3H-l,4-benzodiazepines

Chemical Name 7-Chloro-N-methyl-5-phenyl-3H-l,4-benzodiazepin-2-amino-4-oxide hydrochloride... 

Ninety-eight grams of 6-chloro-2-chloromethyl-4-phenylquinazoline 3-oxide hydrochloride were introduced into 600 cc of ice cold 25% methanolic methylamine. The mixture was initially cooled to about 30°C and then stirred at room temperature. After 15 hours the reaction product which precipitated was filtered off. The mother liquor was concentrated in vacuo to dryness. The residue was dissolved in methylene chloride, washed with water and dried with sodium sulfate. The methylene chloride solution was concentrated in vacuo and the crystalline residue was boiled with a small amount of acetone to dissolve the more soluble impurities. The mixture was then cooled at 5°C for 10 hours and filtered. The crystalline product, 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepine 4-oxide, was recrystallized from ethanol forming light yellow plates, MP 236° to 236.5°C. 

A solution of 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepine 4-oxide in an equivalent amount of methanolic hydrochloric acid was diluted with ether and petroleum ether. 

A solution of 3 g of 2-amino-2 -(2-chlorobenzoyl)acetanilide in 50 ml of pyridine was refluxed for 24 hours after which time the pyridine was removed in vacuo. The residue was recrystallized from methanol and a mixture of dichloromethane and ether giving crystals of 5-(2-chlorophenyl)-3H-l,4-benzodiazepin-2(lH)-one melting at 212° to 213°C. 

To a solution of 13.5 g of 5-(2-chlorophenyl)-3H-l,4-benzodiazepin-2(lH)-one in 60 ml of concentrated sulfuric acid, a solution of 5.5 g of potassium nitrate in 20 ml concentrated sulfuric acid was added dropwise. The solution then was heated in a bath at 45° to 50°C for 2.5 hours, cooled and poured on ice. After neutralizing with ammonia, the formed precipitate was filtered off and boiled with ethanol. A small amount of white insoluble material was then filtered off. The alcoholic solution on concentration yielded crystals of 7-nitro-5-(2-chlorophenyl)-3H-l,4-benzodiazepin-2(lH)-one which, after recrystallization from dichloromethane, melted at 238° to 240°C. 

To a stirred suspension of 10 grams (35 mmol) of 7-chloro-5-phenyl-3H-l,4-benzodiazepin-2(lH)-one 4-oxide in approximately 150 ml of methanol was added in portions an excess of a solution of diazomethane in ether. After about one hour, almost complete solution had occurred and the reaction mixture was filtered. The filtrate was concentrated in vacuum to a small volume and diluted with ether and petroleum ether. The reaction product, 7-chloro-l-methyl-5-phenyl-3H-l,4-benzodiazepin-2(lH)-one 4-oxide, crystallized in colorless prisms. The product was filtered off and recrystallized from acetone, MP 188°-189°C. 

A mixture of 3 grams (0.01 mol) of 7-chloro-l-methyl-5-phenyl-3H-l,4-benzodiazepin-2(lH)-one 4-oxide, 30 ml of chloroform and 1 ml of phosphorus trichloride was refluxed for one hour. The reaction mixture was then poured on ice and stirred with an excess of 40% sodium hydroxide solution. The chloroform was then separated, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride and crystallized by the addition of petroleum ether. The product, 7-chloro-l-methyl-5-phenyl-3H-l,4-benzodiazepin-2(lH)-one, was recrystallized from a mixture of acetone and petroleum ether forming colorless plates melting at 125°-126°C. 

A solution of 23.7 grams of 2-bromoacetamido-2 -fluorobenzophenone in tetrahydrofuran (100 cc) was added to liquid ammonia (approximately 500 cc) and allowed to evaporate overnight. The residue was treated with water (1 liter) and the crystals filtered off and refluxed in toluene (100 cc) for 30 minutes. The mixture was treated with decolorizing carbon (Norite) and filtered over Hyflo. The solution was concentrated to a small volume (25 cc) cooled, diluted with 20 cc of ether and allowed to stand. The product was recrystallized from acetone/hexane to give 5-(2-fluorophenyl)-3H-l,4-benzodiazepin-2(lH)-one as white needles melting at 180° to 181°C. 

