1. Field of the Invention
The present invention relates to the preparation of 1-carbacephems, such as the 1-carba(1-dethia)-3-cephem-4-carboxylic acids, and relates particularly to compounds and methods useful in such preparation. The invention provides novel methods which are readily performed and give high yield of product. Also provided are novel compounds which are useful for a variety of purposes, including as intermediates in the inventive processes.
2. Description of the Prior Art
The 1-carba(1-dethia)-3-cephem-4-carboxylic acids, hereafter the 1-carbacephalosporins or cephalosporin analogs, are known to be useful as antibiotics. Because of the importance of these newer .beta.-lactam antibiotics, there is a need for improved methods for their preparation.
The preparation of 1-carbacephalosporins and C-3 substituted methyl derivatives thereof is taught broadly by Christensen et al. in U.S. Pat. No. 4,226,866. Hirata et al., in U.K. Patent Application No. 2041923, teach a process for preparing 3-H and 3-halo 1-carbacephalosporins, while Hatanaka et al., Tetrahedron Letters, 24, No. 44, pp. 4837-4838 (1983), teach a process for preparing a 3-hydroxy-(.+-.)-1-carbacephalosporin.
In U.S. Pat. No. 4,665,171, issued to Evans et al. on May 12, 1987, there is described the [2+2] cycloaddition reaction of a chiral auxiliary and an imine to produce the chiral azetidinone. Specifically, a 4(S)-aryloxazolidin-2-one-3-ylacetyl halide, i.e. the chiral auxiliary, is reacted with an imine derived from a benzylamine and a 3-arylacrolein (e.g., cinnamaldehyde) to yield a 3.beta.-[4(S)-aryloxazolidin-2-one-3-yl]azetidin-2-one intermediate. The intermediates are characterized by a four member nitrogen ring having coupled thereto an N-benzyl group, the chiral auxiliary, and a --C2--R' group (where R' is phenyl, furyl or naphthyl).
As described by Evans, the intermediate compounds are converted to 1-carbacephalosporins through a multistep process. However, in order to be useful for the synthesis of carbacephems, the intermediates must first be modified by the removal of the chiral auxiliary and the N-benzyl group by a classical birch reduction. The resulting compound is reacylated with phenoxyacetyl chloride and elaborated to the diazo ketone, and then to the key enol intermediate. The enol is in turn converted to the loracarbef nucleus by standard enol chlorination and side-chain cleavage.
The Evans procedure is a useful synthesis route, but has several disadvantages. The exchange of the protective groups is especially undesirable. The chiral auxiliary is replaced by a V-side chain, and the N-benzyl group is reduced to the N-H function necessary for the key diazo insertion reaction. The only known method for removing the chiral auxiliary is a birch reduction, which method is incompatible with the 3-chlorocephem nucleus. Also, the diazo insertion chemistry is dependent on the use of a rhodium catalyst, which is undesirable because of cost and negative environmental impact.
Synthesis of carbacephems using a modified Dieckmann cyclization is described in B. G. Jackson et al., "Synthesis of Carbacephem Antibiotics: Synthesis Via Dieckmann Reaction Using Phenyl Esters to Direct the Regioselectivity of the Cyclization," Tetrahedron Letters, Vol. 31, No. 44, pp. 6317-6320 (1990). However, the Dieckman process depended on the resolution of a mixture of key amino acids by the selective enzymatic acylation of only the desired amino acid isomer. The resulting acylated product is converted to a key precursor, which upon base cyclization gives the enol.
This achiral Dieckman procedure suffers from several undesirable aspects. As with the Evans route, the Dieckmann procedure requires the side chain to be changed after the [2+2] cycloaddition reaction to form the azetidinone. Resolution limits the potential overall yield because half of the key intermediate azetidinone must be discarded. Also, the necessity of changing the ester protective groups (from methyl to .rho.-nitrobenzyl) adds steps and decreases efficiency of the process.
There has remained a need for a simplified chiral method of preparing carbacephems. The present invention satisfies this need by providing a synthesis route which is chiral, eliminates the need to change side chains, and yields the desired nucleus in high overall yield. These methods and new intermediate .beta.-lactam containing compounds represent significant advances over the prior art.
USPTO Backgrounds
USPTO Backgrounds