Back to results
US 4,053,286 AGranted
Process for the preparation of cephalosporin antibiotics
AssigneeMerck & Co., Inc.
InventorLeonard M. Weinstock
Life of this patent
Estimating the term…
Abstract
An improved process for preparing the compound 7.beta.-(2-thienylacetamido)-7-methoxy-3-carbamoyloxymethyl-3-cephem-4-car boxylic acid or its esters, from the compound 7.beta.-(D-5-amino-5-carboxyvaleramido)-3-carbamoyloxymethyl-7-methoxy-3-c ephem-4-carboxylic acid, by conducting the transacylation of the latter compound in the presence of commercially available alumino-silicate zeolites, also known as "molecular sieves." The process can be employed to prepare a cephalosporin with a desired 7-acylamido group from cephalosporins having a broad range of different 7-acylamido groups without having to isolate and purify a 7-amino intermediate. The final products have utility as broad spectrum antibiotics.
Claims18
The process of preparing a compound of the formula:
- ##STR7## wherein R.sub.1 is hydrogen or methoxy;
- A is carbamoyloxy or loweralkanoyloxy;
- R' is an acyl group having the formula:
- ##STR8## wherein Y is hydrogen, carboxy, --NHR.sub.2 or --OR.sub.5 ;
- R.sub.2 is hydrogen, trichloroethoyxcarbonyl, tertiary butoxycarbonyl, benzoylmethoxycarbonyl, trimethylsilyl, p-methoxybenzyloxy, 2-nitrophenylsulfenyl, 2,4,-dinitrophenylsulfenyl, chloroacetyl, p-nitrophenylthio, p-nitrobenzenesulfonyl, p-toluenesulfonyl, methanesulfonyl, benzoyl, p-chlorobenzoyl, p-nitrobenzoyl or toluoyl;
- R.sub.3 is phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 1-tetrazoyl, C.sub.1 -C.sub.4 loweralkylphenyl, halophenyl, hydroxyphenyl, a C.sub.1 -C.sub.4 loweralkyloxyphenyl;
- R.sub.4 is methyl, ethyl, tertiary butyl, phthalimidomethyl, succinimidomethyl, phenacyl, p-bromophenacyl, 2,2,2-trichloroethyl, 2-methylthioethyl, 2-(p-methylphenyl)ethyl, 2-(p-methylphenyl)sulfonylethyl, 2-methylaminoethyl, 2-chloro-(or bromo)ethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, 3,5-dinitrobenzyl, 2,4,6-trimethylbenzyl, 3,5-dichloro-4-hydroxybenzyl, benzhydryl, p-methoxybenzhydryl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, p-nitrophenyl or 3,5-dinitrophenyl, acetyl, benzoyl or thienylacetyl;
- R.sub.5 is hydrogen, methyl, ethyl, phenacyl, p-bromophenacyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, 3,5-dinitrobenzyl, 2,4,6-trimethylbenzyl, benzhydryl, p-methoxybenzhydryl or methoxymethyl;
- which consisting essentially of reacting a compound of the formula:
- ##STR9## wherein B' is ##STR10## wherein R.sub.2, R.sub.4 are as defined above;
- or an acyl group R' which is different than the final desired substituent;
- with an acylating agent having the formula:
- ##STR11## wherein R.sub.3 and Y are the same as before defined, in the presence of a synthetic zeolite of the type 3A, 4A, 5A, or 13X, containing from about 0 to 30% by weight water of hydration;
- and then cleaving B' by either prolonging the reaction time to between about 30 minutes to about 30 hours;
- or by adding a loweralkanol of 1 to 6 carbon atoms, loweralkylthiol of 1 to 6 carbon atoms, benzyl alcohol or hydrochloric acid to yield the final product, and recovering the final product.
12 more elements
The process of preparing the compound:
- ##STR12## wherein R.sub.4 is hydrogen, or methyl, ethyl, tertiary butyl, phthalimidomethyl, succinimidomethyl, phenacyl, p-bromophenacyl, 2,2,2-trichloroethyl, 2-methoxythioethyl, 2-(p-methylphenyl)-ethyl, 2-(p-methylphenyl)sulfonylethyl, 2-methylaminoethyl, 2-chloro(or bromo)ethyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, 3,5-dinitrobenzyl, 2,4,6-trimethylbenzyl, 3,5-dichloro-4-hydroxybenzyl, benzhydryl, p-methoxybenzhydryl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl p-nitrophenyl, 3,5-dinitrophenyl, acetyl, benzoyl or thienylacetyl;
- and A is carbamoyloxy or acetoxy;
- which consists essentially of reacting the starting compound of the formula:
- ##STR13## wherein A is carbamoyloxy or acetoxy;
- and R.sub.2 is hydrogen, or trichloroethoxycarbonyl, tertiary butoxycarbonyl, benzoylmethoxycarbonyl, trimethylsilyl, p-methoxybenzyloxy 2-nitrophenylsulfenyl, 2,4-dinitrophenylsulfenyl, chloroacetyl, p-nitrophenylthio, p-nitrobenzenesulfonyl, p-toluenesulfonyl, methanesulfonyl, benzoyl, p-chlorobenzyl, p-nitrobenzoyl, or toluoyl;
- with 2 to 4 molar excess of 2-(2-thienyl)-acetyl chloride;
- from about 0.5 to about 2 times (weight basis) of a synthetic zeolite, type 3A, 4A, 5A, or 13X, containing from about 0 to 30% by weight water of hydration;
- at a temperature of between about 50.degree.-90.degree. C.;
- in an inert solvent;
- for a period of from about 30 minutes to 30 hours;
- then optionally adding from about 0.5 molar equivalent to about 3 molar equivalents, based on the amount of the starting compound, of a cleaving agent which is (1) lower alcohol of 1-6 carbon atoms, (2) loweralkyl thiol of 1-6 carbon atoms, (3) benzyl alcohol, or (4) hydrochloric acid, and recovering the desired product.
8 more elements
Dependencies are inferred from the claim text.