Process for the synthesis of cefaclor

Inventors

Moody, Harold Monro • Dooren, Theodorus Johannes Godfried Maria Van

Assignees

Centrient Pharmaceuticals Netherlands BV

Abstract

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 (A400) of less than 0.250.

Core Innovation

The invention relates to an enzymatic synthesis of cefaclor by reacting 7-amino-3-chloro cephalosporanic acid (7-ACCA) with D-phenylglycine in an activated form, in a reaction mixture in the presence of penicillin acylase, optionally immobilized. A key aspect is how the substrate is supplied during the enzymatic condensation reaction, including embodiments in which at least part of 7-ACCA and/or the activated D-phenylglycine is fed during the reaction, including continuous dosing.

The process maintains a low PGa:7-ACCA molar ratio, with explicit ranges below 2, preferably below 1.8, and down to 1.2. The description also includes recovery of cefaclor from an aqueous mixture and yielding cefaclor in substantially pure form, including cefaclor monohydrate formation.

The disclosed approach is reported to provide high conversions and reduced by-product formation, improving cefaclor recoverability. Low coloration is described using an A400 criterion, and the document includes representative examples and a comparative example with a non-fed case showing viscous suspension and poor separation.

Claims Coverage

The claim set centers on enzymatic cefaclor synthesis using penicillin acylase, with controlled addition of the activated D-phenylglycine derivative during the reaction and an explicit molar ratio relative to 7-ACCA. One dependent feature adds a temperature constraint.

Overall, the claims cover enzymatic cefaclor synthesis with a mutant E. coli penicillin acylase beta subunit, constant-rate addition of D-phenylglycine methyl ester during the reaction, a total 1.1 molar ratio relative to 7-ACCA, pH 7, and an optional temperature range of 5 to 35°C.

Stated Advantages

Documented Applications