Query Query
Results
Date
46 reactions in Reaxys
2017-08-07 03h:54m:55s (EST)
O N
1. Query
N
Cl
Search as: As drawn
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
1/21
2017-08-07 04:56:59
O–
11
O H 311C
N
O O
I
CH 3
O
N
N
Cl
N
Cl
O O
Na +
Rx-ID: 8615208 View in Reaxys 1/46 Yield
Conditions & References
89 %
in acetone, Time= 0.25h, T= -15 - 95 °C , Methylation Sassaman, Mark B.; Panico, Mariarosaria; Schmall, Bernard; Eckelman, William C.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 42; nb. 13; (1999); p. 1229 - 1233 View in Reaxys
O
H N
N
H 311C
11CH
O
Cl
I
H 311C
3
N
N
OH
Cl
Rx-ID: 8639331 View in Reaxys 2/46 Yield
Conditions & References
47 %
With sodium hydroxide in water, acetone, Time= 0.25h, T= 95 °C , Methylation Sassaman, Mark B.; Panico, Mariarosaria; Schmall, Bernard; Eckelman, William C.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 42; nb. 13; (1999); p. 1229 - 1233 View in Reaxys
O
Cl
N
N
O
Cl
N H 2N
N OH
Rx-ID: 2097663 View in Reaxys 3/46 Yield
Conditions & References
89.3 %
With sodium hydrogensulfite in ethanol, water, Time= 12h, Heating Gates, Marshall; Journal of Organic Chemistry; vol. 45; nb. 9; (1980); p. 1675 - 1681 View in Reaxys
O
H N
O
Cl
O
O O
N O
O
N
HN
O
N
N H
HN
Cl
Cl
Cl
Rx-ID: 2184630 View in Reaxys 4/46 Yield 21 %, 5 %
Conditions & References With sulfuric acid in methanol, Time= 3.25h, Heating, Yield given Gates, Marshall; Journal of Organic Chemistry; vol. 45; nb. 9; (1980); p. 1675 - 1681 View in Reaxys
5%
With sulfuric acid in methanol, Time= 3.25h, Heating, Yields of byproduct given
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
2/21
2017-08-07 04:56:59
Gates, Marshall; Journal of Organic Chemistry; vol. 45; nb. 9; (1980); p. 1675 - 1681 View in Reaxys
O
O
H N
O
N
Cl
N
N
N
Cl
O
Rx-ID: 2889657 View in Reaxys 5/46 Yield
Conditions & References Time= 0.5h, T= 130 °C , Mechanism Pinto; Fryer; Journal of Heterocyclic Chemistry; vol. 30; nb. 4; (1993); p. 939 - 943 View in Reaxys
O
Cl
N
H N
O
N
N O
N
Cl
N
Cl
Cl
N
N
Cl
Cl
O N
Rx-ID: 3676949 View in Reaxys 6/46 Yield
Conditions & References
0.6 %, 0.5 With potassium permanganate in water, Time= 1.16667h, T= 15 °C %, 41.7 %, Milkowski; Hueschens; Kuchenbecker; Journal of Heterocyclic Chemistry; vol. 17; nb. 2; (1980); p. 373 - 376 5.1 % View in Reaxys 0.6 %, 0.5 %, 5.1 %, 41.7 %
With potassium permanganate in water, Time= 1.16667h, T= 15 °C Milkowski; Hueschens; Kuchenbecker; Journal of Heterocyclic Chemistry; vol. 17; nb. 2; (1980); p. 373 - 376 View in Reaxys
O
N
Cl N
Cl
O N Cl
O
Rx-ID: 4114855 View in Reaxys 7/46 Yield 96.09%
Conditions & References 9 : EXAMPLE 9 EXAMPLE 9 A mixture of hexamethylenetetramine (17.5 g., 0.125 mol), methanol (135.5 ml) and 2(2-chloro-N-methylacetamido)-5-chlorobenzophenone (80.5 g., 0.25 mol) was saturated with ammonia. Heat the stirred mixture slowly to reflux with a steady stream of ammonia flowing through the mixture. During the course of the reaction STR5 was prepared. The product was not isolated. Hold at reflux for 6 hours. Stop the flow of ammonia and remove the solvent under vacuum. Take up the residue in a mixture of toluene (500 ml.) and hot water (500 ml). Separate the toluene phase and add to it, with stirring, 3N nitric acid (169 ml). The crystals which separate are filtered, wash with toluene (50 mls) and resuspended in a mixture of toluene (250 ml) and water (250 ml). Concentrated ammonia (30 ml) is added to pH 8.
