / 15 h / 30 °C / Irradiation 2: 58 percent / trifluoroacetic acid / CH2Cl2 / 2 h / -78 °C 3: 86 percent / pyridine / 15 h 4: 1.) NaBH4; 2.) KOH / 1.) DMSO, 150 deg C, 1 h; 2.) aq. EtOH, reflux, 2 h With pyridine, potassium hydroxide, sodium tetrahydroborate, trifluoroacetic acid in dichloromethane, acetonitrile

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Bach, Thorsten; Schroeder, Juergen; Tetrahedron Letters; vol. 38; nb. 21; (1997); p. 3707 - 3710 View in Reaxys

OH H

Rx-ID: 17420268 View in Reaxys 224/592 Yield

Conditions & References Reaction Steps: 2 1: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 2: 90 percent / ammonium formate / Pd/C / 1 h / Heating With ammonium formate, potassium carbonate, palladium on activated charcoal in acetonitrile Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys

H H 2N

OH H

H HN

OH H

Rx-ID: 17421017 View in Reaxys 225/592 Yield

Conditions & References Reaction Steps: 8 1: 93 percent / xylene / 2 h / Heating 2: 85 percent / ZnCl2 / benzene / 12 h / Heating 3: 70 percent / NBS, CaCl2 / benzene / 0.33 h / Irradiation 4: Raney Ni W2 / ethanol / 6 h 5: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 6: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 7: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 8: 90 percent / ammonium formate / Pd/C / 1 h / Heating With N-bromosuccinmide, lithium aluminium tetrahydride, Raney Ni W2, ammonium formate, potassium carbonate, hydrazine hydrate, calcium chloride, zinc(II) chloride, palladium on activated charcoal in tetrahydrofuran, ethanol, acetonitrile, xylene, benzene Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 9 1: 93 percent / xylene / 2 h / Heating 2: 85 percent / ZnCl2 / benzene / 12 h / Heating 3: 70 percent / NBS, CaCl2 / benzene / 0.33 h / Irradiation 4: Raney Ni W2 / ethanol / 6 h 5: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 6: 94.5 percent / pyridine / CHCl3 / 6 h / Ambient temperature 7: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 8: 98 percent / K2CO3 / acetonitrile / 2 h / Heating

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9: 90 percent / ammonium formate / Pd/C / 1 h / Heating With pyridine, N-bromosuccinmide, lithium aluminium tetrahydride, Raney Ni W2, ammonium formate, potassium carbonate, hydrazine hydrate, calcium chloride, zinc(II) chloride, palladium on activated charcoal in tetrahydrofuran, ethanol, chloroform, acetonitrile, xylene, benzene Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 8 1: 93 percent / xylene / 2 h / Heating 2: 85 percent / ZnCl2 / benzene / 12 h / Heating 3: 70 percent / NBS, CaCl2 / benzene / 0.33 h / Irradiation 4: 96 percent / Raney Ni / ethanol / 6 h 5: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 6: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 7: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 8: 90 percent / ammonium formate / Pd/C / 1 h / Heating With N-bromosuccinmide, lithium aluminium tetrahydride, ammonium formate, nickel, potassium carbonate, hydrazine hydrate, calcium chloride, zinc(II) chloride, palladium on activated charcoal in tetrahydrofuran, ethanol, acetonitrile, xylene, benzene Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 9 1: 93 percent / xylene / 2 h / Heating 2: 85 percent / ZnCl2 / benzene / 12 h / Heating 3: 70 percent / NBS, CaCl2 / benzene / 0.33 h / Irradiation 4: 96 percent / Raney Ni / ethanol / 6 h 5: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 6: 94.5 percent / pyridine / CHCl3 / 6 h / Ambient temperature 7: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 8: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 9: 90 percent / ammonium formate / Pd/C / 1 h / Heating With pyridine, N-bromosuccinmide, lithium aluminium tetrahydride, ammonium formate, nickel, potassium carbonate, hydrazine hydrate, calcium chloride, zinc(II) chloride, palladium on activated charcoal in tetrahydrofuran, ethanol, chloroform, acetonitrile, xylene, benzene Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys

O H HO

N H H

H HN

OH H

Rx-ID: 17421065 View in Reaxys 226/592 Yield

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Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 4 1: 94.5 percent / pyridine / CHCl3 / 6 h / Ambient temperature 2: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 3: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 4: 90 percent / ammonium formate / Pd/C / 1 h / Heating With pyridine, lithium aluminium tetrahydride, ammonium formate, potassium carbonate, palladium on activated charcoal in tetrahydrofuran, chloroform, acetonitrile Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys

O HO N OH O

H HN

OH H

Rx-ID: 17422574 View in Reaxys 227/592 Yield

Conditions & References Reaction Steps: 7 1: 85 percent / ZnCl2 / benzene / 12 h / Heating 2: 70 percent / NBS, CaCl2 / benzene / 0.33 h / Irradiation 3: Raney Ni W2 / ethanol / 6 h 4: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 5: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 6: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 7: 90 percent / ammonium formate / Pd/C / 1 h / Heating With N-bromosuccinmide, lithium aluminium tetrahydride, Raney Ni W2, ammonium formate, potassium carbonate, hydrazine hydrate, calcium chloride, zinc(II) chloride, palladium on activated charcoal in tetrahydrofuran, ethanol, acetonitrile, benzene Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 8 1: 85 percent / ZnCl2 / benzene / 12 h / Heating 2: 70 percent / NBS, CaCl2 / benzene / 0.33 h / Irradiation 3: Raney Ni W2 / ethanol / 6 h 4: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 5: 94.5 percent / pyridine / CHCl3 / 6 h / Ambient temperature 6: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 7: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 8: 90 percent / ammonium formate / Pd/C / 1 h / Heating With pyridine, N-bromosuccinmide, lithium aluminium tetrahydride, Raney Ni W2, ammonium formate, potassium carbonate, hydrazine hydrate, calcium chloride, zinc(II) chloride, palladium on activated charcoal in tetrahydrofuran, ethanol, chloroform, acetonitrile, benzene Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 7 1: 85 percent / ZnCl2 / benzene / 12 h / Heating 2: 70 percent / NBS, CaCl2 / benzene / 0.33 h / Irradiation

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3: 96 percent / Raney Ni / ethanol / 6 h 4: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 5: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 6: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 7: 90 percent / ammonium formate / Pd/C / 1 h / Heating With N-bromosuccinmide, lithium aluminium tetrahydride, ammonium formate, nickel, potassium carbonate, hydrazine hydrate, calcium chloride, zinc(II) chloride, palladium on activated charcoal in tetrahydrofuran, ethanol, acetonitrile, benzene Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 8 1: 85 percent / ZnCl2 / benzene / 12 h / Heating 2: 70 percent / NBS, CaCl2 / benzene / 0.33 h / Irradiation 3: 96 percent / Raney Ni / ethanol / 6 h 4: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 5: 94.5 percent / pyridine / CHCl3 / 6 h / Ambient temperature 6: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 7: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 8: 90 percent / ammonium formate / Pd/C / 1 h / Heating With pyridine, N-bromosuccinmide, lithium aluminium tetrahydride, ammonium formate, nickel, potassium carbonate, hydrazine hydrate, calcium chloride, zinc(II) chloride, palladium on activated charcoal in tetrahydrofuran, ethanol, chloroform, acetonitrile, benzene Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys

O O

H N

OH H

Rx-ID: 17439736 View in Reaxys 228/592 Yield

Conditions & References Reaction Steps: 3 1: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 2: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 3: 90 percent / ammonium formate / Pd/C / 1 h / Heating With lithium aluminium tetrahydride, ammonium formate, potassium carbonate, palladium on activated charcoal in tetrahydrofuran, acetonitrile Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys

O O N

H HN

OH H

Rx-ID: 17444867 View in Reaxys 229/592

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Yield

Conditions & References Reaction Steps: 4 1: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 2: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 3: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 4: 90 percent / ammonium formate / Pd/C / 1 h / Heating With lithium aluminium tetrahydride, ammonium formate, potassium carbonate, hydrazine hydrate, palladium on activated charcoal in tetrahydrofuran, acetonitrile Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 5 1: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 2: 94.5 percent / pyridine / CHCl3 / 6 h / Ambient temperature 3: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 4: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 5: 90 percent / ammonium formate / Pd/C / 1 h / Heating With pyridine, lithium aluminium tetrahydride, ammonium formate, potassium carbonate, hydrazine hydrate, palladium on activated charcoal in tetrahydrofuran, chloroform, acetonitrile Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys

O O N O

OH H

Rx-ID: 17444969 View in Reaxys 230/592 Yield

Conditions & References Reaction Steps: 6 1: 70 percent / NBS, CaCl2 / benzene / 0.33 h / Irradiation 2: Raney Ni W2 / ethanol / 6 h 3: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 4: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 5: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 6: 90 percent / ammonium formate / Pd/C / 1 h / Heating With N-bromosuccinmide, lithium aluminium tetrahydride, Raney Ni W2, ammonium formate, potassium carbonate, hydrazine hydrate, calcium chloride, palladium on activated charcoal in tetrahydrofuran, ethanol, acetonitrile, benzene Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 7 1: 70 percent / NBS, CaCl2 / benzene / 0.33 h / Irradiation 2: Raney Ni W2 / ethanol / 6 h 3: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 4: 94.5 percent / pyridine / CHCl3 / 6 h / Ambient temperature 5: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 6: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 7: 90 percent / ammonium formate / Pd/C / 1 h / Heating

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With pyridine, N-bromosuccinmide, lithium aluminium tetrahydride, Raney Ni W2, ammonium formate, potassium carbonate, hydrazine hydrate, calcium chloride, palladium on activated charcoal in tetrahydrofuran, ethanol, chloroform, acetonitrile, benzene Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 6 1: 70 percent / NBS, CaCl2 / benzene / 0.33 h / Irradiation 2: 96 percent / Raney Ni / ethanol / 6 h 3: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 4: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 5: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 6: 90 percent / ammonium formate / Pd/C / 1 h / Heating With N-bromosuccinmide, lithium aluminium tetrahydride, ammonium formate, nickel, potassium carbonate, hydrazine hydrate, calcium chloride, palladium on activated charcoal in tetrahydrofuran, ethanol, acetonitrile, benzene Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 7 1: 70 percent / NBS, CaCl2 / benzene / 0.33 h / Irradiation 2: 96 percent / Raney Ni / ethanol / 6 h 3: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 4: 94.5 percent / pyridine / CHCl3 / 6 h / Ambient temperature 5: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 6: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 7: 90 percent / ammonium formate / Pd/C / 1 h / Heating With pyridine, N-bromosuccinmide, lithium aluminium tetrahydride, ammonium formate, nickel, potassium carbonate, hydrazine hydrate, calcium chloride, palladium on activated charcoal in tetrahydrofuran, ethanol, chloroform, acetonitrile, benzene Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys

O O

H HN

OH H

Br O

Rx-ID: 17445019 View in Reaxys 231/592 Yield

Conditions & References Reaction Steps: 5 1: Raney Ni W2 / ethanol / 6 h 2: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 3: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 4: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 5: 90 percent / ammonium formate / Pd/C / 1 h / Heating With lithium aluminium tetrahydride, Raney Ni W2, ammonium formate, potassium carbonate, hydrazine hydrate, palladium on activated charcoal in tetrahydrofuran, ethanol, acetonitrile Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys

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Reaction Steps: 6 1: Raney Ni W2 / ethanol / 6 h 2: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 3: 94.5 percent / pyridine / CHCl3 / 6 h / Ambient temperature 4: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 5: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 6: 90 percent / ammonium formate / Pd/C / 1 h / Heating With pyridine, lithium aluminium tetrahydride, Raney Ni W2, ammonium formate, potassium carbonate, hydrazine hydrate, palladium on activated charcoal in tetrahydrofuran, ethanol, chloroform, acetonitrile Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 5 1: 96 percent / Raney Ni / ethanol / 6 h 2: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 3: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 4: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 5: 90 percent / ammonium formate / Pd/C / 1 h / Heating With lithium aluminium tetrahydride, ammonium formate, nickel, potassium carbonate, hydrazine hydrate, palladium on activated charcoal in tetrahydrofuran, ethanol, acetonitrile Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys Reaction Steps: 6 1: 96 percent / Raney Ni / ethanol / 6 h 2: 90 percent / NH2NH2*H2O / acetonitrile / 6 h / Heating 3: 94.5 percent / pyridine / CHCl3 / 6 h / Ambient temperature 4: 10 percent / LiAlH4 / tetrahydrofuran / 2 h / Heating 5: 98 percent / K2CO3 / acetonitrile / 2 h / Heating 6: 90 percent / ammonium formate / Pd/C / 1 h / Heating With pyridine, lithium aluminium tetrahydride, ammonium formate, nickel, potassium carbonate, hydrazine hydrate, palladium on activated charcoal in tetrahydrofuran, ethanol, chloroform, acetonitrile Akamanchi; Ranbhan; Shah; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 35; nb. 4; (1996); p. 293 - 302 View in Reaxys

OH N

H 2N O

H HN

OH H

Rx-ID: 17942190 View in Reaxys 232/592 Yield

Conditions & References Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 23 deg C, 8 h 2: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 1.5 h With sodium hydroxide, sodium hydrogencarbonate, lithium chloride, lithium diisopropyl amide Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 23 deg C, 8 h

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2: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 1.5 h With sodium hydroxide, sodium hydrogencarbonate, lithium chloride, lithium diisopropyl amide Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 23 deg C, 8 h 2: H2O / 10 h / Heating With water, lithium chloride, lithium diisopropyl amide Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 10 h 2: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 2 h With sodium hydroxide, sodium hydrogencarbonate, lithium chloride, lithium diisopropyl amide Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1 h 2: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 3 h With sodium hydroxide, sodium hydrogencarbonate, lithium chloride, lithium diisopropyl amide Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1 h 2: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 3 h With sodium hydroxide, sodium hydrogencarbonate, lithium chloride, lithium diisopropyl amide Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1 h 2: H2O / 18 h / Heating With water, lithium chloride, lithium diisopropyl amide Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1.5 h 2: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 1.5 h With sodium hydroxide, sodium hydrogencarbonate, lithium chloride, lithium diisopropyl amide Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1.5 h 2: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 1.5 h With sodium hydroxide, sodium hydrogencarbonate, lithium chloride, lithium diisopropyl amide

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Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1.5 h 2: H2O / 10 h / Heating With water, lithium chloride, lithium diisopropyl amide Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 0.3 h 2: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 1.5 h With sodium hydroxide, sodium hydrogencarbonate, lithium chloride, lithium diisopropyl amide Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 0.3 h 2: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 1.5 h With sodium hydroxide, sodium hydrogencarbonate, lithium chloride, lithium diisopropyl amide Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 2 1: 1.) LDA, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 0.3 h 2: H2O / 10 h / Heating With water, lithium chloride, lithium diisopropyl amide Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

OH N H

N O

H HN

OH H

Rx-ID: 17946195 View in Reaxys 233/592 Yield

Conditions & References Reaction Steps: 2 1: 1.) n-BuLi, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1 h 2: 1.) aq. NaOH / 1.) methanol, reflux, 24 h With sodium hydroxide, n-butyllithium, lithium chloride Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

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NH 2

OH N

Rx-ID: 17947579 View in Reaxys 234/592 Yield

Conditions & References Reaction Steps: 4 1: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 1.5 h 3: 1.) n-BuLi, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1 h 4: 1.) aq. NaOH / 1.) methanol, reflux, 24 h With sodium hydroxide, n-butyllithium, sodium hydrogencarbonate, lithium chloride Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 4 1: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 1.5 h 3: 1.) n-BuLi, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1 h 4: 1.) aq. NaOH / 1.) methanol, reflux, 24 h With sodium hydroxide, n-butyllithium, sodium hydrogencarbonate, lithium chloride Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 4 1: H2O / 10 h / Heating 3: 1.) n-BuLi, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1 h 4: 1.) aq. NaOH / 1.) methanol, reflux, 24 h With sodium hydroxide, n-butyllithium, water, lithium chloride Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

NH 2

OH N

H HN

OH H

Rx-ID: 17958548 View in Reaxys 235/592 Yield

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NH 2

OH N

Rx-ID: 17958914 View in Reaxys 236/592 Yield

Conditions & References Reaction Steps: 4 1: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 2 h 3: 1.) n-BuLi, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1 h 4: 1.) aq. NaOH / 1.) methanol, reflux, 24 h With sodium hydroxide, n-butyllithium, sodium hydrogencarbonate, lithium chloride Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

NH 2

OH N

H O

OH H

Rx-ID: 17959293 View in Reaxys 237/592 Yield

Conditions & References Reaction Steps: 4 1: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 3 h 3: 1.) n-BuLi, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1 h 4: 1.) aq. NaOH / 1.) methanol, reflux, 24 h With sodium hydroxide, n-butyllithium, sodium hydrogencarbonate, lithium chloride Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 4 1: 1.) aq. NaOH, 2.) aq. sodium bicarbonate / 1.) reflux, 2.) 3 h 3: 1.) n-BuLi, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1 h 4: 1.) aq. NaOH / 1.) methanol, reflux, 24 h With sodium hydroxide, n-butyllithium, sodium hydrogencarbonate, lithium chloride Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys Reaction Steps: 4 1: H2O / 18 h / Heating 3: 1.) n-BuLi, LiCl / 1.) THF, -78 deg C, 2.) THF, 0 deg C, 1 h 4: 1.) aq. NaOH / 1.) methanol, reflux, 24 h With sodium hydroxide, n-butyllithium, water, lithium chloride Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

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O N

H HN

OH H

Rx-ID: 18294059 View in Reaxys 238/592 Yield

Conditions & References Reaction Steps: 2 1: 100 percent / diethylamine / Pd(0) (in situ from Pd(OAc)2 and m.sulfonated triphenylphosphine) / H2O; various solvent(s) / 0.33 h / 5 molpercent catalyst 2: 100 percent / diethylamine / Pd(0) (in situ from Pd(OAc)2 and m.sulfonated triphenylphosphine) / H2O; acetonitrile / 0.25 h / 5 molpercent catalyst With diethylamine, Pd(0) (in situ from Pd(OAc)2 and m.sulfonated triphenylphosphine) in water, acetonitrile Lemaire-Audoire; Lemaire-Audoire, Sandrine; Savignac; Savignac, Monique; Blart; Blart, Errol; Pourcelot; Pourcelot, Guy; Genet; Genet, Jean Pierre; Bernard; Bernard, Jean-Marie; Tetrahedron Letters; vol. 35; nb. 47; (1994); p. 8783 - 8786 View in Reaxys

H N

Rx-ID: 19230807 View in Reaxys 239/592 Yield

Conditions & References Reaction Steps: 2 1: PhMe2SiH / trifluoroacetic acid / 2.5 h / 0 °C 2: 80 percent / lithium aluminium hydride / tetrahydrofuran / 60 °C With lithium aluminium tetrahydride, dimethylphenylsilane in tetrahydrofuran, trifluoroacetic acid Fujita, Makoto; Hiyama, Tamejiro; Journal of the American Chemical Society; vol. 106; nb. 16; (1984); p. 4629 4630 View in Reaxys

H H 2N

OH H N

N H

(1S,2R)-1-methylamino-1-phenyl-propan-2-ol (C10H15NO)

Rx-ID: 19970176 View in Reaxys 240/592 Yield

Conditions & References Reaction Steps: 3 1: 77 percent / benzene / 3 h / Heating 2: 70 percent / diethyl ether / 18 h / Ambient temperature 3: conc HCl, H2 / 10percent Pd-carbon / ethanol / 12 h / 45 °C / 4045.3 Torr With hydrogenchloride, hydrogen, palladium on activated charcoal in diethyl ether, ethanol, benzene Takahashi; Inagaki; Chemical and Pharmaceutical Bulletin; vol. 30; nb. 3; (1982); p. 922 - 926 View in Reaxys Reaction Steps: 3 1: benzene 2: 79 percent / tetrahydrofuran / 40 deg C, 6 h, RT, 37 h 3: conc. HCl, hydrogen / 10percent Pd-carbon / ethanol / 8 h / 50 - 60 °C / 4413.05 Torr With hydrogenchloride, hydrogen, palladium on activated charcoal in tetrahydrofuran, ethanol, benzene Takahashi; Tomita; Noguchi; Chemical and Pharmaceutical Bulletin; vol. 29; nb. 11; (1981); p. 3387 - 3391 View in Reaxys

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Reaction Steps: 3 1: 79 percent / benzene / 36 h / Ambient temperature 2: 70 percent / lithium aluminium hydride / diethyl ether / 3.25 h / Heating 3: conc. HCl, hydrogen / 10percent Pd-carbon / ethanol / 12 h / 45 °C / 4045.3 Torr With hydrogenchloride, lithium aluminium tetrahydride, hydrogen, palladium on activated charcoal in diethyl ether, ethanol, benzene Takahashi; Tomita; Noguchi; Chemical and Pharmaceutical Bulletin; vol. 29; nb. 11; (1981); p. 3387 - 3391 View in Reaxys

OH E

H N

(1S,2R)-1-methylamino-1-phenyl-propan-2-ol (C10H15NO)

Rx-ID: 19982855 View in Reaxys 241/592 Yield

Conditions & References Reaction Steps: 2 1: 70 percent / diethyl ether / 18 h / Ambient temperature 2: conc HCl, H2 / 10percent Pd-carbon / ethanol / 12 h / 45 °C / 4045.3 Torr With hydrogenchloride, hydrogen, palladium on activated charcoal in diethyl ether, ethanol Takahashi; Inagaki; Chemical and Pharmaceutical Bulletin; vol. 30; nb. 3; (1982); p. 922 - 926 View in Reaxys

OH E

H N

(1S,2R)-1-methylamino-1-phenyl-propan-2-ol (C10H15NO)

Rx-ID: 20079638 View in Reaxys 242/592 Yield

Conditions & References Reaction Steps: 2 1: 79 percent / tetrahydrofuran / 40 deg C, 6 h, RT, 37 h 2: conc. HCl, hydrogen / 10percent Pd-carbon / ethanol / 8 h / 50 - 60 °C / 4413.05 Torr With hydrogenchloride, hydrogen, palladium on activated charcoal in tetrahydrofuran, ethanol Takahashi; Tomita; Noguchi; Chemical and Pharmaceutical Bulletin; vol. 29; nb. 11; (1981); p. 3387 - 3391 View in Reaxys

OH N

H N

(1S,2R)-1-methylamino-1-phenyl-propan-2-ol (C10H15NO)

Rx-ID: 20080032 View in Reaxys 243/592 Yield

Conditions & References Reaction Steps: 2 1: 70 percent / lithium aluminium hydride / diethyl ether / 3.25 h / Heating 2: conc. HCl, hydrogen / 10percent Pd-carbon / ethanol / 12 h / 45 °C / 4045.3 Torr With hydrogenchloride, lithium aluminium tetrahydride, hydrogen, palladium on activated charcoal in diethyl ether, ethanol Takahashi; Tomita; Noguchi; Chemical and Pharmaceutical Bulletin; vol. 29; nb. 11; (1981); p. 3387 - 3391 View in Reaxys

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NH 2

Rx-ID: 20214944 View in Reaxys 244/592 Yield

Conditions & References Reaction Steps: 2 1: 51 percent / xylene / 24 h / 170 °C 2: 90 percent / LiAlH4 / diethyl ether / 2 h / 55 °C With lithium aluminium tetrahydride in diethyl ether, xylene Koehl, M; Spreitzer, H.; Fleischhacker, W.; Monatshefte fuer Chemie; vol. 123; nb. 10; (1992); p. 911 - 918 View in Reaxys

H N

Rx-ID: 21451827 View in Reaxys 245/592 Yield

Conditions & References Reaction Steps: 2 2: H2O With water Abdallah, Hassan; Gree, Rene; Carrie, Robert; Tetrahedron Letters; vol. 23; nb. 5; (1982); p. 503 - 506 View in Reaxys

N O

racemate

Rx-ID: 21459495 View in Reaxys 246/592 Yield

Conditions & References Reaction Steps: 3 1: 96 percent / Heating 2: 79 percent / H2 / PtO2 / acetic acid / 0.5 h 3: 95 percent / KOH With potassium hydroxide, hydrogen, platinum(IV) oxide in acetic acid Shono,Tatsuya; Matsumura, Yoshihiro; Kanazawa, Takenobu; Tetrahedron Letters; vol. 24; nb. 42; (1983); p. 4577 - 4580 View in Reaxys

H O

NH racemate

Rx-ID: 21469471 View in Reaxys 247/592

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Yield

Conditions & References Reaction Steps: 4 1: 47 percent / 1) LDA 2: 96 percent / Heating 3: 79 percent / H2 / PtO2 / acetic acid / 0.5 h 4: 95 percent / KOH With potassium hydroxide, hydrogen, lithium diisopropyl amide, platinum(IV) oxide in acetic acid Shono,Tatsuya; Matsumura, Yoshihiro; Kanazawa, Takenobu; Tetrahedron Letters; vol. 24; nb. 42; (1983); p. 4577 - 4580 View in Reaxys Reaction Steps: 4 1: potassium dicarbonate 2: alcohol; zinc dust; acetic acid 3: water 4: coppered zinc; diluted acetic acid With ethanol, coppered zinc, potassium dicarbonate, water, acetic acid, zinc Nagai; Kanao; Justus Liebigs Annalen der Chemie; vol. 470; (1929); p. 174; Chem. Zentralbl.; vol. 99; nb. II; (1928); p. 2553 View in Reaxys Reaction Steps: 3 1: copper acetylenide 2: HgSO4; aqueous methanol.H2SO4 3: platinum; methanol / 36775.4 Torr / Hydrogenation With methanol, sulfuric acid, copper(I) monacetylide, mercuric sulphate, platinum Murahashi; Hagihara; Memoirs of the Institute of Scientific and Industrial Research, Osaka University; vol. 6; (1948); p. 96,98 View in Reaxys

N O

racemate

Rx-ID: 21472673 View in Reaxys 248/592 Yield

Conditions & References Reaction Steps: 2 1: 79 percent / H2 / PtO2 / acetic acid / 0.5 h 2: 95 percent / KOH With potassium hydroxide, hydrogen, platinum(IV) oxide in acetic acid Shono,Tatsuya; Matsumura, Yoshihiro; Kanazawa, Takenobu; Tetrahedron Letters; vol. 24; nb. 42; (1983); p. 4577 - 4580 View in Reaxys

H N

H O

OH H

Rx-ID: 21492926 View in Reaxys 249/592 Yield

Conditions & References Reaction Steps: 3

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1: 62 percent / Et3SiH, CF3COOH / 0 °C 2: 65 percent / thionyl chloride / 24 h / 0 - 60 °C 3: 65 percent / LiAlH4 / tetrahydrofuran / Ambient temperature With triethylsilane, lithium aluminium tetrahydride, thionyl chloride, trifluoroacetic acid in tetrahydrofuran Kano, Shinzo; Yokomatsu, Tsutomu; Iwasawa, Haruo; Shibuya, Shiroshi; Tetrahedron Letters; vol. 28; nb. 50; (1987); p. 6331 - 6334 View in Reaxys

H N

H O

OH H

Rx-ID: 21506774 View in Reaxys 250/592 Yield

Conditions & References Reaction Steps: 2 1: 65 percent / thionyl chloride / 24 h / 0 - 60 °C 2: 65 percent / LiAlH4 / tetrahydrofuran / Ambient temperature With lithium aluminium tetrahydride, thionyl chloride in tetrahydrofuran Kano, Shinzo; Yokomatsu, Tsutomu; Iwasawa, Haruo; Shibuya, Shiroshi; Tetrahedron Letters; vol. 28; nb. 50; (1987); p. 6331 - 6334 View in Reaxys

H HN

OH H

Rx-ID: 21510308 View in Reaxys 251/592 Yield

Conditions & References Reaction Steps: 4 1: diethyl ether 2: 62 percent / Et3SiH, CF3COOH / 0 °C 3: 65 percent / thionyl chloride / 24 h / 0 - 60 °C 4: 65 percent / LiAlH4 / tetrahydrofuran / Ambient temperature With triethylsilane, lithium aluminium tetrahydride, thionyl chloride, trifluoroacetic acid in tetrahydrofuran, diethyl ether Kano, Shinzo; Yokomatsu, Tsutomu; Iwasawa, Haruo; Shibuya, Shiroshi; Tetrahedron Letters; vol. 28; nb. 50; (1987); p. 6331 - 6334 View in Reaxys

H N Si O

Rx-ID: 21726026 View in Reaxys 252/592 Yield

Conditions & References Reaction Steps: 2 1: 2.) 2 M HCl / 1.) ether, reflux, 2 h 2: 2.) NaBH4 / 1.) ether, 0 deg C, 30 min, 2.) from 10 deg C to RT With hydrogenchloride, sodium tetrahydroborate

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Jackson, W. Roy; Jacobs, Howard A.; Jayatilake, Gamini S.; Matthews, Barry R.; Watson, Keith G.; Australian Journal of Chemistry; vol. 43; nb. 12; (1990); p. 2045 - 2062 View in Reaxys

HO O H

racemate

Rx-ID: 21999728 View in Reaxys 253/592 Yield

Conditions & References Reaction Steps: 3 1: alcohol; zinc dust; acetic acid 2: water 3: coppered zinc; diluted acetic acid With ethanol, coppered zinc, water, acetic acid, zinc Nagai; Kanao; Justus Liebigs Annalen der Chemie; vol. 470; (1929); p. 174; Chem. Zentralbl.; vol. 99; nb. II; (1928); p. 2553 View in Reaxys Kanao; Yakugaku Zasshi; vol. 49; (1929); p. 26; ; Chem. Zentralbl.; vol. 100; nb. I; (1929); p. 2411 View in Reaxys

HO O N O

NH racemate

Rx-ID: 21999729 View in Reaxys 254/592 Yield

H N

H HN

OH H

racemate

Rx-ID: 22003663 View in Reaxys 255/592 Yield

Conditions & References Reaction Steps: 2 1: water 2: coppered zinc; diluted acetic acid With coppered zinc, water, acetic acid

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Nagai; Kanao; Justus Liebigs Annalen der Chemie; vol. 470; (1929); p. 174; Chem. Zentralbl.; vol. 99; nb. II; (1928); p. 2553 View in Reaxys Kanao; Yakugaku Zasshi; vol. 49; (1929); p. 26; ; Chem. Zentralbl.; vol. 100; nb. I; (1929); p. 2411 View in Reaxys

H N

NH racemate

Rx-ID: 22003664 View in Reaxys 256/592 Yield

Conditions & References Reaction Steps: 2 1: water 2: coppered zinc; diluted acetic acid With coppered zinc, water, acetic acid Nagai; Kanao; Justus Liebigs Annalen der Chemie; vol. 470; (1929); p. 174; Chem. Zentralbl.; vol. 99; nb. II; (1928); p. 2553 View in Reaxys Kanao; Yakugaku Zasshi; vol. 49; (1929); p. 26; ; Chem. Zentralbl.; vol. 100; nb. I; (1929); p. 2411 View in Reaxys

O NH HN

OH H

racemate

Rx-ID: 22006170 View in Reaxys 257/592 Yield

Conditions & References Reaction Steps: 2 1: durch Verseifung und nachfolgende Reduktion 2: Ersetzen der Diazogruppe durch Wasserstoff.Diazotization Patent; I.G.Farbenind.; DE481436; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 16; p. 2833 View in Reaxys

O NH HN

NH racemate

Rx-ID: 22006171 View in Reaxys 258/592 Yield

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H N

racemate

NH racemate

Rx-ID: 22009419 View in Reaxys 259/592 Yield

Conditions & References Reaction Steps: 2 2: aqueous HCl With hydrogenchloride Pfanz; Wieduwilt; Archiv der Pharmazie (Weinheim, Germany); vol. 288; (1955); p. 563,578 View in Reaxys

H HN

NH racemate

racemate

Rx-ID: 22021036 View in Reaxys 260/592 Yield

Conditions & References Reaction Steps: 3 1: SOCl2 3: aqueous HCl With hydrogenchloride, thionyl chloride Pfanz; Wieduwilt; Archiv der Pharmazie (Weinheim, Germany); vol. 288; (1955); p. 563,578 View in Reaxys

H H

OH H

racemate

Rx-ID: 22021607 View in Reaxys 261/592 Yield

Conditions & References Reaction Steps: 4 1: potassium dicarbonate 2: alcohol; zinc dust; acetic acid 3: water 4: coppered zinc; diluted acetic acid With ethanol, coppered zinc, potassium dicarbonate, water, acetic acid, zinc Nagai; Kanao; Justus Liebigs Annalen der Chemie; vol. 470; (1929); p. 174; Chem. Zentralbl.; vol. 99; nb. II; (1928); p. 2553 View in Reaxys

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O Br

NH racemate

Rx-ID: 22023933 View in Reaxys 262/592 Yield

Conditions & References Reaction Steps: 2 1: ethanol 2: palladium; aqueous hydrochloric acid / Hydrogenation With hydrogenchloride, ethanol, palladium Patent; I.G. Farbenind.; DE524717; (1927); Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 17; p. 2515 View in Reaxys Reaction Steps: 2 1: benzene / 0 °C 2: sodium amalgam With sodium amalgam, benzene Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 89 View in Reaxys Reaction Steps: 2 2: sodium amalgam With sodium amalgam Fourneau; Kanao; Bulletin de la Societe Chimique de France; vol. <4> 35; (1924); p. 620 View in Reaxys

O Br

H HN

OH H

racemate

Rx-ID: 22064588 View in Reaxys 263/592 Yield

Conditions & References Reaction Steps: 2 1: benzene / 0 °C 2: sodium amalgam With sodium amalgam, benzene Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 89 View in Reaxys Reaction Steps: 2 1: aluminium isopropylate; isopropyl alcohol 2: methanol / beim 4-woechigen Behandeln unter Lichtausschluss With methanol, aluminum isopropoxide, isopropyl alcohol Stevens; Allenby; DuBois; Journal of the American Chemical Society; vol. 62; (1940); p. 1424,1427 View in Reaxys Reaction Steps: 2 2: sodium amalgam With sodium amalgam Fourneau; Kanao; Bulletin de la Societe Chimique de France; vol. <4> 35; (1924); p. 620 View in Reaxys

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OH H

NH racemate

Rx-ID: 22095955 View in Reaxys 264/592 Yield

Conditions & References Reaction Steps: 2 1: HgSO4; aqueous methanol.H2SO4 2: platinum; methanol / 36775.4 Torr / Hydrogenation With methanol, sulfuric acid, mercuric sulphate, platinum Murahashi; Hagihara; Memoirs of the Institute of Scientific and Industrial Research, Osaka University; vol. 6; (1948); p. 96,98 View in Reaxys

H N

Rx-ID: 22222162 View in Reaxys 265/592 Yield

Conditions & References Reaction Steps: 3 1: palladium/charcoal; aqueous methanol. HCl / Hydrogenation 3: NaBH4 With hydrogenchloride, sodium tetrahydroborate, palladium on activated charcoal Takamatsu; Yakugaku Zasshi; vol. 76; (1956); p. 1227; ; (1957); p. 4304 View in Reaxys Reaction Steps: 2 2: palladium/charcoal; acetic acid; HClO4 / Hydrogenation With palladium on activated charcoal, perchloric acid, acetic acid Takamatsu; Yakugaku Zasshi; vol. 76; (1956); p. 1227; ; (1957); p. 4304 View in Reaxys

O N

H HN

OH H

Rx-ID: 22222163 View in Reaxys 266/592 Yield

Conditions & References Reaction Steps: 2 2: palladium/charcoal; acetic acid; HClO4 / Hydrogenation With palladium on activated charcoal, perchloric acid, acetic acid Takamatsu; Yakugaku Zasshi; vol. 76; (1956); p. 1227; ; (1957); p. 4304 View in Reaxys

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H N

Rx-ID: 22224125 View in Reaxys 267/592 Yield

Conditions & References Reaction Steps: 2 2: NaBH4 With sodium tetrahydroborate Takamatsu; Yakugaku Zasshi; vol. 76; (1956); p. 1227; ; (1957); p. 4304 View in Reaxys

ephedrine salt

H N

Rx-ID: 24035769 View in Reaxys 268/592 Yield

Conditions & References

98%

14 : EXAMPLE 14 EXAMPLE 14 Resolution of (R,S)-2-(N-benzyloxycarbonyl)-4-oxo-4-(2'-methoxyphenyl) butyric acid into its enantiomers by crystallization of its diastereoisomeric salt of ephedrine. Dissolve (R,S)-2-(N-benzyloxycarbonylamino)-4-oxo-4-(2'-methoxyphenyl)butyric acid (0.61 g, 1.7 mmoles) in dry ethyl ether (10 ml), warm the obtained solution at 30° C. and add a solution obtained dissolving (-)-Ephedrine (0.300 g, 1.8 mmoles) in dry ethyl ether (25 ml), warm the resulting suspension for 5 min, then cool to room temperature. Filter the precipitate salt and wash it twice with dry ethyl ether to obtain the ephedrine salt as colourless powder (0.87 g,98percent). [α]D 25° C.=-16.25 C (C=0.5,abs.EtOH). Dissolve the obtained salt into ethyl acetate (40 ml), at reflux Temperature, by adding isopropanol (2 ml), then cool the obtained solution at room temperature. After standing at room temperature 72 hours, 0.192 g (44percent) of colourless crystals ([α]D 25° C.=-30.56° C. (C=0.5, abs.EtOH); m.p. 159-161° C.)) are obtained. The mother liquor is evaporated in vacuo to provide a colourless amorphous solid (0.66 9) named solid B. Dissolve the above crystals in warm ethyl acetate (14 ml) and add absolute ethanol (5.5 ml), warm the suspension to reflux for 5 minutes to complete dissolution, then cool to room temperature. After sanding at room temperature 16 hours, 0.113 g of colourless crystals ([α]D 25° C.=-32.0 (C=0.65, abs.EtOH)); m.p. 163°-65° C. are separated. Dissolve the above crystals (0.100 g) in warm ethanol (2 ml) then cool the obtained solution at room temperature. After standing at room temperature 16 hours 0.085 g (20percent) of colourless needles ([α]D 25° C.=-39.9° C. (C=0.1, abs. EtOH); m.p. 166-67° C.)) are separated. 1H-NMR (80 MHz; DMSOd ) ppm: 0.8 (3H, d), 2.5 (3H, s), 3.0-3.4 (3H, m), 3.85 (3H, s), 4.25 (1H, q), 5.0 (2H, s), 6 5.05 (1H, d), 6.9-7.6 (14H, m). C29H34N3O1 Calculated: C 66.70; H 6.56; N 5.36 Found: C 66.52: H 6.64: N 5.28 Patent; VARASI, MARIO; GIORDANI, ANTONIO; SPECIALE, CARMELA; CINI, MASSIMO; BIANCHETTI, ALBERTO; US2001/8947; (2001); (A1) English View in Reaxys

H N

Rx-ID: 24467924 View in Reaxys 269/592

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Yield

Conditions & References

17.88 g (73%)

1.A : A. A. (-)-Pseudoeohedrine In a 500-mL, 3-necked flask equipped with overhead stirrer, addition funnel and nitrogen inlet, (-)-pseudoephedrine hydrochloride (30.01 g, 149 mmole, 1.0 eq) was dissolved in 234 mL of distilled H2 O. With constant stirring, 2.5N NaOH (66 mL, 165 mmole, 1.1 eq) was added via the addition funnel over 5 min resulting in the formation of a white precipitate (pH of the mixture=14). The mixture was stirred in an ice bath for 3 h. The white solid was collected via vacuum filtration and washed with distilled H2 O (3*200 mL) until the pH of the filtrate was 10. Drying in vacuo gave 17.88 g (73percent) of (-)-pseudoephedrine as a white solid. Patent; Bristol-Myers Squibb Company; US5332840; (1994); (A1) English View in Reaxys III : Preparation of d-pseudoephedrine from 1-ephedrine Step III: Next, 165 parts of aqueous HCl (160 parts of water and 5 parts of HCl) was added to the reaction mixture and the stirred mixture again heated at 90° C. for 4 hours. Recovery: Aqueous 50 percent sodium hydroxide (246 parts) was added to the stirred mixture over a 2 hour period. An aqueous and organic layer resulted which were separated. The upper toluene layer was dried by azeotropic distillation. Analysis of this toluene layer revealed the presence of d-pseudoephedrine in 98.7 percent of theoretical yield, based on starting materials, and 1.3 percent of unreacted 1-ephedrine. This toluene solution was cooled to approximately -5° C. which caused the d-pseudoephedrine to precipitate. The d-pseudoephedrine was collected by filtration, dried under vacuum and analyzed. The dried product represented a 91 percent overall yield of d-pseudoephedrine and had an analysis of 99+ percent purity. Patent; The Dow Chemical Company; US4237304; (1980); (A1) English View in Reaxys Additional primary amines suitable for the process of the invention are those represented by the following formulae: ... 3-(benzylamino)propionitrile 3,3'-iminodipropionitrile (r)-(-)-isoproterenol (1r,2r)-(-)-pseudoephedrine l-adrenaline synephrine 2-(methylamino)ethanol ... Patent; ELI LILLY AND COMPANY; EP825164; (1998); (A2) English View in Reaxys

Rx-ID: 24904552 View in Reaxys 270/592 Yield

Conditions & References 3 : 3R-Formyltetrahydropyran EXAMPLE 3 3R-Formyltetrahydropyran Title product of Example 1 (48.1 g) and H2 O (1 liter) were stirred at 23° C. Dissolution was almost complete after 10 minutes and was complete after less than 1 hour. The initially observed pH was 3.21.

