GB1347208A - Method of preparing alpha-carboxybenzylpenicillin - Google Patents

Abstract

1347208 Preparing α-carboxybenzylpenicillin INSTYTUT PRZEMYSLU FARMACEUTYCNEGO 25 April 1972 [5 May 1971] 19122/72 Heading C2A α-Carboxybenzylpenicillin and salts thereof, having the Formula (1): in which X is hydrogen or the cation of an alkali metal or alkaline earth metal, are prepared by condensing 6-aminopenicillanic acid (6-APA) or a salt thereof with an acylating derivative of an N-substituted or unsubstituted monoamide of phenylmalonic acid, said acid having the Formula (2): wherein R 1 and R 2 each represents hydrogen, a straight or branched aliphatic radical (preferably having 1 to 4 carbons), a cycloaliphatic radical, a substituted or unsubstituted aryl radical or an alkylaryl radical, and R 1 and R 2 may be identical or different; to give an amide of α- carboxybenzylpenicillin of Formula (3): wherein R 1 , R 2 and X have the aforesaid meanings; and then hydrolysing the said amide (3) to give the desired compound (1). The preferred acylating derivative of the compound (2) is its mixed anhydride with an alkyl (e.g. ethyl) chloroformate. The condensation with 6-APA is carried out in organic or organic-aqueous (e.g. acetone/water) medium containing sodium bicarbonate. The amide (3) may be hydrolysed directly in the reaction mixture, preferably after evaporation of the organic solvent, or may be first isolated and re-crystallized. The hydrolysis step is effected in aqueous solution at a pH below 8À5, if required with warming, e.g. to about 35‹ C., using a saturated solution of borax, sodium bicarbonate or disodium phosphate. The product (1) is then isolated by acidifying the solution, extracting the product with ether and precipitating as the Na salt by adding ethereal sodium ethylcapronate. Reference has been directed by the Comptroller to Specification 1,004,670.