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
3/21
2017-08-07 04:56:59
The toluene phase is separated, washed with water (250 ml) and then distilled to dryness in vacuo yielding 96.09percent of 7-chloro-1-methyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, melting point 125° to 127° C. With 1,3,5,7-tetra-azatricyclo[5.1.1.13,5]decane, ammonia, nitric acid in methanol, water, toluene Patent; Hoffmann-La Roche Inc.; US3996209; (1976); (A1) English View in Reaxys 90 %
With 1,3,5,7-tetra-azatricyclo[5.1.1.13,5]decane, [HHMTA]Cl in ethanol, Heating Clarke, George M.; Lee, J. Barry; Swinbourne, Frederick J.; Williamson, Basil; Journal of Chemical Research, Miniprint; nb. 12; (1980); p. 4777 - 4793 View in Reaxys 10 : EXAMPLE 10 EXAMPLE 10 A mixture of ethanol (600 ml) and hexamethylenetetramine (39.1 g., 0.279 mol) was stirred and saturated with ammonia. With ammonia bubbling into the mixture it was slowly heated to reflux. Over a period of 41/2 hours, 2-(2-chloro-N-methylacetamido)-5-chlorobenzophenone (40 g., 0.124 mol) was added in increments yielding STR6 which was not isolated. Refluxing was continued for 2 hours longer. The reaction mixture was then distilled to dryness in vacuo at 50° C. The residue was stirred with toluene (250 ml), heated to reflux and heated with two increments of para-toluene sulfonic acid. Reflux was continued for one hour. After cooling to 70° C., the toluene was washed with hot water to remove soluble salts and distilled to dryness in vacuo. The residue was dissolved in hot ethanol (111 mol) and the solution cooled at -10° C. for one hour. The crystalline 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one obtained was isolated and weighed 29 g., melting point 129° to 131° C. Concentration of the mother liquor by ca. 50percent gave a second crop weighing 2.0 g. melting at 127° C. With 1,3,5,7-tetra-azatricyclo[5.1.1.13,5]decane in ethanol, toluene Patent; Hoffmann-La Roche Inc.; US3996209; (1976); (A1) English View in Reaxys
O– –O
O
N
N
Cl
N
N
Cl
Rx-ID: 5114681 View in Reaxys 8/46 Yield
Conditions & References With hydrogenchloride in ethanol, T= 20 °C , var. pH, var. temp., E(a), ΔH(excit.), ΔS(excit.), ΔG(excit.), Thermodynamic data, Mechanism, Kinetics Yang, Shen K.; Journal of the Chinese Chemical Society; vol. 45; nb. 5; (1998); p. 635 - 642 View in Reaxys
O
H N
N
O
Cl
I
N
N
Cl
Rx-ID: 5288415 View in Reaxys 9/46
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
4/21
2017-08-07 04:56:59
Yield
Conditions & References
76 %
With P-tris(dimethylamino)-C-dimethylphosphonium ylide in tetrahydrofuran, Time= 3h, T= -78 - 20 °C , Methylation Goumri-Magnet; Guerret; Gornitzka; Cazaux; Bigg; Palacios; Bertrand; Journal of Organic Chemistry; vol. 64; nb. 10; (1999); p. 3741 - 3744 View in Reaxys With NaOD in water-d2, acetone, Heating, Methylation Sassaman, Mark B.; Panico, Mariarosaria; Schmall, Bernard; Eckelman, William C.; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 42; nb. 13; (1999); p. 1229 - 1233 View in Reaxys
O
O
O
N
S O
H N
O
Cl
N
N
Cl
O
Rx-ID: 5337547 View in Reaxys 10/46 Yield
Conditions & References
85 %
Synthesis of 7-chloro-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (diazepam) (4) To a vigorously stirredmixture of nordiazepam (1) (0.27 g, 1 mmol) andpowder of K2CO3 (0.42 g, 3 mmol), dimethyl sulfate(0.37 mL, 4 mmol) was added. The progress of the reactionwas monitored by TLC. After completion of thereaction (2 h), water (3 9 10 mL) was added and the7-chloro-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (diazepam) was easily isolated by a simple filtration in85 percent yield and high purity. m.p = 130–132° C [129–132° C (Grant et al., 2010)]; IR (KBr, cm-1): 701, 1653,1675, 2939, 2978; 1H NMR(CDCl3, 400 MHz):δ 4.34 (s,2H), 5.22 (s, 3H), 7.43 (d, 4H, J = 11.4 Hz), 7.56 (d, 1H,J = 6.9 Hz), 7.77 (d, 2H, J = 6.7 Hz), 8.52 (d, 1H,J = 8.2). With potassium carbonate in neat (no solvent), Time= 2h, T= 20 °C Massah, Ahmad R.; Gharaghani, Sajjad; Lordejani, Hamid Ardeshiri; Asakere, Nahad; Medicinal Chemistry Research; vol. 25; nb. 8; (2016); p. 1538 - 1550 View in Reaxys With sodium methylate in methanol, T= 5 °C , Methylation Markovic, Dean; Hamersak, Zdenko; Visnjevac, Aleksandar; Kojic-Prodic, Biserka; Sunjic, Vitomir; Helvetica Chimica Acta; vol. 83; nb. 3; (2000); p. 603 - 615 View in Reaxys
O
N
N
Cl
Rx-ID: 6057831 View in Reaxys 11/46 Yield
Conditions & References Aki,O. et al.; Chemical and Pharmaceutical Bulletin; vol. 20; (1972); p. 2372 - 2376 View in Reaxys Yamamoto et al.; Chemische Berichte; vol. 101; nb. 12; (1968); p. 4245 View in Reaxys Patent; Sumitomo Chem. Co.; ZA6803041; (1967); ; vol. 71; nb. 124519m; (1969) View in Reaxys Patent; Hoffmann-LaRoche; US3996209; (1976); ; vol. 86; nb. 140097 View in Reaxys Natsugari et al.; Chemical and Pharmaceutical Bulletin; vol. 27; (1979); p. 2084,2090 View in Reaxys Vane; Benz; Organic Mass Spectrometry; vol. 14; (1979); p. 233,234