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It rose to 3.48 after 10 minutes, to 4.09 after 1 hour and 4.32 after 2 hours, where it remained constant over the ensuing 0.5 hour. After stirring for a total of 2.5 hours, the aqueous solution was extracted 1*364 ml CH2 Cl2 and 3*150 ml CH2 Cl2. The four organic layers were combined, dried (MgSO4) and stripped to yield present title product as a colorless oil, 8.8 g; [alpha]D 23 =+2.84° (c=0.634, CHCl3). (+)-Ephedrine is recovered from the mother liquor by basification and extraction into CH2 Cl2. Title product is prepared in like manner from the corresponding p-toluenesulfonate salt. 3S-Formyltetrahydropyran, having equal but opposite sign of rotation, is prepared in like manner from the R-camphorsulfonic acid salt or the p-toluenesulfonate salt of 3,4S-dimethyl-5R-phenyl-2S-(3S-tetrahydropyranyl)-oxazolidine. Patent; Pfizer Inc; US5149821; (1992); (A1) English View in Reaxys

D-threo-3-(3,4-dibenzyloxyphenyl)-N-pmethoxybenzyloxycarbonylserine

H N

Rx-ID: 25138513 View in Reaxys 271/592 Yield

Conditions & References 2.b : Preparation of L-threo-adrenalinecarboxylic acid (b) The salt of D-threo-3-(3,4-dibenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine with (-)-ephedrine (8.6 g) obtained as above was added to a mixture of ethyl acetate (100 ml) and 3N hydrochloric acid (60 ml) to effect extraction of the free acid compound. The ethyl acetate layer separated was washed with 3N hydrochloric acid (60 ml) and then with water (30 ml), and the water-washings were extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and dried over anhydrous sodium sulfate and concentrated to dryness. The resulting solid residue was recrystallized from a mixture of chloroform and hexane to yield D-threo-3-(3,4-dibenzyloxyphenyl)-N-p-methoxybenzyloxycarbonylserine (6.35 g). Melting point: 130.5°-131.5° C. [α]D 25: +18° (c 0.91, chloroform-methanol=10:1) Elemental analysis: Calculated for C32 H31 NO8: C 68.93, H 5.60, N 2.51percent; Found: C 68.98, H 5.67, N 2.40percent Patent; Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai; US4833268; (1989); (A1) English View in Reaxys

(1R,2S)-ephedrine salt of (S)-6-fluoro-4-ureidochroman-4-carboxylic acid

H N

Rx-ID: 25148013 View in Reaxys 272/592 Yield

Conditions & References 4.A : METHOD A METHOD A A slurry of 35.6 g (0.14 mole) of 6-fluoro-4-ureidochroman-4-carboxylic acid in 1.07 liters of acetone was stirred at reflux (59° C.) for 30 minutes, and then it was cooled to 54° C. To the resulting slurry was added 24.4 g (0.148 mole) of (1R,2S)-ephedrine all in one portion. The slurry thinned and a near solution resulted. After less than two minutes at 55° C. rapid crystallization began. The slurry was refluxed for 2 hours, cooled to 40° C. and the crystalline solid was recovered by filtration to give 26.1 g of the (1R,2S)-ephedrine salt of (S)-6-fluoro-4-ureidochroman-4-carboxylic acid, mp 204 (dec), [alpha]D 25 =+37.0 (c=1, methanol). The mothers liquors were cooled to room temperature and the further solid was recovered by filtration to give 1.3 g of material, mp 180°-185° C. (dec), [alpha]D 25 =0 (C=1, methanol).

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The filtrate was evaporated in vacuo to give 32.9 g of a mixture of the (1R,2S)-ephedrine salts of (R)-6-fluoro-4-ureidochroman-4-carboxylic acid and (RS)-6-fluoro-4-ureidochroman-4-carboxylic acid, mp 72°-90° C., [alpha]D 25 =-55.7° (C=1, methanol). Patent; Pfizer Inc.; US4551542; (1985); (A1) English View in Reaxys

H N

Rx-ID: 28455482 View in Reaxys 273/592 Yield

Conditions & References

67 %

With palladium dihydroxide, hydrogen in ethanol, T= 20 °C , p= 2585.81Torr , Inert atmosphere Kim, Yongeun; Ha, Hyun-Joon; Yun, Sae Young; Lee, Won Koo; Chemical Communications; nb. 36; (2008); p. 4363 - 4365 View in Reaxys

N O

racemate

Rx-ID: 29474957 View in Reaxys 274/592 Yield

Conditions & References With water, potassium hydroxide in ethanol, Time= 2h, Reflux Schulze, Matthias; Synthetic Communications; vol. 40; nb. 10; (2010); p. 1461 - 1476 View in Reaxys

H 2N

O– H

NH 2 N

H O

H N

Rx-ID: 29581123 View in Reaxys 275/592 Yield

Conditions & References With 1,3-bis[tris(hydroxymethyl)methylamino]-propane, Ephedra sinica Stapf (1R,2S)-norephedrine N-methyltransferase, glycerol, threo-1,4-dimercapto-2,3-butanediol, T= 37 °C , pH= 8.5, aq. buffer, Enzymatic reaction Krizevski, Raz; Bar, Einat; Shalit, Or; Sitrit, Yaron; Ben-Shabat, Shimon; Lewinsohn, Efraim; Phytochemistry; vol. 71; nb. 8-9; (2010); p. 895 - 903 View in Reaxys

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HN O O

Rx-ID: 32043573 View in Reaxys 276/592 Yield

Conditions & References With lithium aluminium tetrahydride in tetrahydrofuran, T= -5 °C , Reflux Nag, Sangram; Lehmann, Lutz; Heinrich, Tobias; Thiele, Andrea; Kettschau, Georg; Nakao, Ryuji; Gulyas, Balazs; Halldin, Christer; Journal of Medicinal Chemistry; vol. 54; nb. 20; (2011); p. 7023 - 7029 View in Reaxys

H N

Rx-ID: 36491909 View in Reaxys 277/592 Yield

Conditions & References Reaction Steps: 3 1: pyruvate decarboxylase / |Enzymatic reaction 2: |Acidic conditions 3: |Acidic conditions With pyruvate decarboxylase Salouros, Helen; Sutton, Gordon J.; Howes, Joanna; Hibbert, D. Brynn; Collins, Michael; Analytical Chemistry; vol. 85; nb. 19; (2013); p. 9400 - 9408 View in Reaxys

H N

Rx-ID: 36491911 View in Reaxys 278/592 Yield

Conditions & References With sodium tetrahydroborate Salouros, Helen; Sutton, Gordon J.; Howes, Joanna; Hibbert, D. Brynn; Collins, Michael; Analytical Chemistry; vol. 85; nb. 19; (2013); p. 9400 - 9408 View in Reaxys

H N

Rx-ID: 36491912 View in Reaxys 279/592 Yield

Conditions & References Reaction Steps: 2 1: sodium tetrahydroborate 2: |Acidic conditions With sodium tetrahydroborate Salouros, Helen; Sutton, Gordon J.; Howes, Joanna; Hibbert, D. Brynn; Collins, Michael; Analytical Chemistry; vol. 85; nb. 19; (2013); p. 9400 - 9408

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View in Reaxys

Rx-ID: 36491916 View in Reaxys 280/592 Yield

Conditions & References Reaction Steps: 2 1: bromine 2: sodium tetrahydroborate With sodium tetrahydroborate, bromine Salouros, Helen; Sutton, Gordon J.; Howes, Joanna; Hibbert, D. Brynn; Collins, Michael; Analytical Chemistry; vol. 85; nb. 19; (2013); p. 9400 - 9408 View in Reaxys

H N

Rx-ID: 36491917 View in Reaxys 281/592 Yield

Conditions & References Reaction Steps: 3 1: bromine 2: sodium tetrahydroborate 3: |Acidic conditions With sodium tetrahydroborate, bromine Salouros, Helen; Sutton, Gordon J.; Howes, Joanna; Hibbert, D. Brynn; Collins, Michael; Analytical Chemistry; vol. 85; nb. 19; (2013); p. 9400 - 9408 View in Reaxys

H 2N HO

Rx-ID: 36491918 View in Reaxys 282/592 Yield

Conditions & References Acidic conditions Salouros, Helen; Sutton, Gordon J.; Howes, Joanna; Hibbert, D. Brynn; Collins, Michael; Analytical Chemistry; vol. 85; nb. 19; (2013); p. 9400 - 9408 View in Reaxys

H N HO

Rx-ID: 36491919 View in Reaxys 283/592 Yield

Conditions & References Reaction Steps: 2

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1: |Acidic conditions 2: |Acidic conditions Salouros, Helen; Sutton, Gordon J.; Howes, Joanna; Hibbert, D. Brynn; Collins, Michael; Analytical Chemistry; vol. 85; nb. 19; (2013); p. 9400 - 9408 View in Reaxys

H N

O O

Rx-ID: 41227745 View in Reaxys 284/592 Yield

Conditions & References (1R,2S)-2-(methylamino)-1-phenylpropan-1-ol hydrochloride (1): To a solution of benzyl carbamate 16 (0.10 g) in methanol was added 10percent Pd/C (10 mg). The resulting solution was stirred under hydrogen (1 atmosphere) for 12 h at room temperature until completion of the reaction as monitored by thin-layer chromatography (TLC). The reaction mixture was filtered through a celite pad to remove the catalyst, and the filtrate was concentrated in vacuo to get (1R, 2S)-ephedrine as colourless oil to which methanolic HCl (3N, 3mL) was added and stirred for 30 min. The reaction mixture was concentrated to give (1R, 2S)-ephedrine hydrochloride 1 as a colorless solid (52 mg). With palladium 10 on activated carbon, hydrogen in methanol, Time= 12h, T= 20 °C , p= 760.051Torr , enantioselective reaction Lalwani, Komal G.; Sudalai, Arumugam; Tetrahedron Letters; vol. 56; nb. 46; (2015); p. 6488 - 6490 View in Reaxys

H N

O– Li+

Rx-ID: 2104782 View in Reaxys 285/592 Yield

Conditions & References With lithium hexamethyldisilazane in tetrahydrofuran, T= 25 °C , ΔH(deprotonation), Thermodynamic data Nichols, Michael A.; McPhail, Andrew T.; Arnett, Edward M.; Journal of the American Chemical Society; vol. 113; nb. 16; (1991); p. 6222 - 6233 View in Reaxys

H N

H HN

O– Li+

OH H

Rx-ID: 2498566 View in Reaxys 286/592 Yield

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NH OH

OH 2 O

H N

HO O

OH O

Rx-ID: 31615932 View in Reaxys 287/592 Yield

Conditions & References

64 %

3 :Example 3 : (li~,2i~)-4-oxo-l,2-cyclopentanedicarboxylic acid and recovery of ephedrine.; To a solution of (li~, 2i~)-4-oxo-l,2-cyclopentanedicarboxylic acid salt with (lR,2S)-(-)- ephedrine (1 :2) (251 g, 0.5 mol) was added 8 N aqueous KOH (199.21 g, 1.10 mole) and the mixture was stirred for 5 minutes. 2-Methyltetrahydrofuran (688 ml) was added and the mixture was stirred vigorously for 20 minutes. The two layers were separated and the aqueous phase was acidified with HC1. The 2-methyltetrahydrofuran organic phase contained the ephedrine, which could be recycled from that phase. The aqueous phase was then evaporated to dryness on the rotavapor and the residue recrystallized from water (50 ml) to yield 55.15 g (64 percent yield) of (li~,2i~)-4-oxo-l,2-cyclopentanedicarboxylic acid as an off white solid. The 2-methyltetrahydrofuran solution of ephedrine was evaporated to dryness on the rotavapor to yield crude ephedrine as a yellow oil, which solidified on standing after 3 days. The crude ephedrine was dissolved in 2-methyltetrahydrofuran (400 ml) and the mixture made acidic with HC1 in isopropanol. The solid material was filtered and washed with 2-methyltetrahydrofuran (50 ml). The solid ephedrine hydrochloride was dried under vacuum at 50°C before being dissolved in water (300 ml) at 40°C.Sufficient potassium carbonate was added portionwise to the warm aqueous solution, until a two-phase system was obtained. 2-Methyltetrahydrofuran (200 ml) was added and the mixture stirred vigorously for 5 minutes. The two layers were separated and the aqueous phase extracted with 2-methyltetrahydrofuran (200 ml). The combined organic layers were dried over Na2S04, filtered and evaporated to dryness to yield 124.7 g (75percent yield) of recovered ephedrine as a white solid. Stage 1: With potassium hydroxide in water, Time= 0.0833333h Stage 2: With hydrogenchloride in water Patent; ORTHO-MCNEIL-JANSSEN PHARMACEUTICALS, INC; ORMEROD, Dominic John; DEPRE, Dominique Paul Michel; HORVATH, Andras; WO2011/113859; (2011); (A1) English View in Reaxys

H OH

Rx-ID: 8582749 View in Reaxys 288/592 Yield

Conditions & References

90 %, 80 %

H N

O– Na +

Rx-ID: 2104788 View in Reaxys 289/592 Yield

Conditions & References With sodium hydride in tetrahydrofuran, nujol, Time= 24h Duthaler, Rudolf O.; Maienfisch, Peter; Helvetica Chimica Acta; vol. 67; nb. 3; (1984); p. 845 - 855 View in Reaxys

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H 2N

NH 2

Rx-ID: 4345990 View in Reaxys 290/592 Yield

Conditions & References With water, lithium chloride, lithium diisopropyl amide, Yield given. Multistep reaction Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

H N

NH 2

Rx-ID: 3202900 View in Reaxys 291/592 Yield

Conditions & References With hydrogenchloride, hydrogen, palladium on activated charcoal in ethanol, Time= 12h, T= 45 °C , p= 4045.3Torr Takahashi; Inagaki; Chemical and Pharmaceutical Bulletin; vol. 30; nb. 3; (1982); p. 922 - 926 View in Reaxys

H N

Rx-ID: 61101 View in Reaxys 292/592 Yield

Conditions & References Steldt; Chen; Journal of the American Pharmaceutical Association (1912-1977); vol. 29; (1940); p. 106 View in Reaxys

H N

Rx-ID: 211597 View in Reaxys 293/592 Yield

Conditions & References Krishna; Ghose; Journal of the Society of Chemical Industry, London; vol. 48; (1929); p. 67,69 View in Reaxys

Cl Cl

H N

OH H N

OH Cl

Rx-ID: 220790 View in Reaxys 294/592 Yield

Conditions & References Miller; Journal of the American Pharmaceutical Association (1912-1977); vol. 37; (1948); p. 226

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View in Reaxys

H N

racemate

Rx-ID: 2198867 View in Reaxys 295/592 Yield

Conditions & References Saigo, Kazuhiko; Okuda, Yoshiyuki; Wakabayashi, Sumio; Hoshiko, Tomonori; Nohira, Hiroyuki; Chemistry Letters; (1981); p. 857 - 860 View in Reaxys

H N

O N

OH OH

O O

Rx-ID: 3239207 View in Reaxys 296/592 Yield

Conditions & References

52 %, 64 %

With hydrogen, palladium on activated charcoal in ethanol, Time= 25h, p= 1500.1Torr , Ambient temperature Hussain; Wyatt; Tetrahedron; vol. 49; nb. 10; (1993); p. 2123 - 2130 View in Reaxys

H N

OH threo threo

Cl H HN

Rx-ID: 3605593 View in Reaxys 297/592 Yield

Conditions & References Prelog, Vladimir; Mutak, Stjepan; Helvetica Chimica Acta; vol. 66; nb. 7; (1983); p. 2274 - 2278 View in Reaxys

H N

OH Cl

Rx-ID: 8215159 View in Reaxys 298/592 Yield

Conditions & References die von Sawa, Shionogi Kenkyusho Nempo 2 <1952> 25 (C.A. 51 <1957> 10423b) beschriebene Bildungsweise (Ausbeute) liess sich nicht reproduzieren Nguyen-Hoang-Nam et al.; Journal of Labelled Compounds; vol. 4; (1968); p. 325,328 View in Reaxys

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H N

N-methyl-<l-ephedrine>

OH Cl

Rx-ID: 8241951 View in Reaxys 299/592 Yield

Conditions & References With hydrogenchloride Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 57 View in Reaxys Schmidt; Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 64,66 View in Reaxys hydrochloric acid H N

d-pseudoephedrine-O-sulfuric acid ester

d-pseudoephedrine hydrochloride

Rx-ID: 8275716 View in Reaxys 300/592 Yield

Conditions & References Schmidt; Archiv der Pharmazie (Weinheim, Germany); vol. 252; (1914); p. 121; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 52 View in Reaxys

O H

Cl H HN

Rx-ID: 8578263 View in Reaxys 301/592 Yield

Conditions & References

92 %

With hydrogenchloride, Time= 2h, Heating, Hydrolysis Vidyasagar Reddy; Venkat Rao; Sreevani; Iyengar; Tetrahedron Letters; vol. 41; nb. 6; (2000); p. 953 - 954 View in Reaxys

Cl H HN

Rx-ID: 10557584 View in Reaxys 302/592 Yield

Conditions & References 3 : Preparation of Pseudoephedrine Hydrochloride Powder for Reconstitution Nitrogen is bubbled into the obtained molten mixture under superatmospheric pressure. Then, the molten mixture is cooled under superatmospheric pressure and then the pressure was released. The obtained solid mixture is ground to obtain a popping powder. Psuedoephedrine beads are mixed together with the obtained popping powder to yield pseudoephedrine hydrochloride powder. Patent; CTS Chemical Industries, Ltd.; US2005/89567; (2005); (A1) English View in Reaxys

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O N O

H HN

phosphorus pentabromide

Rx-ID: 15935378 View in Reaxys 303/592 Yield

Conditions & References Reaction Steps: 2 1: 93 percent / NaCNBH3; TMSCl / acetonitrile / 0.5 h / 20 °C 2: 92 percent / conc. HCl / 2 h / Heating With hydrogenchloride, chloro-trimethyl-silane, sodium cyanoborohydride in acetonitrile, 1: Reduction / 2: Hydrolysis Vidyasagar Reddy; Venkat Rao; Sreevani; Iyengar; Tetrahedron Letters; vol. 41; nb. 6; (2000); p. 953 - 954 View in Reaxys

H N

(1S,2R)-1-methylamino-1-phenyl-propan-2-ol (C10H15NO)

H N

OH Cl

Rx-ID: 19593545 View in Reaxys 304/592 Yield

Conditions & References Reaction Steps: 4 1: 4 Angstroem molecular sieves / CH2Cl2 / 24 h / Ambient temperature 2: 1) 4 Angstroem molecular sieves, 2) tetrabutylammonium periodate / 1) dichloromethane, room temperature, 24 h, 2) dichloromethane, -65 deg C to room temperature, 2 h 3: 49 percent / barium chlorate monohydrate / osmium(VIII) oxide / H2O; 2-methyl-propan-2-ol / 28 h / 20 °C 4: 52 percent / H2 / 5percent palladium on carbon / ethanol / 25 h / 1500.1 Torr / Ambient temperature With barium chlorate monohydrate, 4 A molecular sieve, hydrogen, tetrabutylammonium (meta)periodate, palladium on activated charcoal, osmium(VIII) oxide in ethanol, dichloromethane, water, tert-butyl alcohol Hussain; Wyatt; Tetrahedron; vol. 49; nb. 10; (1993); p. 2123 - 2130 View in Reaxys

N O E

H N

OH Cl

Rx-ID: 19623484 View in Reaxys 305/592 Yield

Conditions & References Reaction Steps: 3 1: 1) 4 Angstroem molecular sieves, 2) tetrabutylammonium periodate / 1) dichloromethane, room temperature, 24 h, 2) dichloromethane, -65 deg C to room temperature, 2 h 2: 49 percent / barium chlorate monohydrate / osmium(VIII) oxide / H2O; 2-methyl-propan-2-ol / 28 h / 20 °C 3: 52 percent / H2 / 5percent palladium on carbon / ethanol / 25 h / 1500.1 Torr / Ambient temperature With barium chlorate monohydrate, 4 A molecular sieve, hydrogen, tetrabutylammonium (meta)periodate, palladium on activated charcoal, osmium(VIII) oxide in ethanol, water, tert-butyl alcohol Hussain; Wyatt; Tetrahedron; vol. 49; nb. 10; (1993); p. 2123 - 2130 View in Reaxys

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O N

H N

OH Cl

O H O

H N

Rx-ID: 19625713 View in Reaxys 306/592 Yield

Conditions & References Reaction Steps: 2 1: 49 percent / barium chlorate monohydrate / osmium(VIII) oxide / H2O; 2-methyl-propan-2-ol / 28 h / 20 °C 2: 52 percent / H2 / 5percent palladium on carbon / ethanol / 25 h / 1500.1 Torr / Ambient temperature With barium chlorate monohydrate, hydrogen, palladium on activated charcoal, osmium(VIII) oxide in ethanol, water, tert-butyl alcohol Hussain; Wyatt; Tetrahedron; vol. 49; nb. 10; (1993); p. 2123 - 2130 View in Reaxys

H N

O H

OH O

H N

ephedrine salt

OH Cl

Rx-ID: 24361498 View in Reaxys 307/592 Yield 40%

Conditions & References 5 : EXAMPLE 5 EXAMPLE 5 8.25 g (50 mmol) of D,L-ephedrine and 5.88 g (25 mmol) of D-2,4-dichlorophenoxypropionic acid were taken up in 100 ml of toluene. Heating to reflux was followed by slow cooling, and the crystals were filtered off with suction and washed with toluene. Drying resulted in 4.2 g (42percent) of ephedrine salt. Liberation of the base as in Example 1 and conversion thereof into the hydrochloride resulted in L-ephedrine hydrochloride in an overall yield of 40percent, [α]D 20: -33.7°. Patent; BASF Aktiengesellschaft; US6015903; (2000); (A1) English View in Reaxys

(1R,2S)-(-)-2-(Methylamino)-1-phenyl-1propanol,HCl (Ephedrine.HCl)

H N

OH Cl

Rx-ID: 24392515 View in Reaxys 308/592 Yield 7.4 g (83%)

Conditions & References 2 : (1R,2S)-(-)-2-(Methylamino)-1-phenyl-1-propanol,HCl (Ephedrine.HCl). EXAMPLE 2 (1R,2S)-(-)-2-(Methylamino)-1-phenyl-1-propanol,HCl (Ephedrine.HCl). Deprotection of the compound prepared according to Example 1 (12.3 g) was performed with LiAlH4 in THF. The crude product (8.1 g contaminated with TBSOH) was dissolved in 100 ml of anhydrous ether and cooled in an ice bath. Dry HCl gas was passed until the amine was neutralized. The precipitate was filtered off, washed with anhydrous ether and dried. Yield: 7.4 g (83percent) ephedrine.HCl. Analytical data were identical to those of an authentic sample. Patent; Duphar International Research B.V.; US5189219; (1993); (A1) English

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View in Reaxys

H N

OH Cl

Rx-ID: 25212568 View in Reaxys 309/592 Yield

Conditions & References 1.C : STEP C: STEP C: Hemisuccinate of d-allethrolone A solution of 35 ml of an aqueous hydrochloric acid solution of 22° Be in 250 ml of water was added with stirring to a suspension of 150 g of the dextro ephedrine salt of the hemisuccinate of d-allethrolone in 750 ml of benzene at 20° C and after stirring for 1 hour, 2 phases formed. The aqueous phase containing ephedrine hydrochloride was separated by decantation and was reextracted with benzene. The combined benzene extracts were dried and distilled to dryness under reduced pressure. Patent; Roussel-UCLAF; US4005146; (1977); (A1) English View in Reaxys The resolution of the enantiomers of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid was carried out via reaction with the following chiral bases: Brucine Quinine (-)-Cinchonidine (+)-Cinchonine R-(+)-1-Phenylethylamine (1 R,2S)-(-)-Ephedrine hydrochloride (1S,2R)-(+)-Ephedrine hydrochloride. Patent; Laboratorios del Dr. Esteve S.A.; EP1944294; (2008); (A1) English View in Reaxys

H N

OH Cl

Rx-ID: 27824481 View in Reaxys 310/592 Yield

Conditions & References The resolution of the enantiomers of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid was carried out via reaction with the following chiral bases: Brucine Quinine (-)-Cinchonidine (+)-Cinchonine R-(+)-1-Phenylethylamine (1 R,2S)-(-)-Ephedrine hydrochloride (1S,2R)-(+)-Ephedrine hydrochloride. Patent; Laboratorios del Dr. Esteve S.A.; EP1944294; (2008); (A1) English View in Reaxys

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N H H

H N

Cl H

OH Cl

Rx-ID: 29573658 View in Reaxys 311/592 Yield

Conditions & References With ammonia, water, Time= 8h, Reflux Cruz, Alejandro; Padilla-Martinez, Itzia Irene; Garcia-Baez, Efren V.; Tetrahedron Asymmetry; vol. 21; nb. 8; (2010); p. 909 - 913 View in Reaxys

N H H

H N

Rx-ID: 29573659 View in Reaxys 312/592 Yield

Conditions & References With water, sodium hydroxide, Time= 24h Cruz, Alejandro; Padilla-Martinez, Itzia Irene; Garcia-Baez, Efren V.; Tetrahedron Asymmetry; vol. 21; nb. 8; (2010); p. 909 - 913 View in Reaxys

H N

OH Cl

Rx-ID: 41227785 View in Reaxys 313/592 Yield

Conditions & References

52 mg

(1R,2S)-2-(methylamino)-1-phenylpropan-1-ol hydrochloride (1): To a solution of benzyl carbamate 16 (0.10 g) in methanol was added 10percent Pd/C (10 mg). The resulting solution was stirred under hydrogen (1 atmosphere) for 12 h at room temperature until completion of the reaction as monitored by thin-layer chromatography (TLC). The reaction mixture was filtered through a celite pad to remove the catalyst, and the filtrate was concentrated in vacuo to get (1R, 2S)-ephedrine as colourless oil to which methanolic HCl (3N, 3mL) was added and stirred for 30 min. The reaction mixture was concentrated to give (1R, 2S)-ephedrine hydrochloride 1 as a colorless solid (52 mg). With hydrochlorid acid in methanol, Time= 0.5h, p= 760.051Torr , enantioselective reaction Lalwani, Komal G.; Sudalai, Arumugam; Tetrahedron Letters; vol. 56; nb. 46; (2015); p. 6488 - 6490 View in Reaxys

NH 2

OH H

N H

Rx-ID: 4343728 View in Reaxys 314/592 Yield

Conditions & References With sodium hydroxide, sodium hydrogencarbonate, 1.) reflux, 2.) 1.5 h, Yield given. Multistep reaction

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Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

NH 2

OH N

N H

Rx-ID: 4343730 View in Reaxys 315/592 Yield

Conditions & References With sodium hydroxide, sodium hydrogencarbonate, 1.) reflux, 2.) 1.5 h, Yield given. Multistep reaction Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

N threo N threo N

O HO

H N N

OH threo threo

O HO

Rx-ID: 3272392 View in Reaxys 316/592 Yield

Conditions & References With hydrogenchloride, Heating, Rate constant Rucker; Mrongovius; Neugebauer; Archiv der Pharmazie; vol. 315; nb. 10; (1982); p. 839 - 846 View in Reaxys

H N

(v1)

H HN

OH H

Rx-ID: 3553850 View in Reaxys 317/592 Yield

Conditions & References in toluene, T= 19.9 °C , E-1, Rate constant, Equilibrium constant, Thermodynamic data Masalimov, A. S.; Nikol'skii, S. N.; Abdykarimova, A. P.; Prokof'ev, A. I.; Muldakhmetov, Z. M.; Bull. Russ. Acad. Sci. Div. Chem. Sci. (Engl. Transl.); vol. 41; nb. 9.1; (1992); p. 2007 - 2011,1559 - 1562 View in Reaxys

O O

H 2N O

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HO O

N H

Rx-ID: 4343209 View in Reaxys 318/592 Yield

Conditions & References With sodium hydroxide, sodium hydrogencarbonate, lithium chloride, lithium diisopropyl amide, Yield given. Multistep reaction. Yields of byproduct given. Title compound not separated from byproducts Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys With sodium hydroxide, sodium hydrogencarbonate, lithium chloride, lithium diisopropyl amide, Yield given. Multistep reaction. Yields of byproduct given Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

NH 2

OH N

O O

N H

Rx-ID: 4343637 View in Reaxys 319/592 Yield

N O

H N

O OH

Rx-ID: 3934304 View in Reaxys 320/592 Yield

Conditions & References

60 %, 66 %

With di-isopropyl azodicarboxylate, triphenylphosphine in diethyl ether, Ambient temperature Poelert, Martin A.; Hulshof, L. A.; Kellogg, Richard M.; Recueil des Travaux Chimiques des Pays-Bas; vol. 113; nb. 7/8; (1994); p. 355 - 364 View in Reaxys

O O

NH 2

H O

H HO

Rx-ID: 4343736 View in Reaxys 321/592

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Yield

Conditions & References With sodium hydroxide, sodium hydrogencarbonate, 1.) reflux, 2.) 3 h, Yield given. Multistep reaction Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

H N

O NH 2

Rx-ID: 8359392 View in Reaxys 322/592 Yield

Conditions & References Nitroharnstoff, entspr. Amin Patent; Heidenbluth et al.; DD42890; (1964); ; vol. 64; nb. 12651e; (1966) View in Reaxys

H N

Rx-ID: 30082135 View in Reaxys 323/592 Yield

Conditions & References in water Ivanova, Bojidarka; Spiteller, Michael; Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy; vol. 77; nb. 4; (2010); p. 849 - 855 View in Reaxys

O O

H O

N O

H OH

Rx-ID: 4343653 View in Reaxys 324/592 Yield

Conditions & References With sodium hydroxide, 1.) methanol, reflux, 24 h, Yield given. Multistep reaction Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

NH 2

NH OH

Rx-ID: 25894755 View in Reaxys 325/592 Yield

Conditions & References N-Allylglycine ethyl ester. The reaction was repeated on the same scale to yield a total of 22.73 g (127 mmol, 90percent) of the desired amine hydrochloride 21f (R9b=H, m=1) as a white solid: 1H NMR (300 MHz, DMSO-d6) 9.50 (s, 2H), 5.95-5.81 (m, 1H), 5.49-5.37 (m, 2H), 4.21 (q, J=7.2 Hz, 2H), 3.92 (s, 2H), 3.59 (d, J=6.6 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H); MS (ESPOS): 144.1 [M+H]+.

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Pseudoephedrine N-allylglycinamide 21h (R9b=H, m=1). To a flask containing 21f (R9b=H). (20.3 g, 113 mmol, 1.3 equiv) and (1R,2R)-pseudoephedrine 21g (14.4 g, 86.9 mmol, 1 equiv) was added THF (130 mL). The resulting mixture was stirred vigorously for 20 minutes at 20° C. to give a uniform slurry, then treated with solid lithium-tert-butoxide (9.74 g, 122 mmol, 1.4 equiv) added in a single portion. The reaction was stirred at 20° C. for 2 d, after which time analysis revealed both starting materials were still present. The incomplete reaction was treated with H2O (200 mL), then THF was removed in vacuo. The resulting aqueous solution was extracted with CH2Cl2 (2 150 mL), then saturated with NaCl and further extracted with CH2Cl2 (2 100 mL). The organic extracts were dried (K2CO3), filtered and concentrated. The crude product was purified via flash column chromatography on silica gel using 2:2:96 MeOH/Et3N/CH2Cl2 as eluent to give 18 g of product. This material was still substantially contaminated with N-allylglycine ethyl ester, this was removed with gentle heating (60° C.) under vacuum (1.0 mmHg) for 15 h to give 14.88 g (56.8 mmol, 65percent) of the desired glycinamide product 21h (R9b=H, m=1) as a viscous oil: 1H NMR (300 MHz, CDCl3) (Spectrum shows rotamers) 7.41-7.24 (m, 5H), 6.00-5.80 (m, 1H), 5.29-5.07 (m, 2H), 4.64-4.44 (m, 1H), 3.96-3.84 (m, 0.5H), 3.63 (d, J=13.8 Hz, 0.5H), 3.45-3.21 (m, 4H), 2.95 (s, 1.5H), 2.78 (s, 1.5H), 1.11 (d, J=6.9 Hz, 1.5H), 0.98 (d, J=6.9 Hz, 1.5H); MS (ESPOS): 263.2 [M+H] +. HPLC (Symmetry C18, 3.5 μm particle size, 100 Å pore size, 4.6 mm diameter 30 mm length, 2percent-98percent MeCN in H2O w/0.1percent TFA over 10 min, 2 mL/min flow rate): Rt=3.10 min. Patent; Lewis, Jason G.; Anandan, Sampath-Kumar; O'Dowd, Hardwin; Gordeev, Mikhail F.; US2005/43248; (2005); (A1) English View in Reaxys Alkylation of Pseudoephedrine N-allylglycinamide. The mother liquor was concentrated to give 0.57 g of brown oil which was again subjected to flash column chromatography on silica gel (40-50percent EtOAc in hexanes as eluent) to give a further 392 mg (0.94 mmol, 8percent) of desired product 21j (R9=n-propyl, R9b=H, m=1): 1H NMR (300 MHz, CDCl3) (spectrum shows rotamers) 7.50-7.25 (m, 5H), 5.52-5.26 (m, 1H), 5.05-4.96 (m, 1H), 4.63-4.35 (m, 2H), 4.30-3.58 (m, 3H), 2.91 (s, 3H), 2.50-2.34 (m, 1H), 2.20-1.94 (m, 3H), 1.46 (s, 7H), 1.41 (s, 2H), 1.19-1.01 (m, 2H), 0.94-0.85 (m, 3H); MS (ESPOS): 439.3 [M+Na]+. HPLC (Symmetry C18, 3.5 μm particle size, 100 Å pore size, 4.6 mm diameter 30 mm length, 2percent-98percent MeCN in H2O w/0.1percent TFA over 10 min, 2 mL/min flow rate): Rt=6.29 min. Cleavage of Pseudoephedrine Auxiliary 21k (R9=n-propyl, R9b=H, m=1). To a solution of amide 21j (R9=n-propyl, R9b=H, m=1) (3.42 g, 8.22 mmol, 1 equiv) in MeOH (170 mL) at 23° C. was added 1.0 M aqueous NaOH (41.1 mL, 41.1 mmol, 5 equiv). The reaction was refluxed for 24 h (oil-bath temperature at 100° C.), then cooled to 23° C. and concentrated via rotary evaporation to remove most of the MeOH. The resulting aqueous solution was transferred to a separatory funnel, diluted with H2O (100 mL) and extracted with Et2O (100 mL). The ether extract was washed with 0.5 M aqueous NaOH (70 mL) then discarded. The combined basic aqueous layers were acidified to pH 2 with 1.0 N HCl, then extracted with EtOAc (2 200 mL). The organic extracts were dried (MgSO4), filtered and concentrated to give 2.46 g of the desired Boc-protected amino acid 21k (R9=n-propyl, R9b=H, m=1): 1H NMR (300 MHz, CDCl3) (Spectrum shows rotamers) 5.36 (d, J=22.8 Hz, 1H), 5.09 (d, J=4.8 Hz, 0.5H), 4.90 (br s, 0.5H), 4.14-3.97 (m, 1H), 3.83-3.67 (m, 1H), 2.57-2.37 (m, 2H), 1.98 (t, J=7.2 Hz, 2H), 1.48 (s, 6H), 1.47-1.35 (m, 2H), 1.46 (s, 3H), 0.86 (t, J=7.2 Hz, 3H); MS (ESPOS): 292.1 [M+Na]+; MS (ESNEG): 268.2 [M-H]-. Patent; Lewis, Jason G.; Anandan, Sampath-Kumar; O'Dowd, Hardwin; Gordeev, Mikhail F.; US2005/43248; (2005); (A1) English View in Reaxys Pseudoephedrine N-allylglycinamide 21h (R9b=H, m=1) Pseudoephedrine N-allylglycinamide 21h (R9b=H, m=1) To a flask containing 21f (R9b=H). (20.3 g, 113 mmol, 1.3 equiv) and (1R,2R)-pseudoephedrine 21 g (14.4 g, 86.9 mmol, 1 equiv) was added THF (130 mL). The resulting mixture was stirred vigorously for 20 minutes at 20° C. to give a uniform slurry, then treated with solid lithium-tert-butoxide (9.74 g, 122 mmol, 1.4 equiv) added in a single portion.

