Process for 3-alkyl and 3-phenyl cephalosporins
AssigneeEli Lilly and Company
InventorWayne Alfred Spitzer
Life of this patent
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Abstract
7-Amino-(or 7-acylamido)-3-(disubstituted-amino)-3-cephem-4-carboxylic acid esters are prepared with the corresponding 3-chloro-3-cephem ester or 3-alkyl-(or aryl)-sulfonyloxy-3-cephem esters and a secondary amine, e.g., diphenylmethyl 7-[2-(2-thienyl)acetamido]-3-morpholino-3-cephem-4-carboxylate is prepared with the corresponding 3-methyl-sulfonyloxy ester and morpholine. The 3-amino-substituted cephem esters are useful intermediates undergoing reduction with diborane to the corresponding 3H-3-cephem esters or, alternatively, they are reacted with Grignard reagents, e.g., phenylmagnesium bromide to provide, for example, the 3-phenyl-3-cephem ester.
Claims5
The process for preparing a 3-alkyl or 3-phenyl-3-cephem ester of the formula ##STR21## which comprises (1) reacting a compound of the formula ##STR22## in an inert ether solvent at a temperature between about -80.degree. and 5.degree. C. with the Grignard reagent
- BrMgR.sub.5
- wherein R.sub.5 is C.sub.1 -C.sub.4 alkyl, or phenyl, (2) acidifying the reaction mixture and (3) separating the 3-alkyl- or 3-phenyl-3-cephem ester from the reaction mixture;
- where in the above formulas R' is C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.3 cyanoalkyl, phenyl, halophenyl, methylphenyl, hydroxyphenyl, nitrophenyl, aminophenyl, or methoxyphenyl;
- or R' is a group of the formula ##STR23## wherein a and a' are independently hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen, nitro, amino, or carboxy, Z is 0 or S, and m is 0 or 1;
- or R' is a group of the formula ##STR24## wherein P is thienyl, phenyl or ##STR25## wherein a and a' are as defined above;
- Q is hydroxy, amino, carboxy or --SO.sub.3 H;
- or R' is a group of the formula
- R"--CH.sub.2 --
- wherein R" is thienyl, furyl, 2-oxazolyl, 2-thiazdyl, or 1-tetrazdyl;
- R.sub.1 is benzyl, 4-nitrobenzyl, 4-methoxybenzyl, diphenylmethyl, t-butyl or 2,2,2-trichloroethyl;
- and R.sub.2 and R.sub.3 when taken separately are independently C.sub.1 -C.sub.4 alkyl, benzyl or phenethyl, and when taken together with the attached nitrogen are pyrrolidino, piperidino, morpholino, thiomorpholino or a 4-substituted piperazino group of the formula ##STR26## wherein R.sub.4 is C.sub.1 C.sub.4 lower alkyl.
Dependencies are inferred from the claim text.