PROCESS FOR PREPARING AZETIDINONES

摘要

A process for preparing azetidinones of the formulde 1 and 2A and the stereoisomers of the latter of formula 2B 2A 2B wherein R is an -amino-protecting group commnonly used in penicillin chemistry and is selected from the group consisting of H, C1-C6 alkyl, phenyl,(optionally substituted in the o-, m-, or p- positions by CH3, r, Cl, OCN3, or a nitro group), benzyl, 2-thienylmethyl, tetrazol (1-, 2-, or 5-)-ylmethyl, 2-phenyl-5-methylisoxazol-4-yl, phenoxymethyl, and R5O- and R5S, wherein R5 stands for C1-C6 alkyl, phenyl, benzyl or trichloroethyl; it should be noted that the value of R is immaterial to the process described: -l-X is selected from the group consisting of H, SCl, SBr, Cl, Br, and OH. In the case where X is OH the group RCX=N- is better represented as the amide, RCONH-, group; RCX=N may also represent the phthalimido, succinimido-, or tritylaminogroup; R1 is a carboxy-protecting group commonly used in penicillin chemistry and is selected from the group consisting of hydrogen, a cleavable acid protecting group selected from C1-C6 alkyl, methoxymethyl, phenoxymethyl, benzyloxmethyl trichlorethyl, benzyl, ?-halobenzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl and trimethylsilyl; R2 is selected from hydrogen and methoxy; Y and Z are the same or different and each selected from the group consisting of Cl and Br; in addition Z may be I, OCH3, OCOCH3, OCOH, NO3, N3, NH-phenyl SCl,-and SBr; R3 and R4 are the same or different and each selected from the group consisting of H, Cl, Br I, SCl, SBr, OCH3, OC2H5, OCOCH3, OCOH, OH, SCH3, S-phenyl, S-tetrazolyl, S-triazolyl, N3, NO3, CN, N(CH3)2 and NH-phenyl, with the proviso that one of R3 or R4 must be H and that R3 and R4 may only both be H when X is H or in the compounds of formula 2B by treating a 2-(substituted methyl)penicillin or a 3,3-disubstituted cepham derivative with a halogenating agent followed by treatment with a base, or by treating an unsym - azetidinone disulfide with a hologenating agent. These compounds are useful intermediates for the syntheses of modified cephalosporins and of analogues of these compounds in which the sulfur is replaced by oxygen or nitrogen, examples being the so-called 1-oxa-cephalosporins and 1-azacephalosporins.