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The reaction was stirred at 20° C. for 2 d, after which time analysis revealed both starting materials were still present. The incomplete reaction was treated with H2O (200 mL), then THF was removed in vacuo. The resulting aqueous solution was extracted with CH2Cl2 (2 150 mL), then saturated with NaCl and further extracted with CH2Cl2 (2 100 mL). The organic extracts were dried (K2CO3), filtered and concentrated. The crude product was purified via flash column chromatography on silica gel using 2:2:96 MeOH/Et3N/CH2Cl2 as eluant to give 18 g of product. This material was still substantially contaminated with N-allylglycine ethyl ester, this was removed with gentle heating (60° C.) under vacuum (1.0 mmHg) for 15 h to give 14.88 g (56.8 mmol, 65percent) of the desired glycinamide product 21h (R9b=H, m=1) as a viscous oil: 1H NMR (300 MHz, CDCl3) (Spectrum shows rotamers) 7.41-7.24 (m, 5H), 6.00-5.80 (m, 1H), 5.29-5.07 (m, 2H), 4.64-4.44 (m, 1H), 3.96-3.84 (m, 0.5H), 3.63 (d, J=13.8 Hz, 0.5H), 3.45-3.21 (m, 4H), 2.95 (s, 1.5H), 2.78 (s, 1.5H), 1.11 (d, J=6.9 Hz, 1.5H), 0.98 (d, J=6.9 Hz, 1.5H); MS (ESPOS): 263.2 [M+H] +. HPLC (Symmetry C18, 3.5 μm particle size, 100 Å pore size, 4.6 mm diameter 30 mm length, 2percent-98percent MeCN in H2O w/0.1percent TFA over 10 min, 2 mL/min flow rate): Rt=3.10 min. Patent; Lewis, Jason G.; Anandan, Sampath K.; O'Dowd, Hardwin; Gordeev, Mikhail F.; US2005/215488; (2005); (A1) English View in Reaxys

H N

NH O

H N

Rx-ID: 2104771 View in Reaxys 326/592 Yield

Conditions & References

67 %

in methanol Shustov, G. V.; Denisenko, S. N.; Zolotoi, A. B.; D'yachenko, O. A.; Atovmyan, L. O.; Kostyanovskii, R. G.; Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation); vol. 35; nb. 10; (1986); p. 2071 - 2076; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 10; (1986); p. 2266 - 2271 View in Reaxys in methanol, Title compound not separated from byproducts Shustov, G. V.; Denisenko, S. N.; Zolotoi, A. B.; D'yachenko, O. A.; Atovmyan, L. O.; Kostyanovskii, R. G.; Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation); vol. 35; nb. 10; (1986); p. 2071 - 2076; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 10; (1986); p. 2266 - 2271 View in Reaxys

O O

H 2N

O Br

OH H

NH O O

Rx-ID: 4343582 View in Reaxys 327/592 Yield

Conditions & References With sodium hydroxide, sodium hydrogencarbonate, lithium chloride, lithium diisopropyl amide, Yield given. Multistep reaction Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

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H H

H N

I–

water

OH OH

N-methyl-<l-ephedrine>

H HO

Rx-ID: 8427391 View in Reaxys 328/592 Yield

Conditions & References bei der Destillation Schmidt; Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 64,66 View in Reaxys

H H

H N

I–

sodium amalgam

water

OH OH

N-methyl-<l-ephedrine>

H HO

Rx-ID: 8427392 View in Reaxys 329/592 Yield

Conditions & References Schmidt; Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 64,66 View in Reaxys

H N

Cl –

water

H H

H N

OH OH

N-methyl-<l-ephedrine>

H HO

Rx-ID: 8493233 View in Reaxys 330/592

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Yield

Conditions & References bei der Destillation Schmidt; Eberhard; Archiv der Pharmazie (Weinheim, Germany); vol. 253; (1915); p. 64,66 View in Reaxys

H N

HO O

H N

HO H

Rx-ID: 29683369 View in Reaxys 331/592 Yield

Conditions & References

100 %

56 :Salicylic acid (0.691 g, 5 mmol) and ephedrine (0.826 g, 5 mmol) were molten in a hot mortar until a free-flowing clear liquid was obtained. The mixture was cooled to room temperature solidified and was grinded to obtain a colourless powder in quantitative yield. 1H-NMR (300 MHz, d6-DMSO) δ(ppm) = 9.30 (br s, 2H), 7.76 (dd, J1 = 7.66 Hz, J2 = 1.80 Hz, IH), 7.38 (m, 4H), 7.24 (m, 2H), 6.70 (m, 2H), 6.48 (br s, IH), 5.21 (s, IH), 3.41 (m, IH), 2.69 (s, 3H), 0.95 (d, J=6.76 Hz, 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm) = 172.9, 162.1, 141.4, 132.0, 130.3, 128.2, 127.2, 125.8, 119.6, 116.8, 116.0, 69.6, 59.3, 30.6, 9.1. mp 97 °C, T5percentonset 161 °C. , Heating, Neat (no solvent) Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys

(v5)O PH

H N

S P–

O H+

Rx-ID: 3369856 View in Reaxys 332/592 Yield

Conditions & References

91 %

With sulfur in benzene, Heating Turdybekov, K. M.; Lindeman, S. V.; Struckov, Yu. T.; Gazaliev, A. M.; Fazylov, S. D.; et al.; Chemistry of Natural Compounds; vol. 25; (1989); p. 77 - 80; Khimiya Prirodnykh Soedinenii; nb. 1; (1989); p. 88 - 91 View in Reaxys

N O

(v5)

O O

Rx-ID: 5063931 View in Reaxys 333/592 Yield

Conditions & References With sulfur in benzene, Heating, Ring cleavage Fazylov, S. D.; Gazaliev, A. M.; Vlasova, L. M.; Russian Journal of General Chemistry; vol. 66; nb. 5; (1996); p. 850 - 850; Zhurnal Obshchei Khimii; vol. 66; nb. 5; (1996); p. 872 - 872 View in Reaxys

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O N

O O

(v5)O

PH O

O O

Rx-ID: 5063932 View in Reaxys 334/592 Yield

(v5)

O O

Rx-ID: 5063936 View in Reaxys 335/592 Yield

H N

F NH

Rx-ID: 24239463 View in Reaxys 336/592 Yield

Conditions & References EXAMPLES To this solution was then added 5.72 g (0.238 mol) of sodium hydride (washed with hexanes). The solution was heated to 60° C. for 1 hour. To this dark orange solution was added 50 mL of 4-chlorobenzotrifluoride (0.374 mol). The reaction mixture was heated to 115° C. for 6 hours. The reaction was allowed to cool to room temperature and then 1.0 L of water was added to quench the reaction. The reaction mixture was extracted with ethyl ether (2*500 mL), followed by two extractions using toluene (2*500 mL). The organic layers were combined and washed twice with brine. The aqueous layer was separated and the organic layer dried, filtered and rotoevaporated to yield 60.3 g of crude material. This crude material was purified by column chromatography (silica gel) using 5percent methanol:methylene chloride as the eluent. Yield of pure fluoxetine free base (7) was 25.6 g (56percent). Chemical purity=96.9percent 1 H NMR ppm (δ), CDCl3 7.57 (d,2H), 7.44-7.24 (m, 5H), 6.91 (d, 2H), 5.33 (dd, 1H), 2.75 (t, 2H), 2.42 (3H, NCH3), 2.20 (m, 1H), 1.90 (s, 1H). C NMR ppm (δ), CDCl3 160.6, 141.0, 128.8, 127.8, 126.7, 125.8, 122.7, 115.8, 78.7, 48.2, 38.7, 36.4.

Patent; Sepacor Inc.; US5936124; (1999); (A1) English View in Reaxys

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H N O H HN

OH OH

racemate

Rx-ID: 438161 View in Reaxys 337/592 Yield

Conditions & References With water, 2,3-dihydroxybutanedioic acid Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys Kanao; Yakugaku Zasshi; nb. 540; (1927); p. 18; Chem. Zentralbl.; vol. 98; nb. I; (1927); p. 2539 View in Reaxys Nagai; Kanao; Justus Liebigs Annalen der Chemie; vol. 470; (1929); p. 174; Chem. Zentralbl.; vol. 99; nb. II; (1928); p. 2553 View in Reaxys

acidic d tartrate of (-)-ephedrine

HO OH

racemate

Rx-ID: 8491359 View in Reaxys 338/592 Yield

Conditions & References With methanol, (2S,3S)-2,3-dihydroxybutanedioic acid Kanao; Yakugaku Zasshi; nb. 540; (1927); p. 18; Chem. Zentralbl.; vol. 98; nb. I; (1927); p. 2539 View in Reaxys Nagai; Kanao; Justus Liebigs Annalen der Chemie; vol. 470; (1929); p. 174; Chem. Zentralbl.; vol. 99; nb. II; (1928); p. 2553 View in Reaxys

O H HN

OH H

d-tartrate of (-)-pseudoephedrine

H OH

OH H

racemate

Rx-ID: 8492310 View in Reaxys 339/592 Yield

Conditions & References With water, 2,3-dihydroxybutanedioic acid, aus den Mutterlaugen erhaltene Base gibt mit l-Weinsaeure das Verbindung Spaeth; Goehring; Monatshefte fuer Chemie; vol. 41; (1920); p. 325 View in Reaxys Kanao; Yakugaku Zasshi; nb. 540; (1927); p. 18; Chem. Zentralbl.; vol. 98; nb. I; (1927); p. 2539 View in Reaxys Nagai; Kanao; Justus Liebigs Annalen der Chemie; vol. 470; (1929); p. 174; Chem. Zentralbl.; vol. 99; nb. II; (1928); p. 2553 View in Reaxys

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O 1.1

OH OH

H N

Rx-ID: 29683338 View in Reaxys 340/592 Yield

Conditions & References 10 Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys

OH H HO

N H HO

H H

racemate

Rx-ID: 333817 View in Reaxys 341/592 Yield

Conditions & References Manske; Johnson; Journal of the American Chemical Society; vol. 51; (1929); p. 1908 View in Reaxys

OH H HO

H N

OH H

HO O

Rx-ID: 2104662 View in Reaxys 342/592 Yield

Conditions & References in dimethyl sulfoxide, T= 25 °C , -ΔH, Thermodynamic data Arnett, Edward M.; Zingg, S. Patricia; Journal of the American Chemical Society; vol. 103; nb. 5; (1981); p. 1221 1222 View in Reaxys in dimethyl sulfoxide, T= 25 °C , Equilibrium constant Zingg, S. P.; Arnett, Edward M.; McPhail, Andrew T.; Bothner-By, Aksel A.; Gilkerson, W. R.; Journal of the American Chemical Society; vol. 110; nb. 5; (1988); p. 1565 - 1580 View in Reaxys

H N

H HO

H O

HO O

Rx-ID: 2104664 View in Reaxys 343/592 Yield

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in dimethyl sulfoxide, T= 25 °C , Equilibrium constant Zingg, S. P.; Arnett, Edward M.; McPhail, Andrew T.; Bothner-By, Aksel A.; Gilkerson, W. R.; Journal of the American Chemical Society; vol. 110; nb. 5; (1988); p. 1565 - 1580 View in Reaxys

OH N H HO

H HO

H H

Rx-ID: 2104665 View in Reaxys 344/592 Yield

H N

H N O

Rx-ID: 2104666 View in Reaxys 345/592 Yield

H N

OH OH

H H

N H OH

Rx-ID: 2104714 View in Reaxys 346/592 Yield

115/209

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Zingg, S. P.; Arnett, Edward M.; McPhail, Andrew T.; Bothner-By, Aksel A.; Gilkerson, W. R.; Journal of the American Chemical Society; vol. 110; nb. 5; (1988); p. 1565 - 1580 View in Reaxys

Rx-ID: 2138535 View in Reaxys 347/592 Yield

H N

Rx-ID: 2138544 View in Reaxys 348/592 Yield

O H

OH OH

H N

OH HO H

H NH

Rx-ID: 2164208 View in Reaxys 349/592 Yield

116/209

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Zingg, S. P.; Arnett, Edward M.; McPhail, Andrew T.; Bothner-By, Aksel A.; Gilkerson, W. R.; Journal of the American Chemical Society; vol. 110; nb. 5; (1988); p. 1565 - 1580 View in Reaxys

OH H HO

H H

N H OH

(+)-ephedrine-(+)-mandelate

racemate

Rx-ID: 8446630 View in Reaxys 350/592 Yield

Conditions & References With ethanol, aus den Mutterlauge erhaelt man durch Zerlegung mit Alkali und Umsetzung mit d(-)-Mandelsaeure Manske; Johnson; Journal of the American Chemical Society; vol. 51; (1929); p. 1908 View in Reaxys

H N

OH OH

H N

Rx-ID: 30082134 View in Reaxys 351/592 Yield

Conditions & References in water Ivanova, Bojidarka; Spiteller, Michael; Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy; vol. 77; nb. 4; (2010); p. 849 - 855 View in Reaxys

Si B

Rx-ID: 10043568 View in Reaxys 352/592 Yield

Conditions & References

98 %, 92 %

in diethyl ether, T= -78 - 20 °C Hernandez, Eliud; Soderquist, John A.; Organic Letters; vol. 7; nb. 24; (2005); p. 5397 - 5400 View in Reaxys

Si O NH

Si B

H N

Rx-ID: 10043569 View in Reaxys 353/592 Yield 98 %, 92 %

Conditions & References in diethyl ether, T= -78 - 20 °C Hernandez, Eliud; Soderquist, John A.; Organic Letters; vol. 7; nb. 24; (2005); p. 5397 - 5400 View in Reaxys

117/209

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H N

Rx-ID: 5065749 View in Reaxys 354/592 Yield

Conditions & References in benzene, Time= 2h, T= 20 - 25 °C , Ring cleavage Fazylov, S. D.; Gazaliev, A. M.; Vlasova, L. M.; Russian Journal of General Chemistry; vol. 66; nb. 5; (1996); p. 850 - 850; Zhurnal Obshchei Khimii; vol. 66; nb. 5; (1996); p. 872 - 872 View in Reaxys

O N

H N

Rx-ID: 5065750 View in Reaxys 355/592 Yield

P O

H N

P O

Rx-ID: 5065760 View in Reaxys 356/592 Yield

OH O

O O NH 2

O O

H HN

Rx-ID: 4347415 View in Reaxys 357/592 Yield

118/209

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View in Reaxys

HO H

H 2 H

N+ H

–O

(v2)

O2-

O (v6) O–

(v7)

6+ 2-O Mo OH O22

NHH (v2)

(v3)(v2)

racemate

Rx-ID: 32463504 View in Reaxys 358/592 Yield

Conditions & References in water, at 30-35°C and pH=7 for 25 min; monitoring by UV Zayed; El-Rasheedy, El-Gazy A.; Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy; vol. 88; (2012); p. 156 - 161 ; (from Gmelin) View in Reaxys OH

H N

O HN

Rx-ID: 25155771 View in Reaxys 359/592 Yield

Conditions & References 3 : (+)-2,3-Dihydroindole-2-Carboxylic Acid (+)-Ephedrine Salt EXAMPLE 3 (+)-2,3-Dihydroindole-2-Carboxylic Acid (+)-Ephedrine Salt The (+)-2,3-dihydroindole-2-carboxylic acid (8.88 g., 0.0544 m.), and (+)-ephedrine (9.0 g., 0.0544 m.) were dissolved in 300 ml. acetonitrile and the slightly cloudy solution gravity filtered. The clear solution was stirred magnetically after seeding for 1.5 hr. The crude salts were filtered and dried over P2 O5 to provide two crops: (1) 6.70 g., m.p. 134°-140° C. and (2) 0.800 g., m.p. 125°-131° C. The combined crops were recrystallized with seeding from acetonitrile (200 ml.) and filtered (3.5 hr.) to provide the pure salt 4.575 g., m.p. 153°-155° C. (51percent yield). The salt should be protected from moist air and not washed. Analysis for: C19 H24 N2 O3: Calculated: C, 69.45; H, 7.37; N, 8.53; Found: C, 69.07; H, 7.27; N, 8.45. Patent; American Home Products Corporation; US4520205; (1985); (A1) English View in Reaxys

H N

O racemate

Rx-ID: 4810691 View in Reaxys 360/592 Yield

Conditions & References

46 %

in diethyl ether Plucinska, Krystyna; Kasprzykowski, Franciszek; Kozian, Elzbieta; Tetrahedron Letters; vol. 38; nb. 5; (1997); p. 861 - 864 View in Reaxys O

H N

K+

H N

O–

O racemate

Rx-ID: 9393256 View in Reaxys 361/592

119/209

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Yield

Conditions & References

46.1 %

Khanjin, Nikolai A.; Hesse, Manfred; Helvetica Chimica Acta; vol. 86; nb. 6; (2003); p. 2028 - 2057 View in Reaxys

K+

H N

O–

O racemate

Rx-ID: 9394259 View in Reaxys 362/592 Yield

Conditions & References

23 %

Khanjin, Nikolai A.; Hesse, Manfred; Helvetica Chimica Acta; vol. 86; nb. 6; (2003); p. 2028 - 2057 View in Reaxys

O O

O HO

H N

Rx-ID: 14163753 View in Reaxys 363/592 Yield

Conditions & References Reaction Steps: 4 1: 52.5 percent / HCl / toluene / 4 h / cooling 2: 77.6 percent / Na2CO3 / acetone 3: 82 percent / KOH / ethanol With hydrogenchloride, potassium hydroxide, sodium carbonate in ethanol, acetone, toluene Khanjin, Nikolai A.; Hesse, Manfred; Helvetica Chimica Acta; vol. 86; nb. 6; (2003); p. 2028 - 2057 View in Reaxys

O O

O HO

H N

Rx-ID: 14163754 View in Reaxys 364/592 Yield

O HO

H N

O O

racemate

Rx-ID: 14170383 View in Reaxys 365/592 Yield

Conditions & References Reaction Steps: 2 1: 82 percent / KOH / ethanol With potassium hydroxide in ethanol Khanjin, Nikolai A.; Hesse, Manfred; Helvetica Chimica Acta; vol. 86; nb. 6; (2003); p. 2028 - 2057

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View in Reaxys O O

O HO

H N

O O

racemate

Rx-ID: 14170384 View in Reaxys 366/592 Yield

O O

HO OH

H N

racemate

Rx-ID: 14200932 View in Reaxys 367/592 Yield

Conditions & References Reaction Steps: 3 1: 77.6 percent / Na2CO3 / acetone 2: 82 percent / KOH / ethanol With potassium hydroxide, sodium carbonate in ethanol, acetone Khanjin, Nikolai A.; Hesse, Manfred; Helvetica Chimica Acta; vol. 86; nb. 6; (2003); p. 2028 - 2057 View in Reaxys O

O O

HO OH

H N

racemate

Rx-ID: 14200933 View in Reaxys 368/592 Yield

O 1.2

OH OH

H N

Rx-ID: 29683337 View in Reaxys 369/592 Yield

121/209

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N OH

Rx-ID: 28208972 View in Reaxys 370/592 Yield

Conditions & References

25 %

Stage 1: With methyllithium, lithium chloride in tetrahydrofuran, formaldehyde diethyl acetal, T= -78 °C , Inert atmosphere Stage 2: in tetrahydrofuran, formaldehyde diethyl acetal, hexane, T= -78 - -40 °C , Inert atmosphere Stage 3: in tetrahydrofuran, formaldehyde diethyl acetal, hexane, T= -40 °C , Inert atmosphere, optical yield given as percent de, diastereoselective reaction Kummer, David A.; Chain, William J.; Morales, Marvin R.; Quiroga, Olga; Myers, Andrew G.; Journal of the American Chemical Society; vol. 130; nb. 40; (2008); p. 13231 - 13233 View in Reaxys

H N

P O

H N

S P–

O H+

Rx-ID: 3380522 View in Reaxys 371/592 Yield

Conditions & References

96 %

Cl O

O NH 2

N O

H HN

Rx-ID: 4345487 View in Reaxys 372/592 Yield

122/209

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OH H N

O N H

H N

Rx-ID: 1891624 View in Reaxys 373/592 Yield

Conditions & References in ethanol, water, water-EtOH 4:1 Gorman, Ann; Gould, Robert O.; Gray, Alexandra M.; Taylor, Paul; Walkinshaw, Malcolm D.; Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999); (1986); p. 739 - 746 View in Reaxys

O 1.3

OH OH

H N

Rx-ID: 29683336 View in Reaxys 374/592 Yield

H N

Rx-ID: 8367685 View in Reaxys 375/592 Yield

Conditions & References (-)-Ephedrin, Saeure I Patent; Beecham; GB1030389; (1966); ; vol. 65; nb. 8682h; (1966) View in Reaxys

O HO

OH OH

HO OH

H N H

acidic d tartrate of (+)-ephedrine H

racemate

Rx-ID: 8491360 View in Reaxys 376/592 Yield

123/209

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H N

racemate

Rx-ID: 2074023 View in Reaxys 377/592 Yield

Conditions & References Gais, Hans-Joachim; Lukas, Karl L.; Ball, Walter A.; Braun, Siegmar; Lindner, Hans J.; Liebigs Annalen der Chemie; nb. 4; (1986); p. 687 - 716 View in Reaxys

H HN

H N

OH H N

racemate

Rx-ID: 2199517 View in Reaxys 378/592 Yield

Conditions & References

76 %

in ethanol, Time= 10h, Ambient temperature Gais, Hans-Joachim; Lukas, Karl L.; Ball, Walter A.; Braun, Siegmar; Lindner, Hans J.; Liebigs Annalen der Chemie; nb. 4; (1986); p. 687 - 716 View in Reaxys

H N

OH H N

racemate

Rx-ID: 2199518 View in Reaxys 379/592 Yield

Conditions & References

75 %

Gais, Hans-Joachim; Lukas, Karl L.; Ball, Walter A.; Braun, Siegmar; Lindner, Hans J.; Liebigs Annalen der Chemie; nb. 4; (1986); p. 687 - 716 View in Reaxys Gais, Hans-Joachim; Lukas, Karl L.; Ball, Walter A.; Braun, Siegmar; Lindner, Hans J.; Liebigs Annalen der Chemie; nb. 4; (1986); p. 687 - 716 View in Reaxys

O H HN

H N

racemate racemate

Rx-ID: 2220690 View in Reaxys 380/592 Yield

Conditions & References Gais, Hans-Joachim; Lukas, Karl L.; Ball, Walter A.; Braun, Siegmar; Lindner, Hans J.; Liebigs Annalen der Chemie; nb. 4; (1986); p. 687 - 716 View in Reaxys

124/209

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OH H N

racemate

Rx-ID: 20631102 View in Reaxys 381/592 Yield

Conditions & References Reaction Steps: 2 1: 99 percent / pig liver esterase, Na2HPO4, KH2PO4, 2N NaOH / 216 h / 25 °C With sodium hydroxide, disodium hydrogenphosphate, potassium dihydrogenphosphate, pig liver esterase Gais, Hans-Joachim; Lukas, Karl L.; Ball, Walter A.; Braun, Siegmar; Lindner, Hans J.; Liebigs Annalen der Chemie; nb. 4; (1986); p. 687 - 716 View in Reaxys O

OH H N

racemate

Rx-ID: 20633617 View in Reaxys 382/592 Yield

Conditions & References Reaction Steps: 2 1: 15 percent Gais, Hans-Joachim; Lukas, Karl L.; Ball, Walter A.; Braun, Siegmar; Lindner, Hans J.; Liebigs Annalen der Chemie; nb. 4; (1986); p. 687 - 716 View in Reaxys O

OH H N

racemate

Rx-ID: 20633618 View in Reaxys 383/592 Yield

Conditions & References Reaction Steps: 2 1: 17 percent Gais, Hans-Joachim; Lukas, Karl L.; Ball, Walter A.; Braun, Siegmar; Lindner, Hans J.; Liebigs Annalen der Chemie; nb. 4; (1986); p. 687 - 716 View in Reaxys

O NH 2

O O

Rx-ID: 4347416 View in Reaxys 384/592 Yield

Conditions & References With sodium hydroxide, sodium hydrogencarbonate, 1.) reflux, 2.) 2 h, Yield given. Multistep reaction Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

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Cl NH 2

OH N

N H

Rx-ID: 4345478 View in Reaxys 385/592 Yield

O O

O S

OH HN

Rx-ID: 28118055 View in Reaxys 386/592 Yield

Conditions & References 1.24 :[(S)-2-ACETYLTHIOMETHYL-3-METHYLBUTANOIC ACID] (+) -ephedrine salt Intermediate 24: A mixture of [DIETHYL ISOPROPYLMALONATE (1WT)] and 2M aqueous sodium hydroxide (2. 2equivalents, 5. 45volumes) was heated at 80 [+] [5°C] for 2 hours. Upon completion of the reaction the contents were acidified with conc HCI (1.13 wt). 60percent aqueous dimethylamine (0.41 Wt) was added followed by 37percent wt/wt aqueous formaldehyde (0.49 Wt) and the reaction was then stirred at [905°C] for 16 hours. The solution was cooled to [205°C] and conc HCI (0.83 Wt) and MIBK (4volumes) were added. The layers were separated and the organic layer was washed with water (1 volume). The MIBK layer was then concentrated under reduced pressure to about 1. 4volumes. Cesium carbonate (0.039wt) was then added and the mixture was heated at [405°C.] Thioacetic acid (0.36 Wt) was added and the mixture was stirred for at least 12 hours at [405°C.] The reaction mixture was cooled to [205°C] and 20percent potassium bicarbonate (2. 25volumes) was added. The layers were separated and the organic layer was washed with 20percent potassium bicarbonate (0. 9volumes). The combined aqueous layers were adjusted to pH 1 with conc HCI (1.18 Wt) then the acidified layer was extracted with isopropyl acetate (2x2volumes). The combined organic layers were then washed with water [(1VOLUMES)] and the mixture concentrated to 2volumes by vacuum distillation then isopropyl acetate (4. 9volumes) was added. (+) -Ephedrine hydrochloride (0.86 Wt) was suspended in isopropyl acetate (4. 2volumes) and water (0.7 volumes). 10.8M sodium hydroxide (0.58 Wt) was added and stirred to give a biphasic solution. The phases were separated and organic phase was washed with water (0. 35volumes) and the solvent reduced to 3.5 volumes by vacuum distillation. 40percent of the ephedrine solution (1. 4volumes) was added to the racemate solution. The crystallisation was seeded and stirred for an hour at [20°C,] then the remaining ephedrine was added over 2-3 hours. The crystallisation was cooled to 0 [5°C] and stirred for at least 2 hours. The slurry was filtered and the filter cake was washed with isopropyl acetate (2x2. 8volumes) and dried in a vacuum oven at [50+5°C.] Expected yield: 33percent theory; 58percent [W/W.] HPLC (2minute method) RT 0.86minute 27. [1percent] area, 1.34minute 71.9percent area Stage 1: With sodium hydroxide in water, Time= 2h, T= 80 °C Stage 2: With dimethyl amine in water, Time= 16h, T= 90 °C Stage 3: With caesium carbonate, more than 3 stages Patent; GLAXO GROUP LIMITED; WO2003/104200; (2003); (A1) English View in Reaxys

O 1.4

OH OH

H N

Rx-ID: 29683335 View in Reaxys 387/592

126/209

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Yield

H N

O H N

OH O O

H racemate

Rx-ID: 2104762 View in Reaxys 388/592 Yield

Conditions & References

48 %

in benzene, Time= 0.25h, Ambient temperature Cardwell, Kevin; Hewitt, Brian; Ladlow, Mark; Magnus, Philip; Journal of the American Chemical Society; vol. 110; nb. 7; (1988); p. 2242 - 2248 View in Reaxys

OH OH

O H N

OH O O

racemate

Rx-ID: 2138553 View in Reaxys 389/592 Yield

Conditions & References

48 %

O H

O H N

OH O O

Rx-ID: 19525599 View in Reaxys 390/592 Yield

Conditions & References Reaction Steps: 2 1: 91 percent / hexane; CH2Cl2 / 1 h / -10 °C 2: 48 percent / benzene / 0.25 h / Ambient temperature in hexane, dichloromethane, benzene Cardwell, Kevin; Hewitt, Brian; Ladlow, Mark; Magnus, Philip; Journal of the American Chemical Society; vol. 110; nb. 7; (1988); p. 2242 - 2248 View in Reaxys

127/209

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O O

H N

O O

Rx-ID: 19525600 View in Reaxys 391/592 Yield

racemate

Rx-ID: 8385007 View in Reaxys 392/592 Yield

Conditions & References 1-Ephedrin, dl-trans-3,3-Dimethyl-2-cyclopentylidenmethyl-1-cyclopropancarbonsaeure Patent; Roussel-Uc Laf; US3711555; (1973); DE1793721; ; vol. 78; nb. 29437 View in Reaxys

H HN

H H N

OH H

Rx-ID: 1416266 View in Reaxys 393/592 Yield

Conditions & References in ethanol Roth,H.J.; Miller,B.; Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft; vol. 297; (1964); p. 602 - 608 View in Reaxys

H N

P O

S P–

H N

O H+

Rx-ID: 3933283 View in Reaxys 394/592 Yield 93 %

Conditions & References With sulfur in benzene, Heating Turdybekov, K. M.; Lindeman, S. V.; Struckov, Yu. T.; Gazaliev, A. M.; Fazylov, S. D.; et al.; Chemistry of Natural Compounds; vol. 25; (1989); p. 77 - 80; Khimiya Prirodnykh Soedinenii; nb. 1; (1989); p. 88 - 91 View in Reaxys

128/209

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P O

H N

SH P

Rx-ID: 5051182 View in Reaxys 395/592 Yield

O H

P O

H N

SH P

Rx-ID: 5051183 View in Reaxys 396/592 Yield

P O

SH P

H N

Rx-ID: 5051184 View in Reaxys 397/592 Yield

O NH F F HO

Rx-ID: 24409204 View in Reaxys 398/592 Yield

Conditions & References 54.a : a) This oil was dissolved in ether (40 mL) and combined with (1R,2S)-(-)-ephedrine (2.9 g., 17.6 mmol) dissolved in ether (40 mL) and allowed to sit for 16 hours. The solid was filtered off and recrystallized from ethyl acetate (2*40 mL) to give 4.0 g. (2R)-trifluoromethyl-3-acetylthiopropionic acid, ephedrine salt, m.p. 138°-139° C., [α]D =-100.3° (c=1.0, methanol). Patent; E. R. Squibb and Sons, Inc.; US5223516; (1993); (A1) English

129/209

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View in Reaxys

H N

O OH

Rx-ID: 28407057 View in Reaxys 399/592 Yield

Conditions & References in dichloromethane-d2, T= -20 °C Kukula, Pavel; Matousek, Vaclav; Mallat, Tamas; Baiker, Alfons; Chemistry - A European Journal; vol. 14; nb. 9; (2008); p. 2699 - 2708 View in Reaxys O

H N

OH Cl

O OH

H N

N O HCl

Rx-ID: 37586862 View in Reaxys 400/592 Yield

Conditions & References General procedure: The solid Eph complexes with the TCNQ, DDQ, DNB or TBT acceptor were prepared by mixing equimolar amounts of the Ephdonor with each acceptor in pure-grade methanol. The resulting solutions were stirred for approximately 30 min and allowed to evaporate slowly at room temperature, where the complexes were isolated as green, yellow, pale yellow and white powder for Eph–TCNQ, Eph–DDQ, Eph–DNB and Eph–TBT complexes, respectively.The separated complexes were filtered and washed well with methanol. Then, the complexes were collected and dried over anhydrous calcium chloride for 24 h in desiccator. in methanol, Time= 0.5h, T= 20 °C Refat, Moamen S.; Ibrahim, Omar B.; Saad, Hosam A.; Adam, Abdel Majid A.; Journal of Molecular Structure; vol. 1064; nb. 1; (2014); p. 58 - 69 View in Reaxys

H N

OH O

Rx-ID: 29683360 View in Reaxys 401/592 Yield 100 %

Conditions & References 57 :Ibuprofenic acid (0.691 g, 5 mmol) and ephedrine (0.826 g, 5 mmol) were molten in a hot mortar until a freeflowing clear liquid was obtained. The mixture was cooled to room temperature, solidified and was grinded to obtain a colourless powder in quantitative yield. 1H-NMR (300 MHz, d6-DMSO) δ(ppm) = 7.34 (m, 4H), 7.19 (m, 3H), 7.03 (d, J = 7.89 Hz, 2H), 5.80 (br s, IH), 4.97 (d, J = 2.8 Hz, IH), 3.45 (q, J = 7.1 Hz, IH), 3.04 (m, IH), 2.45 (s, 3H), 2.38 (d, J = 7.15 Hz, 2H), 1.78 (sept, J = 6.8 Hz, IH), 1.30 (d, J = 7.17, 3 H), 0.83 (m, 9H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm) = 177.9, 142.4, 140.9, 138.5, 128.5, 127.9, 127.1, 126.7, 125.9, 70.6, 59.8, 46.6, 44.3, 31.5, 29.7, 22.2, 19.5, 10.7. mp 110 0C, T5 /oOnset 238 0C , Heating, Neat (no solvent) Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys

130/209

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HO H N

HCl Cl

O HO

I O

Rx-ID: 42718888 View in Reaxys 402/592 Yield

Conditions & References Synthetic procedure. General procedure: The solid CT complexes, Bar–I2, Bar–HIO3, Bar–CHL, Eph–I2, Eph–HIO3 and Eph–CHL, were prepared according to the literature methods reported [4–10]. Two mmol of each donor (Bar or Eph) (25 mL) was added to 25 mL of methanolic solutions of HIO3 and CHL (2 mmol) or I2 in chloroform and stirred at room temperature for 1 h. Strong change in color was observed upon mixing solutions of the donors with the acceptors. Volume of a solution was reduced by one-half upon evaporation ona water bath. The solution was stored at room temperature, filtered off and washed twice with the minimum amount of the given solvent. Thus synthesized complexes were dried in vacuo for 48 h and characterized by UV-Vis, IR, Raman, and 1H NMR spectroscopy and elemental and thermal analyses. With iodic acid in methanol, chloroform, Time= 1h, T= 20 °C , Concentration Naglah; Al-Omar; Ibrahim; Refat; Adam; Saad; El-Metwaly; Russian Journal of General Chemistry; vol. 86; nb. 4; (2016); p. 965 - 974; Zh. Obshch. Khim.; vol. 86; nb. 4; (2016); p. 965 - 974,10 View in Reaxys

P O

H N

SH P

Rx-ID: 5082687 View in Reaxys 403/592 Yield

O N

SH P

H N

Rx-ID: 5082688 View in Reaxys 404/592 Yield

131/209

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H N

SH P

Rx-ID: 5082689 View in Reaxys 405/592 Yield

Cl HO

H N

O O

Rx-ID: 29683339 View in Reaxys 406/592 Yield

Conditions & References 12 Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys

H N

Cl HO

H N

O O

Rx-ID: 29683356 View in Reaxys 407/592 Yield

Conditions & References

100 %

58 :Clofbric acid (1.073 g, 5 mmol) and ephedrine (0.826 g, 5 mmol) were molten in a hot mortar until a free-flowing clear liquid was obtained. The mixture solidified at room temperature and was grinded to obtain a yellow powder in quantitative yield. 1H-NMR (300 MHz, d6-DMSO) δ(ppm) = 9.36 (br s, 2H), 7.30 (m, 5H), 7.19 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.75 Hz, 2H), 5.10 (s, IH), 3.12 (m, IH), 2.52 (s, 3H), 1.41 (s, 6H), 0.85 (d, J = 6.58 Hz), 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm) = 176.8, 155.5, 141.8, 128.5, 128.0, 126.9, 125.8, 123.4, 119.2, 80.2, 69.8, 59.5, 30.7, 25.8, 9.6. mp 131 °C, T5o/o0nset 166 °C , Heating, Neat (no solvent) Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys

OH N

H N

N H HO

Rx-ID: 32115648 View in Reaxys 408/592

132/209

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Yield

Conditions & References Reaction Steps: 5 1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 3: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 4: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 5: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, formic acid, palladium 10 on activated carbon, 20 palladium hydroxide on charcoal, hydrogen, sodium hydroxide in tetrahydrofuran, methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 3 1.1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 1.2: 0 - 20 °C / pH 11 / Inert atmosphere 2.1: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 3.1: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, formic acid, palladium 10 on activated carbon, sodium hydroxide in methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 4 1.1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 1.2: 0 - 20 °C / pH 11 / Inert atmosphere 2.1: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 3.1: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 4.1: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, formic acid, palladium 10 on activated carbon, 20 palladium hydroxide on charcoal, hydrogen, sodium hydroxide in tetrahydrofuran, methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 5 1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 2: 20 palladium hydroxide on charcoal; hydrogen / 72 h / 3040.2 Torr / Inert atmosphere 3: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 4: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 5: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, formic acid, palladium 10 on activated carbon, 20 palladium hydroxide on charcoal, hydrogen, sodium hydroxide in tetrahydrofuran, methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys

OH HO

H N

N H

O O

Rx-ID: 32115657 View in Reaxys 409/592

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Yield

Conditions & References Reaction Steps: 3 1: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 2: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 3: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, 20 palladium hydroxide on charcoal, hydrogen, sodium hydroxide in tetrahydrofuran, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys

H N

N H

Rx-ID: 32115671 View in Reaxys 410/592 Yield

Conditions & References Reaction Steps: 4 2: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 3: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 4: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, 20 palladium hydroxide on charcoal, hydrogen, sodium hydroxide in tetrahydrofuran, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 4 1: 20 palladium hydroxide on charcoal; hydrogen / 72 h / 3040.2 Torr / Inert atmosphere 2: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 3: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 4: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, 20 palladium hydroxide on charcoal, hydrogen, sodium hydroxide in tetrahydrofuran, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys

