LH-l,4-Benzodiazepin-2-ones

Chemical Name 7-Chloro-5-phenyl-5 -methyltetrahydrooxazolo[5.4-b]-2,3,4,5-tetrahydro-lH-l,4-benzodiazepin-2-one... 

NITRO-5-PHENYL-2,3-DIHYDRO-lH-l,4-BENZODIAZEPIN-2-ONE see DLYOOO p-NTTROPHENYLDIMETHYLTHIONOPHOSPHATE see MNHOOO... 

A phosgene was mixed with ethanol, then cooling by ice-water the solution of 8-chloro-l-phenyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepine-2-one in chloroform was added dropwise, mixed and allowed to stand. Then the reaction mixture was concentrated, and crystals was filtered off. So the 7-chloro-2,3,4,5-tetrahydro-4-oxo-5-phenyl-lH-l,5-benzodiazepine-l-carboxylic acid ethyl ester was obtained, melting point 172°-173°C (dec.). 

Preparation of l-Cyclopropylmethyl-5-Phenyl-7-Chloro-lH-l,4-Benzodiazepine-2(3H)-one To a solution of 39.5 g (0.0845 mol) of 2-(N-phthalimidoacetyl-N-cyclopropylmethyl)amino5-chlorobenzophenone in a mixture of 423 ml of chloroform and 423 ml of ethanol is added 9.52 g (0.1903 mol) of hydrazine hydrate and 9.52 ml of water. This solution is allowed to stand at room temperature. In 3 hours a precipitate begins to form in the solution. After standing 16 to 24 hours a voluminous pulpy white precipitate forms. The solvents are removed under vacuum while keeping the temperature under 40°C and the residue is partitioned between dilute ammonia water and ether. 

The aqueous layer is separated and washed with ether, the ether extracted with 5% hydrochloric acid, the acidic solution is made basic with 10% sodium hydroxide and again extracted with ether. Since some spontaneous crystallization occurs in the ether, the solvent is removed without drying under vacuum and the residue is recrystallized from 35 ml of ethanol giving 18.0 g of l-cyclopropylmethyl-5-phenyl-7-chloro-lH-l,4-benzodiazepine-2(3H)-one, MP 145° to 146°C (65% yield), according to US Patent 3,192,199. 

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-l-(2-piETHYLAMINO)ETHYL)-5-(2-FLUOROPHENYL)-lH-l,4-BENZODIAZEPIN-2(3H)-ONE see FMQOOO... 

A stirred and ice-cooled soln. of 7-chloro-l,3,4,5-tetrahydro-l-methyI-5-phenyl-2H-l,4-benzodiazepin-2-one in diloroform treated with RUO4 in the same solvent during 10 min., allowed to stand 18 hrs. at room temp., more Ru04-soln. added, and allowed to stand for an additional 18 hrs. 7-chloro-l,3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepine. Y 60%. - Similarly from 7-chloro-2,3-dihydro-l-methyl-5-phenyl-lH-l,4-benzodiazepine. Y 55%. F. e. s. A. M. Felix et al., J. Heterocyclic Chem. 5, 731 (1968). 

Alkoxymethyl-4-hydroxy-3,4-dihydro-2(lH)-quinazolones from 4,5-epoxy-l,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-ones... 

Tetrahydro- and 2,3-dihydro-lH-l,4-benzodiazepines from l,3-dihydro-2H-l,4-benzodiazepin-2-ones Retention of nitro groups... 

Mexenone. 2-Hydroxy-4-methoxy-4 -methylbenzophenone, 282 Morin. 2-(2,4-Dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-one, 37 Nitrazepam. 1,3-Dihydro-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2-one, 60 Nizofenone. (2-Chlorophenyl)[2-[2-[(diethylaminojmethyl]-lH-imidazol-l-yl]-5-nitrophenyl]melhanone, 206... 

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. 

C) Preparation of 7-Chloro-2,3-Dihydro-l-Methyl-5-Phenyl-lH-l,4-Benzodiazepine A mixture of 4.7 g (22.6 mol) of 7-chloro-l,2,3,4-tetrahydro-l-methyl-5H-l,4-benzodiazepin-5-one and 100 ml of phosphorus oxychloride was heated in an oil bath at 100°C for 15 minutes. The solution was concentrated to dryness in vacuo. The residue was partitioned between methylene chloride and cold saturated sodium bicarbonate solution. The methylene chloride phase was dried over sodium sulfate and sodium bicarbonate, filtered, diluted with benzene and concentrated in vacuo to produce crude 5,7-dichloro-2,3-dihydro-l-methyl-lH- 1,4-benzodiazepine. 

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. 

Fig. 27 The butterfly like model derived from the common 3D superimposition of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,l-jk][l,4]benzodiazepin-2(lH)-ones (TIBO), Nevirapine and (S)-(-)9b-phenyl-2,3-dihydrothiazolo[2,3-3]isoindol-5-(9bH)-one (compound b, Fig. 25) (Reprinted with permission from [179]. Copyright 1993 American Chemical Society)...

X-ray structures of HIV RT, so structure-based design did not seem to play a role in their discovery. The discovery of NNRTIs appears to have started with selective screening of the compound library in cell culture at Janssen Phar-maceutica in 1987, which led to the discovery of the first generation NNRTIs, the TIBO (tetrahydro-imidazo[4,5,l-jk][l,4]-benzodiazepin-2(lH)one) compounds. Two of these first generation NNRTIs, tivirapine, a TIBO deriva-... 

Research on nonnucleoside inhibitors of HIV-1 reverse transcriptase from 4,5,6,7-tetrahydro-5-methylimidazo[4,5,l-/fc](l,4)benzodiazepin-2(lH)-one (TTBO) to etravirine (TMC125) 05JMC1689. 

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