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References
1
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Rx-ID: 32108208 Find similar reactions
in methanol; dichloromethane
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RESEARCH TRIANGLE INSTITUTE; UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES, C/O NATIONAL INSTITUTES OF HEALTH, OFFICE OF TECHNOLOGY TRANSFER; BLOUGH, Bruce E.; ROTHMAN, Richard; LANDAVAZO, Antonio; PAGE, Kevin M.; DECKER, Ann Marie
Patent: WO2011/146850 A1, 2011 ; Location in patent: Page/Page column 54-55 ; Title/Abstract Full Text Show Details
1:
Pre aration of PAL-592; A solution of 3-methyl-2-phenylmorpholin-2-ol fumarate salt (0.4646g, l eq) in 1 : 1 ethanol:water (3.6mL) was chilled to 0°C under N2 (g). With constant stirring, a solution of sodium borohydride (0.2278g, 4eq) in water (2.5mL) was added drop wise. The reaction was allowed to warm to room temperature and stir overnight. The next morning the reaction was chilled to 0°C and 2.2mL of concentrated hydrochloric acid was added drop wise. The ethanol was then removed under reduced pressure and the crude mixture was diluted with water, chilled to 0°C, made basic by adding 40percent) aqueous sodium hydroxide (tested with litmus), extracted with methylene chloride (3 x 25mL), dried over anhydrous sodium sulfate, filtered, and volatiles removed under reduced pressure to afford 0.200g of solid residue. The intermediate residue dissolved in methylene chloride was then added drop wise to 4.8mL of concentrated sulfuric acid at 0°C and stirred overnight. The next morning the reaction was poured into ice water, the layers were separated, and the aqueous layer was chilled to 0°C. The aqueous layer was then made basic with 40percent aqueous sodium hydroxide (tested with litmus), extracted with methylene chloride (3 x 25mL), dried over anhydrous sodium sulfate, filtered, and volatiles removed under reduced pressure to afford 0.172g of oil. The oil was then dissolved in methylene chloride and 0.068 lg of fumaric acid in methanol was added to form the fumarate salt of the product. Anal. Calcd for 2[CHHi5CNO] [C4H4O4] : C 66.36, H 7.28, N 5.95; Found: C 66.12, H 7.29, N 5.85. 1H NMR (300 MHz, MeOH) δ ppm 1.01 (d, J=6.78 Hz, 3 H) 3.20 - 3.41 (m, 3 H) 3.84 - 3.99 (m, 1 H) 4.13 (d, J=l 4.32 Hz, 1 H) 4.32 (d, J=10.17 Hz, 1 H) 6.70 (s, 1 H) 7.39 (s, 5 H).
2
Synthesize Find similar Stage #1: With sodium tetrahydroborate; water in ethanol T=0 - 20°C; Inert atmosphere; Stage #2: With hydrogenchloride in ethanol; water
T=0°C; Hide Experimental Procedure
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Rx-ID: 32108219 Find similar reactions
RESEARCH TRIANGLE INSTITUTE; UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES, C/O NATIONAL INSTITUTES OF HEALTH, OFFICE OF TECHNOLOGY TRANSFER; BLOUGH, Bruce E.; ROTHMAN, Richard; LANDAVAZO, Antonio; PAGE, Kevin M.; DECKER, Ann Marie
Patent: WO2011/146850 A1, 2011 ; Location in patent: Page/Page column 54-55 ; Title/Abstract Full Text Show Details
1:
Pre aration of PAL-592; A solution of 3-methyl-2-phenylmorpholin-2-ol fumarate salt (0.4646g, l eq) in 1 : 1 ethanol:water (3.6mL) was chilled to 0°C under N2 (g). With constant stirring, a solution of sodium borohydride (0.2278g, 4eq) in water (2.5mL) was added drop wise. The reaction was allowed to warm to room temperature and stir overnight. The next morning the reaction was chilled to 0°C and 2.2mL of concentrated hydrochloric acid was added drop wise. The ethanol was then removed under reduced pressure and the crude mixture was diluted with water, chilled to 0°C, made basic by adding 40percent) aqueous sodium hydroxide (tested with litmus), extracted with methylene chloride (3 x 25mL), dried over anhydrous sodium sulfate, filtered, and volatiles removed under reduced pressure to afford 0.200g of solid residue. The intermediate residue dissolved in methylene chloride was then added drop wise to 4.8mL of concentrated sulfuric acid at 0°C and stirred overnight. The next morning the reaction was poured into ice water, the layers were separated, and the aqueous layer was chilled to 0°C. The aqueous layer was then made basic with 40percent aqueous sodium hydroxide (tested with litmus), extracted with methylene chloride (3 x 25mL), dried over anhydrous sodium sulfate, filtered, and volatiles removed under reduced pressure to afford 0.172g of oil. The oil was then dissolved in methylene chloride and 0.068 lg of fumaric acid in methanol was added to form the fumarate salt of the product. Anal. Calcd for 2[CHHi5CNO] [C4H4O4] : C 66.36, H 7.28, N 5.95; Found: C 66.12, H 7.29, N 5.85. 1H NMR (300 MHz, MeOH) δ ppm 1.01 (d, J=6.78 Hz, 3 H) 3.20 - 3.41 (m, 3 H) 3.84 - 3.99 (m, 1 H) 4.13 (d, J=l 4.32 Hz, 1 H) 4.32 (d, J=10.17 Hz, 1 H) 6.70 (s, 1 H) 7.39 (s, 5 H).