OH N

H N

N H HO

Rx-ID: 32115690 View in Reaxys 411/592 Yield

Conditions & References Reaction Steps: 6 1.1: 9-bora-bicyclo[3.3.1]nonane / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 1.2: 2 h / 20 °C / Inert atmosphere 2.1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 4.1: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 5.1: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 6.1: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere

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With potassium permanganate, formic acid, palladium 10 on activated carbon, 20 palladium hydroxide on charcoal, hydrogen, 9-bora-bicyclo[3.3.1]nonane, sodium hydroxide in tetrahydrofuran, methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 4 1.1: borane-THF / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 1.2: 2 h / 20 °C / Inert atmosphere 2.1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 2.2: 0 - 20 °C / pH 11 / Inert atmosphere 3.1: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 4.1: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, formic acid, borane-THF, palladium 10 on activated carbon, sodium hydroxide in tetrahydrofuran, methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 4 1.1: 9-bora-bicyclo[3.3.1]nonane / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 1.2: 2 h / 20 °C / Inert atmosphere 2.1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 2.2: 0 - 20 °C / pH 11 / Inert atmosphere 3.1: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 4.1: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, formic acid, palladium 10 on activated carbon, 9-bora-bicyclo[3.3.1]nonane, sodium hydroxide in tetrahydrofuran, methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 5 1.1: 9-bora-bicyclo[3.3.1]nonane / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 1.2: 2 h / 20 °C / Inert atmosphere 2.1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 2.2: 0 - 20 °C / pH 11 / Inert atmosphere 3.1: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 4.1: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 5.1: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, formic acid, palladium 10 on activated carbon, 20 palladium hydroxide on charcoal, hydrogen, 9-bora-bicyclo[3.3.1]nonane, sodium hydroxide in tetrahydrofuran, methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 5 1.1: borane-THF / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 1.2: 2 h / 20 °C / Inert atmosphere 2.1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 2.2: 0 - 20 °C / pH 11 / Inert atmosphere 3.1: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 4.1: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 5.1: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere

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With potassium permanganate, formic acid, borane-THF, palladium 10 on activated carbon, 20 palladium hydroxide on charcoal, hydrogen, sodium hydroxide in tetrahydrofuran, methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 6 1.1: 9-bora-bicyclo[3.3.1]nonane / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 1.2: 2 h / 20 °C / Inert atmosphere 2.1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 3.1: 20 palladium hydroxide on charcoal; hydrogen / 72 h / 3040.2 Torr / Inert atmosphere 4.1: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 5.1: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 6.1: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, formic acid, palladium 10 on activated carbon, 20 palladium hydroxide on charcoal, hydrogen, 9-bora-bicyclo[3.3.1]nonane, sodium hydroxide in tetrahydrofuran, methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 6 1.1: borane-THF / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 1.2: 2 h / 20 °C / Inert atmosphere 2.1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 3.1: 20 palladium hydroxide on charcoal; hydrogen / 72 h / 3040.2 Torr / Inert atmosphere 4.1: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 5.1: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 6.1: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, formic acid, borane-THF, palladium 10 on activated carbon, 20 palladium hydroxide on charcoal, hydrogen, sodium hydroxide in tetrahydrofuran, methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 6 1.1: borane-THF / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 1.2: 2 h / 20 °C / Inert atmosphere 2.1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 4.1: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 5.1: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 6.1: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, formic acid, borane-THF, palladium 10 on activated carbon, 20 palladium hydroxide on charcoal, hydrogen, sodium hydroxide in tetrahydrofuran, methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys

O O

H N

N H

O HO

Rx-ID: 32115698 View in Reaxys 412/592 Yield

Conditions & References Reaction Steps: 4

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1.1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 1.2: 0 - 20 °C / pH 11 / Inert atmosphere 2.1: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 3.1: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 4.1: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, formic acid, palladium 10 on activated carbon, 20 palladium hydroxide on charcoal, hydrogen, sodium hydroxide in tetrahydrofuran, methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 3 1.1: palladium 10 on activated carbon; formic acid / methanol / 4 h / Reflux; Inert atmosphere 1.2: 0 - 20 °C / pH 11 / Inert atmosphere 2.1: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 3.1: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, formic acid, palladium 10 on activated carbon, sodium hydroxide in methanol, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys Reaction Steps: 4 2: 20 palladium hydroxide on charcoal; hydrogen / tetrahydrofuran / 2 h / 20 °C / 760.05 Torr / Inert atmosphere 3: potassium permanganate; sodium hydroxide / water; tert-butyl alcohol / 16 h / 20 °C / Darkness; Inert atmosphere 4: ethyl acetate / 0.25 h / 60 °C / Inert atmosphere With potassium permanganate, 20 palladium hydroxide on charcoal, hydrogen, sodium hydroxide in tetrahydrofuran, water, ethyl acetate, tert-butyl alcohol Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys

H N

N H

HN HO

Rx-ID: 32115700 View in Reaxys 413/592 Yield

Conditions & References in ethyl acetate, Time= 0.25h, T= 60 °C , Inert atmosphere Aitken, David J.; Drouin, Ludovic; Goretta, Sarah; Guillot, Regis; Ollivier, Jean; Spiga, Marco; Organic and Biomolecular Chemistry; vol. 9; nb. 21; (2011); p. 7517 - 7524 View in Reaxys

H N

H O

N H O

Rx-ID: 28818956 View in Reaxys 414/592 Yield

Conditions & References in acetonitrile Nguyen, T. Hien; Ansell, Richard J.; Organic and Biomolecular Chemistry; vol. 7; nb. 6; (2009); p. 1211 - 1220

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View in Reaxys

O Li

N OH

Rx-ID: 28208971 View in Reaxys 415/592 Yield

Conditions & References

22 %, 2 %

N HN

O NH

N O

N H

F F

Rx-ID: 24385954 View in Reaxys 416/592 Yield

Conditions & References 53.b : b) b) (2S)-Trifluoromethyl-3-acetylthiopropionic acid, ephedrine salt 2-Trifluoromethyl-3-acetylthiopropionic acid (7.18 g., 33.2 mmol) in ether (100 mL) was treated with (1S,2R)-(+)ephedrine (2.73 g., 16.6 mmol) in ether (100 mL) and allowed to sit for 18 hours. The reaction mixture was then filtered to give 5.37 g. of a solid which was recrystallized from ethyl acetate (4*40 mL) to give 3.47 g. of (2S)-trifluoromethyl-3-acetylthiopropionic acid, ephedrine salt, m.p. 139°-140° C., [α]D =+100.0° (C =1.0, methanol). Patent; E. R. Squibb and Sons, Inc.; US5223516; (1993); (A1) English View in Reaxys

O HO

OH N H

H N

Rx-ID: 8368597 View in Reaxys 417/592 Yield

Conditions & References Ephedrin*HCl, Na-D-pantothenoat, Me. Patent; Daiichi Seiyaku Co.; JP829062; (1960); ; vol. 60; nb. 659e; (1964) View in Reaxys Ephedrin*H2SO4, Ca-pantothenat (IV), W. Patent; Daiichi Seiyaku Co.; JP829062; (1960); ; vol. 60; nb. 659e; (1964)

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View in Reaxys

Cl O

NH 2

H O

N H

Rx-ID: 4345488 View in Reaxys 418/592 Yield

H N

OH H N

O HO

Rx-ID: 2092917 View in Reaxys 419/592 Yield

Conditions & References

70 %

in benzene, Heating Sunjic, Vitomir; Habus, Ivan; Comisso, Giovanni; Moimas, Flavio; Gazzetta Chimica Italiana; vol. 119; nb. 4; (1989); p. 229 - 234 View in Reaxys Br O

H N

Rx-ID: 24337062 View in Reaxys 420/592 Yield

Conditions & References R.87 : α-Bromo-(2-methylphenyl)acetic acid, (-)-ephedrine salt REFERENCE EXAMPLE 87 α-Bromo-(2-methylphenyl)acetic acid, (-)-ephedrine salt A solution of (-)-ephedrine (27.17 g) in ethyl acetate (198 ml) was added dropwise over 3 hours to a stirred solution of α-bromo-(2-methylphenyl)acetic acid (39.7 g) and tetra-n-butylammonium bromide (5.75 g) in ethyl acetate (278 ml) keeping the temperature between 20° C. and 23° C. The resulting suspension was stirred at 20-23° C. for 2 hours and filtered. Some of the filtrate (300-350 ml) was used to aid transfer of the reaction mixture to the filter. The product was washed twice with ethyl acetate (100 ml), then washed three times with tert-butyl methyl ether (100 ml) and dried at 35-40° C./40-50 torr to give the title compound (47.2 g), ee 78percent (for α-bromo-(2-methylphenyl)acetic acid) was determined by chiral HPLC using a Chiralpak AS column (Diacel) and a mobile phase of heptane/ isopropanol/trifluoroacetic acid (960/40/2, by volume), with UV detection at 254 nM. Patent; Rhone-Poulenc Rorer Limited; US6048893; (2000); (A1) English View in Reaxys R.87 : α-Bromo-(2-methylphenyl)acetic Acid, (-)-Ephedrine Salt REFERENCE EXAMPLE 87 α-Bromo-(2-methylphenyl)acetic Acid, (-)-Ephedrine Salt

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A solution of (-)-ephedrine (27.17 g) in ethyl acetate (198 ml) was added dropwise over 3 hours to a stirred solution of α-bromo-(2-methylphenyl)acetic acid (39.7 g) and tetra-n-butylammonium bromide (5.75 g) in ethyl acetate (278 ml) keeping the temperature between 20° C. and 23° C. The resulting suspension was stirred at 20-23° C. for 2 hours and filtered. Some of the filtrate (300-350ml) was used to aid transfer of the reaction mixture to the filter. The product was washed twice with ethyl acetate (100 ml), then washed three times with tert-butyl methyl ether (100 ml) and dried at 35-40° C./40-50 torr to give the title compound (47.2 g), ee 78percent (for α-bromo-(2-methylphenyl)acetic acid) was determined by chiral HPLC using a Chiralpak AS column (Diacel) and a mobile phase of heptane/ isopropanol/trifluoroacetic acid (960/40/2, by volume), with UV detection at 254 nM. Patent; Rhone-Poulenc Rorer Limited; US6124343; (2000); (A1) English View in Reaxys

HO H N

OH P

H N

O HO

Rx-ID: 9393255 View in Reaxys 421/592 Yield

Conditions & References

90 %

Stage 1: in ethanol, Heating Stage 2: in acetic acid, Heating Stage 3: in diethyl ether, acetic acid, T= 4 °C Gardner, Stuart; Motevalli, Majid; Shastri, Kirtida; Sullivan, Alice C.; Wyatt, Peter B.; New Journal of Chemistry; vol. 26; nb. 4; (2002); p. 433 - 439 View in Reaxys

H N

O O

O F

HO F

F F

N H

Rx-ID: 29104406 View in Reaxys 422/592 Yield

Conditions & References

100 %

in dichloromethane, Time= 1h Schulz, Peter S.; Schneiders, Karola; Wasserscheid, Peter; Tetrahedron Asymmetry; vol. 20; nb. 21; (2009); p. 2479 - 2481 View in Reaxys

HN OH S O O

Rx-ID: 24558297 View in Reaxys 423/592 Yield

Conditions & References 2.a : a a (S)-2-[(Acetylthio)methyl]benzenepropanoic acid, ephedrine salt A solution of (1R,2S)-(-)-ephedrine (17.3 g., 105 mmol.) in diethyl ether (175 ml.) was added in one portion to a solution of 2-[(acetylthio)methyl]benzenepropanoic acid (50.0 g., 210 mmol.) in diethyl ether (175 ml.). After standing at room temperature for 16 hours, the crystallized ephedrine salt was collected by filtration (19.7 g.); m.p. 114°- 125°; [α]D =-40.6° (c=1, methanol). An additional amount of solid

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8.9 g., m.p. 121°-126°; [α]D =-47.2°, (c=1,[methanol)] separated from the filtrate after remaining at room temperature for 20 hours. The solids were combined and recrystallized from acetonitrile (1500 ml.). After 16 hours at room temperature, 20.8 g. of solid was collected; m.p. 125°-130° C.; [α]D =-47.5° (c=1, methanol). This material was recrystallized in the same manner from acetonitrile (300 ml.) to give 18.74 g., m.p. 128°-130° C.; [α]D =-48.9° (c=1, methanol). A third recrystallization from acetonitrile (225 ml.) afforded 17.4 g. of solid (S)-2-[(acetylthio)methyl]benzenepropionic acid, ephedrine salt; m.p. 128°-129°; [α]D =-50.1° (c=1, methanol). Anal. calc'd. for C12 H14 O3 Sodsold;C&10 H15 NO: C,65.48; H,7.24; N,3.47; S,7.95 Found: C,65.46; H,7.34; N,3.21; S, 8.00. Patent; Bristol-Myers Squibb Co.; US5504080; (1996); (A1) English View in Reaxys 1.a : a a (S)-2-[(Acetylthio)methyl]benzenepropanoic acid, ephedrine salt A solution of (1R,2S)-(-)-ephedrine (17.3 g., 105 mmol.) in diethyl ether (175 ml.) was added in one portion to a solution of 2-[(acetylthio)methyl]benzenepropanoic acid (50.0 g., 210 mmol.) in diethyl ether (175 ml.). After standing at room temperature for 16 hours, the crystallized ephedrine salt was collected by filtration (19.7 g.); m.p. 114°-125°; [α]D =-40.6° (c=1, methanol). An additional amount of solid [8.9 g., m.p. 121°-126°; [α]D =-47.2°, (c=1, methanol)] separated from the filtrate after remaining at room temperature for 20 hours. The solids were combined and recrystallized from acetonitrile (1500 ml.). After 16 hours at room temperature, 20.8 g. of solid was collected; m.p. 125°-130° C.; [α]D =-47.5° (c=1, methanol). This material was recrystallized in the same manner from acetonitrile (300 ml.) to give 18.74 g., m.p. 128°-130° C.; [α]D =-48.9° (c=1, methanol). A third recrystallization from acetonitrile (225 ml.) afforded 17.4 g. of solid (S)-2-[(acetylthio)methyl]benzenepropionic acid, ephedrine salt; m.p. 128°-129°; [α]D =150.1° (c=1, methanol). Anal. calc'd. for C12 H14 O3 S. C10 H15 NO: C,65.48; H,7.24; N,3.47; S,7.95 Found: C,65.46; H,7.34; N,3.21; S,8.00. Patent; E. R. Squibb and Sons, Inc.; US5552397; (1996); (A1) English View in Reaxys 12.a : a a (S)-2-[(Acetylthio)methyl]benzenepropanoic acid, ephedrine salt A solution of (1R,2S)-(-)-ephedrine (17.3 g., 105 mmol.) in diethyl ether (175 ml.) was added in one portion to a solution of 2-[(acetylthio)methyl]benzenepropanoic acid (50.0 g., 210 mmol.) in diethyl ether (175 ml.). After standing at room temperature for 16 hours, the crystallized ephedrine salt was collected by filtration (19.7 g.); m.p. 114°-125°; [α]D =-40.6° (c=1, methanol). An additional amount of solid [8.9 g, m.p. 121°-126°; [α]D =-47.2° (c=1, methanol)] separated from the filtrate after remaining at room temperature for 20 hours. The solids were combined and recrystallized from acetonitrile (1500 ml.). After 16 hours at room temperature, 20.8 g. of solid was collected; m.p. 125°-130° C.; [α]D =-48.9° (c=1, methanol). This material was recrystallized in the same manner from acetonitrile (300 ml.) to give 18.7 g., m.p. 128°-130°; [α]D =-48.9° (c=1, methanol). A third recrystallization from acetonitrile (225 ml.) afforded 17.4 g of solid (S) -2-[(acetylthio)methyl]benzenepropanoic acid, ephedrine salt; m.p. 128°-129°; [α]D =-50.1° (c=1, methanol). Patent; Bristol-Myers Squibb Company; US5508272; (1996); (A1) English View in Reaxys

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H N

O H

OH O

(-)-enantiomer

Rx-ID: 2104732 View in Reaxys 424/592 Yield

Conditions & References in ethanol, Heating, H2O / water also used Haest, A. D. van der; Wynberg, H.; Leusen, F. J. J.; Bruggink, A.; Recueil des Travaux Chimiques des Pays-Bas; vol. 109; nb. 10; (1990); p. 523 - 528 View in Reaxys

O O

N H H

O P

(-)-enantiomer

Rx-ID: 2498558 View in Reaxys 425/592 Yield

OH H 2N

O Br

OH H

NH O

Rx-ID: 4345989 View in Reaxys 426/592 Yield

H 2N O

HO HO

NH O

Rx-ID: 25082189 View in Reaxys 427/592 Yield

Conditions & References 5.B : Method B Method B Title product of Example 2 (100 g) was stirred at reflux (65°) in 374 ml methanol for 30 minutes, then cooled to 59°.

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Water (7.42 ml) and L-(-)-ephedrine (68 g) were added, resulting in heavy precipitation. The slurry was refluxed at 66° for 45 minutes, cooled to 27° and highly purified title product directly recovered by filtration, 70.4 g, [alpha]D 25 =+44.36 (c=1.04 in methanol). The filtrate was evaporated to yield the crude diastereomeric salt, L-(-)-ephedrine R-6-fluoro-4-ureidochroman-4-carboxylate, 116.3 g. Patent; Pfizer Inc.; US4435578; (1984); (A1) English View in Reaxys

Rx-ID: 4471799 View in Reaxys 428/592 Yield

Conditions & References

in dichloromethane, Time= 0.5h, Ambient temperature Tochtermann, Werner; Mattauch, Anne-Katrin; Kasch, Michael; Peters, Eva-Maria; Peters, Karl; Von Schnering, Hans Georg; Liebigs Annales; nb. 3; (1996); p. 317 - 322 View in Reaxys

O HO

O racemate

O OH

E O

Rx-ID: 28691304 View in Reaxys 429/592 Yield

Conditions & References 3.a :3a) Enantiomer Separation with (+)-ephedrine To a solution of racemic trans-2,7-diisopropyloct-4-ene-1,8-dionic acid (10 g, 39 mmol) in acetone (80 ml) was added (+)-ephedrine (10.2 g, 61.7 mmol). After the mixture had been stirred at RT for 1 h, the crystals were filtered off and washed with hexane to obtain (+)ephedrine*(-)-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid with a diastereomer ratio of 82:18 (HPLC). Recrystallization from acetone gave 4.9 g of the (+)-ephedrine*(-)-(2S,7S)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid with a diastereomer ratio of 98:2 (HPLC). The other enantiomer, the (+)-(2R,7R)-trans-2,7-diisopropyloct-4-ene-1,8-dionic acid, can be isolated from the mother solution. in acetone, Time= 1h, T= 20 °C Patent; REUTER CHEMISCHER APPARATEBAU KG; US2009/221848; (2009); (A1) English View in Reaxys

H N

O HN

NH racemate

HO O (+)-enantiomer

(+)-enantiomer,rel-configuration

Rx-ID: 2198862 View in Reaxys 430/592 Yield 70 %

Conditions & References in ethanol, Time= 0.5h, Heating

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Saigo, Kazuhiko; Okuda, Yoshiyuki; Wakabayashi, Sumio; Hoshiko, Tomonori; Nohira, Hiroyuki; Chemistry Letters; (1981); p. 857 - 860 View in Reaxys

H N

OH O

N H OH

O P

(-)-enantiomer

Rx-ID: 2104733 View in Reaxys 431/592 Yield

O O

H HN

H N

OH O

OH H

OH O

(-)-enantiomer

Rx-ID: 2498559 View in Reaxys 432/592 Yield

O OH

OH NH

H HN

OH H

Rx-ID: 2138536 View in Reaxys 433/592 Yield

Conditions & References in diethyl ether Gudmundsdottir, Anna D.; Li, Winnie; Scheffer, John R.; Rettig, Steven; Trotter, James; Molecular Crystals and Liquid Crystals Science and Technology, Section A: Molecular Crystals and Liquid Crystals; vol. 240; (1994); p. 81 88 View in Reaxys

O OH

H HN

OH H

T-4

H NH

T-4 H T-4

H T-4

Rx-ID: 2138542 View in Reaxys 434/592 Yield

Conditions & References Gudmundsdottir, Anna D.; Scheffer, John R.; Trotter, James; Tetrahedron Letters; vol. 35; nb. 9; (1994); p. 1397 - 1400

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View in Reaxys

O H N

OH NH

Rx-ID: 2172984 View in Reaxys 435/592 Yield

H N

H T-4

H NH

T-4 H T-4

H T-4

Rx-ID: 2172987 View in Reaxys 436/592 Yield

Conditions & References Gudmundsdottir, Anna D.; Scheffer, John R.; Trotter, James; Tetrahedron Letters; vol. 35; nb. 9; (1994); p. 1397 - 1400 View in Reaxys

H N

H Cl

O HCl

Rx-ID: 37586861 View in Reaxys 437/592 Yield

Conditions & References General procedure: The solid Eph complexes with the TCNQ, DDQ, DNB or TBTacceptor were prepared by mixing equimolar amounts of the Ephdonor with each acceptor in pure-grade methanol. The resulting solutions were stirred for approximately 30 min and allowed toevaporate slowly at room temperature, where the complexes were isolated as green, yellow, pale yellow and white powder for Eph–TCNQ, Eph–DDQ, Eph–DNB and Eph–TBT complexes, respectively.The separated complexes were filtered and washed well with methanol. Then, the complexes were collected and dried over anhydrous calcium chloride for 24 h in desiccator. in methanol, Time= 0.5h, T= 20 °C Refat, Moamen S.; Ibrahim, Omar B.; Saad, Hosam A.; Adam, Abdel Majid A.; Journal of Molecular Structure; vol. 1064; nb. 1; (2014); p. 58 - 69 View in Reaxys

S H N

S OH

Rx-ID: 41647666 View in Reaxys 438/592 Yield

Conditions & References in chloroform-d1, Inert atmosphere, Solvent

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Pokora-Sobczak, Patrycja; Mielniczak, Grazyna; Krasowska, Dorota; Chrzanowski, Jacek; Zajc, Adrian; Drabowicz, Jzef; Phosphorus, Sulfur and Silicon and the Related Elements; vol. 190; nb. 5-6; (2015); p. 694 - 699 View in Reaxys

S HO

(v5)

S HO

Rx-ID: 41647672 View in Reaxys 439/592 Yield

Conditions & References Reaction Steps: 2 1: triethylamine; sulfur / benzene / 2 h / 60 °C / |Inert atmosphere 2: chloroform-d1 / |Inert atmosphere With sulfur, triethylamine in chloroform-d1, benzene Pokora-Sobczak, Patrycja; Mielniczak, Grazyna; Krasowska, Dorota; Chrzanowski, Jacek; Zajc, Adrian; Drabowicz, Jzef; Phosphorus, Sulfur and Silicon and the Related Elements; vol. 190; nb. 5-6; (2015); p. 694 - 699 View in Reaxys

S HO

S OH

Rx-ID: 41647679 View in Reaxys 440/592 Yield

Conditions & References Reaction Steps: 3 1.1: magnesium; iodine / diethyl ether / 4 h / 20 °C / |Inert atmosphere; |Reflux 1.2: -10 - 0 °C / |Inert atmosphere 2.1: triethylamine; sulfur / benzene / 2 h / 60 °C / |Inert atmosphere 3.1: chloroform-d1 / |Inert atmosphere With iodine, sulfur, magnesium, triethylamine in diethyl ether, chloroform-d1, benzene Pokora-Sobczak, Patrycja; Mielniczak, Grazyna; Krasowska, Dorota; Chrzanowski, Jacek; Zajc, Adrian; Drabowicz, Jzef; Phosphorus, Sulfur and Silicon and the Related Elements; vol. 190; nb. 5-6; (2015); p. 694 - 699 View in Reaxys

N H O

H N

H H

OH O

H HO

N H

Rx-ID: 1723950 View in Reaxys 441/592 Yield

Conditions & References in ethanol, water, water-EtOH 1:4 Gorman, Ann; Gould, Robert O.; Gray, Alexandra M.; Taylor, Paul; Walkinshaw, Malcolm D.; Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999); (1986); p. 739 - 746 View in Reaxys

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N NH 2

N H

Rx-ID: 36571759 View in Reaxys 442/592 Yield

Conditions & References Reaction Steps: 2 1.1: sodium hydroxide / tetrahydrofuran; water / 15 - 25 °C 1.2: 17 h / 15 - 25 °C 2.1: ethyl acetate / 20 - 70 °C With sodium hydroxide in tetrahydrofuran, water, ethyl acetate Boesch, Heinz; Cesco-Cancian, Sergio; Hecker, Leonard R.; Hoekstra, William J.; Justus, Michael; Maryanoff, Cynthia A.; Scott, Lorraine; Shah, Rekha D.; Solms, Guenter; Sorgi, Kirk L.; Stefanick, Stephen M.; Thurnheer, Urs; Villani Jr., Frank J.; Walker, Donald G.; Organic Process Research and Development; vol. 5; nb. 1; (2001); p. 23 - 27 View in Reaxys

H N

OH O

N H

O O

OH N H

Rx-ID: 36571765 View in Reaxys 443/592 Yield

Conditions & References

42 %

in ethyl acetate, T= 20 - 70 °C Boesch, Heinz; Cesco-Cancian, Sergio; Hecker, Leonard R.; Hoekstra, William J.; Justus, Michael; Maryanoff, Cynthia A.; Scott, Lorraine; Shah, Rekha D.; Solms, Guenter; Sorgi, Kirk L.; Stefanick, Stephen M.; Thurnheer, Urs; Villani Jr., Frank J.; Walker, Donald G.; Organic Process Research and Development; vol. 5; nb. 1; (2001); p. 23 - 27 View in Reaxys

O O

N H

O O

OH N H

Rx-ID: 36571766 View in Reaxys 444/592 Yield

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HO O

O O

N H

Rx-ID: 24987903 View in Reaxys 445/592 Yield

Conditions & References

75.8%

7.D : D. Combined the mother liquors from Crop F and Crop E, and concentrated to 7.31 g of Crop G. Crop G was converted back to the free acid using the method which was used to obtain Crop C and there was obtained 3.0 g of Crop H. This was treated as was the initial R,S-material with 1.9 g of d-ephedrine. Recrystallization of the salt from 17 ml of acetonitrile afforded 2.4 g Crop J, mp 127-130° C. Crop J was recrystallized to 2.06 g of Crop K, mp 130-134° C dec. Combined Crops B and K (6.52 g) were recrystallized from 40 ml of acetonitrile affording 6.06 g of the d-ephedrine salt of R-N-acetyl-α-hydroxymethyl-tyrosine methyl ether (75.8percent overall). The free acid was regenerated in the same manner that the combined mother liquors of Crops A and B were converted to Crop C and there was obtained 3.50 g of R-N-acetyl-α-hydroxymethyl-tyrosine methyl ether: [α]D =+92° (C, 1.35, 0.27 N NaOH). Patent; Merck and Co., Inc.; US4695588; (1987); (A1) English View in Reaxys

HO O NH HO

N H

Rx-ID: 25012080 View in Reaxys 446/592 Yield

Conditions & References 7.D : D. Ten g of R,S-N-acetyl-α-hydroxymethyl-tyrosine methyl ether and 6.18 g of d-ephedrine were dissolved in 50 ml of methanol. The solution was concentrated to dryness in vacuo and then redissolved in 50 ml of warm acetonitrile. Crystallization afforded 7.34 g of the d-ephedrine salt of R-N-acetyl-α-hydroxymethyl-tyrosine methyl ether, mp 125-131° C. (Crop A). Crop A was recrystallized from 40 ml of acetonitrile affording 4.78 g of Crop B, mp 130°-134° C. Patent; Merck and Co., Inc.; US4695588; (1987); (A1) English View in Reaxys O

H N

HO HO

OH OH HN

H H

OH H

racemate

Rx-ID: 23152036 View in Reaxys 447/592 Yield 92 %

Conditions & References 1 : Example 1; Isolation of (1R,2R)-1-hydroxy-N-methyl-1-phenyl-2-propanaminium [(1R,2R,4aS,8aS)- [2-hydroxy-2,5,5,8a-tetramethyldecahydronaphtalen-1-yl]acetate (a compound of formula (I)) In a 2 liter, three-necked, round-bottomed flask equipped with a reflux condenser, a mechanical stirrer and containing 1.0 1 of dry tetrahydrofuran (THF) were introduced 268.4 g (1.00 mole) of [(2RS)-HYDROXY-ACID] (obtained according to EP 550889) and 119.8 g (0.725 mole) of [(1R,] 2R) -pseudoephedrine. The resulting suspension was heated to reflux for 1 hour and the temperature was then gradually lowered to room temperature over 2 h 30 min. The suspension was filtered and the precipitate washed twice with 250 ml of dry THF. The resulting solid was dried under vacuum to give 199.1 g (0.459 mole, yield = 92percent) of the title salt. [1H-NMR] : 7.35-7. 23 (m, [5H,] [PHH) ;] 4.28 (d, 1H, J = 7.6 Hz, CH (OH) ) ; 2.69 (dq, J = 7.6 and 6.6 [HZ, 1H, CH (NH2 (CH3)] ; 2.36 (s, 3H, NH2CH3) ; 2. 33 (dd, J = 16,4. 2 Hz, [1H,] CHCOO); 2.02 (dd, [J =] 16,6. 3 Hz, 1 H, CHCOO); 1.75 (dd, [J =] 6.3 4.2 Hz, 1H, CH (CH2) COO); 1.72-1. 03 (m, [10H,] [5CH2)] ; 0.96 (s, 3H, CH3CH (OH) ) ; 0.91 (m, [1H,] CHC (CH3) 2);

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0.84 (s, 3H, C (CH3) 2); 0.76 (s, 3H, C (CH3) 2); 0.75 (d, J = 6.6 Hz, 3H, [CH3CHNH2 (CH3]] ; 0.73 (s, 3H, [CCH3).] [13C-NMR] : 176.6 (s); 143.1 (s); 127.8 (d); 127.1 (d); 127.0 (d); 75.6 (d); 70.9 (s); 60.2 (d); 56.3 (d); 55.5 (d); 43.7 (t); 41.4 (t); 38.57 (s); 37.9 (t); 33.2 (q); 32.8 (s); 32.5 (q) ; 30.5 (t); 24.0 (q) ; 21.3 (q) ; 19.9 (t); 17.9 (t); 14.9 (q) ; 14.4 [(q).] in tetrahydrofuran, Time= 3.5h, T= 20 °C , Heating / reflux, Resolution of racemate Patent; FIRMENICH SA; WO2004/13069; (2004); (A1) English View in Reaxys

H N

HO H

H N

Rx-ID: 29683375 View in Reaxys 448/592 Yield

Conditions & References 9 :Salicylic acid or ephedrine free base (0.5, 1, 1.5 or 2 eq.) and ephedrinium salicylate were suspended in acetone (20 ml) and stirred at room temperature until a clear solution was obtained. The solvent was evaporated and remaining volatile material removed under vacuum (0.01 mbar, 40 °C). 1H-NMR (300 MHz, d6-DMSO) δ(ppm) = 9.30 (br s, 2H)5 7.76 (dd, J1 = 7.7 Hz, J2 = 1.8 Hz, IH), 7.38 (m, 4H), 7.24 (m, 2H), 6.70 (m, 2H), 6.48 (br s, IH), 5.21 (s, IH), 3.41 (m, IH), 2.69 (s, 3H), 0.95 (d, J = 6.8 Hz, 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm) = 172.9, 162.1, 141.4, 132.0, 130.3, 128.2, 127.2, 125.8, 119.6, 116.8, 116.0, 69.6, 59.3, 30.6, 9.1. in acetone, T= 20 °C , Product distribution / selectivity Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys

H N

OH O

N H OH

O P

(-)-enantiomer

Rx-ID: 2104734 View in Reaxys 449/592 Yield

O O

H HN

H O

OH H

H N

Cl (-)-enantiomer

OH O

Cl (-)-enantiomer

Rx-ID: 2498560 View in Reaxys 450/592 Yield

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View in Reaxys

HO OH

H N

O O

HO O

H N

O O

Rx-ID: 2469260 View in Reaxys 451/592 Yield

Conditions & References With hydrogen, palladium on activated charcoal in ethanol, Time= 0.333333h, Ambient temperature Sit; Parker; Motoc; Han; Balasubramanian; Catt; Brown; Harte; Thompson; Wright; Journal of Medicinal Chemistry; vol. 33; nb. 11; (1990); p. 2982 - 2999 View in Reaxys

O N

N H

O O

OH N H

Rx-ID: 36571747 View in Reaxys 452/592 Yield

Conditions & References Reaction Steps: 3 1.1: ammonium acetate / ethanol / |Reflux 2.1: sodium hydroxide / tetrahydrofuran; water / 15 - 25 °C 2.2: 17 h / 15 - 25 °C 3.1: ethyl acetate / 20 - 70 °C With ammonium acetate, sodium hydroxide in tetrahydrofuran, ethanol, water, ethyl acetate Boesch, Heinz; Cesco-Cancian, Sergio; Hecker, Leonard R.; Hoekstra, William J.; Justus, Michael; Maryanoff, Cynthia A.; Scott, Lorraine; Shah, Rekha D.; Solms, Guenter; Sorgi, Kirk L.; Stefanick, Stephen M.; Thurnheer, Urs; Villani Jr., Frank J.; Walker, Donald G.; Organic Process Research and Development; vol. 5; nb. 1; (2001); p. 23 - 27 View in Reaxys

N NH 2

N H

O O

OH N H

Rx-ID: 36571751 View in Reaxys 453/592 Yield

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H N

OH O

N H

O O

OH N H

Rx-ID: 36571755 View in Reaxys 454/592 Yield

Conditions & References in ethyl acetate, T= 20 - 70 °C Boesch, Heinz; Cesco-Cancian, Sergio; Hecker, Leonard R.; Hoekstra, William J.; Justus, Michael; Maryanoff, Cynthia A.; Scott, Lorraine; Shah, Rekha D.; Solms, Guenter; Sorgi, Kirk L.; Stefanick, Stephen M.; Thurnheer, Urs; Villani Jr., Frank J.; Walker, Donald G.; Organic Process Research and Development; vol. 5; nb. 1; (2001); p. 23 - 27 View in Reaxys

O F

O O S F

N H

O S

O S O

N H

S O

Rx-ID: 31549017 View in Reaxys 455/592 Yield

Conditions & References in water, Time= 18h, T= 20 °C , Cooling with ice De Rooy, Sergio L.; Li, Min; Bwambok, David K.; El-Zahab, Bilal; Challa, Santhosh; Warner, Isiah M.; Chirality; vol. 23; nb. 1; (2011); p. 54 - 62 View in Reaxys

H N

O O HO

O O

Rx-ID: 25079121 View in Reaxys 456/592 Yield

Conditions & References 8 : EXAMPLE 8 EXAMPLE 8 A solution of 71.0 g (0.24 mol) of 5-benzoyl-6-methyl-2-benzodioxolecarboxylic acid (melting point 120°-122°, cf. Example 1), in 200 ml of acetonitrile and a solution of 41.2 g (0.25 mol) of D-ephedrine (base) in 300 ml of acetonitrile, each at approximately 30°, are combined and cooled in an ice bath and the crystals that are deposited are filtered off. The resulting crystal fraction is recrystallized four times from acetonitrile, yielding the D-ephedrine salt of (+)-5-benzoyl-6-methyl-2-benzodioxolecarboxylic acid in the form of colourless, fine needles having a melting point of 149°-150° (sinters from 145°). Patent; Ciba-Geigy Corporation; US4414214; (1983); (A1) English View in Reaxys Patent; Ciba-Geigy Corporation; US4517184; (1985); (A1) English View in Reaxys

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H N

O H N

N H

Rx-ID: 5338342 View in Reaxys 457/592 Yield

Conditions & References 3.A : EXAMPLE 3 A solution of Example 1 Part D(1) compound [C00034] [00122] (2.563 gm, 8.98 mmol) in CH3CN (20 mL) was treated with (1R,2S)-(-)-ephedrine (1.522 gm, 9.2 mmol) and stirred until homogeneous. Most of the solvent was removed by rotary evaporation and the residue was dissolved in Et2O (25 mL) and treated with hexane (16 mL) in portions until the mixture was slightly turbid. The solution was seeded and let stand overnight at room temperature. The precipitate was collected by filtration and rinsed with 1:1 Et2O:hexanes and dried to afford 2.101 gm of white crystals ([a]D=-16.4° (c 0.6, CH2Cl2)). The solid (2.087 gm) was dissolved in CH2Cl2, concentrated and diluted with Et2O (18 mL) and hexane (8 mL) and seeded. The precipitate was collected by filtration and washed with 1:1-Et2O:hexanes followed by hexanes to give title compound (1.995 gm) which was diastereomerically enriched in one isomer but not diastereomerically pure ([a]D=-17.0° (c 0.6, CH2Cl2)). [00123] mp 110-114° C. [00124] Material suitable for x-ray crystallographic analysis was obtained by repeated recrystallization of the solid from CH3CN. mp 117-119° C.; ([α]D=-19.7° (c 0.4, CH2Cl2)). in acetonitrile, T= 20 °C Patent; Bristol-Myers Squibb Company; US6777550; (2004); (B1) English View in Reaxys

H N

H O

N H O

Rx-ID: 28818958 View in Reaxys 458/592 Yield

Conditions & References in acetonitrile Nguyen, T. Hien; Ansell, Richard J.; Organic and Biomolecular Chemistry; vol. 7; nb. 6; (2009); p. 1211 - 1220 View in Reaxys

H N

O NH OH

O O

Rx-ID: 25157758 View in Reaxys 459/592 Yield

Conditions & References R.2.2 : REFERENCE EXAMPLE 2 (1)-2 Racemic 2-acetamino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthoic acid (17.3 g) and l-ephedrine (10 g) were dissolved in methanol (250 ml) while heating and allowed to stand at room temperature 5 hours. The precipitated crystals were collected by filtration and recrystallized from methanol to give the l-ephedrine salt of d-2-acetamino-1,2,3,4-tetrahydro-5,8-dimethoxy-2-naphthoic acid (9.0 g). M.P., 247°-250° C. [α]D 20 +37.8° (c=0.5, dimethylformamide). Patent; Sumitomo Chemical Co., Ltd.; US4540695; (1985); (A1) English View in Reaxys

