PROCESS FOR THE PREPARATION OF CEPHALOSPORINS

摘要

1289814 Preparing 3-deacetyl-cephalosporins E R SQUIBB & SONS Inc 13 Jan 1970 [17 Jan 1969] 1682/70 Heading C2A 3-Deacetyl-cephalosporins of formula wherein R represents C 1 -C 7 alkyl, phenyl, X- substituted phenyl, naphthyl, X-substituted naphthyl, pyridyl, pyrryl, furyl, thienyl, pyridyl-(C 1 -C 7 ) alkyl, pyrryl-(C 1 -C 7 ) alkyl, furyl- (C 1 -C 7 ) alkyl, thienyl-(C 1 -C 7 ) alkyl, or wherein R2 is C 1 -C 5 alkyl, phenyl, X-substituted phenyl, naphthyl, X-substitutednaphthyl, cyclohexadienyl, pyridyl, furyl, pyrryl, thienyl, pyridyl-(C 1 -C 7 )alkyl,pyrryl-(C 1 -C 7 )alkyl, furyl- (C 1 -C 7 ) alkyl or thienyl-(C 1 -C 7 ) alkyl; R3 is C 1 -C 7 alkyl, monocyclic aryl or monocyclic aryl-(C 1 -C 7 ) alkyl; R4 and R5 are each hydrogen, C 1 -C 7 alkyl, monocyclic aryl or monocyclic aryl-(C 1 -C 7 ) alkyl; n is 1, 2 or 3 ; X is C 1 -C 7 alkyl, C 1 -C 7 alkoxy or halo; and R1 is triphenylmethyl, diphenylmethyl or benzyl, are prepared by hydrolysing the corresponding cephalosporanic acid lactones of formula wherein R and R1 are as before, at a pH of about 6 to 11.5 and a temperature between ambient and 100‹ C. The aqueous reaction medium preferably includes a solvent for the lactone, e.g. dimethylsulphoxide, dimethylformamide, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, ethylene glycol or dioxane. The pH may be achieved by use of a hydroxide of K, Na, Mg, Li, or Ca, or a buffer solution, e.g. of potassium phosphate, boric acid/borax or NaHCO 3 /Na 2 CO 3 . The presence of hydrogen-bonding nucleophilic hetero-atom functions (e.g. amino, sulphydryl and phenolic hydroxy) is undesirable and interferes with the hydrolysis procedure and buffers containing such groups are preferably not used. The compounds prepared by the said process are useful intermediates for preparing antibiotically active cephalosporins. For example the 3-hydroxyl group may be acylated with benzoyl chloride, the R group which acts to protect the7-amino group during this acylation then being removed, either with an aqueous acid to give 3-benzoyloxy-7-aminocephalosporanic acid, or together with the 3-benzoyloxy group by hydrogenolysis to give 3-deacetoxy-7-aminocephalosporanic acid. Alternatively the 3- hydroxyl group may be alkylated with diazomethane or diphenyl diazomethane, the product treated with acetic anhydride and pyridine to acylate the 3-hydroxy group, and then subjected to hydrogenolysis to give 7-aminocephalosporanic acid. The 7-amino compounds may be N-acylated to give known cephalosporin antibiotics.