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
5/21
2017-08-07 04:56:59
View in Reaxys Bell et al.; Journal of Organic Chemistry; vol. 27; (1962); p. 562,563 View in Reaxys Sternbach; Reeder; Journal of Organic Chemistry; vol. 26; (1961); p. 4936,4939 View in Reaxys Meguro; Kuwada; Yakugaku Zasshi; vol. 93; (1973); p. 1263,1266; ; vol. 80; nb. 27224; (1974) View in Reaxys Patent; Takeda Chem. Ind., Ltd.; DE1944404; (1968); ; vol. 72; nb. 100775m; (1970) View in Reaxys Patent; Hoffmann-La Roche; BE620773; (1962); ; vol. 59; nb. 10094e; (1963) View in Reaxys Patent; Delmar Chem. Ltd.; NL6500446; (1964); ; vol. 64; nb. 5120; (1966) View in Reaxys Patent; Hoffmann-La Roche; DE1145626; (1963); ; vol. 60; nb. 12033h; (1964) View in Reaxys Patent; Hoffmann-La Roche; DE1136709; (1962); ; vol. 59; nb. 12827; (1963) View in Reaxys Patent; Reeder; Sternbach; US3136815; (1960); ; vol. 61; nb. 9515f; (1964) View in Reaxys Patent; Hoffmann-La Roche; CH414652; (1959); ; vol. 68; nb. 69054s; (1968) View in Reaxys Patent; Hoffmann-La Roche Inc.; US3131178; (1964); ; vol. 61; nb. 4383c; (1964) View in Reaxys Patent; Hoffmann-La Roche; US3402171; (1960); ; vol. 70; nb. 37850y; (1969) View in Reaxys Ishuzimi et al.; Chemical and Pharmaceutical Bulletin; vol. 23; (1975); p. 2169,2171 View in Reaxys Hsi; Journal of Labelled Compounds; vol. 10; (1974); p. 389,394 View in Reaxys Patent; Bahr et al.; DD61268; (1968); ; vol. 70; nb. 68444y; (1969) View in Reaxys Bogatskii et al.; Pharmaceutical Chemistry Journal; nb. 1; (1970); p. 3; Khimiko-Farmatsevticheskii Zhurnal; nb. 1; (1970); p. 5 View in Reaxys Andronati et al.; J. Gen. Chem. USSR (Engl. Transl.); vol. 40; (1970); p. 1881,1862,1863,1868 View in Reaxys Ellaithy et al.; Collection of Czechoslovak Chemical Communications; vol. 41; (1976); p. 3014,3016,3017,3019 View in Reaxys Oelschlaeger et al.; Collection of Czechoslovak Chemical Communications; vol. 31; (1966); p. 1264,1270 View in Reaxys Patent; Hoffmann-La Roche; ZA6800796; (1967); ; vol. 70; nb. 78029f; (1969) View in Reaxys Patent; Lab. Pharmedical; DE2159920; (1972); ; vol. 77; nb. 114440 View in Reaxys Patent; Schering; US4155904; (1979); ; vol. 91; nb. 108016 View in Reaxys Patent; Sumitomo Ltd.; DE2151540; (1972); ; vol. 77; nb. 126709 View in Reaxys Patent; Scherico Ltd.; DE2640599; (1978); ; vol. 88; nb. 190921 View in Reaxys Schmitt et al.; Industrie Chimique Belge; vol. 32; (1967); p. 184,185-187; ; vol. 70; nb. 96776b; (1969) View in Reaxys Schmitt et al.; Chimica Therapeutica; vol. 4; (1969); p. 239,244 View in Reaxys Patent; Etabl.Clin-Byla; NL6507637; (1964); ; vol. 64; nb. 15902g; (1966) View in Reaxys Nedenskov; Mandrup; Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry; vol. 31; (1977); p. 701,704 View in Reaxys Sugasawa et al.; Journal of Heterocyclic Chemistry; vol. 16; (1979); p. 445,448 View in Reaxys
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
6/21
2017-08-07 04:56:59
Patent; Hoffmann-La Roche; CH599176; (1978); US3873525; ; vol. 83; nb. 58894 View in Reaxys Patent; Sumitomo; DE2017060; (1970); ; vol. 74; nb. 22904; (1971) View in Reaxys Patent; Sumitomo Chemical Co., Ltd.; JP6917138; (1966); ; vol. 72; nb. 12779k; (1970) View in Reaxys Patent; CRC; DE2016084; (1971); ; vol. 75; nb. 36155; (1971) View in Reaxys Patent; Specta Intern.; FR2260580; (1975); DE2504937; (1975); ; vol. 84; nb. 44186 View in Reaxys Patent; Hoffmann-LaRoche; US3322753; (1965); ; vol. 68; nb. 39663x View in Reaxys Patent; Hoffmann-LaRoche; AT334376; (1977); DE2233482; ; vol. 78; nb. 111385 View in Reaxys Shenoy et al.; Indian Journal of Pharmacy; vol. 3; nb. 2; (1972); p. 48 View in Reaxys Patent; Hoffmann-LaRoche; US3376290; (1965); ; vol. 69; nb. 59299g; (1968) View in Reaxys Patent; Reeder; Sternbach; US3141890; (1962); US3136815; (1960); ; vol. 61; nb. 9514e; (1964) View in Reaxys Patent; Polfa; PL60627; (1970); ; vol. 74; nb. 88082q; (1971) View in Reaxys Blazevic; Kajfez; Journal of Heterocyclic Chemistry; vol. 7; (1970); p. 1173 View in Reaxys Patent; Chugai Seiyakn Kabushiki Kaisha; Japan; DE1957420; (1970) View in Reaxys Patent; Takeda yakukhin Kogyo; JP26302; (1969); Ref. Zh., Khim.; vol. 13; nb. N455P; (1970) View in Reaxys Patent; Hoffmann-La Roche F. und Co. AG; FR1503346; (1967); ; vol. 70; nb. 35610t; (1969) View in Reaxys Patent; F. Hoffmann-La Roche and Co. AG; CH567006; (1975); ; vol. 79; nb. 42575 View in Reaxys Patent; Sumitomo; DE2113122; (1971); ; vol. 76; nb. 3914f; (1972) View in Reaxys Patent; Sumitomo Chemical Company; CH599175; (1978); DE2508332; ; vol. 83; nb. 206341 View in Reaxys Patent; Japan Synthetic. Chem. Ind. Co. Ltd.; JP7031303; (1970); ; vol. 74; nb. 53864 View in Reaxys Patent; Kali-Chemie AG; DE2221536; (1972); ; vol. 80; nb. 37190 View in Reaxys Patent; Aktieselskabet Dumex; ZA6705130; (1966); ; vol. 70; nb. 28964m; (1969) View in Reaxys Inaba et al.; Chemical and Pharmaceutical Bulletin; vol. 23; (1975); p. 2421,2422, 