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HO OH

OH O

O O O

Rx-ID: 23058722 View in Reaxys 460/592 Yield

Conditions & References 1 :To a solution of 1- [2- (TERT-BUTOXYCARBONYL)-4-METHOXYBUTYL] CYCLOPENTANE CARBOXYLIC acid (WO 0202513) (3.90 kg, 13.0 mol) in heptane (58.5 L, total solution weight 44.0 kg) was added (1 S, 2S)- (+)-PSEUDOEPHEDRINE (2.13 kg, 12.9 mol) under an atmosphere of nitrogen at 20 °C. The suspension was then heated to 70 °C with stirring until a clear solution was obtained. The solution was then cooled to 40 °C and a sample of authentic crystallised title compound (0.8 g) was added to seed the CRYSTALLISATION. The temperature of the mixture was maintained at 40 °C for 2 hours and then the slurry was cooled to 20 °C over 6 hours. The product was then collected by filtration and was washed with heptane (2 x 2.3 L) then dried under vacuum for 22 hours at 50 °C to give (1 S, 2S)-1-HYDROXY-N-METHYL-1-PHENYL-2-PROPANAMINIUM 1- [ (2S)-2- (TERT-BUTOXY carbonyl)-4-methoxybutyl] cyclopentane carboxylate (3.20 kg, 6.87 mol, 53percent yield as an 86: 14 mixture of diastereoisomeric salts as measured BYAPOS;H NMR). The product (3.20 kg, 6.87 mol) was then suspended in heptane (30 L) and heated to 70 °C until a clear solution was obtained. The resultant solution was then cooled to 58 °C and a sample of authentic crystallised title compound (1.0 g) was added to seed the crystallisation. The solution was then held at 58 °C for 1 hour and was then cooled to 20 °C over 6 hours. The slurry was then granulated at 20 °C for 12 hours. The product was collected by filtration and was washed with heptane (2 x 2 L). Drying in a vacuum oven at 50 °C for 22.5 hours gave (1 S, 2S)-1-HYDROXY-N-METHYL-1-PHENYL-2-PROPANAMINIUM 1-[(2S)-2-(TERT- BUTOXYCARBONYL)-4-METHOXYBUTYL] CYCLOPENTANE CARBOXYLATE as a white crystalline solid (2.35 kg, 5.0 mol, 73percent yield). m. p. (heptane); 95 °C ;APOS;H-NMR (CDCI3, 300 MHz), A : 1.08 (d, 3 H), 1.48 (s, 10 H), 1.56-1. 74 (m, 4 H), 1.74-1. 90 (m, 2 H), 1.90-2. 03 (m, 2 H), 2.03- 2.27 (m, 2 H), 2.4-2. 53 (m, 1 H), 2.66 (s, 3 H), 3.08 (dq, 1 H), 3.24 (s, 3 H), 3.38 (q, 2 H), 4.58 (d, 1 H), 7.27-7. 45 (m, 5 H), 7.70 (s, br, 3 H); Anal. found C, 67.06 ; H, 9.35 ; N, 3.04 ; C26H43NO6 requires C, 67.07 ; H, 9.31 ; N, 3. 01percent. The title compound was obtained by breaking the salt as follows. To a stirred suspension of (1 S, 2S)-1-HYDROXY-N-METHYL- 1-phenyl-2-propanaminium 1-[(2S)-2(tert-butoxycarbonyl)-4-methoxybutyl]cyclopentane carboxylate (210 g, 0.45 mol) in deionised water (1.26 L) and isopropyl acetate (1.47 L) was added aqueous hydrochloric acid (99.5 ml of a 5 M solution, 0.50 mol) until the pH of the aqueous layer was between pH 2 and 3. The layers were then separated, and the aqueous phase was extracted with isopropyl acetate (630 ml). The organic extracts were then combined and washed with saturated brine solution (420 ML). The organic phase was then concentrated by distillation at atmospheric pressure (to remove 1.4 L of isopropyl acetate) to the title compound as a solution in isopropyl acetate which was used directly in the next step. An aliquot can be taken and the solvent removed to give an analytical sample ;'H NMR (CDCI3 300MHZ) 8 : 1.44 (s, 9 H), 1.48-1. 59 (m, 2 H), 1.59- 1.72 (m, 5 H), 1.72-1. 93 (m, 2 H), 2.03-2. 18 (m, 3 H), 2.35-2. 46 (m, 1 H), 3.31 (s, 3 H), 3.38 (t, 2 H); LRMS (EL) : m/z 244 [M-C4H8] +, 227 [M-C4HG0] +, 199 [M-C4Hg02C] + ; GC (injector program: initial temp. 0 °C, rate 150 °C/MIN, final temp. 230 °C ; oven program: initial temp. 100 °C, rate 10 °C/MIN, final temp. 230 °C, final time 20 min; column, BP-21 25 m x 0. 25mm ID x 0.25um FT; detection FID) Retention Time 16.0 min; HPLC (column : CHIRALPAK AD (25 x 0.46 cm); mobile phase: HEXANE/IPA/ACETIC acid (98/2/0.1 v/v/v) ; Rinsing mobile phase: hexane/IPA/DEA (80/20/. 5 v/v/v) ; flow rate: 1.0 ml/min ; temperature: ambient; injection volume : 20 UL ; detection: ELSD) Run time: 20 mins followed by 10 mins rinse with hexane/IPA/DEA (80/20/. 5 V/V/V), followed by 10 mins rinse with HEXANE/IPA/ACETIC acid (98/2/0.1 v/v/v) ; Retention Time: minor enantiomer 15.5 min (3.3percent), major enantiomer 17.5 min (96.7percent). in n-heptane, T= 20 - 70 °C Patent; PFIZER LIMITED; PFIZER INC.; WO2004/56750; (2004); (A1) English View in Reaxys

HO OH O O O

Rx-ID: 23969604 View in Reaxys 461/592 Yield

Conditions & References 69 : 1-[(2S)-2-(tert-Butoxycarbonyl)-4-methoxybutyl]cyclopentanecarboxylic acid

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The product was then collected by filtration and was washed with heptane (2*2.3 L) then dried under vacuum for 22 hours at 50° C. to give (1 S,2S)-1-hydroxy-N-methyl-1-phenyl-2-propanaminium 1-[(2S)-2-(tert-butoxy carbonyl)-4methoxybutyl]cyclopentane carboxylate (3.20 kg, 6.87 mol, 53percent yield as an 86:14 mixture of diastereoisomeric salts as measured by 1H NMR). Patent; Challenger, Stephen; Cook, Andrew Simon; Gillmore, Adam Thomas; Middleton, Donald Stuart; Pryde, David Cameron; Stobie, Alan; US2003/105132; (2003); (A1) English View in Reaxys 69 : 1-[(2S)-2-(tert-Butoxycarbonyl)-4-methoxybutyl]cyclopentanecarboxylic acid The product (3.20 kg, 6.87 mol) was then suspended in heptane (30 L) and heated to 70° C. until a clear solution was obtained. The resultant solution was then cooled to 58° C. and a sample of authentic crystallized title compound (1.0 g) was added to seed the crystallisation. The solution was then held at 58° C. for 1 hour and was then cooled to 20° C. over 6 hours. The slurry was then granulated at 20° C. for 12 hours. The product was then collected by filtration and was washed with heptane (2*2 L). Drying in a vacuum oven at 50° C. for 22.5 hours gave (1S,2S)-1-hydroxy-N-methyl-1-phenyl-2-propanaminium 1[(2S)-2-(tert-butoxycarbonyl)-4-methoxybutyl]cyclopentane carboxylate as a white crystalline solid (2.35 kg, 5.0 mol, 73percent yield). m.p. (heptane); 95° C.; 1H-NMR (CDCl3, 300 MHz), δ: 1.08 (d, 3H), 1.48 (s, 10H), 1.56-1.74 (m, 4H), 1.74-1.90 (m, 2H), 1.90-2.03 (m, 2H), 2.03-2.27 (m, 2H), 2.4-2.53 (m, 1H), 2.66 (s, 3H), 3.08 (dq, 1H), 3.24 (s, 3H), 3.38 (q, 2H), 4.58 (d, 1H), 7.27-7.45 (m, 5H), 7.70 (s, br, 3H); Anal. found C, 67.06; H, 9.35; N, 3.04; C26H43NO6 requires C, 67.07; H, 9.31; N, 3.01percent. Patent; Challenger, Stephen; Cook, Andrew Simon; Gillmore, Adam Thomas; Middleton, Donald Stuart; Pryde, David Cameron; Stobie, Alan; US2003/105132; (2003); (A1) English View in Reaxys

N H

O O

OH N H

N Cl

Rx-ID: 36571749 View in Reaxys 462/592 Yield

N NH 2

N H

O O

OH N H

N Cl

Rx-ID: 36571753 View in Reaxys 463/592 Yield

Conditions & References Reaction Steps: 2 1.1: sodium hydroxide / tetrahydrofuran; water / 15 - 25 °C

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1.2: 17 h / 15 - 25 °C 2.1: ethyl acetate / 20 - 70 °C With sodium hydroxide in tetrahydrofuran, water, ethyl acetate Boesch, Heinz; Cesco-Cancian, Sergio; Hecker, Leonard R.; Hoekstra, William J.; Justus, Michael; Maryanoff, Cynthia A.; Scott, Lorraine; Shah, Rekha D.; Solms, Guenter; Sorgi, Kirk L.; Stefanick, Stephen M.; Thurnheer, Urs; Villani Jr., Frank J.; Walker, Donald G.; Organic Process Research and Development; vol. 5; nb. 1; (2001); p. 23 - 27 View in Reaxys

H N

OH O

N H

O O

OH N H

N Cl

Rx-ID: 36571757 View in Reaxys 464/592 Yield

H N

HO H

OH 2 OH

H N

Rx-ID: 29683388 View in Reaxys 465/592 Yield

H N

F F

O F

OH O

F O F

H N

OH O

Rx-ID: 40309247 View in Reaxys 466/592 Yield

Conditions & References in benzene-d6

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Nemes, Anik; Cska, Tams; Bni, Szabolcs; Farkas, Viktor; Rbai, Jzsef; Szab, Dnes; Journal of Organic Chemistry; vol. 80; nb. 12; (2015); p. 6267 - 6274 View in Reaxys

H N

OH N

H N Cl

Rx-ID: 8557898 View in Reaxys 467/592 Yield

Conditions & References in diethyl ether, Resolution Zabel, Manfred; Breu, Josef; Rau, Franz; Range, Klaus-Juergen; Krey, Volker; Uffrecht, Anka; Buschauer, Armin; Acta Crystallographica Section C: Crystal Structure Communications; vol. 56; nb. 2; (2000); p. 250 - 251 View in Reaxys O

H N

OH O

O OH

H N

OH O

(-)-enantiomer

Rx-ID: 2104736 View in Reaxys 468/592 Yield

H N

OH O

O O

H Cl

OH O

(+)-enantiomer

Rx-ID: 2104737 View in Reaxys 469/592 Yield

H N

OH O

H H

N H OH

H Cl (-)-enantiomer

O P

(-)-enantiomer

Rx-ID: 2104738 View in Reaxys 470/592 Yield

Conditions & References in ethanol, Heating, H2O / water also used

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Haest, A. D. van der; Wynberg, H.; Leusen, F. J. J.; Bruggink, A.; Recueil des Travaux Chimiques des Pays-Bas; vol. 109; nb. 10; (1990); p. 523 - 528 View in Reaxys

O O

OH H

N H H

O P

(-)-enantiomer

Rx-ID: 2498562 View in Reaxys 471/592 Yield

O N

SH HO

OH S

O HO

N SH

OH S

Rx-ID: 11062303 View in Reaxys 472/592 Yield

Conditions & References

41.8 %

in ethanol Gazaliev; Nurkenov; Kulakov; Ainabaev; Bessonov; Russian Journal of Applied Chemistry; vol. 79; nb. 3; (2006); p. 508 - 510 View in Reaxys

H N

O N

SH HO

O HO

N SH

OH S

Rx-ID: 11062310 View in Reaxys 473/592 Yield

Conditions & References

57.5 %

in ethanol Gazaliev; Nurkenov; Kulakov; Ainabaev; Bessonov; Russian Journal of Applied Chemistry; vol. 79; nb. 3; (2006); p. 508 - 510 View in Reaxys

O HO

N SH

OH S

Rx-ID: 11594434 View in Reaxys 474/592 Yield

Conditions & References Reaction Steps: 2 1: 39.7 percent / ethanol / 1 h / 20 °C 2: 57.5 percent / ethanol in ethanol

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Gazaliev; Nurkenov; Kulakov; Ainabaev; Bessonov; Russian Journal of Applied Chemistry; vol. 79; nb. 3; (2006); p. 508 - 510 View in Reaxys

N SH

OH S

Rx-ID: 11594435 View in Reaxys 475/592 Yield

Conditions & References Reaction Steps: 2 1: 39.7 percent / ethanol / 1 h / 20 °C 2: 41.8 percent / ethanol in ethanol Gazaliev; Nurkenov; Kulakov; Ainabaev; Bessonov; Russian Journal of Applied Chemistry; vol. 79; nb. 3; (2006); p. 508 - 510 View in Reaxys

O HO

N SH

OH S

Rx-ID: 11599101 View in Reaxys 476/592 Yield

Conditions & References Reaction Steps: 3 1: 90.2 percent / ethanol / 0.33 h / 60 - 65 °C 2: 39.7 percent / ethanol / 1 h / 20 °C 3: 57.5 percent / ethanol in ethanol Gazaliev; Nurkenov; Kulakov; Ainabaev; Bessonov; Russian Journal of Applied Chemistry; vol. 79; nb. 3; (2006); p. 508 - 510 View in Reaxys

O HO

OH HO

O HO

N SH

OH S

Rx-ID: 11599102 View in Reaxys 477/592 Yield

Conditions & References Reaction Steps: 3 1: 90.2 percent / ethanol / 0.33 h / 60 - 65 °C 2: 39.7 percent / ethanol / 1 h / 20 °C 3: 41.8 percent / ethanol in ethanol Gazaliev; Nurkenov; Kulakov; Ainabaev; Bessonov; Russian Journal of Applied Chemistry; vol. 79; nb. 3; (2006); p. 508 - 510 View in Reaxys

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[6-(5-chloro-2-methoxybenzyl)-1-(2,4,6-trimethoxybenzyl)-1,3,4,6-tetrahydro-2H,5H-1,4-diazepin-2,5-dion-4-yl]-CO-OPh-X (X=4-NO2 or 2-Cl)

H 2N

O HO

N SH

OH S

Rx-ID: 11616234 View in Reaxys 478/592 Yield

[6-(5-chloro-2-methoxybenzyl)-1-(2,4,6-trimethoxybenzyl)-1,3,4,6-tetrahydro-2H,5H-1,4-diazepin-2,5-dion-4-yl]-CO-OPh-X (X=4-NO2 or 2-Cl)

H 2N

O HO

N SH

OH S

Rx-ID: 11616236 View in Reaxys 479/592 Yield

O O O

Cl N

N H 2N

H HN

OH H

NH O

O O

Rx-ID: 4347410 View in Reaxys 480/592 Yield

Conditions & References With sodium hydroxide, Multistep reaction Myers, Andrew G.; Gleason, James L.; Yoon, Taeyoung; Journal of the American Chemical Society; vol. 117; nb. 32; (1995); p. 8488 - 8489 View in Reaxys

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H N

N H OH

O P

(-)-enantiomer

Rx-ID: 2104735 View in Reaxys 481/592 Yield

O O

H N

OH O

(-)-enantiomer

Rx-ID: 2498561 View in Reaxys 482/592 Yield

H N

F F

OH O

F F

F F Cl

Rx-ID: 23409826 View in Reaxys 483/592 Yield

Conditions & References 1; 9 :Previous resolution of CPTA has been reported in U. S. Patent No. 3,517, 050, in which cinchonidine was used as the chiral base, and the (+)-enantiomer of CPTA precipitated as the diastereomeric salt. One major drawback to this procedure was that the desired (-)- enantiomer remained in the mother liquor, making separation of a pure (-)enantiomer fraction difficult. [0092] This example shows the results of resolving a racemic mixture of CPTA using A variety of different chiral bases to obtain a solid enantiomerically enriched (-) -isomer. Unlike the previous method, methods of the present invention allow the solid enantiomerically enriched (-) -CPTA to be readily isolated from the solution. [0093] Racemic CPTA was prepared by the potassium hydroxide hydrolysis of racemic halofenate. For chiral base screening, equal molar mixtures of CPTA and the chiral base were mixed in ethanol, methanol and acetone in glass vials, and the solutions were allowed to stand undisturbed. After holding overnight at ambient temperature, the samples that remained in solution were placed in a refrigerator at 5 C. After holding overnight in the refrigerator, a small amount of water was added to the samples that remained a solution in ethanol. After four days at ambient temperature, the aqueous ethanol solutions were placed back in the refrigerator. All of the samples remained in the refrigerator, and were periodically checked for precipitate formation over the course of a month. A list of the bases and solvent conditions examined, and temperatures at which crystalline salts were found is shown in Table 1. Table 1. Bases Examined for CPTA Resolution. Solvent System Base EtOH EtOH (aq) Acetone MeOH S- (-)-Methylbenzylamine E E E E Quinine C (22 C) C (22 C) C (22 C) Quinidine E E L-Tyrosine Hydrazide C (22 C) L-Leucine Methyl Ester Hydrochloride* E E 1-2-Amino-l-butanol E E E E Brucine E E E E (S)-(+)-2-Pyrrolidine-methanol E E E E (S)-(+)-2-Amino-3-methyl-1-butanol E (S)- (+)-2-Amino-1-propanol E (S)-(-)-2-Amino-3-phenyl-1-propanol E (1 S, 2S)-(+)-Pseudoephedrine E E E E (1S,2S)-(+)-2-Amino-1-phenyl-1,3-propanediol E E E E (1 S, 2S)-(+)-2-Amino-1(4-nitrophenyl)-1, 3-propandiol C (5 C) (lR, 2S)- (-)-Norephedrine E E E E (1R,2R)-(-)-Ephedrine (1R,2R)-(-)-2-Amino-1-(4-nitrophenyl)-1, 3-propandiol C (22 C) (+)-Cinchonone E E E E (-)-Cinchonidine C (22 C) (-)-Strychnine E E E E E-Evaluated C-Crystallized at (Temperature) *-With 1 MOL/MOL of Aqueous Sodium Hydroxide [0094] Four chiral

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bases, quinine, L-tyrosine hydrazide, (-) -cinchonidine, and both enantiomers of 2-amino-1-(4-nitrophenyl)-1, 3-propandiol, were found to give crystalline salts from racemic CPTA. For samples that crystallized, the solid was isolated by filtration, and both the solid phase and mother liquor were analyzed by chiral HPLC to determine the enantiomeric composition of both streams. The results from the screen are shown in Table 2. Three of the bases shown in Table 2 gave the (+) -enantiomer enrichment in the solid phase. Table 2. Results from Chiral Base Screen. Solid Mother Liquor percent Yield Base percent (+) percent (-) percent (+) percent (-) Calculated Solvent Temp C L-Tyrosine Hydrazide Acetone 22 86. 6 13. 4 40. 7 59.3 20.3 (-) -Cinchonidine Ethanol 22 66.8 33.2 12. 0 88.0 69.3 (1S, 2S)- (+)-2Amino-1- (4- Ethanol 22 93. 2 6.8 28.5 71. 5 33. 2 nitrophenyl)-1, 3-propandiol Quinine Ethanol 22 39.9 60.1 60.1 39.9 50.1 Acetone 22 28. 2 71.8 58.9 41. 1 28. 9 Acetone* 5 23. 0 77.0 83. 5 16. 5 55. 4 Methanol 22 25. 8 74.2 53.0 47. 0 10. 9 2-Propanol 30 43. 2 56.8 64.3 35. 7 67. 6 2-Propanol** 30 40. 4 59.6 78.8 21. 1 75. 0 2-Propanol* 21 42.3 57.7 59.1 40.9 53.9 *-More Dilute **-Slower Cooling Profile [0095] Included in Table 2 is the percent yield of solid calculated from the isomeric ratio in the solid and mother liquor streams. The equation used is shown below. The maximum theoretical yield with 100percent isomeric purity is 50percent. Yields over 50percent indicate inclusion of the other isomer. Equation to calculate yield from isomer ratios. Set: a = area percent Component 1 in starting material; b = area percent Component 2 in starting material; x = area percent Component 1 in isolated; y = area percent Component 2 in isolated; w = area percent Component 1 in mother liquor; z = area percent Component 2 in mother liquor; E = g material isolated; F = g material in mother liquor. And: A+B=100percent ; E+F=L Then: XE +WF=A ; YE+ZF=B Solving: XE + W (1-E) = A ; YE + Z (1-E) = B E = isolated yield = (A-W)/ (X-W) = (B-Z)/ (Y-Z) This example shows representative results of chiral resolution screening in methanol using a variety of chiral bases. [0117J A sample of 2.00 g of CPTA was dissolved in 8. 03 g of HPLC grade methanol to give a solution. Glass vials were individually charged with the amounts of each base listed in Table 7, and the amount of the CPTA solution calculated to give a 1 to 1 molar ratio of acid to base was added. Additionally, 0.300 mL of 1 N sodium hydroxide was added to vial 27J. The vials were allowed to stand overnight at ambient temperature. Vial 27B solidified, and an additional 300 PL of methanol was added before the sample was analyzed as described above. The remaining vials were placed in the refrigerator. No additional precipitates were noted after one month. Table 7. Base Screening in Methanol. Base wt CPTA solution (g) wt base (g) 27A (1R,2S)-(-)-Ephedrine 0. 4896 g 0. 0478 g 27B Quinine 0. 1420 0. 0282 27C (+)-Cinchonine 0. 1822 0. 0324 2 7-D 1-2-Amino-l-butanol 1. 0012 0. 0539 27E S- (-)-Methylbenzylamine 0. 7892 0. 0576 27F (1S,2S)-(+)-Pseudoephedrine 0.7600 0. 0749 27G Brucine 0. 1891 0. 0436 27H Quinidine 0. 5845 0. 1144 27I ( S, 2S)- (+)-2-Amino-1-phenyl-1, 3-propandiol 0. 3032 0. 0299 27J L-Leucine Methyl Ester Hydrochloride 0. 5033 0. 0545 27K (S)-(+)-2-Pyrrolidine-methanol 0.7133 0.0434 27L (1R,2S)-(-)-Norephedrine 1.1788 0.1070 27M (-)-Strychnine 0. 4525 0. 0905 27N (S)-(+)-2-Amino-3-methyl-1-butanol 0.1478 0. 0092 270 (S)(+)-2-Amino-l-propanol 0.9268 0.0417 27P (S)- (-)-2-mino-3-phenyl-l-propanol 0. 3406 0. 0307 With sodium hydroxide in methanol, water, T= 20 °C , Resolution of racemate, Purification / work up Patent; METABOLEX, INC.; WO2004/112774; (2004); (A1) English View in Reaxys

Cl F F

H HN

OH H

H N

OH O F F

F Cl

Rx-ID: 23411497 View in Reaxys 484/592 Yield

Conditions & References 1; 7 :Previous resolution of CPTA has been reported in U. S. Patent No. 3,517, 050, in which cinchonidine was used as the chiral base, and the (+)-enantiomer of CPTA precipitated as the diastereomeric salt. One major drawback to this procedure was that the desired (-)- enantiomer remained in the mother liquor, making separation of a pure (-)enantiomer fraction difficult. [0092] This example shows the results of resolving a racemic mixture of CPTA using A variety of different chiral bases to obtain a solid enantiomerically enriched (-) -isomer. Unlike the previous method, methods of the present invention allow the solid enantiomerically enriched (-) -CPTA to be readily isolated from the solution. [0093] Racemic CPTA was prepared by the potassium hydroxide hydrolysis of racemic halofenate. For chiral base screening, equal molar mixtures of CPTA and the chiral base were mixed in ethanol, methanol and acetone in glass vials, and the solutions were allowed to stand undisturbed. After holding overnight at ambient temperature, the samples that remained in solution were placed in a refrigerator at 5 C. After holding overnight in the refrigerator, a small amount of water was added to the samples that remained a solution in ethanol. After four days at ambient temperature, the aqueous ethanol solutions were placed back in the refrigerator. All of the samples remained in the refrigerator, and were periodically checked for precipitate formation over the course of a month. A list of the bases and solvent conditions examined, and temperatures at which crystalline salts were found is shown in Table 1. Table

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1. Bases Examined for CPTA Resolution. Solvent System Base EtOH EtOH (aq) Acetone MeOH S- (-)-Methylbenzylamine E E E E Quinine C (22 C) C (22 C) C (22 C) Quinidine E E L-Tyrosine Hydrazide C (22 C) L-Leucine Methyl Ester Hydrochloride* E E 1-2-Amino-l-butanol E E E E Brucine E E E E (S)-(+)-2-Pyrrolidine-methanol E E E E (S)-(+)-2-Amino-3-methyl-1-butanol E (S)- (+)-2-Amino-1-propanol E (S)-(-)-2-Amino-3-phenyl-1-propanol E (1 S, 2S)-(+)-Pseudoephedrine E E E E (1S,2S)-(+)-2-Amino-1-phenyl-1,3-propanediol E E E E (1 S, 2S)-(+)-2-Amino-1(4-nitrophenyl)-1, 3-propandiol C (5 C) (lR, 2S)- (-)-Norephedrine E E E E (1R,2R)-(-)-Ephedrine (1R,2R)-(-)-2-Amino-1-(4-nitrophenyl)-1, 3-propandiol C (22 C) (+)-Cinchonone E E E E (-)-Cinchonidine C (22 C) (-)-Strychnine E E E E E-Evaluated C-Crystallized at (Temperature) *-With 1 MOL/MOL of Aqueous Sodium Hydroxide [0094] Four chiral bases, quinine, L-tyrosine hydrazide, (-) -cinchonidine, and both enantiomers of 2-amino-1-(4-nitrophenyl)-1, 3-propandiol, were found to give crystalline salts from racemic CPTA. For samples that crystallized, the solid was isolated by filtration, and both the solid phase and mother liquor were analyzed by chiral HPLC to determine the enantiomeric composition of both streams. The results from the screen are shown in Table 2. Three of the bases shown in Table 2 gave the (+) -enantiomer enrichment in the solid phase. Table 2. Results from Chiral Base Screen. Solid Mother Liquor percent Yield Base percent (+) percent (-) percent (+) percent (-) Calculated Solvent Temp C L-Tyrosine Hydrazide Acetone 22 86. 6 13. 4 40. 7 59.3 20.3 (-) -Cinchonidine Ethanol 22 66.8 33.2 12. 0 88.0 69.3 (1S, 2S)- (+)-2Amino-1- (4- Ethanol 22 93. 2 6.8 28.5 71. 5 33. 2 nitrophenyl)-1, 3-propandiol Quinine Ethanol 22 39.9 60.1 60.1 39.9 50.1 Acetone 22 28. 2 71.8 58.9 41. 1 28. 9 Acetone* 5 23. 0 77.0 83. 5 16. 5 55. 4 Methanol 22 25. 8 74.2 53.0 47. 0 10. 9 2-Propanol 30 43. 2 56.8 64.3 35. 7 67. 6 2-Propanol** 30 40. 4 59.6 78.8 21. 1 75. 0 2-Propanol* 21 42.3 57.7 59.1 40.9 53.9 *-More Dilute **-Slower Cooling Profile [0095] Included in Table 2 is the percent yield of solid calculated from the isomeric ratio in the solid and mother liquor streams. The equation used is shown below. The maximum theoretical yield with 100percent isomeric purity is 50percent. Yields over 50percent indicate inclusion of the other isomer. Equation to calculate yield from isomer ratios. Set: a = area percent Component 1 in starting material; b = area percent Component 2 in starting material; x = area percent Component 1 in isolated; y = area percent Component 2 in isolated; w = area percent Component 1 in mother liquor; z = area percent Component 2 in mother liquor; E = g material isolated; F = g material in mother liquor. And: A+B=100percent ; E+F=L Then: XE +WF=A ; YE+ZF=B Solving: XE + W (1-E) = A ; YE + Z (1-E) = B E = isolated yield = (A-W)/ (X-W) = (B-Z)/ (Y-Z)This example shows representative results of chiral resolution screening in ethanol using a variety of chiral bases. [0113] A sample of 1.16 g (3.51 mmol) of CPTA was dissolved in 6.98 g of ethanol to give a solution (0.431 mmol/g). Glass vials were individually charged with the amounts of each base listed in Table 5, and the amount of the ethanolic CPTA solution calculated to give a 1 to 1 molar ratio of acid to base was added. In some cases, a small amount of ethanol was added to wet the base prior to addition of the CPTA solution. The vials were allowed to stand overnight at ambient temperature. Vials 7G and 71 gave precipitates. A sample of each supernate was removed and analyzed by chiral HPLC analysis. The solids were isolated by filtration, and also analyzed. Some of the results are shown in Table 2 (see Example 1 above). The remaining vials were placed in a refrigerator at 5 C. After one day, 7E give a precipitate. The sample was analyzed as previously described. The remaining vials were charged with 50 I1L of water, and held at ambient temperature for three days before placing in the refrigerator. No additional precipitates were noted after one month. Table 5. Base Screening in Ethanol. wtCPTA Wt EtOH Water Base Solution (g) Base (g) Added Added 7A Sb Methylbenzylamine 0. 8836 0. 4620 O g 0. 05 g 7B 1-2-Amino-l-butanol 0. 8198 0. 0314 0 0. 05 7C (lR, 2S)- (-)-Norephedrine 0. 5273 0. 0342 0. 2007 0. 05 7D S, 2S)- (+)-Pseudoephedrine 0. 7295 0. 0515 0.1459 0. 05 7E (1S,2S)-(+)-2-Amino-1-(4-nitrophenyl)-1,3- 0.5580 0. 0510 0. 1228 0 propanediol 7F (1, 2S)- (+)-2-Amino-1phenyl-1, 3-propanediol 0. 5640 0. 0405 0.1287 0.05 7G (-)-Cinchonidine 0. 3484 0. 4390 0. 3637 0 7H (+)-Cinchonine 0. 6409 0. 0796 0. 2103 0. 05 71 Quinine 0.5391 0. 0750 0. 1735 0 7J (-)-Strychnine 0. 5812 0. 0828 0. 2295 0. 05 7K Brucine 0. 7566 0. 1287 0 0. 05 7L (S)-(+j-2-pyrrolidine-methanol 0. 8681 0. 0383 0 0. 05 in ethanol, water, T= 20 °C , Resolution of racemate, Purification / work up Patent; METABOLEX, INC.; WO2004/112774; (2004); (A1) English View in Reaxys 1; 9 :Previous resolution of CPTA has been reported in U. S. Patent No. 3,517, 050, in which cinchonidine was used as the chiral base, and the (+)-enantiomer of CPTA precipitated as the diastereomeric salt. One major drawback to this procedure was that the desired (-)- enantiomer remained in the mother liquor, making separation of a pure (-)enantiomer fraction difficult. [0092] This example shows the results of resolving a racemic mixture of CPTA using A variety of different chiral bases to obtain a solid enantiomerically enriched (-) -isomer. Unlike the previous method, methods of the present invention allow the solid enantiomerically enriched (-) -CPTA to be readily isolated from the solution. [0093] Racemic CPTA was prepared by the potassium hydroxide hydrolysis of racemic halofenate. For chiral base screening, equal molar mixtures of CPTA and the chiral base were mixed in ethanol, methanol and acetone in glass vials, and the solutions were allowed to stand undisturbed. After holding overnight at ambient temperature, the samples that remained in solution were placed in a refrigerator at 5 C. After holding overnight in the refrigerator, a small amount of water was added to the samples that remained a solution in ethanol. After four days at ambient temperature, the aqueous ethanol solutions were placed back in the refrigerator. All of the samples remained in the refrigerator, and were periodically checked for precipitate formation over the course of a month. A list of the bases

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and solvent conditions examined, and temperatures at which crystalline salts were found is shown in Table 1. Table 1. Bases Examined for CPTA Resolution. Solvent System Base EtOH EtOH (aq) Acetone MeOH S- (-)-Methylbenzylamine E E E E Quinine C (22 C) C (22 C) C (22 C) Quinidine E E L-Tyrosine Hydrazide C (22 C) L-Leucine Methyl Ester Hydrochloride* E E 1-2-Amino-l-butanol E E E E Brucine E E E E (S)-(+)-2-Pyrrolidine-methanol E E E E (S)-(+)-2-Amino-3-methyl-1-butanol E (S)- (+)-2-Amino-1-propanol E (S)-(-)-2-Amino-3-phenyl-1-propanol E (1 S, 2S)-(+)-Pseudoephedrine E E E E (1S,2S)-(+)-2-Amino-1-phenyl-1,3-propanediol E E E E (1 S, 2S)-(+)-2-Amino-1(4-nitrophenyl)-1, 3-propandiol C (5 C) (lR, 2S)- (-)-Norephedrine E E E E (1R,2R)-(-)-Ephedrine (1R,2R)-(-)-2-Amino-1-(4-nitrophenyl)-1, 3-propandiol C (22 C) (+)-Cinchonone E E E E (-)-Cinchonidine C (22 C) (-)-Strychnine E E E E E-Evaluated C-Crystallized at (Temperature) *-With 1 MOL/MOL of Aqueous Sodium Hydroxide [0094] Four chiral bases, quinine, L-tyrosine hydrazide, (-) -cinchonidine, and both enantiomers of 2-amino-1-(4-nitrophenyl)-1, 3-propandiol, were found to give crystalline salts from racemic CPTA. For samples that crystallized, the solid was isolated by filtration, and both the solid phase and mother liquor were analyzed by chiral HPLC to determine the enantiomeric composition of both streams. The results from the screen are shown in Table 2. Three of the bases shown in Table 2 gave the (+) -enantiomer enrichment in the solid phase. Table 2. Results from Chiral Base Screen. Solid Mother Liquor percent Yield Base percent (+) percent (-) percent (+) percent (-) Calculated Solvent Temp C L-Tyrosine Hydrazide Acetone 22 86. 6 13. 4 40. 7 59.3 20.3 (-) -Cinchonidine Ethanol 22 66.8 33.2 12. 0 88.0 69.3 (1S, 2S)- (+)-2Amino-1- (4- Ethanol 22 93. 2 6.8 28.5 71. 5 33. 2 nitrophenyl)-1, 3-propandiol Quinine Ethanol 22 39.9 60.1 60.1 39.9 50.1 Acetone 22 28. 2 71.8 58.9 41. 1 28. 9 Acetone* 5 23. 0 77.0 83. 5 16. 5 55. 4 Methanol 22 25. 8 74.2 53.0 47. 0 10. 9 2-Propanol 30 43. 2 56.8 64.3 35. 7 67. 6 2-Propanol** 30 40. 4 59.6 78.8 21. 1 75. 0 2-Propanol* 21 42.3 57.7 59.1 40.9 53.9 *-More Dilute **-Slower Cooling Profile [0095] Included in Table 2 is the percent yield of solid calculated from the isomeric ratio in the solid and mother liquor streams. The equation used is shown below. The maximum theoretical yield with 100percent isomeric purity is 50percent. Yields over 50percent indicate inclusion of the other isomer. Equation to calculate yield from isomer ratios. Set: a = area percent Component 1 in starting material; b = area percent Component 2 in starting material; x = area percent Component 1 in isolated; y = area percent Component 2 in isolated; w = area percent Component 1 in mother liquor; z = area percent Component 2 in mother liquor; E = g material isolated; F = g material in mother liquor. And: A+B=100percent ; E+F=L Then: XE +WF=A ; YE+ZF=B Solving: XE + W (1-E) = A ; YE + Z (1-E) = B E = isolated yield = (A-W)/ (X-W) = (B-Z)/ (Y-Z) This example shows representative results of chiral resolution screening in methanol using a variety of chiral bases. [0117J A sample of 2.00 g of CPTA was dissolved in 8. 03 g of HPLC grade methanol to give a solution. Glass vials were individually charged with the amounts of each base listed in Table 7, and the amount of the CPTA solution calculated to give a 1 to 1 molar ratio of acid to base was added. Additionally, 0.300 mL of 1 N sodium hydroxide was added to vial 27J. The vials were allowed to stand overnight at ambient temperature. Vial 27B solidified, and an additional 300 PL of methanol was added before the sample was analyzed as described above. The remaining vials were placed in the refrigerator. No additional precipitates were noted after one month. Table 7. Base Screening in Methanol. Base wt CPTA solution (g) wt base (g) 27A (1R,2S)-(-)-Ephedrine 0. 4896 g 0. 0478 g 27B Quinine 0. 1420 0. 0282 27C (+)-Cinchonine 0. 1822 0. 0324 2 7-D 1-2-Amino-l-butanol 1. 0012 0. 0539 27E S- (-)-Methylbenzylamine 0. 7892 0. 0576 27F (1S,2S)-(+)-Pseudoephedrine 0.7600 0. 0749 27G Brucine 0. 1891 0. 0436 27H Quinidine 0. 5845 0. 1144 27I ( S, 2S)- (+)-2-Amino-1-phenyl-1, 3-propandiol 0. 3032 0. 0299 27J L-Leucine Methyl Ester Hydrochloride 0. 5033 0. 0545 27K (S)-(+)-2-Pyrrolidine-methanol 0.7133 0.0434 27L (1R,2S)-(-)-Norephedrine 1.1788 0.1070 27M (-)-Strychnine 0. 4525 0. 0905 27N (S)-(+)-2-Amino-3-methyl-1-butanol 0.1478 0. 0092 270 (S)(+)-2-Amino-l-propanol 0.9268 0.0417 27P (S)- (-)-2-mino-3-phenyl-l-propanol 0. 3406 0. 0307 With sodium hydroxide in methanol, water, T= 20 °C , Resolution of racemate, Purification / work up Patent; METABOLEX, INC.; WO2004/112774; (2004); (A1) English View in Reaxys 1; 8 :Previous resolution of CPTA has been reported in U. S. Patent No. 3,517, 050, in which cinchonidine was used as the chiral base, and the (+)-enantiomer of CPTA precipitated as the diastereomeric salt. One major drawback to this procedure was that the desired (-)- enantiomer remained in the mother liquor, making separation of a pure (-)enantiomer fraction difficult. [0092] This example shows the results of resolving a racemic mixture of CPTA using A variety of different chiral bases to obtain a solid enantiomerically enriched (-) -isomer. Unlike the previous method, methods of the present invention allow the solid enantiomerically enriched (-) -CPTA to be readily isolated from the solution. [0093] Racemic CPTA was prepared by the potassium hydroxide hydrolysis of racemic halofenate. For chiral base screening, equal molar mixtures of CPTA and the chiral base were mixed in ethanol, methanol and acetone in glass vials, and the solutions were allowed to stand undisturbed. After holding overnight at ambient temperature, the samples that remained in solution were placed in a refrigerator at 5 C. After holding overnight in the refrigerator, a small amount of water was added to the samples that remained a solution in ethanol. After four days at ambient temperature, the aqueous ethanol solutions were placed back in the refrigerator. All of the samples remained in the refrigerator, and were periodically checked for precipitate formation over the course of a month. A list of the bases and solvent conditions examined, and temperatures at which crystalline salts were found is shown in Table 1. Table 1. Bases Examined for CPTA Resolution. Solvent System Base EtOH EtOH (aq) Acetone MeOH S- (-)-Methylben-