A mixture of 16.8 g of 2 -aminobenzophenone, 11.9 g of glycine ethyl ester hydrochloride and 200 cc of pyridine was heated to reflux. After one hour, 20 cc of pyridine was distilled off. The solution was refluxed for 15 hours, then 11.9 g of glycine ethyl ester hydrochloride was added and the refluxing was continued for an additional 4 hours. The reaction mixture was continued for an additional 4 hours. The reaction mixture was concentrated in vacuo, then diluted with ether and water. The reaction product, 5-phenyl-3H-l,4-benzodiazepin-2(lH)-one, crystallized out, was filtered off, and then recrystallized from acetone in the form of colorless rhombic prisms, MP 182°C to 183°C. 

A suspension of 22.8 g (0.05 mol) of 2-(N-propargyl)-phthalimidoacetamido-5-chlorobenzophenone in 250 ml ethanol containing 7.5 g hydrazine hydrate (0.15 mol) was heated under reflux for 2 hours, at the end of which time the reaction mixture was set aside overnight at ambient (25°C) temperature. Thereafter, the crystalline phthalyl hydrazide which had precipitated out was removed by filtration and washed with 3 x 50 ml aliquots of chloroform. The filtrate and washings were diluted with water and exhaustively extracted with chloroform. The chloroform extract was then evaporated and the residue washed with 100 ml hexane to promote crystallization. The crude 7-chloro-l-propargyl-3H-l,4-benzodiazepine-2(lH)-one was recrystallized from a methanol-water mixture to give 10.5 g (71.4%) of the pure product. Melting point 140°C to 142°C. 

H-l,4-Benzodiazepin 2-Hydroxy-5-methyl- -4-oxid E9d, 401 (2-CHjCl —4-R — quinazolin-3-oxid/NaOH)... 

H-l,4-Benzodiazepin 7-Chlor-2-hydroxy-5-(2-thienyl)- -4-oxid E9d, 401 (2-CH2Cl — 4-Het — 6-Br — quinazolin — 3-oxid/NaOH) lOH-Phenothiazine 3-Chlor-9-methyl-l-nitro- E9a, 536 [6-SH —2-R —anilin 4- 3,5-Cl2 — 1,2-(N02)2 — benzene] Thioformimidsaure N-(4-Nitro-phenyl)- -chlorid-phenylester E4, 548 (R —NH —CHO + SOCl2/ R—SCI)... 

SYNS ALBORAL AMIPROL ANSIOLISINA APAURIN APOZEPAM ATENSINE ATILEN BIALZEPAM CALMOCITENE CERCINE 7-CHLORO-l,3-DIHYDRO-l-METHYL-5-PHENYL-2H-l,4-BENZODIAZEPIN-2-ONE 7-CHLORO-1-METHYL-5-3H-l,4-BENZODIAZEPIN-2(lH)-ONE 7-CHLORO-l-METHYL-2-OXO-5-PHENYL-3H-1,4-BENZODIAZEPINE... 

CHLORO-2-METHYLAMINO-5-PHENYL-3H-1.4-BENZODIAZEPIN 4-OXIDE 7-CHLORO-N-METHYL-5-PHENYL-3H-l,4-BENZODIAZEPIN-2-AMINE-4-OXIDE... 

CHLOROMETHYLOXIRANE see EAZ500 2-(CHLOROMETHYL)OXIRANE see EAZ500 7-CHLORO-l-METHYL-2-OXO-5-PHENYL-3H-l,4-BENZODIAZEPINE see DCK759... 

Chlordiazepoxide is 7-Chloro-2-(methylamino)-5-phenyl-3H-l,4-benzodiazepine 4-oxide. 

Chlordiazepoxide is prepared by the reaction scheme shown in Figure 6. 6-chloro-2-chloromethyl-4-phenyl-quinazoline 3-oxide is reacted with methylamine which presumably attacks the quinazoline at the 2 position. The nucleophilic attack is followed by enlargement of the ring to yield the 7-chloro-2-(methylamino)-5-phenyl-3H-l,4-benzodiazepine 4-oxide13. A complete review of the chemistry of benzodiazepines presents alternative pathways14. 

Ethyl N-allyl-N-(o-nitrobenzoyl)glycinate in ethanol added to a hot mixture of iron filings, acetic acid, ethanol, and water at a rate causing steady reflux, stirring and refluxing continued 3 hrs. 4-allyl-3H-l,4-benzodiazepine-2,5-... 

H-l,4-Benzodiazepin-2(IH) -one 4-oxides from 2-acetamino-3H-l,4-benzodiazepine 4-oxides s. 17,983... 

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