2423, 2424 View in Reaxys Camps et al.; Anales de Quimica (1968-1979); vol. 70; (1974); p. 848 View in Reaxys Patent; Dumex Ltd.; ZA6707791; (1968); ; vol. 70; nb. 57916c; (1969) View in Reaxys Patent; Sumitomo Chemical Co. Ltd.; FR2002315; (1969); ; vol. 72; nb. 67002g; (1970) View in Reaxys Patent; Hoffmann-La Roche; CH414652; (1966); US3427304 View in Reaxys Patent; Hoffmann-La Roche; NL6407739; (1965); ; vol. 62; nb. 16281b; (1965) View in Reaxys Patent; Hoffmann-La Roche and Co.; AT341527; (1973); DE2340159; ; vol. 80; nb. 133491; (1974) View in Reaxys Patent; Cassella; DE1942743; (1971); ; vol. 74; nb. 100116; (1971) View in Reaxys Patent; Sumitomo Chemical Co., Ltd.,; DE1920207; (1970); ; vol. 72; nb. 90540q; (1970) View in Reaxys Patent; Hoffmann-LaRoche Inc.; US3681341; (1970); ; vol. 77; nb. 126706
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
7/21
2017-08-07 04:56:59
View in Reaxys Patent; Hoffmann-LaRoche; NL6407796; (1963); ; vol. 63; nb. 1808g; (1965) View in Reaxys Patent; Rexolin Chem. Akt.; NL6613087; (1967); ; vol. 67; nb. 82225 View in Reaxys Patent; Sankyo Co. Ltd.; DE2164154; (1971); ; vol. 77; nb. 126704 View in Reaxys Patent; Gedeon Richter Veg. Gyar R:T.; HU155373; (1966); ; vol. 70; nb. 87865c; (1969) View in Reaxys Patent; Hoffmann-LaRoche; US3546212; (1970); ; vol. 74; nb. 112062 View in Reaxys Patent; Hoffmann-La Roche Inc.; US3534021; (1970); ; vol. 74; nb. 53870; (1971) View in Reaxys Patent; Sumitomo Chemical; JP7006029; (1966); ; vol. 72; nb. 121597v; (1970) View in Reaxys Patent; HeimittelW. Wien GmbH; AT339319; (1977); DE2333382; ; vol. 82; nb. 171106 View in Reaxys Patent; Krka tovarna zdravil; CH567487; (1972); DE2211647; ; vol. 79; nb. 115647; (1973) View in Reaxys Petersen; Lakowitz; Acta chemica Scandinavica; vol. 23; nb. 3; (1969); p. 971 - 974 View in Reaxys Felix et al.; Journal of Heterocyclic Chemistry; vol. 5; (1968); p. 731 View in Reaxys Sternbach et al.; Journal of Organic Chemistry; vol. 27; (1962); p. 3781,3782, 3786 View in Reaxys 3 : EXAMPLE 3 Diazepam: m.p. 130°-134° C. (psychotropic agent; crystalline powder) Patent; Research Development Corp. of Japan; Stanley Electric Co., Ltd.; US5354563; (1994); (A1) English View in Reaxys 17 : Percutaneous Absorption Diazepam EXAMPLE 17 Percutaneous Absorption Diazepam The procedure of example 15 was repeated except that 14 C diazepam, diluted 1,000 fold with cold diazepam, was used. The propylene glycol solution contained 18.9 mg/ml of diazepam and 2percent (w/v) of cyclopentadecanone. Patent; Conrex Pharmaceutical Corporation; US5731303; (1998); (A1) English View in Reaxys non-steroidal anti-inflammatory agents selected from the group consisting of indomethacin, ibuprofen, sulindac, diclofenac, ketorolac and naproxen; dexametasone; anti-glaucoma agents selected from pilocarpine or thymolol; lidocaine; codeine; alpha-tocopherol; thymine; diazepam; Patent; Lipotec S.A.; US5736161; (1998); (A1) English View in Reaxys The compounds and symbols utilized in the figures were: ... 2. 7-chloro-5-(4-methoxyphenyl)-1-methyl-3H-1,4-benzodiazepin-2(1H)-one (°); 3. 5-(4-chlorophenyl)-7-fluoro-1-methyl-3H-1,4-benzodiazepin-2(1H)-one (); 4. diazepam () and 5. 1-methyl-5-(4-fluorophenyl)-3H-1,4-benzodiazepin-2(1H)-one (). Patent; Hoffmann-La Roche Inc.; US4898861; (1990); (A1) English
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
8/21
2017-08-07 04:56:59
View in Reaxys Values for the compounds are plotted in FIG. 4, each value being the mean of at least four experiments. ... 1. Diazepam (12) 2. 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one(5) 3. 1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(8) ... Patent; Hoffmann-La Roche Inc.; US4898861; (1990); (A1) English View in Reaxys 16 : 7-Chloro-1-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepine (B) EXAMPLE 16 7-Chloro-1-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f]-1,4-diazepine (B) 6 g. of compound 4361 CB are heated under reflux for 15 minutes in 25 ml. of acetic acid. The acetic acid is removed in vacuo and the residue is taken up in water and a little ether. A yellowish solid separates; m.p. 130°C.; the yield is substantially quantitative. It is recrystallized from diisopropyl ether. Yellowish crystals are obtained (4.4 g.); m.p. 132°C.: yield 85percent in the first batch. The product is identical with the known product (see reference above in Example 14). Patent; Clin Midy; US3966793; (1976); (A1) English View in Reaxys 2 : EXAMPLE 2 EXAMPLE 2 Example 1-(2) was repeated, except that the solvent pyridine was replaced by toluene and the reflux was conducted for 4.5 hours, to obtain 1-methyl-5-phenyl- 7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one having a melting point of 127° to 130° C. Patent; Sumitomo Chemical Company, Limited; US3991048; (1976); (A1) English View in Reaxys 14. and at least one number selected from the group consisting of ... Phenacemide Dipyridamol Indomethacin Nicotinamide Diazepam Disodium chromoglycate Levamisole Aldosterone ... Patent; The Regents of the University of Michigan; US4034087; (1977); (A1) English View in Reaxys
