Eli Lilly and Company

John P Gardner

Billy G Jackson

John Robert Rizzo

Eddie V Tao

James A Aikins

Tony Yantao Zhang

Karl M Searl

Steven J Cyr

Michael T Fecteau

William David Miller

Stephen J Savage

Steven Savage

Steven Gallerani

The present invention relates to a process for the preparation of a biphenyl compound comprising combining a phenyl boronic acid derivative with an halobenzene derivative in the presence of a suitable additive in a suitable organic solvent with a suitable catalyst and a suitable base.

Process for preparing biphenyl compounds

The instant invention provides intermediates and processes for the preparation of compounds of formula IV ##STR1## wherein: n is 0, 1, or 2;

Intermediates and a process for preparing benzo[B]thiophenes

The invention relates to an improved process for preparing cephalosporins by reaction compounds such as 7-amino-cephalosporanic acid, 7-amino-3-deacetoxy-cephalosporanic acid or their derivatives with derivatives of .alpha.-amino acids in the presence of a properly immobilized penicillin acylase enzyme under the following conditions, independently, or in combination: (1) at a temperature ranging from 0.degree. C. to +20.degree. C.; or (2) at ambient pH; with a high molar ratio of .alpha.-amino acid to a cephalosporanic nucleus.

Process for preparing cephalosporins with penicillin acylase without pH

7.beta.-Amino-3-hydroxy-1-carba(1-dethia)-3-cephem-4-carboxylic acid esters are provided via cyclization of compounds of Formula IIA below. ##STR1## The 7.beta.-Amino-3-hydroxy-l-carba(1-dethia)-3-cephem-4-carboxylic acid esters are useful chiral intermediates in the synthesis of .beta.-lactam antibiotics.

Azetidinone intermediates to carbacephalosporins and process

7.beta.-Amino-3-hydroxy-1-carba(1-dethia)-3-cephem-4-carboxylic acid esters are provided via cyclization of cis-3-(substituted amino)-1-(2-substituted 2-oxoethyl)-4-substituted azetidinones. The 7.beta.-amino-3-hydroxy-1-carba (1-dethia)-3-cephem-4-carboxylic acid esters are useful chiral intermediates to .beta.-lactam antibiotics.

7.beta.-Amino-3-hydroxy-1-carba(1-dethia)-3-cephem-4-carboxylic acid esters are provided via cyclization of cis-3-(substituted amino)-1-(2-substituted 2-oxoethyl)-4-substituted azetidinones. The 7.beta.-amino-3-hydroxy-1-carba(1-dethia)-3-cephem-4-carboxylic acid esters are useful chiral intermediates to .beta.-lactam antibiotics.

Provided is a process for isolating cefaclor from an acylation reaction mixture by adding anthraquinone-1,5-disulfonic acid to the mixture. The acid highly selectively precipitates with cefaclor so that isolation and recovery is streamlined.

Process for isolation of cefaclor after enzymatic acylation

Crystalline p-nitrobenzyl 7.beta.-phenoxyacetylamino-3-hydroxy-1-carba(dethia)-3-cephem-4-carboxylat e and the crystalline mono-acetic acid solvate thereof are provided by mixing a carboxylic acid or a sulfonic acid with a solution of the 3-hydroxy ester in DMF or DMAC. Acetic acid provides the crystalline acetic acid solvate while other acids provide crystalline non-solvated 3-hydroxy ester. The crystalline forms are useful purified intermediates to antibiotics.

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Indianapolis, IN, United States of America

John P Gardner