Citric Acid → 5,6-Dihydroimidazo[1,2-a][1]benzazepin-4-one

Participants

Reaction Conditions

Reaction Steps

Charge a reactor with 281 kg of 2-MeTHF and 31 kg of Diisopropylamine Cool to −80 to −70° C., and charge 86 kg of n-butyl lithium in n-hexane slowly maintaining the temperature a at −80 to −70° C. and stir for 1 to 3 h. Charge 195.8 kg solution of ethyl 3-(2-(1H-imidazol-1-yl)phenyl)propanoate in 2-MeTHF into the reactor slowly at −80 to −70° C., and stir for 2 to 4 h at −80 to −70° C. (in process HPLC<3%, ethyl 3-(2-(1H-imidazol-1-yl)phenyl)propanoate). Charge 47.8 kg of ethanol into the reactor slowly at −80 to −70° C., and stir for 0.5 to 2 h at −80 to 70° C. Charge 310 kg of MTBE into the reactor slowly, maintaining internal temp below −25° C. Adjust pH to 7.5 with 292 kg of 10% Citric acid aqueous solution. Adjust the temperature to about 0° C. Separate out aqueous layer, and wash organic layer with 202 kg of 25% NaCl aqueous. Separate the layers, concentrate the organic layer under reduced pressure to 41 to 82 L, maintaining the internal temp below 40° C. Extract the aqueous layer with 200 kg of dichloromethane. Combine the organic layers, and stir for 0.5 to 1 h at 15 to 25° C. Filter through a pad of silicon dioxide (20 kg), and wash the pad with 60 kg of dichloromethane. Concentrate the filtrate under reduced pressure to 82 to 123 L, maintaining the internal temperature below 40° C. Charge 170 kg of MTBE to the residue, and concentrate under reduced pressure to 82 to 123 L, maintaining the internal temperature below 50° C. Charge 208 kg of MTBE, and stir for 10 to 15 minutes (in-process control indicated 10.8% 2-MeTHF and 4.6% DCM). Charge 279 kg of MTBE and concentrate under reduced pressure to 82 to 123 L, maintaining an internal temperature below 50° C. (residual 2-MeTHF %=1.6%, residual DCM %=2.7%). Charge 14.5 kg of Methyl acetate into the residue, and heat the mixture to reflux for 30 to 60 minutes. Cool the mixture to 0 to 15° C. and stir for 6 to 8 h at 0 to 15° C. Isolate the solid by centrifugation, and wash the cake with 35 kg of MTBE. Dry the resulting solid to give 15.8 kg of 5,6-dihydroimidazo[1,2-a][1]benzazepin-4-one. LC/MS=199 (M+1), 419 (2M+23).

Provenance & Evidence