O O
N
HN
N
Cl
Cl
Rx-ID: 18048009 View in Reaxys 12/46 Yield
Conditions & References Reaction Steps: 2 1: 92 percent / aq.NaHCO3 / toluene / 2 h / 40 °C 2: 65 percent / NH3 / ethanol / 2 h / 80 °C
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
9/21
2017-08-07 04:56:59
With ammonia, sodium hydrogencarbonate in ethanol, toluene Clarke, George M.; Lee, J. Barry; Swinbourne, Frederick J.; Williamson, Basil; Journal of Chemical Research, Miniprint; nb. 12; (1980); p. 4745 - 4761 View in Reaxys Reaction Steps: 3 1: 1.45 g / CH2Cl2 / Ambient temperature 2: 82.2 percent / NH2OH*HCl / pyridine / 45 h / 70 °C 3: 89.3 percent / NaHSO3 / ethanol; H2O / 12 h / Heating With hydroxylamine hydrochloride, sodium hydrogensulfite in pyridine, ethanol, dichloromethane, water Gates, Marshall; Journal of Organic Chemistry; vol. 45; nb. 9; (1980); p. 1675 - 1681 View in Reaxys
H N
O
O
Cl
O N
N
N
Cl
O
Rx-ID: 21245679 View in Reaxys 13/46 Yield
Conditions & References Reaction Steps: 2 1: 82.2 percent / NH2OH*HCl / pyridine / 45 h / 70 °C 2: 89.3 percent / NaHSO3 / ethanol; H2O / 12 h / Heating With hydroxylamine hydrochloride, sodium hydrogensulfite in pyridine, ethanol, water Gates, Marshall; Journal of Organic Chemistry; vol. 45; nb. 9; (1980); p. 1675 - 1681 View in Reaxys
O
H N
N
O
Cl
N
N
Cl
Rx-ID: 25341481 View in Reaxys 14/46 Yield
Conditions & References 4 : 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one EXAMPLE 4 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one Dissolve 5.4 g. (0.02 moles) of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (e.g. product of Example 3) in 35 ml. of dichloromethane and add to this solution 1.2 g. of NaOH (1.5 moles) dissolved in 17 ml. of water. Cool the mixture with good agitation to 0° C. and add slowly 3.8 g. (0.03 moles) of dimethyl sulfate with good cooling and stirring. After all the dimethyl sulfate is added remove the cooling bath and continue stirring for an additional 2 hours. Add water and methylene chloride to the reaction mixture. Separate the layers and wash the methylene chloride layers with water. Dry the organic solution over anhydrous sodium sulfate and evaporate. After recrystallization, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one is obtained which after drying under vacuum at 110° C. shows a melting point of 129.5°-130.5° (corr.) and no depression on mixed melt with an authentic sample. With sodium hydroxide, dimethyl sulfate in dichloromethane, water Patent; Schering Corporation; US4155904; (1979); (A1) English View in Reaxys
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
10/21
2017-08-07 04:56:59
O
N
Cl N
Cl
O N Br
O
Rx-ID: 25345316 View in Reaxys 15/46 Yield
Conditions & References 2 : 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one EXAMPLE 2 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one Reflux 1.8 g. (0.005 moles) of 2-(2-bromo-N-methylacetamido)-5-chlorobenzophenone, 2.8 g. (0.020 moles) of hexamethylenetetramine and 1.96 g. (0.020 moles) of ammonium bromide together for 2 hours in 14 ml. of 85percent (v/v) aqueous isopropyl alcohol. Pour the reaction mixture into water and extract the product with benzene. Wash the benzene solution with water, dry over anhydrous sodium sulfate, filter and evaporate to dryness. After recrystallization, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one is obtained. The material gives a single spot by thin layer chromatography, and after drying under vacuum at 110° C., shows no depression on mixed melting point with an authentic sample (M.P. 129.5°-130.5° C.). With tetrabutylammonium fluoride, 1,3,5,7-tetra-azatricyclo[5.1.1.13,5]decane in aqueous isopropyl alcohol Patent; Schering Corporation; US4155904; (1979); (A1) English View in Reaxys
O
O
N
O N
N
O
H 2N
N
Cl
Cl
H
O Cl
Rx-ID: 41975305 View in Reaxys 16/46 Yield
Conditions & References
67 %
Stage 1: With iron, ammonium chloride in ethanol, Time= 6h, T= 80 °C Stage 2: With acetic acid in ethanol, Time= 3h, Reflux Wu, Yinuo; Sun, Lei; Chen, Yunyun; Zhou, Qian; Huang, Jia-Wu; Miao, Hui; Luo, Hai-Bin; Journal of Organic Chemistry; vol. 81; nb. 3; (2016); p. 1244 - 1250 View in Reaxys
O
N
O N
Cl
HO O
Rx-ID: 41975307 View in Reaxys 17/46 Yield
Conditions & References Reaction Steps: 2 1.1: palladium diacetate; ammonium peroxydisulfate / diethylene glycol dimethyl ether / 18 h / 20 °C / |Sealed tube 2.1: iron; ammonium chloride / ethanol / 6 h / 80 °C 2.2: 3 h / |Reflux With ammonium peroxydisulfate, palladium diacetate, iron, ammonium chloride in ethanol, diethylene glycol dimethyl ether Wu, Yinuo; Sun, Lei; Chen, Yunyun; Zhou, Qian; Huang, Jia-Wu; Miao, Hui; Luo, Hai-Bin; Journal of Organic Chemistry; vol. 81; nb. 3; (2016); p. 1244 - 1250
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