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zylamine E E E E Quinine C (22 C) C (22 C) C (22 C) Quinidine E E L-Tyrosine Hydrazide C (22 C) L-Leucine Methyl Ester Hydrochloride* E E 1-2-Amino-l-butanol E E E E Brucine E E E E (S)-(+)-2-Pyrrolidine-methanol E E E E (S)-(+)-2-Amino-3-methyl-1-butanol E (S)- (+)-2-Amino-1-propanol E (S)-(-)-2-Amino-3-phenyl-1-propanol E (1 S, 2S)-(+)-Pseudoephedrine E E E E (1S,2S)-(+)-2-Amino-1-phenyl-1,3-propanediol E E E E (1 S, 2S)-(+)-2-Amino-1(4-nitrophenyl)-1, 3-propandiol C (5 C) (lR, 2S)- (-)-Norephedrine E E E E (1R,2R)-(-)-Ephedrine (1R,2R)-(-)-2-Amino-1-(4-nitrophenyl)-1, 3-propandiol C (22 C) (+)-Cinchonone E E E E (-)-Cinchonidine C (22 C) (-)-Strychnine E E E E E-Evaluated C-Crystallized at (Temperature) *-With 1 MOL/MOL of Aqueous Sodium Hydroxide [0094] Four chiral bases, quinine, L-tyrosine hydrazide, (-) -cinchonidine, and both enantiomers of 2-amino-1-(4-nitrophenyl)-1, 3-propandiol, were found to give crystalline salts from racemic CPTA. For samples that crystallized, the solid was isolated by filtration, and both the solid phase and mother liquor were analyzed by chiral HPLC to determine the enantiomeric composition of both streams. The results from the screen are shown in Table 2. Three of the bases shown in Table 2 gave the (+) -enantiomer enrichment in the solid phase. Table 2. Results from Chiral Base Screen. Solid Mother Liquor percent Yield Base percent (+) percent (-) percent (+) percent (-) Calculated Solvent Temp C L-Tyrosine Hydrazide Acetone 22 86. 6 13. 4 40. 7 59.3 20.3 (-) -Cinchonidine Ethanol 22 66.8 33.2 12. 0 88.0 69.3 (1S, 2S)- (+)-2Amino-1- (4- Ethanol 22 93. 2 6.8 28.5 71. 5 33. 2 nitrophenyl)-1, 3-propandiol Quinine Ethanol 22 39.9 60.1 60.1 39.9 50.1 Acetone 22 28. 2 71.8 58.9 41. 1 28. 9 Acetone* 5 23. 0 77.0 83. 5 16. 5 55. 4 Methanol 22 25. 8 74.2 53.0 47. 0 10. 9 2-Propanol 30 43. 2 56.8 64.3 35. 7 67. 6 2-Propanol** 30 40. 4 59.6 78.8 21. 1 75. 0 2-Propanol* 21 42.3 57.7 59.1 40.9 53.9 *-More Dilute **-Slower Cooling Profile [0095] Included in Table 2 is the percent yield of solid calculated from the isomeric ratio in the solid and mother liquor streams. The equation used is shown below. The maximum theoretical yield with 100percent isomeric purity is 50percent. Yields over 50percent indicate inclusion of the other isomer. Equation to calculate yield from isomer ratios. Set: a = area percent Component 1 in starting material; b = area percent Component 2 in starting material; x = area percent Component 1 in isolated; y = area percent Component 2 in isolated; w = area percent Component 1 in mother liquor; z = area percent Component 2 in mother liquor; E = g material isolated; F = g material in mother liquor. And: A+B=100percent ; E+F=L Then: XE +WF=A ; YE+ZF=B Solving: XE + W (1-E) = A ; YE + Z (1-E) = B E = isolated yield = (A-W)/ (X-W) = (B-Z)/ (Y-Z) This example shows representative results of chiral resolution screening in acetone using a variety of chiral bases. [0115] A sample of 1. 67 g of CPTA was dissolved in 7.57 g of HPLC grade acetone to give a solution. Glass vials were individually charged with the amounts of each base listed in Table 6, and the amount of the CPTA solution calculated to give a 1 to 1 molar ratio of acid to base was added. In some cases, a small amount of acetone was added and the mixture was warmed to about 40 C to give a solution. Additionally, 0.300 mL of 1 N sodium hydroxide was added to vial 16M. The vials were allowed to stand overnight at ambient temperature. Vial 16D formed a precipitate, and was analyzed as described above. Some of the results are summarized in Table 2 (see Example 1). The remaining vials were placed in the refrigerator. Vial 16 N formed a precipitate, and was analyzed. Vial 16G formed a very light precipitate. After one week, vial 16L was found to contain a precipitate. The sample was analyzed as previously indicated. No additional precipitates were noted. Table 6. Base Screening in Acetone. wt CPTA Wt Acetone Base Solution (g) Base (g) Added (g) 16A (lR, 2S)- (-)-Norephedrine 0. 8568 0.0704 16B (1 S, 2S)- (+)-2-Amino-1-phenyl-1, 3-propanediol 0. 1824 0. 0168 16C S-(-)-Methylbenzylamine 0.8948 0. 0592 16D Quinine 0. 1968 0. 0347 0. 85 16E (S)- (+}-2-pyrrolidine-methanol 0. 81 1 0. 0452 16F Brucine 0. 2163 0. 0463 16G (+)-Cinchonine 0. 3987 0. 0630 16H (I S, 2S)- (+)-Pseudoephedrine 1. 0835 0. 0974 161 (-)-Strychnine 0. 1462 0. 0265 0. 25 16J Quinidine 0.3753 0. 0663 16K 1-2-Amino-l-butanol 0. 7248 0. 0353 16L L-Tyrosine Hydrazide 0. 4508 0. 0472 0. 39 16M LLeucine Methyl Ester Hydrochloride 0. 5585 0. 0544 16N Quinine 0.4712 0.0829 2.00 16O (+)-Cinchonine 0.3363 0.0539 0.30 in water, acetone, T= 20 - 40 °C , Resolution of racemate, Purification / work up Patent; METABOLEX, INC.; WO2004/112774; (2004); (A1) English View in Reaxys

Cl F F

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O O

F OH

O O

OH Cl

(+)-enantiomer

(-)-enantiomer

Rx-ID: 25672787 View in Reaxys 485/592 Yield

Conditions & References I.A :For chiral base screening, equal molar mixtures of chiral base and sodium hydroxide were mixed with two equivalents of CPTA in water in glass vials, and the solutions were heated to 100° C., and EtOH was added until all solids dissolved, allowed to stand undisturbed. After cooling to ambient temperature, the crystalline salt precipitate was isolated by filtration, and both the solid phase and mother liquor were analyzed by chiral HPLC to determine the enantiomeric composition of both streams. The results from the screen are shown in Table 1. With sodium hydroxide in ethanol, water, T= 20 - 100 °C , Resolution of racemate Patent; Metabolex, Inc.; US2007/73082; (2007); (A1) English View in Reaxys

O trans OH trans

N Br

H N

O H N

T-4

N Br

T-4

trans trans

S OH

rel-configuration

Rx-ID: 34372619 View in Reaxys 486/592 Yield

Conditions & References 2 :Step 2: (li?,2i?)-2-(methylamino)-l-phenylpropan-l-ol (0.25 g, 1.50 mmol) was added to a solution of racemic tr -4[l-(5-bromo-l,3-thiazol-2-yl)-l-hydroxyethyl]cyclohexanecarboxylic acid (500 mg, 1.50 mmol) and the resulting solution was stirred at room temperature overnight, at which point crystallization occured. The resulting solid was collected by filtration and washed with 1 :1 EtOAc.'hexane. The resulting mother liquor was concentrated in vacuo and then isopropanol (3.5 mL) and (lS,2S)-2-(methylamino)-l-phenylpropan-l-ol were added. The reaction was stirred overnight, at which point crystallization occured. Then EtOAc (3 mL) was added and after 20 minutes, the solid was collected via filtration and the filter cake was washed with EtO Ac and then dried under a nitrogen bag to afford ( 1 S,2S)- 1 hydroxy-N-methyl- 1 - phenylpropan-2-aminium trans A-[(IR or lS)-l-(5-bromo-l,3-thiazol-2-yl)-l- hydroxyethyl]cyclohexanecarboxylate as a white solid. MS ESI calc'd. for Ci2Hi7BrN03S [M+ H]+ 334, 336, found 334, 336. 1H NMR (500 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.30 - 7.27 (m, 4H), 7.25 - 7.19 (m, 1H), 5.95 (s, 1H), 4.20 (d, J= 7.7, 1H), 2.60 - 2.52 (m, 1H), 2.29 (s, 3H), 2.03 - 1.92 (m, 1H), 1.92 - 1.86 (m, 1H), 1.86 - 1.78 (m, 2H), 1.63 - 1.52 (m, 1H), 1.48 1.37 (m, 4H), 1.27 - 1.08 (m, 4H), 1.06 - 0.89 (m, 1H), 0.68 (d, J= 6.4, 3H). , T= 20 °C Patent; MERCK SHARP and DOHME CORP.; ALTMAN, Michael, D.; CHILDERS, Kaleen Konrad; DI FRANCESCO, Maria Emilia; ELLIS, John Michael; FISCHER, Christian; GRIMM, Jonathan; HAIDLE, Andrew, M.; KATTAR, Solomon, D.; NORTHRUP, Alan, B.; OTTE, Ryan, D.; PETROCCHI, Alessia; SCHELL, Adam, J.; ZHOU, Hua; WO2012/154519; (2012); (A1) English View in Reaxys

O trans O trans

N Br S

O H N

T-4

N Br

T-4

trans trans HO

S OH

rel-configuration

Rx-ID: 34372838 View in Reaxys 487/592 Yield

Conditions & References Reaction Steps: 2 1: sodium hydroxide; water / methanol / 3 h / 70 °C 2: 20 °C With water, sodium hydroxide in methanol

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Patent; MERCK SHARP and DOHME CORP.; ALTMAN, Michael, D.; CHILDERS, Kaleen Konrad; DI FRANCESCO, Maria Emilia; ELLIS, John Michael; FISCHER, Christian; GRIMM, Jonathan; HAIDLE, Andrew, M.; KATTAR, Solomon, D.; NORTHRUP, Alan, B.; OTTE, Ryan, D.; PETROCCHI, Alessia; SCHELL, Adam, J.; ZHOU, Hua; WO2012/154519; (2012); (A1) English View in Reaxys

O N

N H

O O

OH N H

N Cl Cl

Rx-ID: 36571750 View in Reaxys 488/592 Yield

O Cl

NH 2

N H

O O

OH N H

N Cl Cl

Rx-ID: 36571754 View in Reaxys 489/592 Yield

H N

N H

O O

OH N H

N Cl Cl

Rx-ID: 36571758 View in Reaxys 490/592 Yield

Conditions & References in ethyl acetate, T= 20 - 70 °C

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Boesch, Heinz; Cesco-Cancian, Sergio; Hecker, Leonard R.; Hoekstra, William J.; Justus, Michael; Maryanoff, Cynthia A.; Scott, Lorraine; Shah, Rekha D.; Solms, Guenter; Sorgi, Kirk L.; Stefanick, Stephen M.; Thurnheer, Urs; Villani Jr., Frank J.; Walker, Donald G.; Organic Process Research and Development; vol. 5; nb. 1; (2001); p. 23 - 27 View in Reaxys

H N

OH O

Rx-ID: 30649823 View in Reaxys 491/592 Yield

Conditions & References Reaction Steps: 3 1.1: caesium carbonate / N,N-dimethyl-formamide / 16 h / 20 - 25 °C 2.1: water; lithium hydroxide hydrate / tetrahydrofuran; methanol / 18 h / 0 - 25 °C 2.2: pH 4 3.1: isopropyl alcohol; water / Heating With water, caesium carbonate, lithium hydroxide hydrate in tetrahydrofuran, methanol, water, N,N-dimethyl-formamide, isopropyl alcohol Patent; PFIZER INC.; BROWN, Matthew Frank; MARFAT, Anthony; MELNICK, Michael Joseph; REILLY, Usa; WO2011/45703; (2011); (A2) English View in Reaxys

H N

O OH

Rx-ID: 30649848 View in Reaxys 492/592 Yield

Conditions & References Reaction Steps: 4 1.1: 1H-imidazole; triphenylphosphine; iodine / dichloromethane / 1 h / 0 - 25 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 16 h / 20 - 25 °C 3.1: water; lithium hydroxide hydrate / tetrahydrofuran; methanol / 18 h / 0 - 25 °C 3.2: pH 4 4.1: isopropyl alcohol; water / Heating With 1H-imidazole, water, iodine, caesium carbonate, triphenylphosphine, lithium hydroxide hydrate in tetrahydrofuran, methanol, dichloromethane, water, N,N-dimethyl-formamide, isopropyl alcohol Patent; PFIZER INC.; BROWN, Matthew Frank; MARFAT, Anthony; MELNICK, Michael Joseph; REILLY, Usa; WO2011/45703; (2011); (A2) English View in Reaxys

O OH

H N

O OH

Rx-ID: 30649879 View in Reaxys 493/592 Yield 36 %

Conditions & References 7.A :A) Resolution of II: 2-methyl-2-methylsulfonyl-4-(4-bromophenyl)butanoic acidIlaA mixture of (+/-)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoic acid (17.3 g, 51.6 mmol) and (-) ephedrine (8.5 g 51.6 mmol) was dissolved in a mixture of IPA (175 mL) and water (2.5 mL) by the application of some heat. The clear solution was diluted with the same amount of solvents and seeded. Crystallization started rapidly and more IPA (50 mL) and water (1 mL) were added. Crystallization was allowed to proceed over 2 daysand the solid was isolated. This afforded 12.45 g of the ephedrine salt of Ila (48percent) with an ee of 74percent. Recrystallization of this material from IPA-water (200

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mL + 3 mL) afforded 10 g of the salt with an ee of 97.4percent. This was triturated with IPA (200 mL) to afford 9.5 g (36percent) of the salt with an ee of 99+percent. Liberation of the salt with 1 N HCI followes by EtOAc extraction afforded 5.7 g of acid Ila. in water, isopropyl alcohol, Heating Patent; PFIZER INC.; BROWN, Matthew Frank; MARFAT, Anthony; MELNICK, Michael Joseph; REILLY, Usa; WO2011/45703; (2011); (A2) English View in Reaxys

H N

O OH

Rx-ID: 30649929 View in Reaxys 494/592 Yield

Conditions & References Reaction Steps: 2 1.1: water; lithium hydroxide hydrate / tetrahydrofuran; methanol / 18 h / 0 - 25 °C 1.2: pH 4 2.1: isopropyl alcohol; water / Heating With water, lithium hydroxide hydrate in tetrahydrofuran, methanol, water, isopropyl alcohol Patent; PFIZER INC.; BROWN, Matthew Frank; MARFAT, Anthony; MELNICK, Michael Joseph; REILLY, Usa; WO2011/45703; (2011); (A2) English View in Reaxys

NH OH

OH 2 O

OH O

Rx-ID: 31615828 View in Reaxys 495/592 Yield

Conditions & References

32 %

2 Patent; ORTHO-MCNEIL-JANSSEN PHARMACEUTICALS, INC; ORMEROD, Dominic John; DEPRE, Dominique Paul Michel; HORVATH, Andras; WO2011/113859; (2011); (A1) English View in Reaxys

trans OH trans OH trans trans O

H N

OH OH 2

OH O

Rx-ID: 31615833 View in Reaxys 496/592 Yield 35 %

Conditions & References 2 :Example 2: Resolution of 4-oxo-l,2-cyclopentanedicarboxylic acid with (-)-ephedrine. Preparation of 4-oxo-l,2-cyclopentanedicarboxylic acid bis ephedrine salt, i.e. (1R,2S)- (-)-ephedrine [(li~,2i~)-4-oxo-l,2-cyclopentanedicarboxylic acid compound with (7R,2S)-(-)-ephedrine (1 :2)]; (lR,2S)-(-)-ephedrine (20.16 g, 0.12 mol) was added to a suspension of trans-4-oxo- 1 ,2-cyclopentanedicarboxylic acid (10 g, 58 mmol) in acetone (200 ml) and water (26 ml). The mixture was heated to reflux until a homogeneous solution was formed. Allow the mixture to cool slowly to 22°C. The solids were filtered and washed with acetone. The solid material was dried under vacuum at 50°C to yield 10.3 g (35 percent)of (lR,2R)-4-oxo-l,2-cyclopentanedicarboxylic acid compound with (lR,2S)-(-)- ephedrine (1 :2) as a white solid.[<x]D: - 69.11H-NMR (400 MHz, DMSO-d6) δ ppm 0.86 (d, J = 6.8 Hz, 6H) 2.29 - 2.39 (m, 1H) 2.39 - 2.47 (m,

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1H) 2.49 (s, 6H) 2.96 - 3.12 (m, 4H) 4.89 (d, J = 3.3 Hz, 2H) 7.19 - 7.32 (m, 2H) 7.33 - 7.54 (m, 8H). 13C-NMR (150 MHz, DMSO-d6) 11.17, 31.81, 42.12, 44.06, 59.55, 71.08, 125.97, 126.92, 127.93, 142.17, 175.74, 176.47, 215.40. in water, acetone, Reflux Patent; ORTHO-MCNEIL-JANSSEN PHARMACEUTICALS, INC; ORMEROD, Dominic John; DEPRE, Dominique Paul Michel; HORVATH, Andras; WO2011/113859; (2011); (A1) English View in Reaxys

H+

Cl SP-4 Au Cl Cl H

H NH

(v1) –

(v4)Cl –

(v1)

–Cl

(v4) Cl – Au3+

SP-4 Cl –

(v1)

H HO

(v1)

racemate

H+

racemate

Rx-ID: 35691676 View in Reaxys 497/592 Yield

Conditions & References With hydrogenchloride in water, Time= 336 - 672h Wood, Matthew R.; Lalancette, Roger A.; Acta Crystallographica Section C: Crystal Structure Communications; vol. 69; nb. 4; (2013); p. 388 - 393 View in Reaxys H

0.5

(v3)

HN H

(v4) (v3)

OH P

O Mo

(v6)

O OH (v4) P

(v3)

O Mo

(v6)

O O

(v3)

H O

(v3)

(-)-enantiomer

(v3)

Rx-ID: 26992707 View in Reaxys 498/592 Yield

Conditions & References

67 %

in cyclohexane, under N2 or Ar, Mo-complex dissolved in MeOH/H2o (4/1), acidified to pH2 (0.5 N HCl), extd. (CHCl3), extracts dried, concd., dissolved in C6H12, (-)-ephedrine*0.5 H2O added, stand at room temp.; recrystd. (C6H12); NMR Reiff, Louis P.; Rossman, David I.; Szafraniec, Leonard J.; Aaron, Herbert S.; Inorganic Chemistry; vol. 25; (1986); p. 1451 - 1455 ; (from Gmelin) View in Reaxys

N H

O O

OH N H

Rx-ID: 36571748 View in Reaxys 499/592 Yield

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View in Reaxys

O N

Br NH 2

N H

O O

OH N H

Rx-ID: 36571752 View in Reaxys 500/592 Yield

H N

N H

O O

OH N H

Rx-ID: 36571756 View in Reaxys 501/592 Yield

OH HO

O NH

Rx-ID: 10736586 View in Reaxys 502/592 Yield

Conditions & References 228.1 : Step 1: Step 1: (2R,3R)-2-Cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoic Acid (-)-(1R,2S)-Ephedrine Salt The ML A was liberated to the acid by ether/1N hydrochloric acid extraction to give the chirally enriched starting acid (11.2 g, 32.4 mmol) which was dissolved in methanol (100 ml) and a solution of (-)-(1R,2S)-ephedrine (5.9 g, 35.7 mmol) in methanol (50 ml) was added. The clear solution was treated with ether (200 ml) and kept in a refrigerator overnight. The crystals were filtered and washed with ether to give a white solid. (11.6 g, 99.8percent ee). The filtrate, designated ML B (6 g (-)-ephedrine salt) was converted to the (+)-ephedrine salt and combined with the crystalline residue AA described in Example 227-Step 1 and used to prepare the SS acid. mp 196 (dec); [α]D25=+258.90° (c=7.933 MG/0.793 ML, DMSO); Anal. Calcd for C22H19NO3. C10H15NO: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.06; H, 6.85; N, 5.26

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Chiral LC analysis were performed on the methyl ester as described in Example 227-Step 1. Patent; Wyeth; US2005/256132; (2005); (A1) English View in Reaxys OH

H N

O NH

O racemate

Rx-ID: 23409825 View in Reaxys 503/592 Yield

Conditions & References 228.1 : Example 228 - Step 1; (2R,3R)-2-Cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoic acid (-)-(1R,2S)-ephedrine salt The ML A was liberated to the acid by ether/1 N hydrochloric acid extraction to give the chirally enriched starting acid (11. 2g, 32.4 MMOL) which was dissolved in methanol (100 ML) and a solution of (-)-(1R, 2S) -ephedrine (5.9 g, 35.7 MMOL) in methanol (50 ML) was added. The clear solution was treated with ether (200 M .) and kept in a refrigerator overnight. The crystals were filtered and washed with ether to give a white SOLID. (11. 6g, 99. 8 percent ee). The filtrate, designated ML B (6g (-)-ephedrine salt) was converted to the (+)-ephedrine salt and combined with the crystalline residue AA described in Example 227--Step 1 and used to prepare the SS acid. mp 196 (dec); M°= +258. 90° (c = 7.933MG/0. 793ML, DMSO); Anal. Calcd for C22H19NO3. C10H15NO : C, 75.27 ; H, 6.71 ; N, 5.49. Found: C, 75.06 ; H, 6.85 ; N, 5.26 Chiral LC analysis were performed on the methyl ester as described in Example 227--Step 1. in methanol Patent; WYETH; WO2004/99150; (2004); (A2) English View in Reaxys OH

O NH

O racemate

Rx-ID: 23415548 View in Reaxys 504/592 Yield 36 %

Conditions & References 227.1 : Example 227 - Step 1; (2S,3S)-2-Cyano-3-(2-methoxyphenyl)-2-methyl-3-(1-naphthyl)propanoic Acid (+)-(1S,2R)-Ephedrine Salt (+) Ephedrine hydrochloride (11. 4 g, 56.5 MMOL) was liberated in a mixture of ether (200ML) and 10percent sodium carbonate solution (100 ML). The aqueous phase was extracted with ether (50 ML). THE COMBINED ETHER EXTRACTS DRIED OVER ANHYDROUS sodium sulfate and filtered directly into A solution of 2-CYANO-3- (2-METHOXYPHENYL)-2- METHYL-3- (1-NAPHTHYL) propanoic acid (17. 84 g, 51. 65 MMOL) in ether (150 ML). The mixture was concentrated in vacuo to a foam, which was taken up in hot methanol (200 ML), cooled to ambient temperature and diluted with ether (250 ML). The clear solution was seeded with an authentic sample of pure diastereomeric salt and left in a refrigerator overnight. The clear supernatant was decanted off and the residue rinsed with ether. The crystalline residue was designated AA (8 g, y=30 percent, 95percent ee). All filtrates were kept and designated as ML A The crystalline residue AA (8 g, 95percent ee) was combined with (+)-ephedrine salt from ML B (4 g). The combined salts were crystallized from hot methanol (150 ml)/ether (200 ml) and after standing overnight gave the title compound as a white SOLID (8 9 g, 99percent EE). The filtrate was concentrated in vacuo and crystallized from methanol (75 ml)/ether (100 ml) to yield an additional amount. (1. 6 g, 98.8 percent ee). The total yield of the (+) ephedrine salt was 10. 5 g (36percent of theory). The absolute configuration was assigned by single crystal X-ray diffraction. Mp 196 °C (dec); [a]D25= -270.1° (1percent DMSO); MS (ESI) m/z 344; Anal. Calcd for C22HI9NOS. CIOHISNO : C, 75.27 ; H, 6.71 ; N, 5.49. Found: C, 75. 10 ; H, 6.80 ; N, 5.39. Chiral LC analysis were performed on the methyl ester. A sample of the salt was liberated by extraction with ether and 1 N hydrochloric acid. Organic phase was dried over magnesium sulfate, concentrated (under a stream of nitrogen) to a solid. This material was taken up in a small amount of methanol and treated with a few drops of a solution of 2M (TRIMETHYLSILYL)-DI-

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AZOMETHANE in hexane, then evaporated under A stream of nitrogen to give a solid that was submitted as such for chiral LC analysis. Stage 1: With sodium carbonate in diethyl ether, water Stage 2: in diethyl ether Patent; WYETH; WO2004/99150; (2004); (A2) English View in Reaxys

O N

SH HO

OH S

O HO

N SH

OH S

Rx-ID: 11062304 View in Reaxys 505/592 Yield

Conditions & References

51.1 %

in ethanol Gazaliev; Nurkenov; Kulakov; Ainabaev; Bessonov; Russian Journal of Applied Chemistry; vol. 79; nb. 3; (2006); p. 508 - 510 View in Reaxys

H N

O N

O HO

SH HO

HO HN

N SH

OH S

Rx-ID: 11062312 View in Reaxys 506/592 Yield

Conditions & References

70.9 %

in ethanol Gazaliev; Nurkenov; Kulakov; Ainabaev; Bessonov; Russian Journal of Applied Chemistry; vol. 79; nb. 3; (2006); p. 508 - 510 View in Reaxys

OH HO

O HO

N SH

OH S

Rx-ID: 11599127 View in Reaxys 507/592 Yield

Conditions & References Reaction Steps: 3 1: 91.8 percent / ethanol / 0.33 h / 60 - 65 °C 2: 41.6 percent / ethanol / 1 h / 20 °C 3: 70.9 percent / ethanol in ethanol Gazaliev; Nurkenov; Kulakov; Ainabaev; Bessonov; Russian Journal of Applied Chemistry; vol. 79; nb. 3; (2006); p. 508 - 510 View in Reaxys

OH HO

O HO

N SH

OH S

Rx-ID: 11599128 View in Reaxys 508/592

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Yield

Conditions & References Reaction Steps: 3 1: 91.8 percent / ethanol / 0.33 h / 60 - 65 °C 2: 41.6 percent / ethanol / 1 h / 20 °C 3: 51.1 percent / ethanol in ethanol Gazaliev; Nurkenov; Kulakov; Ainabaev; Bessonov; Russian Journal of Applied Chemistry; vol. 79; nb. 3; (2006); p. 508 - 510 View in Reaxys

HO HN

O HO

N H HO

O HO

N SH

OH S

Rx-ID: 11607554 View in Reaxys 509/592 Yield

Conditions & References Reaction Steps: 2 1: 41.6 percent / ethanol / 1 h / 20 °C 2: 70.9 percent / ethanol in ethanol Gazaliev; Nurkenov; Kulakov; Ainabaev; Bessonov; Russian Journal of Applied Chemistry; vol. 79; nb. 3; (2006); p. 508 - 510 View in Reaxys

HO HN

O HO

N H HO

O HO

N SH

OH S

Rx-ID: 11607555 View in Reaxys 510/592 Yield

Conditions & References Reaction Steps: 2 1: 41.6 percent / ethanol / 1 h / 20 °C 2: 51.1 percent / ethanol in ethanol Gazaliev; Nurkenov; Kulakov; Ainabaev; Bessonov; Russian Journal of Applied Chemistry; vol. 79; nb. 3; (2006); p. 508 - 510 View in Reaxys

H 2N

[6-(5-chloro-2-methoxybenzyl)-1-(2,4,6-trimethoxybenzyl)-1,3,4,6-tetrahydro-2H,5H-1,4-diazepin-2,5-dion-4-yl]-CO-OPh-X (X=4-NO2 or 2-Cl)

HO HN

O HO

N SH

OH S

Rx-ID: 11616235 View in Reaxys 511/592 Yield

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[6-(5-chloro-2-methoxybenzyl)-1-(2,4,6-trimethoxybenzyl)-1,3,4,6-tetrahydro-2H,5H-1,4-diazepin-2,5-dion-4-yl]-CO-OPh-X (X=4-NO2 or 2-Cl)

H 2N

O HO

N SH

OH S

Rx-ID: 11616237 View in Reaxys 512/592 Yield

OH O O

H N

N H

O O

N O

H OH

Rx-ID: 25907054 View in Reaxys 513/592 Yield

Conditions & References 4.a :Step a: Synthesis of L-Ephederine salt of 5-(carboxymethyl)-3-[3-(2,3-dihydro-1H-inden-2-yloxy)-4-methoxyphenyl]-4,5-dihydroisoxazole-5-carboxylic acid 5-(Carboxymethyl)-3-[3-(cyclopentyloxy)-4-methoxyphenyl]-4,5-dihydroisoxazole-5-carboxylic acid (prepared following the procedure as described in WO 05/021515) (7 g, 0.017 mol) and L-Ephederine (5.63 g, 0.034 mol) were dissolved in acetone (300 mL) and the mixture was refluxed for 4 hours. The reaction mixture was slowly brought to room temperature and maintained at room temperature for 24-36 hours to yield the title compound. Yield: 9.3 g. in acetone, Time= 28 - 40h, T= 20 °C , Heating / reflux Patent; Ranbaxy Laboratories Limited; EP1840123; (2007); (A1) English View in Reaxys

O OH

H N

OH O

Rx-ID: 2104717 View in Reaxys 514/592 Yield 69.2 %

Conditions & References in ethyl acetate, T= 50 °C Marki; Crameri; Eigenmann; Krasso; Ramuz; Bernauer; Goodman; Melmon; Helvetica Chimica Acta; vol. 71; nb. 2; (1988); p. 320 - 336 View in Reaxys

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O OH O

OH NH

H O

OH O

Rx-ID: 2138546 View in Reaxys 515/592 Yield

Conditions & References in ethyl acetate, T= 50 °C Marki; Crameri; Eigenmann; Krasso; Ramuz; Bernauer; Goodman; Melmon; Helvetica Chimica Acta; vol. 71; nb. 2; (1988); p. 320 - 336 View in Reaxys

OH HO

Rx-ID: 19111446 View in Reaxys 516/592 Yield

Conditions & References Reaction Steps: 2 1: 29.6 percent / K2CO3, KI / methanol / 18 h / Heating 2: ethyl acetate / 50 °C With potassium carbonate, potassium iodide in methanol, ethyl acetate Marki; Crameri; Eigenmann; Krasso; Ramuz; Bernauer; Goodman; Melmon; Helvetica Chimica Acta; vol. 71; nb. 2; (1988); p. 320 - 336 View in Reaxys

OH HO O

OH O

Rx-ID: 19111447 View in Reaxys 517/592 Yield

Conditions & References Reaction Steps: 2 1: 29.6 percent / K2CO3, KI / methanol / 18 h / Heating 2: 69.2 percent / ethyl acetate / 50 °C With potassium carbonate, potassium iodide in methanol, ethyl acetate Marki; Crameri; Eigenmann; Krasso; Ramuz; Bernauer; Goodman; Melmon; Helvetica Chimica Acta; vol. 71; nb. 2; (1988); p. 320 - 336 View in Reaxys

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metal

Rx-ID: 19118573 View in Reaxys 518/592 Yield

metal

Rx-ID: 19118574 View in Reaxys 519/592 Yield

thiopyrocatechol

OH O

Rx-ID: 19118763 View in Reaxys 520/592 Yield

Conditions & References Reaction Steps: 3 1: 130 g / NaOH / H2O / 24 h / Ambient temperature 2: 29.6 percent / K2CO3, KI / methanol / 18 h / Heating 3: ethyl acetate / 50 °C With sodium hydroxide, potassium carbonate, potassium iodide in methanol, water, ethyl acetate

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Marki; Crameri; Eigenmann; Krasso; Ramuz; Bernauer; Goodman; Melmon; Helvetica Chimica Acta; vol. 71; nb. 2; (1988); p. 320 - 336 View in Reaxys

thiopyrocatechol

OH O

Rx-ID: 19118764 View in Reaxys 521/592 Yield

Conditions & References Reaction Steps: 3 1: 130 g / NaOH / H2O / 24 h / Ambient temperature 2: 29.6 percent / K2CO3, KI / methanol / 18 h / Heating 3: 69.2 percent / ethyl acetate / 50 °C With sodium hydroxide, potassium carbonate, potassium iodide in methanol, water, ethyl acetate Marki; Crameri; Eigenmann; Krasso; Ramuz; Bernauer; Goodman; Melmon; Helvetica Chimica Acta; vol. 71; nb. 2; (1988); p. 320 - 336 View in Reaxys

NH N

H N

OH NH N

Rx-ID: 31080507 View in Reaxys 522/592 Yield

Conditions & References Reaction Steps: 5 1.1: tert-butyl methyl ether / 2.17 h / 15 - 32 °C / Industry scale 1.2: 2 h / Industry scale 2.1: potassium tert-butylate / tetrahydrofuran / 3 h / 20 - 32 °C / Industry scale 2.2: 0.5 h / 40 - 50 °C / Industry scale 2.3: 40 °C / pH 8 - 9 / Industry scale 3.1: hydrogen; potassium tert-butylate / Pearlman's catalist / tetrahydrofuran / 45 - 55 °C / 3361.55 - 4137.29 Torr / Industry scale 4.1: hydrogenchloride / water; isopropanol acetate / Industry scale 5.1: acetonitrile / 50 °C With hydrogenchloride, potassium tert-butylate, hydrogen, Pearlman's catalist in tetrahydrofuran, tert-butyl methyl ether, isopropanol acetate, water, acetonitrile Patent; ArQule, Inc.; US2011/160242; (2011); (A1) English View in Reaxys Reaction Steps: 4 1.1: tert-butyl methyl ether / 0.1 h / 20 - 32 °C / |Inert atmosphere 1.2: 0.1 h / 25 °C / |Inert atmosphere 2.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 20 - 32 °C / |Inert atmosphere 2.2: 0.1 h / 0.4 - 0.5 °C 2.3: 0.01 h / 20 - 32 °C 3.1: potassium tert-butylate; palladium hydroxide on carbon; hydrogen / tetrahydrofuran / 12 h / 0.45 - 0.5 °C / 3360.34 Torr 4.1: water; methanol / 3 h / 0.55 - 20 °C / |Inert atmosphere

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With palladium hydroxide on carbon, potassium tert-butylate, hydrogen in tetrahydrofuran, methanol, tert-butyl methyl ether, water Patent; ARQULE, INC.; Nakamura, Yoshitaka; Ooyama, Jo; US2013/281699; (2013); (A1) English View in Reaxys

O O O

H N

OH N

NH N

Rx-ID: 31080511 View in Reaxys 523/592 Yield

Conditions & References Reaction Steps: 4 1.1: potassium tert-butylate / tetrahydrofuran / 3 h / 20 - 32 °C / Industry scale 1.2: 0.5 h / 40 - 50 °C / Industry scale 1.3: 40 °C / pH 8 - 9 / Industry scale 2.1: hydrogen; potassium tert-butylate / Pearlman's catalist / tetrahydrofuran / 45 - 55 °C / 3361.55 - 4137.29 Torr / Industry scale 3.1: hydrogenchloride / water; isopropanol acetate / Industry scale 4.1: acetonitrile / 50 °C With hydrogenchloride, potassium tert-butylate, hydrogen, Pearlman's catalist in tetrahydrofuran, isopropanol acetate, water, acetonitrile Patent; ArQule, Inc.; US2011/160242; (2011); (A1) English View in Reaxys Reaction Steps: 3 1.1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 20 - 32 °C / |Inert atmosphere 1.2: 0.1 h / 0.4 - 0.5 °C 1.3: 0.01 h / 20 - 32 °C 2.1: potassium tert-butylate; palladium hydroxide on carbon; hydrogen / tetrahydrofuran / 12 h / 0.45 - 0.5 °C / 3360.34 Torr 3.1: water; methanol / 3 h / 0.55 - 20 °C / |Inert atmosphere With palladium hydroxide on carbon, potassium tert-butylate, hydrogen in tetrahydrofuran, methanol, water Patent; ARQULE, INC.; Nakamura, Yoshitaka; Ooyama, Jo; US2013/281699; (2013); (A1) English View in Reaxys

O NH

H N

Rx-ID: 31080513 View in Reaxys 524/592 Yield

Conditions & References Reaction Steps: 3 1: hydrogen; potassium tert-butylate / Pearlman's catalist / tetrahydrofuran / 45 - 55 °C / 3361.55 - 4137.29 Torr / Industry scale 2: hydrogenchloride / water; isopropanol acetate / Industry scale 3: acetonitrile / 50 °C With hydrogenchloride, potassium tert-butylate, hydrogen, Pearlman's catalist in tetrahydrofuran, isopropanol acetate, water, acetonitrile Patent; ArQule, Inc.; US2011/160242; (2011); (A1) English

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View in Reaxys Reaction Steps: 2 1: potassium tert-butylate; palladium hydroxide on carbon; hydrogen / tetrahydrofuran / 12 h / 0.45 - 0.5 °C / 3360.34 Torr 2: water; methanol / 3 h / 0.55 - 20 °C / |Inert atmosphere With palladium hydroxide on carbon, potassium tert-butylate, hydrogen in tetrahydrofuran, methanol, water Patent; ARQULE, INC.; Nakamura, Yoshitaka; Ooyama, Jo; US2013/281699; (2013); (A1) English View in Reaxys

