Carbon Dioxide → ethyl (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylate

Participants

Reaction Steps

25.4 g (100 mmol) of (S)-5-chloro-6-fluoro-1,10a-dihydro-2H-azeto[2,1-c][1,4]benzodiazepine-4,10(9H)-dione were dissolved in 125 ml of N,N-dimethylformamide, treated at -30° with 4.8 g (110 mmol) of sodium hydride dispersion (55-65% in oil, washed with n-hexane) and deprotonated for 40 min. at -30° to -18°. A solution of 26.86 g (100 mmol) of phosphoric acid diphenyl ester chloride in 5 ml of N,N-dimethylformamide was added at -60° and the mixture was stirred at max. -45° for 35 min. In the meanwhile and separately, 12.3 g (110 mmol) of potassium tert.-butylate were dissolved in 30 ml of N,N-dimethylformamide and treated at -60° C. with 12.2 g (107 mmol) of ethyl isocyanoacetate. The deprotonated ethyl isocyanoacetate was cooled to -70° and the reaction mixture was added dropwise using a dropping funnel cooled with dry ice at max. -65° within 5/4 hours. The mixture was stirred in an acetone/dry ice bath for 1 hour, neutralized with 12 ml of acetic acid and poured into 500 ml of ice-water. The mixture was extracted five times with methylene chloride (a total of 1.2 l), dried over magnesium sulfate and evaporated to dryness. By chromatography of the residue on 1.5 kg of silica gel while eluting with ethyl acetate there were obtained 14.4 g (41%) of ethyl (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylate of m.p. 161°-163°.

Provenance & Evidence