Alprazolam → U 43465F

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A stirred solution of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (3.09 g., 0.01 mole) in dry dimethylformamide (50 ml.) was cooled in an ice bath, under nitrogen, and treated successively with N,N,N',N'-tetramethyldiaminomethane (1.229 g., 0.012 mole) and dropwise with acetyl chloride (0.923 ml., 0.013 mole). The cloudy mixture was kept in the ice bath for 1 hour and 55 minutes and poured into a mixture of ice and saturated sodium bicarbonate. The solution was saturated with sodium chloride and extracted five times with chloroform. The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo using xylene and toluene to help remove residual dimethylformamide. A solution of the resulting oil in absolute ethanol was acidified to a pH 3.5-4with a solution of p-toluenesulfonic acid (1 equivalent) in absolute ethanol. The remaining salt was crystallized to give 8-chloro-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine p-toluenesulfonate in three crops: 3.69 g. of melting point 196°-197° C., 0.612 g. of melting point 197°-198° C. and 0.022 g. of melting point 198.5°-199° C. The total yield was 79.9%. Ethanol crystallization of this material usually results in a product which contains residual ethanol or water. To remove the solvent, the first two crops (4.3 g.) were combined, recrystallized once from 95%-100% ethanol, redissolved in 95% ethanol and added slowly to boiling toluene at such a rate that the temperature of the distilling azeotrope remained between 85°-95° C. The level of the boiling mixture was maintained constant by the addition of fresh toluene. After the addition the temperature of the distillate was allowed to rise to 108° C. The mixture was cooled and the finely divided 8-chloro-1-[2-(dimethylamino)ethyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine was collected by filtration to give 3.747 g. of melting point 199°-199.5° C.

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