3
Synthesize Find similar Multi-step reaction with 2 steps 1.1: water; sodium tetrahydroborate / ethanol / 0 - 20 °C / Inert atmosphere 1.2: 0 °C 2.1: dichloromethane; methanol View Scheme
4
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Rx-ID: 32108220 Find similar reactions
RESEARCH TRIANGLE INSTITUTE; UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES, C/O NATIONAL INSTITUTES OF HEALTH, OFFICE OF TECHNOLOGY TRANSFER; BLOUGH, Bruce E.; ROTHMAN, Richard; LANDAVAZO, Antonio; PAGE, Kevin M.; DECKER, Ann Marie
Patent: WO2011/146850 A1, 2011 ; Title/Abstract Full Text Show Details
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With lithium hydroxide hydrate; propane-1-thiol in acetonitrile
T=25°C; 2 h;
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Rx-ID: 29716231 Find similar reactions
Zhou, Ling; Tan, Chong Kiat; Zhou, Jing; Yeung, Ying-Yeung
Journal of the American Chemical Society, 2010 , vol. 132, # 30 p. 10245 - 10247 Title/Abstract Full Text View citing articles Show Details
A
B
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5
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With 1,1'-carbonyldiimidazole in dichloromethane
T=20°C;
Garnier, Jean Marc; Robin, Sylvie; Rousseau, Gerard
European Journal of Organic Chemistry, 2007 , # 20 p. 3281 - 3291 Title/Abstract Full Text View citing articles Show Details
6
Synthesize Find similar Multi-step reaction with 2 steps 1.1: toluene / 18 h / Heating 1.2: 58 percent / Na2CO3 / toluene / 18 h / Heating 2.1: 1,1'-carbonyldiimidazole / CH2Cl2 / 20 °C View Scheme
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Rx-ID: 11423062 Find similar reactions
Garnier, Jean Marc; Robin, Sylvie; Rousseau, Gerard
European Journal of Organic Chemistry, 2007 , # 20 p. 3281 - 3291 Title/Abstract Full Text View citing articles Show Details
7
Synthesize Find similar With hydrogenchloride; sulfuric acid
1) heating, 3 h, 2) ether; Multistep reaction;
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Rx-ID: 5024140 Find similar reactions
Avramova, Petya; Danchev, Nicolai; Buyukliev, Rossen; Bogoslovova, Tatiana
Archiv der Pharmazie, 1998 , vol. 331, # 11 p. 342 - 346 Title/Abstract Full Text View citing articles Show Details
8
Synthesize Find similar Multi-step reaction with 2 steps 1: benzene / 2 h 2: 1) aq. H2SO4, 2) HCl / 1) heating, 3 h, 2) ether View Scheme
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Rx-ID: 16698656 Find similar reactions
Avramova, Petya; Danchev, Nicolai; Buyukliev, Rossen; Bogoslovova, Tatiana
Archiv der Pharmazie, 1998 , vol. 331, # 11 p. 342 - 346 Title/Abstract Full Text View citing articles Show Details
9
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Rx-ID: 2858822 Find similar reactions
64%
With formic acid
T=180°C; 50 h;
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Yordanova; Dantchev; Shvedov; Karanov
Archiv der Pharmazie, 1990 , vol. 323, # 1 p. 41 - 42 Title/Abstract Full Text View citing articles Show Details
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10
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Rx-ID: 2859413 Find similar reactions
80%
With formic acid
T=180°C; 20 h;
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Yordanova; Dantchev; Shvedov; Karanov
Archiv der Pharmazie, 1990 , vol. 323, # 1 p. 41 - 42 Title/Abstract Full Text View citing articles Show Details
11
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T=20°C; 20 h; Irradiation; Yield given;
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Rx-ID: 2210899 Find similar reactions
Marciniec
Pharmazie, 1985 , vol. 40, # 1 p. 30 - 33 Title/Abstract Full Text View citing articles Show Details
