Chemistry of cephalosporin antibiotics. XXI. Conversion of penicillins to cephalexin

Abstract

A laboratory synthesis from the biosynthetic penicillins is described for cephalexin (7), an orally active deacetoxycephalosporin antibiotic. Penicillins V and G were converted to sulfoxide trichloroethyl esters 3a and 3b, respectively, by an esterification to compounds 2a and 2b followed by sulfoxidation. The sulfoxide esters 3a and 3b were rearranged thermally to their corresponding deacetoxycephalosporin esters 4a and 4b. Proof of structure for 4a and 4b was supplied by their independent syntheses from 7-aminodeacetoxycephalosporanic acid (9). N-Deacylation of 4a and 4b afforded a common amino ester, 7-aminodeacetoxycephalosporanic acid trichloroethyl ester (5d). Compound 5d was reacylated in mixed anhydride coupling reactions with A'-trichloroethyloxycarbonyl-D-a-phenylglycine and with A'-íerí-butoxycarbonyl-D-a-phenylglycine. The doubly protected cephalexin derivatives 6 and 12 were deblocked yielding cephalexin in good yield.

Studies on the active site of deacetoxycephalosporin C synthase

“…Synthesis of G-7-ADCA (11) (11) was prepared from 7-ADCA (5.1 mmol, 1.02 g) and phenylacetyl chloride (7.56 mmol, 1 ml) (Chauvette et al, 1971) using THF as the organic solvent and NaOH as the base. The product was solvent extracted into ethyl acetate to give a pale yellow solid (475 mg, 26 %).…”

“…Crawford et al, 1995). Alternatively, useful cephems may be obtained by the chemical ring expansion of the corresponding penicillin (Morin et al, 1963;Chauvette et al, 1971;Colvin, 1992).…”

Thionation of bicyclic ß-lactam compounds by Lawesson’s reagent

“…Compound 3 was synthesized according to Chauvette et al 8 Different conditions for thionation were attempted, starting material was recovered unless high temperature (100°C), two equivalents of Lawesson's reagent, and two hours of reaction were applied. Under these conditions, a compound was isolated in excellent yield (89%) after column chromatography.…”

Am1 Study on the Conformations of Zwitterions of Benzylpenicillin

“…[3] In practice, most penicillins are unstable in aqueous solutions. The dipolar character of the molecule has been expected to influence selective penetration through the porin channels of the cell membrane.…”

“…[5,6,7] In this context, HMO method on methyl perturbations of oxazoles [8] and isoxazoles [9] and AM1 study on conformational analyses [10,11,12] , [1,3]sigmatropic hydrogen migration [13,14,15] , electronic structure [16,17] , correlation studies 18 and computational studies [19] were carried out.…”