GB1358374A - Process for the preparation of cephalosporin derivatives - Google Patents

Abstract

1358374 Preparing 3-methyl-cephalosporins from penicillin sulphoxides TOYO JOZO KK 13 April 1973 [20 April 1972] 17825/73 Heading C2A 7 - Acylamino - 3 - methyl - #<SP>3</SP> - cephem - 4- carboxylic acids and esters thereof, having the general formula wherein A is an acyl radical and R is a carboxylprotecting esterifying group or hydrogen, are prepared by ring-expanding a corresponding 6- acylaminopenicillin sulphoxide ester by heating in the presence of phenacyl bromide: in a reaction-inert organic solvent, and subsequently if desired, de-esterifying the resulting cephalosporin ester. The acyl radical A is preferably one that is stable under the reaction conditions, e.g. phenylacetyl or phenoxyacetyl, or may be a radical giving a desirably active cephalosporin, e.g. thienylacetyl or α-amino-phenylacetyl. If the acyl radical contains a group which would be affected by the reaction, e.g. amino, carboxyl or hydroxyl, this is conventionally protected before the reaction and subsequently de-protected. The esterifying group R is preferably one that is easily removable without affecting the remainder of the cephalosporin molecule, e.g. p-methoxybenzyl, di-p-methoxyphenylmethyl, trityl, diphenylmethyl, benzoyloxymethyl, phenaeyl, p-bromophenacyl, benzhydryl, tert.butyl and trimethylsilyl, which groups are removed by mild hydrolysis. Alternatively the esterifying group may be one that is removed by reduction, such as benzyl, o-nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, phenacyl or p-bromophenacyl. The ring expansion is suitably performed using 0À03 to 0À1 mole phenacyl bromide per mole of penicillin sulphoxide ester, in a solvent such as dimethyl-sulphoxide, -formamide or -aniline, n-butanol, ethylene glycol, diethylene glycol dimethyl ether, methyl isobutyl ketone, methyl amyl ketone, butyl acetate or xylene. The solvent should be one of as high a boiling point as is practicable, the preferred reaction temperature being 100-200‹ C. (e.g. 130‹-170‹ C.). The product is recovered by pouring the reaction mixture into ice-water, causing the desired cephalosporin ester to precipitate. It may be separated by filtration or extraction with a water-immiscible organic solvent (e.g. ethyl acetate) followed by evaporation of the solvent, and is then purified by re-crystallization.