H N

OH HN N

H HN

NH N

racemate

Rx-ID: 31080514 View in Reaxys 525/592 Yield 85.0 %

Conditions & References 3.4 : Step 4: Preparation of (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione mono-(1S,2S)-pseudoephedrine (3R,4R-compound A·PSE) Methanol (415 mL) was added to the compound A (trans-racemate) (50.0 g) obtained in Step 3, and (1S,2S)-pseudoephedrine (22.3 g) was added at room temperature under a nitrogen atmosphere. The mixture was stirred at about 45° C. to about 55° C. for about 3 hours or longer. Then, sodium methoxide/methanol (2.8 mL) was added dropwise, and the reaction mixture was stirred at about 45° C. to about 55° C. for about 16 hours or longer. To the reaction mixture, a mixed solution of 1 M hydrochloric acid (12.4 mL) and water (29 mL) was added dropwise at about 45° C. to about 55° C., and the reaction mixture was stirred at about 45° C. to about 55° C. for about 1 hour. The reaction mixture was cooled to about 15° C. to about 25° C. and then stirred at about 15° C. to about 25° C. for about 2 hours. The deposited crystals of (3R,4R)-compound A·PSE were collected by filtration and washed with a 90percent aqueous methanol solution (125 mL). The crystals of (3R,4R)-compound A·PSE were dried in vacuum at about 50° C. for about 12 hours (49.6 g, yield: 85.0percent). in methanol, water, Time= 3h, T= 0.55 - 20 °C , Inert atmosphere Patent; ARQULE, INC.; Nakamura, Yoshitaka; Ooyama, Jo; US2013/281699; (2013); (A1) English View in Reaxys 6 :Example 6; The present example describes the chiral resolution by diastereomeric salt formation and isolation of (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.; As an alternative to chiral resolution by MCC, a resolution of the enantiomers, Compound 10 and Compound 9, can also be achieved by the preferential formation of a diastereomeric salt of Compound 10.In one example, crude Compound 8 can be converted to (-)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione.(1S,2S)-(+)pseudoephedrine (Compound 10.(1S,2S)-(+)-pseudoephedrine in Scheme I) using the following representative procedure. (1S,2S)-(+)-pseudoephedrine (601 g, 0.6 equiv) is dissolved in acetonitrile (CH3CN) (11.2 L, 5 vol) at about 50° C. and stirred for approximately 30 minutes past dissolution. Crude Compound 8 [2.24 kg, 96.4percent (AUC) by HPLC] is dissolved in CH3CN (11.2 L, 5 vol) at about 50° C. and then polish filtered through a pad of Celite. The Compound 8 solution is added via a drop tank to the (1S,2S)-(+)-pseudoephedrine solution over 20-30 minutes at about 50° C. Once the resulting solution begins to crystallize, shortly after completion of the Compound 8 addition, the mixture is stirred until it slowly cools to ambient temperature, then stirring is continued overnight (about 11 h total of cooling and stirring). The beige granular solids are filtered through an 18 stainless steel nutche filter and rinsed/reslurried using CH3CN (7 L, 3.2 vol). The slurry is filtered, and the solids are slurried again with CH3CN (5 L, 2.3 vol). After drying on the nutche filter for 1 hour a sample is analyzed by HPLC. If the solids contain a higher than desired amount of the undesired diastereomeric salt, the solids can be re-slurried using CH3CN and dried before repeating the analysis. The solids are then dried under hot N2 (51° C.) overnight. Typically, analysis of the Compound 10.(1S, 2S)-(+)-pseudoephedrine shows an overall chemical purity of >99percent (AUC) by HPLC and a chiral purity of >99percent Compound 10. Using 1H NMR analysis, a typical sample is estimated to contain <0.5 wt percent CH3CN.The Compound 10.(1S,2S)-(+)-pseudoephedrine can then be converted to Compound 10 by treatment with acid and crystallization from methanol or ethanol. A representative procedure is as follows: Compound 10.(1S,2S)(+)-pseudoephedrine (50 g) is slurried in Methyltetrahydrofuran (MeTHF) (500 mL) and water (250 mL). 1 M HCl (110 mL) is added to the mixture to reach a final pH of 1.6. The resulting solution with a slight amount of solids is

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stirred for about one hour to dissolve the solids. The organic and aqueous layers are then separated. The organic layer is washed with a water/brine solution (1:1, 250 mL), separated, and 2-B ethanol (1000 mL) is added. The solution is then concentrated down to 200 mL and analyzed for MeTHF content (4.8 wt percent). The solution is polish filtered, and Compound 10 seeds (0.2 g) are added (T=25° C.). The mixture is stirred for about three days with samples being taken periodically and analyzed for Compound 10 remaining in the mother liquor. The resulting slurry is filtered, and the solids are washed with 2-B ethanol (70 mL). The solids are dried for about three hours in a vacuum oven at about 60° C. to give Compound 10 [28.84 g, 82.7percent, 99.60percent (AUC) by HPLC, 0.54 wt percent ethanol, 0.08 wt percent MeTHF] as a beige solid.The diasteromeric salt resolution of Compound 8 to Compound 10 described in Example 6 and the recycling of Compound 9 to Compound 8 described in Example 5 are shown in Scheme V. in acetonitrile, T= 50 °C , Product distribution / selectivity Patent; ArQule, Inc.; US2011/160242; (2011); (A1) English View in Reaxys

H N

OH NH

Rx-ID: 31080517 View in Reaxys 526/592 Yield

Conditions & References Reaction Steps: 2 1.1: sodium hydroxide / ethanol / 13 h / 65 °C / Industry scale 1.2: 60 °C 2.1: acetonitrile / 50 °C With sodium hydroxide in ethanol, acetonitrile Patent; ArQule, Inc.; US2011/160242; (2011); (A1) English View in Reaxys

H N

O O

H N

OH HN

N N racemate

Rx-ID: 31080519 View in Reaxys 527/592 Yield

Conditions & References Reaction Steps: 2 1: hydrogenchloride / water; isopropanol acetate / Industry scale 2: acetonitrile / 50 °C With hydrogenchloride in isopropanol acetate, water, acetonitrile Patent; ArQule, Inc.; US2011/160242; (2011); (A1) English View in Reaxys

H N

F F

O F O

F OH

F F

F H N

F F

F O F

OH O

Rx-ID: 40309250 View in Reaxys 528/592

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Yield

Conditions & References in benzene-d6 Nemes, Anik; Cska, Tams; Bni, Szabolcs; Farkas, Viktor; Rbai, Jzsef; Szab, Dnes; Journal of Organic Chemistry; vol. 80; nb. 12; (2015); p. 6267 - 6274 View in Reaxys

F F

F H N

F O

OH O

Rx-ID: 40309254 View in Reaxys 529/592 Yield

Conditions & References Reaction Steps: 3 1: di-isopropyl azodicarboxylate; triphenylphosphine / diethyl ether / 24 h / 0 - 20 °C 2: sodium hydroxide / methanol; dichloromethane / 24 h / 20 °C 3: benzene-d6 With di-isopropyl azodicarboxylate, triphenylphosphine, sodium hydroxide in methanol, diethyl ether, dichloromethane, benzene-d6 Nemes, Anik; Cska, Tams; Bni, Szabolcs; Farkas, Viktor; Rbai, Jzsef; Szab, Dnes; Journal of Organic Chemistry; vol. 80; nb. 12; (2015); p. 6267 - 6274 View in Reaxys

F OH

F F

O F O

F F

F H N

F O

Rx-ID: 40309261 View in Reaxys 530/592 Yield

Conditions & References Reaction Steps: 2 1: sodium hydroxide / methanol; dichloromethane / 24 h / 20 °C 2: benzene-d6 With sodium hydroxide in methanol, dichloromethane, benzene-d6 Nemes, Anik; Cska, Tams; Bni, Szabolcs; Farkas, Viktor; Rbai, Jzsef; Szab, Dnes; Journal of Organic Chemistry; vol. 80; nb. 12; (2015); p. 6267 - 6274 View in Reaxys

O H N

H N

HO O

OH OH

H N

N H

Rx-ID: 29683393 View in Reaxys 531/592 Yield

Conditions & References 23 :Lidocaine (468.67 mg, 2 mmol) and ephedrinium salicylate (606.72 mg, 2 mmol) were dissolved in 20 ml of acetone and stirred for 15 min at room temperature. The solvent was evaporated and the remaining viscous liquid was dried at 0.01 mbar with stirring for 24 hrs. The desired compound is isolated as a colourless viscous liquid. 1H-NMR (300 MHz, d6- DMSO) δ(ppm) = 9.23 (br s, IH), 7.72 (dd, Jl = 7.6 Hz, J2 = 1.8 Hz, IH), 7.38 (m, 4H), 7.28 (m, IH),

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7.07 (s, 3H), 6.66 (m, 2H), 5.16 (d, J = 2.4 Hz, IH), 3.40 (m, IH), 3.18 (s, 2H), 2.67 (s, 3H), 2.64 (q, J = 7.3 Hz, 4H), 2.14 (s, 6H), 1.08 (t, J = 7.2 Hz, 6H), 0.93 (d, J = 6.8 Hz, 3H). Tg -4 0C; T5o/oonset 149. °C in acetone, Time= 0.25h, T= 20 °C Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys

O OH

O O

O N

F O

O O

F HN

O O

racemate

Rx-ID: 30273698 View in Reaxys 532/592 Yield

Conditions & References 1.2 :In order to avoid loss of uncrystallised compound, the sintered funnel is washed with ethyl acetate. The liquid phases are combined with the mother liquor in a tared round-bottom-flask and the solvent is removed in vacuo. If no loss of compound occurred, the total mass of recovered solid must be close to 1.278 g. The procedure for cis-II-4 release is then applied, affording a viscous solid. The enantiomeric excess of this phase can be measured via chromatography (HPLC or GC) in order to evaluate the proportion of each enantiomers. Generally, the measured ee of the product recovered from the liquid phase is comprised between 15percent and 20percent; in this particular example, 15percent ee (i.e. the recovered mixture is composed of 42.5percent by weight of (α)-cis-II-4 and 57.5percent by weight of (β)-cis-II-4). To this solid, anhydrous (+)-ephedrine is added: 0.889 g of cis-II-4 with an enantiomeric excess comprised between 15percent and 20percent0.389 g of (+)-ephedrinein the case of (+)-ephedrine hemihydrate, the mass to be introduced is 0.410 g, using the same procedure described hereabove. Formation of (+)-ephedrine salts should lead to 1.278 g of solid. In order to allow the formation of only one crystallised salt, the quantity of ethyl acetate to be introduced must be 95.56percent by weight of the global mixture: Product percent by weight Mass (g) (+)-ephedrine salts 4.44 1.278 Ethyl acetate 95.56 27.506 Using the aforementioned procedure, the compound is crystallised in ethyl acetate over 24 hours and filtered through a sintered glass funnel. The obtained salt is enriched in (β)-cis-II-4 with an enantiomeric excess approaching 100percent. The mother liquor is treated as described hereabove, leading to a mixture of both enantiomers of cis-II-4 with a 15percent ee. Therefore, the same percent by weight proportions can be applied for the next crystallisations until the mixture is fully resolved, which is not common. in ethyl acetate, Time= 24h, T= 20 °C , Resolution of racemate Patent; Institut National des Sciences Appliquees de Rouen (INSA); EP2279997; (2011); (A1) English View in Reaxys

O OH

O O

O N

F O

H N

O O

F HN

O O

racemate

Rx-ID: 30273717 View in Reaxys 533/592 Yield 11.1 %

Conditions & References 1.2 :A chiral resolution of racemate cis-II-4 has been also carried out according to the standard procedure described below, in order to obtain cis-II-4 batches enriched in only one of the two optical isomers (cis-II-4a and cis-II-4b) (or almost in a pure form) in a very reproducible manner. Thus, the first crystallisation is based on the following quantities: 1.00 g of crystallised racemic cis-II-4 (2.65 mmol)0.438 g of enantiomerically pure (-)-ephedrine (2.65 mmol)if this crystallisation is carried out using (-)-ephedrine hemihydrate, the initial mass to be introduced is 0.462 g. Dissolution in a minimum of ethyl acetate followed by removal of solvent in vacuo (T=50°C, PNo.6-8mbar) enables elimination of water to obtain a dry solid. Formation of (-)-ephedrine salts should lead to 1.438 g of solid. In order to allow

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the formation of only one crystallised salt, the quantity of ethyl acetate to be introduced must be 96.2percent by weight of the global mixture: Productpercent by weightMass (g) (-)-ephedrine salt 3.8 1.438 Ethyl acetate 96.2 36.400 The reactants are mixed together at room temperature. After few minutes of vigorous stirring (using a magnetic stirrer), the first solid particles are noticed. The mixture is let to stir in these conditions for at least 24 hours, and the crystals are filtered through a sintered glass funnel. The solid is then dried over filter paper and in a ventilated oven at 40°C for few hours. The yield of this crystallisation highly depends on the purity of the initial cis-II-4 batch. In this particular example, a yield of 11.1percent was obtained, corresponding to 160 mg of the resulting salt with an enantiomeric excess approaching 100percent. The pure enantiomer (α)-cis-II-4 is obtained after acid hydrolysis (described below). in ethyl acetate, Time= 24h, T= 20 °C , Resolution of racemate Patent; Institut National des Sciences Appliquees de Rouen (INSA); EP2279997; (2011); (A1) English View in Reaxys

O O

O N

O O

O HN

O O

Rx-ID: 30273747 View in Reaxys 534/592 Yield

Conditions & References Reaction Steps: 2 1.1: water; lithium hydroxide hydrate / tetrahydrofuran / 2 h / 0 °C 1.2: pH 2 2.1: ethyl acetate / 24 h / 20 °C / Resolution of racemate With water, lithium hydroxide hydrate in tetrahydrofuran, ethyl acetate Patent; Institut National des Sciences Appliquees de Rouen (INSA); EP2279997; (2011); (A1) English View in Reaxys

O O

O N

O O

O HN

O O

Rx-ID: 30273748 View in Reaxys 535/592 Yield

HO OH

O O N

HO OH

N O

(+)-enantiomer

O F

N O

O O

NH O

O O

rel-configuration

(-)-enantiomer

rel-configuration

Rx-ID: 30292668 View in Reaxys 536/592

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Yield

Conditions & References Reaction Steps: 2 1.1: water; lithium hydroxide hydrate / tetrahydrofuran / 2 h / 0 °C 1.2: pH 2 2.1: ethyl acetate / 24 h / 20 °C / Resolution of racemate 2.2: 24 h / Resolution of racemate With water, lithium hydroxide hydrate in tetrahydrofuran, ethyl acetate Patent; INSTITUT NATIONAL DES SCIENCES APPLIQUEES DE ROUEN (INSA); JUBAULT, Philippe; QUIRION, Jean-Charles; LEMONNIER, Gerald; LION, Cedric; WO2011/9947; (2011); (A1) English View in Reaxys O

O HO F cis

cis cis N cis

H N

(-)-enantiomer

NH O

HO OH

N O

O F

rel-configuration

N O

(+)-enantiomer

O O

HO OH

(+)-enantiomer

O NH

H N

O O

(-)-enantiomer

rel-configuration

Rx-ID: 30292718 View in Reaxys 537/592 Yield 11.1 %

Conditions & References A chiral resolution of racemate c/s-II-4 has been also carried out according to the standard procedure described below, in order to obtain c/s-II-4 batches enriched in only one of the two optical isomers (c/s-II-4a and c/s-II-4b) (or almost in a pure form) in a very reproducible manner.Thus, the first crystallisation is based on the following quantities:1.00 g of crystallised racemic c/s-II-4 (2.65 mmol)- 0.438 g of enantiomerically pure (-)-ephedrine (2.65 mmol)if this crystallisation is carried out using (-)-ephedrine hemihydrate, the initial mass to be introduced is 0.462 g. Dissolution in a minimum of ethyl acetate followed by removal of solvent in vacuo (T=50°C, PNo.6-8mbar) enables elimination of water to obtain a dry solid.Formation of (-)-ephedrine salts should lead to 1.438 g of solid. In order to allow the formation of only one crystallised salt, the quantity of ethyl acetate to be introduced must be 96.2percent by weight of the global mixture:The reactants are mixed together at room temperature. After few minutes of vigorous stirring (using a magnetic stirrer), the first solid particles are noticed. The mixture is let to stir in these conditions for at least 24 hours, and the crystals are filtered through a sintered glass funnel. The solid is then dried over filter paper and in a ventilated oven at 400C for few hours. The yield of this crystallisation highly depends on the purity of the initial c/s-II-4 batch. In this particular example, a yield of 11.1percent was obtained, corresponding to 160 mg of the resulting salt with an enantiomeric excess approaching 100percent. The pure enantiomer (α)-c/s-II-4 is obtained after acid hydrolysis (described below).In order to avoid loss of uncrystallised compound, the sintered funnel is washed with ethyl acetate. The liquid phases are combined with the mother liquor in a tared round-bottom- flask and the solvent is removed in vacuo. If no loss of compound occurred, the total mass of recovered solid must be close to 1.278 g. The procedure for c/s-II-4 release is then applied, affording a viscous solid. The enantiomeric excess of this phase can be measured via chromatography (HPLC or GC) in order to evaluate the proportion of each enantiomers. Generally, the measured ee of the product recovered from the liquid phase is comprised between 15percent and 20percent; in this particular example, 15percent ee (i.e. the recovered mixture is composed of 42.5percent by weight of (α)-c/s-II-4 and 57.5percent by weight of (β)-c/s-II-4).To this solid, anhydrous (+)-ephedrine is added:- 0.889 g of c/sII-4 with an enantiomeric excess comprised between 15percent and 20percent- 0.389 g of (+)-ephedrinein the case of (+)-ephedrine hemihydrate, the mass to be introduced is 0.410 g, using the same procedure described hereabove.Formation of (+)-ephedrine salts should lead to 1.278 g of solid. In order to allow the formation of only one crystallised salt, the quantity of ethyl acetate to be introduced must be 95.56percent by weight of the global mixture:Using the aforementioned procedure, the compound is crystallised in ethyl acetate over 24 hours and filtered through a sintered glass funnel. The obtained salt is enriched in (β)-c/s-II-4 with an enantiomeric excess approaching 100percent.The mother liquor is treated as described hereabove, leading to a mixture of both enantiomers of c/s-II-4 with a 15percent ee. Therefore, the same percent by weight proportions can be applied for the next crystallisations until the mixture is fully resolved, which is not common.The procedure for the release of c/s-II-4 via acid hydrolysis of cis-II-4 ephedrine salts is as follows:c/s-II-4 can be released either from a solid crystallised salt, or from a liquid phase(mother liquor). In the latter case, removal of the solvent in vacuo is necessary until obtaining a solid. In both

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cases, the free acid is released after addition of a 0.1 M solution of hydrochloric acid, using the proportions described in the following table.(a) molecular weight of the ephedrine salt: 540.60 g.mol" Stage 1: in ethyl acetate, Time= 24h, T= 20 °C , Resolution of racemate Stage 2: in ethyl acetate, Time= 24h, Resolution of racemate Patent; INSTITUT NATIONAL DES SCIENCES APPLIQUEES DE ROUEN (INSA); JUBAULT, Philippe; QUIRION, Jean-Charles; LEMONNIER, Gerald; LION, Cedric; WO2011/9947; (2011); (A1) English View in Reaxys

H N O

OH O

O O

(-)-enantiomer

Rx-ID: 10939271 View in Reaxys 538/592 Yield

Conditions & References 4 :Example 41. First resolution - using (lR,2S)-(-)-Ephedrine 7[00299] The free acid 3-phosphoindole 6 (1.2g, 3.17 mmol) was suspended in 95percent ethanol (12 mL) and stirred at room temp, in a sealed flask. (lR,2S)-(-)-Ephedrine 7 (0.52g, 3.17 mmol) was added in one portion and after 5 mins, a clear solution was observed. After a further 5 mins, rapid precipitation of a white solid was observed and stirring was continued at room temp, for 3h. After this time the precipitated solid was isolated by filtration and washed with 95percent ethanol (2 mL). The filtrate was concentrated in vacuo and both the precipitated solid and residue from the filtrate were dried overnight under vacuum <n="106"/>to yield 558 mg of precipitated solid (purity by chiral HPLC analysis, ratio = 14:86) and 706 mg of filtrate (purity by chiral HPLC analysis, ratio = 74:26).Second resolution[00300] The partially resolved salt of 6 (558 mg, purity by chiral HPLC analysis 14:86) was suspended in 95percent ethanol (12 mL) and stirred at room temp, in a sealed flask for 3h. After this time the solid was isolated by filtration and washed with 95percent ethanol (2 mL). The filtrate was concentrated in vacuo and both the solid and residue from the filtrate were dried overnight under vacuum to yield 236 mg of solid (purity by chiral HPLC analysis, ratio = 1 :99) and 197 mg of filtrate (purity by chiral HPLC analysis, ratio = 25:75). in ethanol, water, Time= 3.16667h, T= 20 °C , Resolution of racemate, Product distribution / selectivity Patent; IDENIX PHARMACEUTICALS, INC.; WO2008/42240; (2008); (A2) English View in Reaxys

NH OH

Cl NH

OH O

O O

(+)-enantiomer

Rx-ID: 10939273 View in Reaxys 539/592 Yield

Conditions & References 4 :2. First resolution - Using (lS,2R)-(+)-Ephedrine 8[00303] The free acid indole 6 (1.2g, 3.17 mmol) was suspended in 95percent ethanol (12 mL) and stirred at room temp, in a sealed flask. (lS,2R)-(+)-Ephedrine 8 (0.55g, 3.17 mmol) was added in one portion and after 5 mins, a clear solution was observed. After a further 5 mins, rapid precipitation of a white solid was observed and stirring was continued at room temp, for 3h. After this time the precipitated solid was isolated by filtration and washed with 95percent ethanol (0.5 mL). The filtrate was concentrated in vacuo and both the precipitated solid and residue from the filtrate were dried overnight under vacuum to yield 618 mg of precipitated solid (purity by chiral HPLC analysis, ratio = 94:6) and 840 mg of filtrate (purity by chiral HPLC analysis, ratio = 25:75).Second resolution[00304] The partially resolved salt (618 mg, purity by chiral HPLC analysis 94:6) was suspended in 95percent ethanol (12 mL) and stirred at room temp, in a sealed flask for 3h. After this time the solid was isolated by filtration and washed with 95percent ethanol (0.5 mL). The filtrate was concentrated in vacuo and both

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the precipitated solid and residue from the filtrate were dried overnight under vacuum to yield 250 mg of solid (purity by chiral HPLC analysis, ratio = 100:0) and 127 mg of filtrate (purity by chiral HPLC analysis, ratio = 85:15). in ethanol, water, Time= 3.16667h, T= 20 °C , Resolution of racemate, Product distribution / selectivity Patent; IDENIX PHARMACEUTICALS, INC.; WO2008/42240; (2008); (A2) English View in Reaxys

H N

O O

Rx-ID: 29683340 View in Reaxys 540/592 Yield

F O F F

O O S

N F HF

F S

O N H

S O

Rx-ID: 31549018 View in Reaxys 541/592 Yield

OH N O

H N

HO O

O OH

Rx-ID: 23832497 View in Reaxys 542/592 Yield 29 - 45 %

Conditions & References 7; 8; 9; 12 :Racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (70 g), (l.S',2i?)-(+)-ephedrine (31.5 g) in ethyl acetate (700 mL) were heated at 55°C with stirring. After cooling to room temperature the reaction mixture was stirred overnight. The precipitated solid was filtered off and the cake was washed with ethyl acetate (2x50 mL), and dried to give 44.93g (45 percent) of (lS,2i?)-(+)-ephedrine salt of (i?)-3-[l-carboxy-l-(5- chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid as a white crystalline solid. Mp.: 1510C, [α]20 589= -45.0° (c=l, MeOH) Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.50; H, 4.59; N, 5.02; Cl, 12.80EXAMPLE 8Racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (50 g), (15,2Λ)-(+)-ephedrine (21.5 g) in ethyl acetate (IL) were heated to 550C with stirring. The solution was seeded with a small amount of the desired (i?)acid ephedrine salt, and the reaction mixture was stirred overnight at the same temperature. The solid was filtered off and the cake was washed with ethyl acetate (2x40 mL) and dried to give 22.64 g (31 percent) of (15',2i?)-(+)eρhedrine salt of (i?)-3-[l-carboxy-l-(5-chloro-2-nitroρhenyl)ethyl]-4- chlorobenzoic acid as a white crystalline solid. Mp.: 154-155°C, [α]20 589= -46.0° (c=l, MeOH) Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.61; H, 4.81; N, 5.05; Cl, 12.81.EXAMPLE 9Racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-

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chlorobenzoic acid (20 g), (l.Sr,2i?)-(+)-ephedrine (4.5 g) in ethyl acetate (200 mL) were heated to 550C. The suspension was stirred for 3 hours at this temperature. The solid formed was filtered off and the cake was washed with ethyl acetate (2x50 mL), and dried to give 8.2 g (37 percent) of(liSr,2i?)-(+)-ephedrine salt of (i?)-3-[l-carboxy-l-(5chloro-2-nitrophenyl)-ethyl]-4- chlorobenzoic acid as white crystalline solid. Mp.: 155-1560C, [α]20 589= -45.0° (c=l, MeOH)Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.51; H, 4.62; N, 5.00; Cl, 12.8.EXAMPLE 12Racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (2.0 g), (15',2i?)-(+)eρhedrine (0.45 g) and ethyl acetate (25 mL) were heated to 60°C with stirring to dissolve the solids. Stirring was maintained for 3 hours at this temperature then the precipitated solid was filtered off and the cake was washed with cold ethyl acetate (2x5 mL) and dried to give 0.41 g (29 percent) of (l1S,2i?)-(+)-ephedrine salt of (i?)-3-[l-carboxy-l(5- chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid as white, crystalline solid. Mp.: 156-157°C, [α]20 589= -45.0° (c=l, MeOH) Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.66; H, 4.57; N, 5.05; Cl, 12.8. in ethyl acetate, Time= 3h, T= 20 - 60 °C , Product distribution / selectivity Patent; SANOFI-AVENTIS; WO2006/82452; (2006); (A1) English View in Reaxys

O O

OH O OH

Cl Cl

H N

O OH

Cl Cl

Rx-ID: 23832498 View in Reaxys 543/592 Yield

Conditions & References

47 %

13 :(i?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)-emyl]-4-chlorobenzoic acid (2.0 g), (1S,2R)-(+)-ephedrine (0.45 g) and ethyl acetate (20 mL) were heated at 55°C with stirring to dissolve the solids. The solution was seeded with a small amount of title compound. After being allowed to cool to room temperature and stirring overnight the solid was filtered off and the cake was washed with ethyl acetate (2x5 mL), and dried to give 1.35 g (47 percent) of (li-,2S)-(+)ephedrine salt of (i?)-3-[l-carboxy-l-(5-chloro-2-nitrophenyl)-ethyl]-4- chlorobenzoic acid ephedrine salt as a white, crystalline solid. Mp.: 148-149°C, [α]20 589= -46.0° (c=l, MeOH) in ethyl acetate, T= 55 °C , Product distribution / selectivity Patent; SANOFI-AVENTIS; WO2006/82452; (2006); (A1) English View in Reaxys

O O

Cl Cl

OH O OH

H N

HO O

O OH

Rx-ID: 23832499 View in Reaxys 544/592 Yield 48 %

Conditions & References 14 :(,S)-3-[l-carboxy-l-(5-chloro-2-nitroplienyl)-ethyl]-4-clilorobenzoic acid (2.0 g), (1.5,2/2)- (+)-ephedrine (0.45 g) and ethyl acetate (20 mL) were heated at 55°C with stirring to dissolve the solids. The solution was seeded with a small amount of title compound. After being allowed to cool to room temperature and stirred overnight the solid was filtered off and the cake was washed with ethyl acetate (2x5 mL), and dried to give 1.4 Ig (48 percent) of (15,2R)-(+)eρhedrine salt of (S)-3-[l-carboxy~l-(5-chloro-2-nitrophenyl)-ethyl]-4- chlorobenzoic acid as a white, crystalline and vaxy solid , [α]20 589=+ 45.0° (c=l, MeOH) Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.78; H, 4.70; N5 5.,00; Cl, 12.80. in ethyl acetate, T= 55 °C Patent; SANOFI-AVENTIS; WO2006/82452; (2006); (A1) English View in Reaxys

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Cl Cl N

H N

O O

O OH

H N

O OH

HO O

H N

O OH

Rx-ID: 23839813 View in Reaxys 545/592 Yield

Conditions & References

46.5 %

10 :Racemic 3-[l-carboxy-l-(5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid (20 g), (li?,25)-(-)-ephedrine (9,08 g) in ethyl acetate (100 mL) were heated to 550C with stirring. The solution was seeded with a small amount of pure (<S)-acid ephedrine salt, the mixture allowed to crystallize overnight while stirring was maintained for 18 hours at room temperature. The solid was filtered off and the cake was washed with ethyl acetate (2x25 mL), and dried to give 13.3 g (46.5 percent) of (li?,26)-(-)-ephedrine salt of (_3)-3-[l-carboxy-l- (5-chloro-2-nitrophenyl)ethyl]-4-chlorobenzoic acid as white crystalline solid. Mp.: 156-157°C, [α]20 589= +43.0° (c=l, MeOH) Anal. Calcd for C26H26Cl2N2O7: C, 56.84; H, 4.77; N, 5.10; Cl, 12.91. Found: C, 56.47; H, 4.59; N, 5.07; Cl, 12.8 in ethyl acetate, T= 55 °C Patent; SANOFI-AVENTIS; WO2006/82452; (2006); (A1) English View in Reaxys HO

2 Na +

O– OH

H HN

OH OH

O–

N H

H OH

racemate

racemate O HO

Rx-ID: 38174342 View in Reaxys 546/592 Yield 87 %

Conditions & References 4 : Example 4 Preparation of Pseudoephedrine Pamoate Disodium pamoate (10.4 g) was dissolved in USP water (73.5 g) and filtered to clarify. The filtrate was returned to a rinsed reactor employing a water rinse (15 g). The solution of disodium pamoate exhibited a pH of about 9.5. Pseudoephedrine HCl (9.3 g) in USP water (53.1 g) was prepared and exhibited a pH of about 6.3. The pseudoephedrine HCl solution was added to the disodium pamoate solution. As the addition continued, the oily mixture became opaque. After complete addition (1 h), the residue in the addition funnel was rinsed into the reaction vessel with USP water (5.0 g). The mixture was heated at about 84° C. for approximately 3.25 h. The mixture was then cooled overnight and solids were collected by filtration. The filter cake was washed with USP water (3×30 g) and dried in a vacuum oven (98-102° C.) for about 5.2 h with a nitrogen sweep. After cooling, the finely powdered 2:1 (by HPLC) pseudoephedrine pamoate solids (15.9 g, 87percent) was characterized by DSC (FIG. 3), FTIR (FIG. 6) and PXRD (FIG. 9). in water, Time= 4.25h, T= 84 °C Patent; King, Clifford Riley; Bristol, David W.; English, Michael L.; US2014/178480; (2014); (A1) English View in Reaxys

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2 Na +

O O–

Cl H

OH OH

O– O

OH HO

NH racemate

racemate

Rx-ID: 38174343 View in Reaxys 547/592 Yield

Conditions & References

39 %

2 : Example 2 Preparation of Ephedrine Pamoate Ephedrine Hydrochloride (6.1 g) was stirred in USP water (45.0 g) to yield a solution pH of about 4.9. In a separate flask a disodium pamoate (6.5 g) solution was prepared using USP water (54.0 g) to yield a solution pH of about 9.5. The ephedrine HCl solution was transferred to a metered addition funnel and added to the disodium pamoate solution over approximately 1 h. When about one-half of the addition was completed, the solution became opaque. USP water (2.6 g) was used to rinse in the residue from the addition funnel. The opaque mixture was heated from about 26° C. to near 80° C. The reaction was stirred at about 80° C. for approximately 4.5 h. A thick residue settled in the reaction vessel as the solution cooled. The solution was decanted and the residue transferred to drying dishes. The residue was dried at about 100° C. under vacuum (nitrogen sweep) for about 5.5 h. Drying was continued for about 66 h, the solid ground with a mortar and pestle to give a dense powder (4.2 g, 39percent). and a DSC analysis indicated a clear melt (Tmax 243.4° C., Tonset 227.7° C., and heat of fusion 142.2 J/g). in water, Time= 5.5h, T= 26 - 80 °C , Time, Temperature Patent; King, Clifford Riley; Bristol, David W.; English, Michael L.; US2014/178480; (2014); (A1) English View in Reaxys

NH 2 2

O S – ON

N 2

Ni 2+

S H

H 2N

H HN

racemate

S N–

Ni 2+

racemate

Rx-ID: 26306842 View in Reaxys 548/592 Yield

Conditions & References With H2O or aq. mineral acid, decompn. with H2O or dild. aq. mineral acid Patent; Rosenzweig, S.; Fuchs, W. M.; US2536095; (1951) View in Reaxys Patent; Rosenzweig, S.; Fuchs, W. M.; 2629682; (1953) ; (from Gmelin) View in Reaxys decompn. on heating Patent; Rosenzweig, S.; Fuchs, W. M.; US2536095; (1951) View in Reaxys Patent; Rosenzweig, S.; Fuchs, W. M.; 2629682; (1953) ; (from Gmelin) View in Reaxys decompn. on heating vol. Ni: MVol.C2; 5.4, page 593 - 602 ; (from Gmelin) View in Reaxys With H2O or aq. mineral acid, decompn. with H2O or dild. aq. mineral acid vol. Ni: MVol.C2; 5.4, page 593 - 602 ; (from Gmelin) View in Reaxys

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O S N– O

NH 2

O 2 S OH

H 2N

N H

Ni 2+

N–

H N

Rx-ID: 26602305 View in Reaxys 549/592 Yield

NH 2 2

O S – ON

N 2

S H

H 2N Ni 2+

N H racemate

H HN

OH H

S N–

Ni 2+

S racemate

Rx-ID: 26602307 View in Reaxys 550/592 Yield

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View in Reaxys

F F

F N N F

O S O

Na +

H N

F N

N F

O–

Rx-ID: 23073093 View in Reaxys 551/592 Yield

Conditions & References 1 : Preparation of (-)-4-[5-(2,4-difluorophenyl)-4,5-dihydro-3-(trifluoromethyl)-1H-pyrazol-1-il]-benzenesulphonate de (+)-ephedrine, (-)-7.bul.(+)-ephedrine In a 2L beaker are introduced sodium sulphonate (+/-)-6 (3.95 g, 9.23 mmol), (+)-ephedrine chlorhydrate (1.86 g, 9.23 mmol) and chloroform (79 mL). The mixture is shaken and heated to reflux for 10 minutes. It is allowed to cool slowly to ambient temperature, precipitating a solid (2.49 g) mixture of the salt (-)-7.bul.(+)-ephedrine (enantiomeric excess above 98percent) and sodium chloride formed in the process. This sample is used directly in the following reaction. If the sample is dissolved with a small amount of AcOEt, Washed with water, dried with MgSO4 and the solvent is evaporated a pure fraction is obtained of the salt (-)-7.bul.(+)-ephedrine: [α]20D=-94.6 (c=2, MeOH); IR (KBr) μ max (cm-1): 3410, 3040, 2860, 2780, 1595, 1570, 1500, 1420; 1H-RMN (CDCl3/CD3OD: 10/1) δ (ppm): 7.7 (d, J=9 Hz, 2H), 7.4-7.2 (m, 5H), 7.1-6.7 (m, 3H), 6.95 (d, J=9 Hz, 2H), 5.65 (dd, J=12.5 Hz, J=6.5 Hz, 1H), 5.3 (d, J=2.2 Hz, 1H), 3.9-3.6 (m, 1H), 3.4-3.1 (m, 1H), 3.0 (dd, J=18.4 Hz, J=5.8 Hz, 1H), 2.76 (s, 3H), 1.9 (wide band, 1H), 1.0 (d, J=6 Hz, 3H). in chloroform, Time= 0.166667h, T= 20 °C , Heating / reflux Patent; Alcon- Marrugat, Montserrat; Pericas-Brondo, Miguel Angel; Cuberes-Altisen, Maria Rosa; FrigolaConstansa, Jordi; US2004/19222; (2004); (A1) English View in Reaxys

O S

O– O

F N

Na +

H N

H HO

N OH

F F

Rx-ID: 23073096 View in Reaxys 552/592 Yield

Conditions & References 2 : Preparation of (-)-4-[1-(2,4-difluorophenyl)-4,5-dihydro-3-(trifluoromethyl)-1H-pyrazol-5-yl]-benzenesulphonate of (+)-ephedrine, (-)-12.bul.(+)-ephedrine. In a 50 mL beaker are introduced sodium sulphonate (+/-)-11 (2.45 g, 5.72 mmol), (+)-ephedrine chlorhydrate (1.15 g, 5.72 mmol) and toluene (24.5 mL). The mixture is shaken and heated to reflux for 10 minutes. It is allowed to cool slowly until reaching ambient temperature, precipitating a solid which is filtered and washed with more toluene. This provides 1.18 g, mixture of the salt (-)-12.bul.(+)-ephedrine (enantiomeric excess of 84percent) and of the sodium chloride formed in the process. This sample is directly used in the following reaction; IR (KBr) μ max (cm-1) 3377, 3031, 1603, 1515, 1399; 1H-RMN (CDCl3/CD3OD: 10/1) δ (ppm): 7.76 (d, J=8 Hz, 2H), 7.4-7.2 (m, 6H), 7.19 (d, J=8 Hz, 2H), 6.75 (m, 2H), 5.6 (m, 1H), 5.35 (s, 1H), 3.65 (m, 1H), 3.3 (m, 1H), 3.15-3.0 (m, 1H), 2.76 (s, 3H), 2.65 (m, 2H), 1.07 (d, J=7 Hz, 3H). in toluene, Time= 0.166667h, T= 20 °C , Heating / reflux Patent; Alcon- Marrugat, Montserrat; Pericas-Brondo, Miguel Angel; Cuberes-Altisen, Maria Rosa; FrigolaConstansa, Jordi; US2004/19222; (2004); (A1) English View in Reaxys

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O HO

H N

O N N

OH O

O O

Rx-ID: 8878093 View in Reaxys 553/592 Yield

Conditions & References

68 %

Stage 1: With 4-methyl-morpholine, isopropanol acetate, Time= 4h, Heating Stage 2:Heating Hilpert, Hans; Tetrahedron; vol. 57; nb. 36; (2001); p. 7675 - 7683 View in Reaxys

