SYNTHESIS, CHARACTERISATION OF IMPURITY PRESENT IN THE MANUFACTURE OF LOPRAZOLAM AND STUDY OF IMPURITY PROFILE BY HPLC

The reaction of 5- (2- chlorophenyl)- 7- nitro- 3H- 1, 4-benzodiazepin-2-thione (I) with glycine (A) by means of Na₂CO₃ in refluxing ethanol in water gives 2-carboxymethylamino-7-nitro-5-(2-chlorophenyl)-3H-1, 4-benzodiazepine(II), which is cyclized by means of dicyclohexylcarbodiimide in methylene chloride to afford 8-nitro-(2-chlorophenyl)-1,2-dihydro-1H,4H-imidazo[1, 2-a] [1, 4]benzodiazepin-1-one (III). The reaction of (III) with dimethylformamide diethylacetal (B) by means of triethylamine in benzene yields 8-nitro-2-(dimethylaminomethylene)-6-(2-chlorophenyl)-1,2-dihydro-1H, 4H-imidazo[1,2a] [1,4]benzodiazepin-1-one(IV), which is treated with N-methylpiperazine (C) in refluxing toluene result 8-nitro-(2-chlorophenyl)-2-(N-methylpiperazin-1- ylmethylene)- 1, 2- dihydro- 1H, 4H- imidazo[1,2a] [1,4] benzodiazepin-1-one (V). This compound is finally treated with methanesulfonic acid. The condensation of 6-(2-chlorophenyl)-1,2-dihydro-8-nitro-1H, 4H-imidazo [1,2-a] [1,4] benzodiazepin-1one, with 1(dimethoxymethyl)-4-methylpiperazine (II) gives the free base of Loprazolam Mesylate (III), which is then treated with methanesulfonic acid. 5-aryl-1, 3-di-hydro-7-substitued-2H-1,4-benzodiazepine-2-thiones were condensed with glycine in aqueous ethanol to give the previously unreported amino acid. Dicyclohexylcarbodiimide in dry methylenechloride cyclized. These acids to the imidazolobenzodiazepines which were found to oil unstable to hydrolytic solvents.