11/21
2017-08-07 04:56:59
View in Reaxys
O
N O
N
N
Cl
Cl
N
Rx-ID: 41975365 View in Reaxys 18/46 Yield
Conditions & References Reaction Steps: 2 1.1: palladium diacetate; ammonium peroxydisulfate / diethylene glycol dimethyl ether / 18 h / 20 °C / |Sealed tube 2.1: iron; ammonium chloride / ethanol / 6 h / 80 °C 2.2: 3 h / |Reflux With ammonium peroxydisulfate, palladium diacetate, iron, ammonium chloride in ethanol, diethylene glycol dimethyl ether Wu, Yinuo; Sun, Lei; Chen, Yunyun; Zhou, Qian; Huang, Jia-Wu; Miao, Hui; Luo, Hai-Bin; Journal of Organic Chemistry; vol. 81; nb. 3; (2016); p. 1244 - 1250 View in Reaxys
O O Cl
N
HN
N
Br
Cl
O
Cl
Rx-ID: 42274263 View in Reaxys 19/46 Yield
Conditions & References Stage 1: in 1-methyl-pyrrolidin-2-one, Time= 0.155h, T= 90 °C , Flow reactor Stage 2: With ammonia in 1-methyl-pyrrolidin-2-one, methanol, water, Time= 0.065h, T= 130 °C , p= 12751.3Torr , Flow reactor Adamo, Andrea; Beingessner, Rachel L.; Behnam, Mohsen; Chen, Jie; Jamison, Timothy F.; Jensen, Klavs F.; Monbaliu, Jean-Christophe M.; Myerson, Allan S.; Revalor, Eve M.; Snead, David R.; Stelzer, Torsten; Weeranoppanant, Nopphon; Wong, Shin Yee; Zhang, Ping; Science; vol. 352; nb. 6281; (2016); p. 61 - 67 View in Reaxys
H N
O O
Cl
O N
O
N
N
Cl
O
Rx-ID: 43901298 View in Reaxys 20/46 Yield
Conditions & References Reaction Steps: 2 1: hydrogen bromide; acetic acid / 16 h / 20 °C / |Inert atmosphere 2: N-ethylmorpholine; / N,N-dimethyl-formamide / 19 h / -20 - 20 °C / |Inert atmosphere With N-ethylmorpholine;, hydrogen bromide, acetic acid in N,N-dimethyl-formamide Patent; REGENTS OF THE UNIVERSITY OF MINNESOTA; SIEGEL, Ronald, A.; KAPOOR, Mamta; CHERYALA, Narsihmulu; GEORG, Gunda, I.; CLOYD, James, C.; (59 pag.); WO2016/149540; (2016); (A1) English View in Reaxys
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
12/21
2017-08-07 04:56:59
O
O
N
NH 2 N
Cl
Cl
Rx-ID: 43958475 View in Reaxys 21/46 Yield
Conditions & References Reaction Steps: 2 1: potassium carbonate; ammonium acetate / neat (no solvent) / 3 h / 20 °C 2: potassium carbonate / neat (no solvent) / 2 h / 20 °C With ammonium acetate, potassium carbonate in neat (no solvent) Massah, Ahmad R.; Gharaghani, Sajjad; Lordejani, Hamid Ardeshiri; Asakere, Nahad; Medicinal Chemistry Research; vol. 25; nb. 8; (2016); p. 1538 - 1550 View in Reaxys O N
O
N
N
F F
F
O
S
N
Cl
O I+
O– O
Rx-ID: 45090527 View in Reaxys 22/46 Yield
Conditions & References
97 %
With tetra-alkylammonium iodide, Heating Linstad, Ethan J.; Vāvere, Amy L.; Hu, Bao; Kempinger, Jayson J.; Snyder, Scott E.; DiMagno, Stephen G.; Organic and Biomolecular Chemistry; vol. 15; nb. 10; (2017); p. 2246 - 2252 View in Reaxys
O
N
H 13 2 C N
Cl
Rx-ID: 6120734 View in Reaxys 23/46 Yield
Conditions & References /BRN= 820081/ (1), Dimethylsulfat, NaOH Corbella et al.; Journal of the Chemical Society, Chemical Communications; (1973); p. 721 View in Reaxys
O–
O
N
N
2H
N
Cl
Li+
N
Cl
Rx-ID: 2634322 View in Reaxys 24/46 Yield 26 %
Conditions & References With water-d2 in tetrahydrofuran
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
13/21
2017-08-07 04:56:59
Reitter; Sachdeva; Wolfe; Journal of Organic Chemistry; vol. 46; nb. 20; (1981); p. 3945 - 3949 View in Reaxys
O
O
N
N
2H
N
N
Cl
Cl
Rx-ID: 21273003 View in Reaxys 25/46 Yield
Conditions & References Reaction Steps: 2 1: Diisopropylamine, n-BuLi / tetrahydrofuran; hexane / -60 °C 2: 26 percent / D2O / tetrahydrofuran With n-butyllithium, water-d2, diisopropylamine in tetrahydrofuran, hexane Reitter; Sachdeva; Wolfe; Journal of Organic Chemistry; vol. 46; nb. 20; (1981); p. 3945 - 3949 View in Reaxys
O
O
N
N
Cl
C
N
N
O
N
N C
H+
Cl
N
H+
Cl
N
H+
Cl(*)
Rx-ID: 6211549 View in Reaxys 26/46 Yield
Conditions & References With protonated dimethyl ether, T= 100 °C , reaction in Finnigan quadrupole ion trap mass spectrometr, Product distribution McCarley, Tracy Donovan; Brodbelt, Jennifer; Analytical Chemistry; vol. 65; nb. 17; (1993); p. 2380 - 2388 View in Reaxys
O
H N
2
H
O
2H
O
O H
N
2H
Cl
S O
N
2
N
Cl
O
Rx-ID: 4533227 View in Reaxys 27/46 Yield
Conditions & References With deuteriated sodium hydroxide, 1.) CH3CN, 5 min, 2.) CH3CN, RT, 5 h, Yield given. Multistep reaction Yang, Shen K.; Tang, Ren; Pu, Quan-Long; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 38; nb. 8; (1996); p. 753 - 759 View in Reaxys
O
2H
O
N
2H
N
N
2H
Cl
2H
N
Cl
O
Rx-ID: 4542847 View in Reaxys 28/46
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
14/21
2017-08-07 04:56:59
Yield
Conditions & References
0.15 g
With phosphorus trichoride in chloroform, Time= 2h, Heating Yang, Shen K.; Tang, Ren; Pu, Quan-Long; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 38; nb. 8; (1996); p. 753 - 759 View in Reaxys
O
O
N
N
2H 2
N
Cl
H
N
Cl
Rx-ID: 4838589 View in Reaxys 29/46 Yield
Conditions & References With NaOD in methanol-d1, Time= 0.5h, T= 25 °C , var. solvents, conc. of NaOD and times; deuterium incorporation, Mechanism Yang, Shen K.; Journal of the Chinese Chemical Society; vol. 44; nb. 4; (1997); p. 401 - 406 View in Reaxys
