PROCEDE DE PREPARATION DES ALPHA-CARBOXYARYLMETHYL- ET ALPHA-CARBOARYLOXYARYLMETHYL PENICILLINES

1377301 Acylating 6-aminopenicillanic acid PFIZER Inc 11 Jan 1972 [1 Oct 1971] 1300/72 Heading C2C 6 - Aminopenicillanio acid (6 - APA) is N- acylated to give α-carboxybenzylpenicillin, α-(5- indanyloxycarbonyl) benzylpenicillin or α-carboxy-3-thienylmethylpenicillin by reacting thionyl chloride in an ether reaction solvent with phenylmalonic acid, 2-phenyl-2-(5-indanyloxycarbonyl) acetic acid, or 3-thienylmalonic acid, and contacting the resulting reaction mixture with an aqueous solution of 6-APA while maintaining the pH at between 5 and 9 to N-acylate the 6-APA. The reaction with thionyl chloride is carried out at about 20-80‹ C., using about equimolar quantities of the reactants, preferably in the presence of dimethylformamide as a catalyst. The ether used as reaction solvent may be isopropyl ether, diethyl ether, tetrahydrofuran, dioxan or dimethoxyethane. The acid chloride solution thus produced is used directly, if desired after dilution with waterimmiscible solvent (e.g. hexane), to acylate the 6-APA. The latter is in aqueous solution, which may contain acetone to reduce hydrolytic sidereactions. The acylation is effected at - 20‹ to 30‹ C., the preferred pH of 6 to 8 being maintained by adding a base. The 2-phenyl-2-(5-indanyloxycarbonyl) acetic acid reactant may be produced in situ by a preliminary reaction of thionyl chloride and phenylmalonic acid in the ether solvent, followed by addition of 5-indanol to give the said reactant. Reference has been directed by the Comptroller to Specification 1,004,670.