Process for the synthesis of cefaclor
The present invention relates to a process for the synthesis of cefaclor, which process comprises reacting 7-amino-3-chloro cephalosporanic acid (7-ACCA) with D-phenylglycine in activated form (PGa) in the presence of an enzyme in a reaction mixture to form cefaclor, wherein at least part of 7-ACCA and/or PGa are added to the reaction mixture during the course of the reaction. The invention also relates to an aqueous mixture comprising an amount of cefaclor of >10 (w/w) %, an amount of 7-amino-3-chloro cephalosporanic acid of <2 (w/w) %, and an amount of D-phenyl glycine of <2 (w/w) % and a process for the recovery of cefaclor from this aqueous mixture. The invention also relates to cefaclor in crystal form having an absorbance at 400 nm (A 400 ) of less than 0.250.
1. A process for the synthesis of cefaclor, said process comprising reacting 7-amino -3-chloro cephalosporanic acid (7-ACCA) and a mutant penicillin acylase of E. coli having a beta subunit wherein said mutant penicillin acylase has L-alanine substituted for L-phenylalanine at position 24 of the beta-subunit with added D-phenylglycine methyl ester in a reaction mixture at a pH of 7 to form cefaclor, wherein the added D-phenylglycine methyl ester is added at a constant rate for at least 90 minutes to the reaction mixture during the course of the reaction, wherein the added D-phenyl glycine methyl ester is added in a total amount to the reaction mixture in a 1.1 molar ratio to the 7-ACCA .
2. The process according to claim 1 , wherein the synthesis reaction is carried out at a temperature of between 5 and 35° C.