A
B
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12
Synthesize Find similar Rx-ID: 2210900 Find similar reactions
in water
Irradiationphotochemical decomposition, λ=254 nm; Kinetics;
Marciniec
Pharmazie, 1985 , vol. 40, # 3 p. 180 - 182 Title/Abstract Full Text View citing articles Show Details
With hydrogenchloride
Heating; Rate constant;
Rucker; Mrongovius; Neugebauer
Archiv der Pharmazie, 1982 , vol. 315, # 10 p. 839 - 846
Title/Abstract Full Text View citing articles Show Details
A
B
C
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13
Synthesize Find similar Rx-ID: 2265074 Find similar reactions
A: 15% B: 45% C: 15%
With sodium periodate; RuO4 in tetrachloromethane; water
7 h;
Perrone; Carbonara; Tortorella
Archiv der Pharmazie, 1984 , vol. 317, # 1 p. 21 - 27 Title/Abstract Full Text View citing articles Show Details
A: 15% B: 45% C: 15%
With sodium periodate; RuO4 in tetrachloromethane; water
7 h;
Perrone; Carbonara; Tortorella
Archiv der Pharmazie, 1984 , vol. 317, # 1 p. 21 - 27 Title/Abstract Full Text View citing articles Show Details
A: 15% B: 45% C: 15%
With sodium periodate; RuO4 in tetrachloromethane; water
7 h;
Perrone; Carbonara; Tortorella
Archiv der Pharmazie, 1984 , vol. 317, # 1 p. 21 - 27 Title/Abstract Full Text View citing articles Show Details
14
Synthesize Find similar With sodium hydroxide
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Perrone, Roberto; Berardi, Francesco; Tortorella, Vincenzo
Gazzetta Chimica Italiana, 1983 , vol. 113, # 7/8 p. 521 - 522 Title/Abstract Full Text Show Details
A
15
Rx-ID: 3254328 Find similar reactions
B
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Rx-ID: 3205582 Find similar reactions
With hydrogenchloride
Heating; Rate constant;
Rucker; Mrongovius; Neugebauer
Archiv der Pharmazie, 1982 , vol. 315, # 10 p. 839 - 846 Title/Abstract Full Text View citing articles Show Details
16
Synthesize Find similar /BRN= 139646/;
Rx-ID: 5439283 Find similar reactions
C.H. Boehringer Sohn Patent: US2835669 , 1953 ; Full Text Show Details
2-(1-Methyl-2-hydroxy-2phenylaethylamino)aethanol, H3PO4;
Egyesult Gyogyszer es Tapszergyar
Patent: HU149550 , 1960 ; Chem.Abstr., 1963 , vol. 58, # 4582d Full Text Show Details
aus C-2-(2-Hydroxyethylamino)-1phenylpropanol, H2SO4;
G.D.Searle and Co.; Patent: GB831933 , 1960 ; Chem.Abstr., 1961 , vol. 55, # 2697b Full Text Show Details
L-1-Phenyl-2-<(β-hydroxyaethyl)amino>-propanol;
Chem.FabrikRavensberg GmbH,
Patent: US3018222 , 1956 ; Chem.Abstr., 1963 , vol. 58, # 6840c Full Text Show Details
d-Norephedrin,(CH2)2O,HBr;
aus ss-Phthalimidoethanol, 1-Phe-
Searle
Patent: US3074941 , 1961 ; Chem.Abstr., 1963 , vol. 59, # 10069c Full Text Show Details
Shozokitagawa
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1-Br-aceton;
Patent: JP623579 , 1962 ; Chem.Abstr., 1963 , vol. 58, # 9092h Full Text Show Details
Morpholin (V) mit H2/Pd-C;
Chem,Fabrik Ravensberg GmbH,
Patent: US3018222 , 1956 ; Chem.Abstr., 1963 , vol. 58, # 6840c Full Text Show Details
Morpholin (VII).HCl mit H2/Pd-C;
Chem,Fabrik Ravensberg GmbH,
Patent: US3018222 , 1956 ; Chem.Abstr., 1963 , vol. 58, # 6840c Full Text Show Details
1-Phenyl-2-(β-hydroxyaethyl)amino-propanol mit H2SO4;
Chem,Fabrik Ravensberg GmbH,
Patent: US3018222 , 1956 ; Chem.Abstr., 1963 , vol. 58, # 6840c Full Text Show Details
trans-5, LiAlH4;
Spassov; Stefanovsky; Kurtev; Fodor
Chemische Berichte, 1972 , vol. 105, # 8 p. 2467 - 2475 Title/Abstract Full Text View citing articles Show Details
1-Phenyl-propin-(2)-ol(1)/Methanol, 1) BF3 + HgO, 2.) sd.wss. methanol.HCl, 3) Ethylamin + H2/Methanol (Raney-Ni);
Ravensberg GmbH