O
H N
2
H
O
N
2
H
2H
N
Cl
2H
N
O
Cl
Rx-ID: 17656262 View in Reaxys 30/46 Yield
Conditions & References Reaction Steps: 2 1: 0.79 g / PCl3 / CHCl3 / 3 h / Heating 2: 1.) 4M NaOD / 1.) CH3CN, 5 min, 2.) CH3CN, RT, 5 h With NaOD, phosphorus trichoride in chloroform Yang, Shen K.; Tang, Ren; Pu, Quan-Long; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 38; nb. 8; (1996); p. 753 - 759 View in Reaxys
O
H N
N O
O
N
2H
Cl
2H
N
Cl
Rx-ID: 17661637 View in Reaxys 31/46 Yield
Conditions & References Reaction Steps: 3 1: 0.92 g / NaOD / CH3OD / 8 h / Heating 2: 0.79 g / PCl3 / CHCl3 / 3 h / Heating 3: 1.) 4M NaOD / 1.) CH3CN, 5 min, 2.) CH3CN, RT, 5 h With NaOD, phosphorus trichoride in methanol-d1, chloroform Yang, Shen K.; Tang, Ren; Pu, Quan-Long; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 38; nb. 8; (1996); p. 753 - 759 View in Reaxys
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
15/21
2017-08-07 04:56:59
O
O
N
N
2H
N
2H
Cl
N
Cl
O
Rx-ID: 17666184 View in Reaxys 32/46 Yield
Conditions & References Reaction Steps: 2 1: 0.9 g / NaOD / CH3OD / 4 h / Ambient temperature 2: 0.15 g / PCl3 / CHCl3 / 2 h / Heating With NaOD, phosphorus trichoride in methanol-d1, chloroform Yang, Shen K.; Tang, Ren; Pu, Quan-Long; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 38; nb. 8; (1996); p. 753 - 759 View in Reaxys
O
N
2
H
2H
Cl
N
N
Cl
2H
N O
Rx-ID: 29822463 View in Reaxys 33/46 Yield
Conditions & References With methanol-d4, potassium tert-butylate, Time= 0.583333h, T= 20 °C Carlier, Paul R.; Sun, Yang-Sheng; Hsu, Danny C.; Chen, Qiao-Hong; Journal of Organic Chemistry; vol. 75; nb. 19; (2010); p. 6588 - 6594 View in Reaxys
O 14C
N
N
Cl
Rx-ID: 6120735 View in Reaxys 34/46 Yield
Conditions & References Benzophenon-Derivat (2), HBr/Eisessig Tegyey Zs.; Maksay; Otvos; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 16; nb. 3; (1979); p. 377 - 385 View in Reaxys 3H
O
N
N
Cl
Rx-ID: 6117995 View in Reaxys 35/46 Yield
Conditions & References 6-Chlor-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-on, 3H-Methyliodid
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
16/21
2017-08-07 04:56:59
Schwob; Wuersch; Journal of Labelled Compounds and Radiopharmaceuticals; vol. 14; nb. 3; (1978); p. 355 - 360 View in Reaxys
O
O
O
N
N
N
H O+
CH +
HO N
Cl
C
O
N
Cl
Cl
H
N
Cl
H2O
N N+
Rx-ID: 6214091 View in Reaxys 36/46 Yield
Conditions & References With dimethyloxonium ion, T= 100 °C , reaction in Finnigan quadrupole ion trap mass spectrometr, Product distribution, Mechanism McCarley, Tracy Donovan; Brodbelt, Jennifer; Analytical Chemistry; vol. 65; nb. 17; (1993); p. 2380 - 2388 View in Reaxys O
Cl
O N
O N Cl
Cl
O
O
N
N
O
Cl
OH
Cl
O
N
NH 2
Cl
O
HN
N
N
Cl
N
O
Cl
Cl
Rx-ID: 4114853 View in Reaxys 37/46 Yield
Conditions & References
65 %
With ammonia in ethanol, Time= 2h, T= 80 °C , further reagent, Mechanism Clarke, George M.; Lee, J. Barry; Swinbourne, Frederick J.; Williamson, Basil; Journal of Chemical Research, Miniprint; nb. 12; (1980); p. 4745 - 4761 View in Reaxys
O
N
Cl
Cl
N
O
OH
Cl
O
NH 2
O
N
Cl
N
O
Cl
N
Cl
N Cl
O
Rx-ID: 4114854 View in Reaxys 38/46 Yield 65 %
Conditions & References With ammonia in ethanol, Time= 2h, T= 80 °C , Further byproducts given Clarke, George M.; Lee, J. Barry; Swinbourne, Frederick J.; Williamson, Basil; Journal of Chemical Research, Miniprint; nb. 12; (1980); p. 4745 - 4761 View in Reaxys
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
17/21
2017-08-07 04:56:59
O
O
O
H N
N
N
Cl
N
H N
O
N
Cl
N
N
Cl
O
Rx-ID: 2889658 View in Reaxys 39/46 Yield
Conditions & References
39 %, 38 %
Time= 0.5h, T= 130 °C Pinto; Fryer; Journal of Heterocyclic Chemistry; vol. 30; nb. 4; (1993); p. 939 - 943 View in Reaxys O
Cl
Cl
N
N
O
H N
N
Cl
N
O
N
Cl
Cl
N
N
N
Cl
Cl
O N
Rx-ID: 3676950 View in Reaxys 40/46 Yield
Conditions & References
21.8 %, 13.1 %, 1.3 %, 2.7 %
With chromium(VI) oxide in pyridine, Time= 93h Milkowski; Hueschens; Kuchenbecker; Journal of Heterocyclic Chemistry; vol. 17; nb. 2; (1980); p. 373 - 376 View in Reaxys
13.1 %, 2.7 %, 1.3 %, 21.8 %
With chromium(VI) oxide in pyridine, Time= 93h Milkowski; Hueschens; Kuchenbecker; Journal of Heterocyclic Chemistry; vol. 17; nb. 2; (1980); p. 373 - 376 View in Reaxys
21.8 %, 2.7 %, 1.3 %, 13.1 %
With chromium(VI) oxide in pyridine, Time= 93h Milkowski; Hueschens; Kuchenbecker; Journal of Heterocyclic Chemistry; vol. 17; nb. 2; (1980); p. 373 - 376 View in Reaxys
O
N
O N
S HO
Cl
O
Rx-ID: 8367990 View in Reaxys 41/46 Yield
Conditions & References Aus den Komponenten Patent; HeimittelW. Wien GmbH; AT339319; (1977); DE2333382; ; vol. 82; nb. 171106 View in Reaxys
O
Cl O
N
Cl N
Cl
Cl
Rx-ID: 8369724 View in Reaxys 42/46
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
18/21
2017-08-07 04:56:59
Yield
Conditions & References Chloralhydrat, Diazepam Podesva et al.; Chimica Therapeutica; vol. 6; (1971); p. 472 View in Reaxys
