Benzodiazepine derivatives

#The present invention relates to benzodiazepine derivatives. More particularly, the invention is concerned with benzodiazepine derivatives, a process for the manufacture thereof and pharmaceutical preparations containing same.

#The benzodiazepine derivatives provided by the present invention are optically active 1,4-benzodiazepine-2-ones of the general formula ##STR2## , wherein R.sub.1 represents a hydrogen atom or a lower alkyl group and R.sub.2 represents a halogen atom,

#Which have the absolute configuration S at the carbon atom in the 3-position.

#82 g of carbobenzoxy-L-alanine are dissolved in 100 ml of absolute tetrahydrofuran, the solution is cooled to -40.degree. C. and treated with 80 g of phosphorus pentachloride. The reaction mixture is stirred at -30.degree. C. for 20 minutes and subsequently added to a shaken solution of 80 g of 2-amino-5-nitro-2'-chlorobenzophenone in 100 ml of absolute tetrahydrofuran. The solution is concentrated on a rotary evaporator at 50.degree.-60.degree. C., treated twice with toluene and evaporated each time. By crystallization of the residue from ether, there is obtained (-)-benzyl-[1-[{2- (ochlorobenzoyl)-4-nitrophenyl}carbamoyl]-ethyl]carbamate which melts at 147.degree. C. and exhibits a rotation of [.alpha]sub.25 .sup.D =-18.2.degree. (in methylene chloride, 1%).

#9.2 g of the foregoing carbamate are stirred in 90 ml of a 30% solution of hydrogen bromide in glacial acetic acid for 2 hours at room temperature and then the mixture is concentrated on a rotary evaporator. The residue is dissolved in water, the aqueous solution washed three times with ether and then made alkaline with sodium bicarbonate. The precipitated product is extracted with methylene chloride, the methylene chloride, the methylene chloride phase dried over sodium sulphate and concentrated. The residue is crystallized from ether and recrystallized from methylene chloride/petroleum ether, there being obtained (+)-2-amino-2'-(o-chlorobenzoyl)-4'-nitropropionoanilide which melts at 132.degree. C. and exhibits a rotation of [.alpha]sub.25 .sup.D =+4.4.degree. (in methylene chloride, 2%).

#35 g of foregoing propionoanilide are heated to reflux in 40 ml of glacial acetic acid and 200 ml of absolute toluene for 15 minutes. The residue obtained after distillation of the solvent is treated with methylene chloride and 10% sodium bicarbonate solution. The methylene chloride solution is washed twice with 10% sodium bicarbonate solution and once with water, dried over sodium sulphate, filtered and concentrated. The residue is taken up in benzene, some racemate formed crystallizing out and being filtered off. The benzene solution is evaporated and the residue crystallized from ether to give (+)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2 -one which melts at 198.degree.-200.degree. C. and exhibits a rotation of [.alpha]sub.25 .sup.D =+252.1.degree. (in methylene chloride, 1%).