Patent: GB816576 , 1955 ; Chem.Abstr., 1960 , # 1564 Full Text Show Details
cis-5, LiAlH4;
Spassov; Stefanovsky; Kurtev; Fodor
Chemische Berichte, 1972 , vol. 105, # 8 p. 2467 - 2475 Title/Abstract Full Text View citing articles Show Details
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Cooper; Irving
Patent: US4255439 A1, 1981 ; Title/Abstract Full Text Show Details
The anorectics which could be used in the present invention include the following: phentermine resin chlorophentermine fenfluramine benzphetamine phenmetrazine diethylpropion phenylpropanolomine
17
Synthesize Find similar With lithium aluminium tetrahydride in diethyl ether
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Rx-ID: 941599 Find similar reactions
Beckett; Salami
The Journal of pharmacy and pharmacology, 1972 , vol. 24, # 11 p. 900 - 902 Title/Abstract Full Text View citing articles Show Details
With titanium(III) chloride in diethyl ether
Beckett; Salami
The Journal of pharmacy and pharmacology, 1972 , vol. 24, # 11 p. 900 - 902 Title/Abstract Full Text View citing articles Show Details
18
Synthesize Find similar entspr. cis-trans-Gemisch;
Rx-ID: 6397813 Find similar reactions
Geigy Chem.
Patent: US3282936 , 1966 ; Chem.Abstr., vol. 66, # 65485 Full Text Show Details
19
Synthesize Find similar With hydrogen bromide
3 h; Heating;
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Rx-ID: 1216186 Find similar reactions
KALM
Journal of medicinal chemistry, 1964 , vol. 7, p. 427 - 433 Title/Abstract Full Text View citing articles Show Details
20
Synthesize Find similar With hydrogen bromide
3 h; Heating;
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Rx-ID: 1216187 Find similar reactions
KALM
Journal of medicinal chemistry, 1964 , vol. 7, p. 427 - 433 Title/Abstract Full Text View citing articles Show Details
21
Synthesize Find similar With sulfuric acid
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Rx-ID: 1216188 Find similar reactions
KALM
Journal of medicinal chemistry, 1964 , vol. 7, p. 427 - 433 Title/Abstract Full Text View citing articles Show Details
22
Synthesize Find similar With toluene-4-sulfonic acid in 1,2,3,4-tetrahydro-naphthalene
T=200 - 210°C;
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Klosa,J.
Journal fuer Praktische Chemie (Leipzig), 1963 , vol. 21, p. 12 - 17 Full Text View citing articles Show Details
23
Synthesize Find similar cis/trans Mischung 1. H2SO4/Δ 2. HCl;
Rx-ID: 1164107 Find similar reactions
Rx-ID: 8405174 Find similar reactions
C.H.Boehringer Sohn Patent: FR1397563 , 1963 ; Chem.Abstr., 1965 , vol. 63, # 4308de Full Text Show Details
24
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Rx-ID: 8394419 Find similar reactions
(+-)-N-(2-Hydroxyethyl)norephedrin-hydrochlorid, konz. H2SO4;
Clarke
Journal of Organic Chemistry, 1962 , vol. 27, p. 3251 Full Text View citing articles Show Details
(+-)-N-(2-Hydroxyethyl)-nor-threoephedrin, konz. H2SO4;
Clarke
Journal of Organic Chemistry, 1962 , vol. 27, p. 3251 Full Text View citing articles Show Details
(+-)-trans-5-Methyl-6-phenyl-3morpholinon, LiAlH4;
Clarke
Journal of Organic Chemistry, 1962 , vol. 27, p. 3251 Full Text View citing articles Show Details
25
Synthesize Find similar (+-)-cis-5-Methyl-6-phenyl-3morpholinon, LiAlH4/ sd. Diethylether;
Rx-ID: 8394420 Find similar reactions
Clarke
Journal of Organic Chemistry, 1962 , vol. 27, p. 3251 Full Text View citing articles Show Details
26
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Rx-ID: 8405173 Find similar reactions
Spofa,Sdruzeni Podniku Pro Zdravotnickou Vyrobu;
Patent: GB899386 , 1959 ;
Chem.Abstr., 1963 , vol. 58, # 6838e Full Text Show Details