O
N
O O
N
S
Cl
HO
Rx-ID: 8376104 View in Reaxys 43/46 Yield
Conditions & References Aus den Komponenten Patent; HeimittelW. Wien GmbH; AT339319; (1977); DE2333382; ; vol. 82; nb. 171106 View in Reaxys
O
Br
N
Br N
O
Cl
Br
Rx-ID: 8369760 View in Reaxys 44/46 Yield
Conditions & References Bromal, Diazepam Podesva et al.; Chimica Therapeutica; vol. 6; (1971); p. 472 View in Reaxys
O O
Cl
NH
HBr
O N
O
H 2N
O
O
H NH
O
O O
N O
O
O
O N
Cl
O
N H
N
H N HN
O
N
Cl
O O
O
Rx-ID: 43901285 View in Reaxys 45/46 Yield 55 %, 39 %
Conditions & References 1 : Di-ferf-butyl (6-((2-((2-Benzoyl-4-chlorophenyl)(methyl)amino)-2-oxoethyl)amino)-6-oxohexane- -diyl)(S dicarbamate (7) Di-ferf-butyl (6-((2-((2-Benzoyl-4-chlorophenyl)(methyl)amino)-2-oxoethyl)amino)-6-oxohexane- -diyl)(S dicarbamate (7): 5 7 8 To aminoketone 5 (2.50 g, 6.52 mmol) and Boc-Z-Lys(Boc)-OSu (6, 2.90 g, 6.52 mmol) in dry DMF (60 mL) was added N-ethylmorpholine (0.825 mL, 6.52 mmol) at -20 °C under nitrogen. The reaction mixture was stirred for 1
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
19/21
2017-08-07 04:56:59
h at the same temperature and 2 h at 0 °C, then stirring was continued for 16 h at room temperature. The reaction was diluted with ethyl acetate (150 mL), washed with water (2 x 100 mL), brine (100 mL), dried over Na2S04, filtered and then the volatiles were evaporated in vacuo. The crude residue was purified by flash column chromatography (silica gel, 0-75percent ethyl acetate in hexanes) to furnish 7 (2.26 g, 55percent) as a colorless powder and diazepam (8, 722 mg, 39percent) as a colorless powder. Compound 7: The presence of rotamers precluded a comprehensive assignment of all proton and carbon resonances. R/ 0.53 (hexanes/ethyl acetate, 1:1); 'H NMR (400 MHz, CDC13) δ 7.79- 7.71 (m, 2H), 7.66-7.41 (m, 5H), 7.32 (dd, J= 8.4, 4.2 Hz, 0.79H), 7.21 (d, J= 8.5 Hz, 0.21H), 6.81 (dt, J= 9.7, 4.6 Hz, 0.76H), 6.69 (d, J= 4.3 Hz, 0.19H), 5.11 (s, 1H), 4.81 - 4.54 (m, 1H), 4.09 (dt, J = 7.1, 3.7 Hz, 1H), 3.89 (dd, J= 17.4, 5.2 Hz, 1H), 3.68 (dd, J= 17.4, 3.7 Hz, lH), 3.24 (s, 0.63H), 3.04 (s, 4.34H), 1.86-1.71 (m, 1H), 1.66-1.53 (m, 1H), 1.52-1.24 (m, 22H); 13C NMR (100 MHz, CDC13) 5 194.54, 193.47, 172.00, 168.67, 156.26, 155.72, 140.24, 139.02, 138.68, 138.20, 136.57, 135.97, 134.84, 134.46, 133.65, 133.16, 132.63, 132.17, 131.25, 130.25, 129.11, 128.63, 80.11, 79.18, 54.48, 42.24, 41.68, 40.24, 38.17, 37.73, 32.70, 29.81, 28.59, 22.73; HRMS (ESI+) calculated for C32H43CIN4O7 [M + Na+] 653.2712, found 653.2710; [a]D 22 -10.6 (c = 0.5, CH3OH). Compound 8: R 0.24 (hexanes/ethyl acetate, 1:1); mp 126-130 °C (lit 129-131.5 °C) (Gates, M., New synthesis of diazepam. Journal of Organic Chemistry 1980, 45, 1675-81); FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDCI3) δ 7.62-7.58 (m, 2H), 7.53-7.45 (m, 2H), 7.41 (dd, J= 8.2, 6.6 Hz, 2H), 7.31-7.27 (m, 2H), 4.83 (d, J= 10.8 Hz, 1H), 3.77 (d, J= 10.8 Hz, 1H), 3.39 (s, 3H); 13C NMR (101 MHz, CDC13) 5 170.13, 169.11, 142.80, 138.37, 131.65, 130.89, 130.27, 130.09, 129.66, 129.46, 128.60, 122.71, 57.18, 35.07; HRMS (ESI+) calculated for C16H13C1N20 [M + H*] 285.0789, found 285.0788. With N-ethylmorpholine; in N,N-dimethyl-formamide, Time= 19h, T= -20 - 20 °C , Inert atmosphere Patent; REGENTS OF THE UNIVERSITY OF MINNESOTA; SIEGEL, Ronald, A.; KAPOOR, Mamta; CHERYALA, Narsihmulu; GEORG, Gunda, I.; CLOYD, James, C.; (59 pag.); WO2016/149540; (2016); (A1) English View in Reaxys
HO O
H OH
O
N
H O
O
H O
OH
HO
N
Cl
O
HO
H
OH
H
H OH
O
OH
H
OH
HO O
O
HO
OH
OHHO
H O
HO
H
HO OH
H H
H O HO
O
H
H
O
OH
O
HO O
HO
OH O
OH O O
N
Cl
O
O
OH
O
HO
OH
OH HO
O
OH OH
O
N HO
HO
OH
OH
O
OH O
O
HO
OH
O
HO OH
HO
O O
O
HO HO
Rx-ID: 39001436 View in Reaxys 46/46 Yield
Conditions & References Preparation of inclusion complexes Process of complexation of diazepam with b-cyclodextrin (CD)was performed by the method of co-precipitation. 27,28 A conicalflask of 250 mL in capacity, placed on a magnetic stirrer, wascharged with 5.675 g of b-cyclodextrin which was dissolved in100 mL of hot distilled water. A solution of 2.8702 g of diazepamin 20 mL ethanol was prepared and on continuous stirring it wasslowly dropwise added into the hot solution of b-CD. The stirringwas continued till cooling the mixture, then it was moved to athermostated shaker IKA-VIBRAX-VXR, Jankle & Kunkei, Germany,and shaking was continued for about 48 h. To achieve equilibrium,the mixture was stored for about 3 days at 277
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
20/21
2017-08-07 04:56:59
K. The precipitatedinclusion complex was filtered off under elevated pressure througha B}uchner funnel and dried for 2 days at 323 K and stored in desiccatorover P2O5. in ethanol, water, Heating Pajzderska; Mielcarek; Wąsicki; Carbohydrate Research; vol. 398; (2014); p. 56 - 62 View in Reaxys
Copyright © 2017 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.
21/21
2017-08-07 04:56:59