Hydrochloric Acid → (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

5.00 kg (17.63 mol) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl]-2-hydroxy-propionic acid (G) and 6.28 kg (19.39 mol) 1-(1H-imidazol-1-yl-carbonyl)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-piperidine (F) were suspended in 40.0 L tert.-amylalcohol, before 20 L solvent were distilled off under normal pressure. Then the reaction mixture was cooled to 25° C., 21.76 kg (38.78 mol) potassium tert.butoxide solution in THF was added, before the mixture was heated to 35° C. for 1.5 hours. After the reaction was complete the mixture was cooled to 25° C. cooled and 9.64 kg (79.33 mol) hydrochloric acid (30%), 25.0 L water and 25.0 L acetone were added successively, before the mixture was inoculated with 5 g ethyl (1R)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-carboxy-2-[4-amino-3-chloro-5-trifluoromethyl-phenyl]-1-piperidinecarboxylate. After stirring overnight the suspension was cooled to 0° C. and stirred for a further hour. The product was separated off, washed twice with 15.0 L water and 15.0 L acetone and dried.

Provenance & Evidence