Eli Lilly and Company

Lowell D Hatfield

Jack W Fisher

Larry C Blaszczak

James E Ray

Richard C Hoying

The present invention is directed to azetidinone compounds of the following formula: ##STR1## which are useful as intermediates to carbacephalosporins: ##STR2## These carbacephalosporins are useful as antibacterials.

Chiral intermediates for the preparation of carbacephems

This invention is directed to carbacephems and methods for their preparation: ##STR1## In the foregoing formulae, R.sup.3 represents phenyl, C.sub.1 -C.sub.4 alkylphenyl, halophenyl, C.sub.1 -C.sub.4 alkoxyphenyl, naphthyl, thienyl, furyl, benzothienyl, or benzofuryl.

Intermediates for the preparation of carbacephems

A chiral process for preparing compounds of the formula: ##STR1## from a compound of the formula: ##STR2## in which the compound formula (IV) is reacted with trimethylsilyl iodide to remove the chiral auxiliary at the 7-position and the carboxy protecting group. The process allows for the retention of the amino and carboxy protecting groups throughout the preparation of Compound IV. Also disclosed are novel intermediates.

Methods and compounds for the preparation of carbacephems

Penicillin and cephalosporin sulfides and sulfoxides are readily converted to sulfones in the presence of ruthenium tetroxide.

Oxidation process

Novel halogenating compounds, derived from triaryl phosphites and chlorine or bromine are employed to convert 7-acylamino-3-hydroxy-3-cephem compounds to 7-acylamino-3-halo-3-cephems and the corresponding C-7 imino halide cephem derivatives. The product 3-halo-3-cephems are antibiotic compounds or intermediates thereto.

Thiazolinoazetidinones and process therefor

Novel halogenating agents are derived from triaryl phosphites and chlorine or bromine. They are useful in converting 7-acylamino-3-hydroxy-3-cephem compounds to 7-acylamino-3-halo-3-cephems and the corresponding C-7 imino halide cephem derivatives.

Halogenating reagents

Process for halogenation of .beta.-lactam compounds

Penicillin and cephalosporin imino halides are prepared by reacting of 6-acylaminopenicillins or 7-acylamino cephalosporins with a novel chlorinating compound derived from a triaryl phosphite and chlorine or bromine. The imino halide products are intermediates in the preparation of antibiotic compounds.

Process for preparation of penicillin and cephalosporin imino halides

Novel azetidinone mercury sulfides are prepared by the reaction of penicillin derived thiazolineazetidinones with a mercuric halide in the presence of an alcohol or glycol. They are useful intermediates in the preparation of cephalosporin compounds.

Azetidinone mercury sulfides and process therefor

The present invention is directed to a process for the displacement of the acetoxy group of a cephalosporanic acid by a sulfur nucleophile, in an organic solvent and under essentially anhydrous conditions.

Cephalosporin displacement reaction

p-Nitrobenzyl esters of cephalosporins are reductively cleaved with zinc and .alpha.-hydroxycarboxylic acids, e.g., the p-nitrobenzyl ester of the cephalosporin antibiotic, cephalexin, is reacted in an inert solvent with zinc and mandelic acid to provide the antibiotic, cephalexin, as the free acid in yields greater than 85 percent.

De-esterification process for cephalosporins

Cephalosporin sulfoxides are reduced to the corresponding cephalosporin with acyl bromides, e.g., acetyl bromide, in the presence of a bromine scavenger, e.g., an olefin, acetylene, phenol, phenol ether, or an organophosphite. For example, p-nitrobenzyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate sulfoxide is reduced with acetyl bromide in the presence of amylene to p-nitrobenzyl 7-phenoxyacetamido-3-methyl-3-cephem-4-carboxylate.

Reduction process for cephalosporin sulfoxides

Penicillin sulfoxides, notably the sulfoxides of penicillin V and penicillin G, are heated with amine salts of dichloromethane phosphonate in 1,1,2-trichloroethane to provide superior yields of deacetoxycephalosporins. The process is especially valuable in providing greater yields of the intermediate in the synthesis of the commercial antibiotic, cephalexin.

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Bargersville, IN, United States of America

Lowell D Hatfield