H N

N N

Rx-ID: 15213408 View in Reaxys 554/592 Yield

Conditions & References Reaction Steps: 4 1.1: 88 percent / HBr/AcOH / 4.5 h / 80 °C 2.1: NaH / dimethylformamide / 1.33 h / 22 °C 2.2: dimethylformamide / 4 h / 0 °C 3.1: H2 / Pd/C / propan-2-ol / 24 h / 25 - 30 °C 4.1: N-methylmorpholine; i-PrOAc / 4 h / Heating 4.2: 68 percent / Heating With 4-methyl-morpholine, isopropanol acetate, hydrogen bromide, hydrogen, sodium hydride, acetic acid, palladium on activated charcoal in N,N-dimethyl-formamide, isopropyl alcohol Hilpert, Hans; Tetrahedron; vol. 57; nb. 36; (2001); p. 7675 - 7683 View in Reaxys

HO H N

O N N

Rx-ID: 15215690 View in Reaxys 555/592 Yield

Conditions & References Reaction Steps: 6 1.1: (R)-(+)-1,1'-bi-2-naphthol; molecular sieves (H2O content 8 percent); (i-PrO)2TiBr2 / CH2Cl2; toluene / 16 h / 22 °C 2.1: 26.68 g / Et3N / toluene / 22 h / -15 °C 3.1: NaH / dimethylformamide / 0.5 h / 22 °C 3.2: dimethylformamide / 28 h / 22 °C 4.1: NaH / dimethylformamide / 1.33 h / 22 °C 4.2: dimethylformamide / 4 h / 0 °C 5.1: H2 / Pd/C / propan-2-ol / 24 h / 25 - 30 °C 6.1: N-methylmorpholine; i-PrOAc / 4 h / Heating 6.2: 68 percent / Heating With 4-methyl-morpholine, molecular sieve, diisopropoxytitanium(IV) dibromide, isopropanol acetate, hydrogen, (R)-2,2'-dihydroxy-1,1'-binaphthyl, sodium hydride, triethylamine, palladium on activated charcoal in dichloromethane, N,N-dimethyl-formamide, isopropyl alcohol, toluene

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Hilpert, Hans; Tetrahedron; vol. 57; nb. 36; (2001); p. 7675 - 7683 View in Reaxys

O N

H N

N N

Rx-ID: 15229286 View in Reaxys 556/592 Yield

Conditions & References Reaction Steps: 3 1.1: NaH / dimethylformamide / 1.33 h / 22 °C 1.2: dimethylformamide / 4 h / 0 °C 2.1: H2 / Pd/C / propan-2-ol / 24 h / 25 - 30 °C 3.1: N-methylmorpholine; i-PrOAc / 4 h / Heating 3.2: 68 percent / Heating With 4-methyl-morpholine, isopropanol acetate, hydrogen, sodium hydride, palladium on activated charcoal in N,Ndimethyl-formamide, isopropyl alcohol Hilpert, Hans; Tetrahedron; vol. 57; nb. 36; (2001); p. 7675 - 7683 View in Reaxys

H N

N N O

Rx-ID: 15236626 View in Reaxys 557/592 Yield

Conditions & References Reaction Steps: 5 1.1: 26.68 g / Et3N / toluene / 22 h / -15 °C 2.1: NaH / dimethylformamide / 0.5 h / 22 °C 2.2: dimethylformamide / 28 h / 22 °C 3.1: NaH / dimethylformamide / 1.33 h / 22 °C 3.2: dimethylformamide / 4 h / 0 °C 4.1: H2 / Pd/C / propan-2-ol / 24 h / 25 - 30 °C 5.1: N-methylmorpholine; i-PrOAc / 4 h / Heating 5.2: 68 percent / Heating With 4-methyl-morpholine, isopropanol acetate, hydrogen, sodium hydride, triethylamine, palladium on activated charcoal in N,N-dimethyl-formamide, isopropyl alcohol, toluene Hilpert, Hans; Tetrahedron; vol. 57; nb. 36; (2001); p. 7675 - 7683 View in Reaxys

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O O O

N O

S H N

O N N

Rx-ID: 15244810 View in Reaxys 558/592 Yield

Conditions & References Reaction Steps: 4 1.1: NaH / dimethylformamide / 0.5 h / 22 °C 1.2: dimethylformamide / 28 h / 22 °C 2.1: NaH / dimethylformamide / 1.33 h / 22 °C 2.2: dimethylformamide / 4 h / 0 °C 3.1: H2 / Pd/C / propan-2-ol / 24 h / 25 - 30 °C 4.1: N-methylmorpholine; i-PrOAc / 4 h / Heating 4.2: 68 percent / Heating With 4-methyl-morpholine, isopropanol acetate, hydrogen, sodium hydride, palladium on activated charcoal in N,Ndimethyl-formamide, isopropyl alcohol Hilpert, Hans; Tetrahedron; vol. 57; nb. 36; (2001); p. 7675 - 7683 View in Reaxys

N N OO

H N

Rx-ID: 15247421 View in Reaxys 559/592 Yield

HO OO

H N

O N N

O O

N O

O O

Rx-ID: 15250665 View in Reaxys 560/592

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Yield

Conditions & References Reaction Steps: 2 1.1: H2 / Pd/C / propan-2-ol / 24 h / 25 - 30 °C 2.1: N-methylmorpholine; i-PrOAc / 4 h / Heating 2.2: 68 percent / Heating With 4-methyl-morpholine, isopropanol acetate, hydrogen, palladium on activated charcoal in isopropyl alcohol Hilpert, Hans; Tetrahedron; vol. 57; nb. 36; (2001); p. 7675 - 7683 View in Reaxys

O Br

H N

O OH

Rx-ID: 35187660 View in Reaxys 561/592 Yield

Conditions & References Reaction Steps: 3 1: potassium carbonate / 60 - 65 °C 2: sodium hydroxide / water / 45 - 50 °C 3: ethanol / 5.83 h / 0 - 75 °C With potassium carbonate, sodium hydroxide in ethanol, water Patent; RANBAXY LABORATORIES LIMITED; VERMA, Shyam Sunder; HANDIQUE, Sourav; AHUJA, Seema; SINGH, Kaptan; PRASAD, Mohan; ARORA, Sudershan, Kumar; WO2013/46135; (2013); (A1) English View in Reaxys

Br OH

H N

Rx-ID: 35187673 View in Reaxys 562/592 Yield

Br OH

H N

O OH

Rx-ID: 35187682 View in Reaxys 563/592 Yield

Conditions & References Reaction Steps: 2 1: sodium hydroxide / water / 45 - 50 °C 2: ethanol / 5.83 h / 0 - 75 °C

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With sodium hydroxide in ethanol, water Patent; RANBAXY LABORATORIES LIMITED; VERMA, Shyam Sunder; HANDIQUE, Sourav; AHUJA, Seema; SINGH, Kaptan; PRASAD, Mohan; ARORA, Sudershan, Kumar; WO2013/46135; (2013); (A1) English View in Reaxys

O OH

Br O

H N

O OH

Rx-ID: 35187694 View in Reaxys 564/592 Yield 220 g

Conditions & References 3 : Example 3: Preparation of R-(-)-3-(2-Benzyloxy-5-Bromo Phenyl)-3-Phenylpropionic Acid (±)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropionic acid (250 g), (1S,2R)- ephedrine hemihydrate (71.1 g), and ethanol (837 mL) were taken together at 25°C to 30°C. The reaction mixture was stirred for 20 minutes. The reaction mixture was refluxed at 70°C to 75°C to obtain a clear solution. The clear solution was stirred for 1 hour, cooled to 20°C to 25°C and stirred for 1.5 hours. The solution was further cooled to 0°C to 5°C and stirred for 3 hours. The solid obtained was filtered, washed with ethanol (250 mL) and dried to obtain a salt of R-(-)3-(2-benzyloxy-5-bromophenyl)-3- phenylpropionic acid (l S,2R)-(+)-ephedrine hemihydrate.Yield: 220 gThe salt of R-(-)3-(2-benzyloxy-5bromophenyl)-3-phenylpropionic acid (1 S,2R)- (+)-ephedrine hemihydrate (220 g) and ethanol (500 mL) were taken together at 25°C to 30°C. The reaction mixture was refluxed at 75°C to 78°C to obtain a clear solution and stirred for an additional hour at 60°C to 65°C. The mixture was cooled to 20°C to 25°C and stirred for 14 hours. The solution was further cooled to 0°C to 5°C and stirred for 3 hours. The solid obtained was filtered, washed with ethanol (250 mL), and dried to obtain a salt of R-(-)3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (l S,2R)-(+)- ephedrine hemihydrate.Yield: 120 gThe salt of R-(-)3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (1 S,2R)-(+)-ephedrine hemihydrate (1 15 g), toluene (400 mL), and distilled water (575 mL) were taken together at 20°C to 25°C and concentrated hydrochloric acid (23 mL) was added to the mixture. The reaction mixture was stirred for 1 hour and the organic layer was separated and washed with 1M hydrochloric acid (1 15 mL) at 20°C to 25°C. The organic layer was concentrated under reduced pressure to obtain the title compound.Yield: 85 g in ethanol, Time= 5.83333h, T= 0 - 75 °C Patent; RANBAXY LABORATORIES LIMITED; VERMA, Shyam Sunder; HANDIQUE, Sourav; AHUJA, Seema; SINGH, Kaptan; PRASAD, Mohan; ARORA, Sudershan, Kumar; WO2013/46135; (2013); (A1) English View in Reaxys

H N

HO O

H HO

HO H

OH OH

H N

Rx-ID: 29683374 View in Reaxys 565/592 Yield

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View in Reaxys

H N

HO HO

Rx-ID: 29683389 View in Reaxys 566/592 Yield

Conditions & References 29 :Promethazine (2 mmol) and ephedrinium salicylate (2 mmol) were dissolved in 25 ml of acetone and stirred for 15 min at room temperature, the solvent was evaporated and remaining volatile material was removed under vacuum (0.01 mbar, 50 0C) to yield the product as colourless viscous glass. 1H-NMR (300 MHz, d-DMSO) δ(ppm) = 7.72 (dd, J1 = 7.7 Hz, J2 = 1.8 Hz, IH), 7.42-7.15 (m, 10H), 7.0 (m, IH), 7.01 (d, J = 7.9 Hz, IH), 6.96 (t, J = 7.2 Hz, 2H), 6.65 (m, 2H), 5.13 (d, J = 2.5 Hz, IH), 4.10 (dd, J1 = 14.0 Hz, J2 = 5.0 Hz, IH), 3.72 (dd, J1 = 14.2 Hz, J2 = 8.6 Hz), 3.37 (m, IH), 3.01 (m, IH), 2.65 (s, 3H), 2.2.9 (s, 6H), 0.99 (d, J = 6.6 Hz, 3H), 0.92 (d, 6.8 Hz, 3H). Tg 14 0C, T5o/oOnset 151 °C. in acetone, Time= 0.25h, T= 20 °C Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys

H N

OH Cl

Na +

O H N

O O

O– S O

Rx-ID: 29683381 View in Reaxys 567/592 Yield 98 %

Conditions & References 59 :Ephedrinium hydrochloride (2.017 g, 10 mmol) and sodium docusate (4.446 g, 10 mmol) were dissolved in 50 ml of acetone/H2O 1:1 and stirred overnight at room temperature. The remaining suspension was diluted with 50 ml OfH2O and extracted with dichloromethane. The organic layer was washed successively with water until no more chloride ions could be detected in the washings (checked by addition OfAgNO3 solution), dried over MgSO4 and the solvent was evaporated. Remaining volatile material was removed under reduced pressure (0.01 mbar) to give ephedrinium docusate [13] in 98percent yield as colourless viscous oil. 1H-NMR (300 MHz, d6-DMSO) δ(ppm) = 8.45 (br s, 2H), 7.34 (m, 5H), 6.13 (d, J = 4.24 Hz, IH), 5.06 (t, J - 3.22 Hz, IH), 3.89 (m, 4H), 3.65 (dd, J1 - 11.47 Hz, J2 = 3.91 Hz, IH), 2.86 (m, 2H), 2.64 (s, 3H), 1.49 (m, 2H), 1.23 (m, 16 H), 0.86 (m, 15 H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm) = 171.0, 168.3, 141.0, 128.2, 127.4, 125.8, 69.6, 66.2, 61.5, 59.0, 38.2, 34.1, 30.7, 29.8, 29.6, 28.4, 23.2, 23.0, 22.5, 13.9, 10.8, 9.2. Tg -25 °C,T5percentOnset 238 0C in water, acetone, T= 20 °C Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys

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O OH H N

N N

Rx-ID: 10570014 View in Reaxys 568/592 Yield

Conditions & References 7; 8 :(+)-2-(7-Chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (8); [0076] A solution of 2-{1-[(7chloro-1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid (74.9 kg, 175.9 mol), (1S, 2R)-ephedrine hemihydrate (32.5 kg, 186.5 mol), 200 proof ethanol (290 Kg) and water (17 L) were stirred and heated to about 35[deg.] C. for 35 minutes. The solution was filtered and then cooled to about 20[deg.] C. until the onset of crystallization. The reaction was further cooled to 0-5[deg.] C. for about 2 hours. The intermediate ephedrine salt was filtered and washed with a cold (0-5[deg.] C.) solution of 200 proof ethanol (206 Kg) and water (10 L). The ephedrine salt was dissolved in 377 L of dichloromethane and stirred with 125 L water and 9.7 kg 37percent hydrochloric acid. The aqueous layer was removed. The organic layer was washed with water (125 L). The organic layer was distilled to 60percent of the original volume. Carbonyldiimidazole was dissolved in CH2Cl2 (128 L) and slowly transferred to the reaction solution. The reaction was complete after 20 minutes. The reaction was washed two times with water (250 L each). The CH2Cl2 solution was distilled atmospherically, the volume being replaced with of 200 proof ethanol (500 Kg). The ethanol solution was cooled at a rate of 20+-5[deg.] C. per hour to 0-5[deg.] C. The solution was then held at 0-5[deg.] C. for 16 hours. The product was filtered and washed with 200 proof ethanol (100 kg). The product was dried for 16 hours under vacuum at 60[deg.] C. This afforded 26.0 Kg of (+)-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5methyl-2-oxohexyl)-1-isoindolinone as a white solid (36percent yield). <1>H-NMR: [delta] 8.87 (d, J=8.8, 1H), 8.61 (m, 2H), 7.93 (d, J=7.0, 1H), 7.74 (m, 4H), 6.05 (m, 1H) 3.62 (m, 1 H), 3.28 (dd, J=7.0, 17.2, 1H), 2.42 (m, 2H), 1.35 (m, 3H), 0.79 (d, J=6.2, 6H); Cl (MS) M+1 at 408, 100percent; [[alpha]]D<20>=+135[deg.] (c=1, dichloromethane). With (1S,2R)-2-methylamino-1-phenyl-1-propanol in ethanol, water, Time= 0.583333h, T= 35 °C Patent; Jennings, Sandra Marie; Stuk, Timothy Lee; US2003/191315; (2003); (A1) English View in Reaxys

H N

Cl 2HO

H N

O O

Rx-ID: 29683355 View in Reaxys 569/592 Yield

Conditions & References 12 :Clofibric acid (1 or 2 eq.) and ephedrine free base (1 or 2 eq.) were molten in a hot mortar until a free-flowing clear liquid was obtained. The mixture was cooled to room temperature and, in case of solid products, grinded to obtain yellow powders. 1H-NMR (300 MHz, (I6-DMSO) δ(ppm) = 9.36 (br s, 2H), 7.30 (m, 5H), 7.19 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 5.10 (s, IH), 3.12 (m, IH), 2.52 (s, 3H), 1.41 (s, 6H), 0.85 (d, J = 6.6 Hz, 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm) = 176.8, 155.5, 141.8, 128.5, 128.0, 126.9, 125.8, 123.4, 119.2, 80.2, 69.8, 59.5, 30.7, 25.8, 9.6. , Neat (no solvent), Heating Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys

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H N

Br Cl

OH S

H N

HCl

Rx-ID: 37586863 View in Reaxys 570/592 Yield

Conditions & References General procedure: The solid Eph complexes with the TCNQ, DDQ, DNB or TBTacceptor were prepared by mixing equimolar amounts of the Ephdonor with each acceptor in pure-grade methanol. The resulting solutions were stirred for approximately 30 min and allowed to evaporate slowly at room temperature, where the complexes were isolated as green, yellow, pale yellow and white powder for Eph–TCNQ, Eph–DDQ, Eph–DNB and Eph–TBT complexes, respectively.The separated complexes were filtered and washed well with methanol. Then, the complexes were collected and dried over anhydrous calcium chloride for 24 h in desiccator. in methanol, Time= 0.5h, T= 20 °C Refat, Moamen S.; Ibrahim, Omar B.; Saad, Hosam A.; Adam, Abdel Majid A.; Journal of Molecular Structure; vol. 1064; nb. 1; (2014); p. 58 - 69 View in Reaxys

O O

O O O

O NH O

H N

O O

O O O

O H O

NH OH

Rx-ID: 11002487 View in Reaxys 571/592 Yield

Conditions & References Stage 1: With quinine powder in ethyl acetate, Resolution of racemate; Complexation, Further stages. Davies, John S.; Enjalbal, Christine; Nguyen, Corrine; Al-Jamri, Loai; Naumer, Christian; Journal of the Chemical Society, Perkin Transactions 1; nb. 17; (2000); p. 2907 - 2915 View in Reaxys

H N

O N H

Rx-ID: 29683394 View in Reaxys 572/592 Yield

Conditions & References 24 :Lidocaine (468.67 mg, 2 mmol) and ephedrinium ibuprofenate (743.02 mg, 2 mmol) were dissolved in 20 ml of acetone and stirred for 15 min at room temperature. The solvent was evaporated and the remaining viscous liquid was dried at 0.01 mbar with stirring for 24 hrs and solidified after 1 week. The desired compound is isolated as a colourless solid. 1H- NMR (300 MHz, d6-DMSO) δ(ρρm) = 9.19 (br s, IH), 7.32 (m, 5H), 7.20 (d, J = 8.1 Hz, 2H), 7.09 (s, 3H), 7.05 (d, J = 8.2 Hz, 2H), 5.03 (m, IH), 3.50 (q, J = 7.1 Hz, IH), 3.13 (m, 3H), 2.62 (q, J = 6.7 Hz, 4H), 2.45 (s, 3H), 2.40 (d, J = 7.1 Hz, 2H), 2.15 (s, 6H), 1.79 (sept, J = 6.7 Hz, IH), 1.32 (d, J = 7.0 Hz, 3H), 1.08 (t, J = 7.0 Hz, 6H), 0.86 (m, 9H). mp 87 °C in acetone, Time= 0.25h, T= 20 °C Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English

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View in Reaxys

H N

HCl

Rx-ID: 37586860 View in Reaxys 573/592 Yield

Conditions & References General procedure: The solid Eph complexes with the TCNQ, DDQ, DNB or TBTacceptor were prepared by mixing equimolar amounts of the Ephdonor with each acceptor in pure-grade methanol. The resulting solutions were stirred for approximately 30 min and allowed to evaporate slowly at room temperature, where the complexes were isolated as green, yellow, pale yellow and white powder for Eph–TCNQ, Eph–DDQ, Eph–DNB and Eph–TBT complexes, respectively.The separated complexes were filtered and washed well with methanol. Then, the complexes were collected and dried over anhydrous calcium chloride for 24 h in desiccator. in methanol, Time= 0.5h, T= 20 °C Refat, Moamen S.; Ibrahim, Omar B.; Saad, Hosam A.; Adam, Abdel Majid A.; Journal of Molecular Structure; vol. 1064; nb. 1; (2014); p. 58 - 69 View in Reaxys O HO

O H N

NH O

O O

Rx-ID: 8388418 View in Reaxys 574/592 Yield

Conditions & References aus d. entspr. Serin und (-)-Ephedrin Patent; Hoffmann La Roche; FR2241302; (1974); DE2439859; ; vol. 83; nb. 10863 View in Reaxys aus d. entspr. Serin und (+)-Ephedrin Patent; Hoffmann La Roche; FR2241302; (1974); DE2439859; ; vol. 83; nb. 10863 View in Reaxys

H N O

O OH

Rx-ID: 23924071 View in Reaxys 575/592 Yield

Conditions & References 34.a :Example 34: (S)-3-[3-("cyclopentyloxy')-4-methoxyphenyl1-U-dioxa-2-azaspiror4.41non- 2-ene (Compound No. 124)Step a: Synthesis of L-Ephedrine salt of 5-(carboxymethyl)-3-[3-(cyclopentyloxy)-4- methoxyphenyI]-4,5-dihydroisoxazole-5-carboxylic acid5 -(carboxymethyl)-3 - [3 -(cyclopentyloxy)-4-methoxyphenyl] -4,5- dihydroisoxazole-5carboxylic acid (disclosed in our copending patent application U.S. serial No.60/498,947) (1.0 g, 2.87 mmol) and LEphedrine (0.95 g, 5.73 mmol) were dissolved in acetone (50 ml) and the mixture was refluxed for 4 h. The reaction

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mixture was slowly brought to room temperature (35 0C) and kept as it is for 24-36 hours to furnish the S-isomer. Yield: 0.3 g. in acetone, Time= 4h, Heating / reflux Patent; RANBAXY LABORATORIES LIMITED; WO2006/85212; (2006); (A2) English View in Reaxys

H N

O HO

H N

Rx-ID: 29683376 View in Reaxys 576/592 Yield

Conditions & References 10 :Salicylic acid or ephedrine free base (0.5, 1, 1.5 or 2 eq.) and ephedrinium salicylate were grinded for 15 minutes in a mortar. Analytical data were similar to those obtained in conventional synthesis. 1H-NMR (300 MHz, d6-DMSO) δ(ppm) = 9.30 (br s, 2H), 7.76 (dd, J1 = 7.7 Hz, J2 = 1.8 Hz, IH), 7.38 (m, 4H), 7.24 (m, 2H), 6.70 (m, 2H), 6.48 (br s, IH), 5.21 (s, IH), 3.41 (m, IH), 2.69 (s, 3H), 0.95 (d, J = 6.8 Hz, 3H). 13C-NMR (75 MHz, d6-DMSO) δ(ppm) = 172.9, 162.1, 141.4, 132.0, 130.3, 128.2, 127.2, 125.8, 119.6, 116.8, 116.0, 69.6, 59.3, 30.6, 9.1. , Time= 0.25h, Neat (no solvent) Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys 2 Na +

O O–

H N

OH OH Cl

O–

HO O

N H OH HO O

Rx-ID: 28046915 View in Reaxys 577/592 Yield 66.6 %

Conditions & References 3 :Example 3; Alternate Preparation of Ephedrine PamoateEphedrine Hydrochloride (7.1 g) was stirred in methanol (62.6 g). Disodium pamoate (8.0 g) was stirred in USP water (71.0 g) and adjusted to about pH 9.5. The methanolic ephedrine hydrochloride solution was added to the disodium pamoate solution over a period of about 1.75 h. The reaction solution was heated to about 60° C. for around 4.5 h then cooled. The reactor was equipped with a distillation head and aqueous methanol was removed by heating. The opaque mixture was cooled and a residue settled to the bottom of the reaction vessel. The solution was carefully decanted and the residue was transferred to a drying dish. The material was placed in a vacuum drying oven (103° C.) for 24 h with a nitrogen sweep. Ephedrine Pamoate was obtained as a solid, 8.4 g (66.6percent) 2:1 ephedrine pamoate (by HPLC assay) and characterized by DSC (FIG. 2), FTIR (FIG. 5) and PXRD (FIG. 8). in methanol, water, Time= 6.25h, T= 60 °C , Product distribution / selectivity Patent; Bristol, David William; King, Clifford Riley; Mitchener, JR., Joseph Pike; Audia, Vicki Haynes; US2008/293695; (2008); (A1) English View in Reaxys

39 %

2 :Example 2; Preparation of Ephedrine PamoateEphedrine Hydrochloride (6.1 g) was stirred in USP water (45.0 g) to yield a solution pH of about 4.9. In a separate flask a disodium pamoate (6.5 g) solution was prepared using USP water (54.0 g) to yield a solution pH of about 9.5. The ephedrine HCl solution was transferred to a metered addition funnel and added to the disodium pamoate solution over approximately 1 h. When about one-half of the addition was completed, the solution became opaque. USP water (2.6 g) was used to rinse in the residue from the addition funnel.

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The opaque mixture was heated from about 26° C. to near 80° C. The reaction was stirred at about 80° C. for approximately 4.5 h. A thick residue settled in the reaction vessel as the solution cooled. The solution was decanted and the residue transferred to drying dishes. The residue was dried at about 100° C. under vacuum (nitrogen sweep) for about 5.5 h. Drying was continued for about 66 h, the solid ground with a mortar and pestle to give a dense powder (4.2 g, 39percent). and a DSC analysis indicated a clear melt (Tmax 243.4° C., Tonset 227.7° C., and heat of fusion 142.2 J/g). in water, Time= 5.5h, T= 26 - 80 °C , Product distribution / selectivity Patent; Bristol, David William; King, Clifford Riley; Mitchener, JR., Joseph Pike; Audia, Vicki Haynes; US2008/293695; (2008); (A1) English View in Reaxys

2 Na +

HO O

O– OH OH

Cl H HN

NH O– O

OH OH

OH O HO

Rx-ID: 28046916 View in Reaxys 578/592 Yield

Conditions & References

87 %

4 :Example 4; Preparation of Pseudoephedrine PamoateDisodium pamoate (10.4 g) was dissolved in USP water (73.5 g) and filtered to clarify. The filtrate was returned to a rinsed reactor employing a water rinse (15 g). The solution of disodium pamoate exhibited a pH of about 9.5. Pseudoephedrine HCl (9.3 g) in USP water (53.1 g) was prepared and exhibited a pH of about 6.3. The pseudoephedrine HCl solution was added to the disodium pamoate solution. As the addition continued, the oily mixture became opaque. After complete addition (1 h), the residue in the addition funnel was rinsed into the reaction vessel with USP water (5.0 g). The mixture was heated at about 84° C. for approximately 3.25 h. The mixture was then cooled overnight and solids were collected by filtration. The filter cake was washed with USP water (3.x.30 g) and dried in a vacuum oven (98-102° C.) for about 5.2 h with a nitrogen sweep. After cooling, the finely powdered 2:1 (by HPLC) pseudoephedrine pamoate solids (15.9 g, 87percent) was characterized by DSC (FIG. 3), FTIR (FIG. 6) and PXRD (FIG. 9). in water, T= 84 °C Patent; Bristol, David William; King, Clifford Riley; Mitchener, JR., Joseph Pike; Audia, Vicki Haynes; US2008/293695; (2008); (A1) English View in Reaxys

S OH

O H N

H N

0.5

O O

Rx-ID: 29683391 View in Reaxys 579/592 Yield

Conditions & References 28 :Promethazine (1 mmol) was added to ephedrinium docusate (2 mmol) and stirred for 15 minutes in acetone. The solvent was evaporated and remaining volatile material was removed under reduced pressure (0.01 mbar, 50 °C). 1H-NMR (300 MHz, d -DMSO) δ(ppm) = 7.39 (d, J = 4.5 Hz), 7.29 (m), 7.19 (m), 7.08 (d, J = 8.1 Hz), 6.95 (t, 7.4 6 Hz), 5.04 (d, J - 2.7 Hz), 4.05 (dd, J1 = 13.81 Hz, J2 = 5.0 Hz), 3.89 (m, 4H), 3.68 (m), 3.35 (m), 2.87 (m), 12.63 (s,), 2.24 (s), 1.49 (m, 2H), 1.23 (m, 16H), 0.84 (m, 18H). 13C-NMR (75 MHz, d6- DMSO) δ(ppm) = 171.0, 168.3, 145.1,

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141.0, 128.1, 127.6, 1227.3, 127.2, 125.8, 124.4, 122.6, 116.2, 69.9, 66.2, 66.1, 61.5, 59.0, 55.6, 49.7, 40.6, 38.2, 38.2, 34.1, 30.8, 29.7, 29.6, 29.5, 28.3, 23.2, 23.0, 22.4, 13.9, 12.2, 10.8, 9.5. in acetone, Time= 0.25h Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys

N OH

N N

H N

O O O

NH N

N HO

NH N

Rx-ID: 28355449 View in Reaxys 580/592 Yield

Conditions & References 13.a :Example 13: Preparation of (56''s)-5-(carboxymethyl)-3-[4-(cyclohexylamino)-l-ethyl-lH- pyrazolo[3,4-lpyridin-5yll-4,5-dihydroisoxazole-5-carboxylic acid (Compound No. 34)Step a: 5-(Carboxymethyl)-3-[4-(cyclohexylamino)-l ethyl- lH-pyrazolo [3,4-δ] pyridin-5-yl]-4,5-dihydroisoxazole-5-carboxylic acid (1 gm, 0.0024 mole) (example 10) and L-ephedrine (870 mg, 0.0053 mole) in ethyl acetate (20 ml) were refluxed for about 4 hours. The reaction mixture was slowly brought to 35 0C and kept as such for 18 hours. The solid crystallized was filtered off under nitrogen, washed with acetone and dried under vacuum.Yield: 750 mg in ethyl acetate, Time= 22h, T= 35 °C , Resolution of racemate, Heating / reflux, Purification / work up Patent; RANBAXY LABORATORIES LIMITED; WO2008/111009; (2008); (A1) English View in Reaxys

H N

H OH

S H N

E HO

Rx-ID: 34192895 View in Reaxys 581/592 Yield 68.9 %

Conditions & References 2 : Preparation of Montelukast L-ephedrine Salt EXAMPLE 2 Preparation of Montelukast L-ephedrine Salt

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In a 3L 4-neck round-bottom flask, 175 g (0.298 mol) Montelucast acid is diluted in 525 ml Acetonitrile and a solution of 56.73 g (0.343 mol) L-(-)-ephedrine in 200 ml Toluene is added under inert atmosphere. 62.5 ml Toluene is used to rinse the surface of the glassware and added to the mixture. The reaction mixture is heated to temperature from about 45 to 50° C. and 962.5 ml Acetonitrile is charged slowly. The reaction mixture is cooled down to temperature of about 38 to 39° C. and is seeded with 0.88 g (0.001 mol) Montelucast salt. The reaction mixture is further cooled down to temperature from about 30 to 32° C., while maintaining stirring for about 4 to 5 hours. 525 ml Toluene-Acetonitrile mixture (15:85v/v) is added to the mixture and the stirring is continued for about 16 hours. The precipitated solid is filtered on Buchner funnel, washed subsequently with 525 ml and 175 ml Toluene-Acetonitrile mixture (15:85v/v) and sucked dry for about 1 hour. The wet cake is charged back to the flask and 1050 ml Acetonitrile is added. The reaction mixture is heated to temperature from about 45 to 47° C. for about 1 hour under stirring and is left to cool down to temperature about 30 to 32° C. for a period of about 1 hour. Stirring is maintained for an additional period of about 1 hour. The material is filtered under nitrogen atmosphere, washed subsequently with 175 ml and 135 ml Acetonitrile and sucked dry. The wet cake is unloaded and dry under vacuum at temperature from about 45 to 50° C. for about 15 hours. Purified Montelukast-L-ephedrine is obtained with a yield of 66percent to 68.9percent. in toluene, acetonitrile, T= 30 - 50 °C , Inert atmosphere Patent; PHARMATHEN S.A.; US2012/259121; (2012); (A1) English View in Reaxys

OH O

S H N

E HO

Rx-ID: 34192896 View in Reaxys 582/592 Yield

Conditions & References Reaction Steps: 2 1.1: N-ethyl-N,N-diisopropylamine; methanesulfonyl chloride / tetrahydrofuran / -15 - -10 °C / Inert atmosphere 1.2: -15 - 20 °C 2.1: toluene; acetonitrile / 30 - 50 °C / Inert atmosphere With methanesulfonyl chloride, N-ethyl-N,N-diisopropylamine in tetrahydrofuran, toluene, acetonitrile Patent; PHARMATHEN S.A.; US2012/259121; (2012); (A1) English View in Reaxys

OH Cl

E OH

S H N

E HO

Rx-ID: 34192897 View in Reaxys 583/592 Yield

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S OH

O H N

H N

O O

Rx-ID: 29683390 View in Reaxys 584/592 Yield

Conditions & References 27 :Promethazine (2 mmol) was added to ephedrinium docusate (2 mmol) and stirred for 15 minutes at 50 °C to obtain a light yellow viscous oil. Identity and purity were confirmed via 1H and 13C NMR. 1H-NMR (300 MHz, dDMSO) δ(ppm) = 7.39 (d, J = 4.5 Hz, 3H), 7.29 (m, IH), 7.19 (m, 4H), 7.08 (d, J = 8.1 Hz, 2H), 6.95 (t, 7.4 Hz, 2H), 5.04 (d, J = 2.7 Hz, IH), 4.05 (dd, Jl = 13.81 Hz, J2 = 5.0 Hz, IH), 3.89 (m, 4H), 3.68 (m, 2H), 3.35 (m, IH), 2.87 (m, 3H), 12.63 (s, 3H), 2.24 (s, 6H), 1.49 (m, 2H), 1.23 (m, 16H), 0.84 (m, 18H). 13C- NMR (75 MHz, de-DMSO) δ(ppm) = 171.0, 168.3, 145.1, 141.0, 128.1, 127.6, 1227.3, 127.2, 125.8, 124.4, 122.6, 116.2, 69.9, 66.2, 66.1, 61.5, 59.0, 55.6, 49.7, 40.6, 38.2, 38.2, 34.1, 30.8, 29.7, 29.6, 29.5, 28.3, 23.2, 23.0, 22.4, 13.9, 12.2, 10.8, 9.5. Tg-19 °C, T5o/ oOnset

164 °C

, Time= 0.25h, T= 50 °C Patent; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA; MONASH UNIVERSITY; ROGERS, Robin, D.; DALY, Daniel, T.; GURAU, Gabriela; MACFARLANE, Douglas; TURANJANIN, Jelena; DEAN, Pamela, M.; QUEEN'S UNIVERSITY BELFAST; SCOTT, Janet, L.; BICA, Katharina; SEDDON, Kenneth, R.; WO2010/78300; (2010); (A1) English View in Reaxys

Cl 2Co

Cl –

racemate

3 HN H

O–

racemate 2 Co 2+ 2

HN H

H OH

racemate H O

Rx-ID: 26305702 View in Reaxys 585/592 Yield

Conditions & References in methanol, formation out of DL-pseudo-ephedrine in methanol and a methanolic CoCl2-solution; Foeldi, Z.; Foeldi, T.; Foeldi, A.; Acta chim. Acad. Sic. Hungar.; vol. 11; (1957); p. 339 - 348 ; (from Gmelin) View in Reaxys in methanol vol. Co: SVol.B1; 75, page 160 - 162 ; (from Gmelin) View in Reaxys

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H N

OH O

H H N

H N

NH NH

NH OH O H N

H N

NH NH

Rx-ID: 32780620 View in Reaxys 586/592 Yield

Conditions & References in water, dimethyl sulfoxide, T= 25 °C , Kinetics Moreno, Daniel; Grenu, Borja Diaz De; Garcia, Begona; Ibeas, Saturnino; Torroba, Tomas; Chemical Communications; vol. 48; nb. 24; (2012); p. 2994 - 2996 View in Reaxys N

O H N

H N O

NH NH

H HN

OH H

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NH OH O H N

H N

Rx-ID: 32780621 View in Reaxys 587/592 Yield

H N

O O

(v4)

O–4

O–

O 4

O2-

4 Ti4+

Rx-ID: 28085657 View in Reaxys 588/592 Yield

Conditions & References

21 %

in dichloromethane, Ar; Ti compd. added to CH2Cl2 soln. of ligand (1:1 molar ratio), refluxed for 5 min; crystd. (1 wk, 4°C) Fric, Helmut; Puchberger, Michael; Schubert, Ulrich; European Journal of Inorganic Chemistry; nb. 9; (2008); p. 1452 - 1461 ; (from Gmelin) View in Reaxys

2 Cl – HN H

Cl 2Co

H – O

racemate 3 Co 2+ 3

H O

racemate

HNH

H OH

racemate

Rx-ID: 26305701 View in Reaxys 589/592 Yield

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vol. Co: SVol.B1; 75, page 160 - 162 ; (from Gmelin) View in Reaxys

O N

NH 2

T-4 T-4 H N N

T-4 N T-4 H N

N O

O O

N O

T-4

H NH 2

T-4

T-4 N

N T-4 N H N H N T-4 N H T-4 N

N T-4 H N

H N

N T-4 N H

N T-4 N T-4 N H

O N

NH 2

O N OH

H N

H N O

T-4 T-4 H N N

T-4 N T-4 N O

O O

N O

T-4

N T-4 N H H

NH 2

T-4

O O

O N

N T-4 H N

N N T-4 T-4 N H

N H T-4 N

T-4

H T-4 N

N T-4 N H H

N O

Rx-ID: 29249747 View in Reaxys 590/592 Yield

Conditions & References pH= 4.76, aq. acetate buffer Wu, Jing; Isaacs, Lyle; Chemistry - A European Journal; vol. 15; nb. 43; (2009); p. 11675 - 11680 View in Reaxys

O N

NH 2

O N H

N O

T-4 N T-4 N

O O

T-4

N T-4 N H

T-4

O O

N T-4 H N

N T-4 N T-4 N H

H NH 2

T-4 T-4 H N N

T-4 N

N T-4 O N H N H N T-4 N H T-4 N

OH H

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O N

NH 2

N N

OH N

H N

H N O

H H

T-4 T-4 H N N

T-4 N T-4 N O

N T-4 N T-4 N H

O O

N O

T-4

N T-4 N H H

NH 2

T-4

O O

N H T-4 N

H T-4 N

N T-4 N H H

O N

T-4 H N

T-4

N O

Rx-ID: 29249749 View in Reaxys 591/592 Yield

Conditions & References pH= 4.76, aq. acetate buffer Wu, Jing; Isaacs, Lyle; Chemistry - A European Journal; vol. 15; nb. 43; (2009); p. 11675 - 11680 View in Reaxys

H N

(v1)

OH N

(v1)

N 11 H

H N H

Rx-ID: 26609566 View in Reaxys 592/592 Yield

Conditions & References in not given, pptn.; Mesnard, P.; Bull. Trav. Soc. Pharm. Bordeaux; vol. 74; (1936); p. 157 - 161; C. I; (1937); p. 1212 View in Reaxys Mesnard, P.; Bull. Trav. Soc. Pharm. Bordeaux; vol. 74; (1936); p. 161 - 164; C. I; (1937); p. 1212 View in Reaxys Mesnard, P.; Bull. Trav. Soc. Pharm. Bordeaux; vol. 74; (1936); p. 35 - 56; C. II; (1936); p. 1732 View in Reaxys vol. Cu: MVol.B3; 60, page 1104 - 1107 ; (from Gmelin) View in Reaxys

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