PROCEDE DE PREPARATION DE COMPOSE DE CEPHALOSPNE

1299734 Preparing 3-Methyl-cephalosporanic acid esters GLAXO LABORATORIES Ltd 10 March 1970 [11 March 1969] 12865/69 Heading C2A 7# -Acylamido-3-methyl-cephalosporanic acid esters are prepared by heating a 6#-acylamidopenicillanic acid 1-oxide ester in a solvent selected from ketones boiling at 75‹ to 120‹ C., esters boiling at 75‹ to 140‹ C., dioxan (the heating being for at least 2 hours at 75‹ to 110‹C. and for at least 45 minutes at higher temperatures in these solvents), and diethylene glycol dimethyl ether, in the presence of a hydrocarbyl sulphonic acid or a phosphorus acid. Suitable ketones and esters are ethyl methyl ketone, isobutyl methyl ketone, methyl n-propyl ketone, n-propyl acetate, n-butyl acetate, iso-butyl acetate, sec-butyl acetate and diethyl carbonate. Hydrocarbyl sulphonic acids may be alkyl, aryl or aralkyl sulphonic acids. Phosphorus acids may be ortho-, poly- or pyrophosphoric acids, phosphonic or phosphorus acids; the phosphonic acids may be aliphatic, araliphatic or aryl and the organic moiety may be substituted e.g. by halogen or nitro. Typical such acids are methane-, ethane-, dichloromethane-, trichloromethane-, iodomethane-, bromobenzene- and nitrobenzenephosphonic acids. The acid is preferably used in a proportion of 0À05 to 0À2 mole and not exceeding 1À0 mole per mole of the penicillin oxide. The reaction is preferably carried out under reflux using a desiccant in the reflux return tube to remove water formed during the reaction. The product is isolated by removing the solvent e.g. by evaporation, and the acid, e.g. by water-washing if the solvent is water-immiscible or else by neutralizing with e.g. CaCO 3 or MgO and filtering, optionally decolorising the charcoal and precipitating the product with water, and crystallising or purifying by chromatography. The penicillin 1-oxide ester is obtained by esterifying the 3-carboxyl group and then oxidising the 1-sulphur group with an oxidising agent in an amount such that at least 1 atom of active oxygen per atom of thiazolidine sulphur is present. Typical oxidising agents are metaperiodic acid, peracetic acid, monoperphthalic acid, m-chloroperbenzoic acid, or t-butylhypochlorite with a weak base, e.g. pyridine. The penicillin 1-oxide ester preferably has protecting groups on any radicles present which are reactive in the various processes.