Process for the production of 7-acylamidocephalosporins
AssigneeMerck & Co., Inc.
InventorsBurton G. Christensen, Lovji D. Cama, Meyer Sletzinger, Sandor Karady
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Abstract
New 7-diacylimido cephalosporins are produced by reacting 7-acylamido cephalosporins with an acylating agent in the presence of a silyl reagent. The 7-diacylimido cephalosporins are cleaved to produce cephalosporins containing a different acylamido moiety. Thus, the aminoadipoyl group of cephalosporins produced by fermentation is replaced by a different acyl group by the process of the present invention. The cephalosporins produced are antibiotics having enhanced activity against gram-negative and gram-positive pathogens.
Claims7
The process for preparing the compound of the formula:
- ##STR16## wherein R.sub.1 is hydrogen or methoxy;
- A is loweralkanoyloxy of 2-6 carbon atoms or carbamoyloxy;
- R.sub.10 is hydrogen, azido, carboxy, or hydroxy;
- R.sub.11 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
- 3-isothiazoyl, 4-isothiazoyl, 5-isothiazoyl, 1,2,5-thiadiazoyl, 4-pyridyl, tetrazoyl, or chlorophenyl;
- X is oxygen or sulfur;
- and
- R.sub.4 is hydrogen, or 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, phenyl, acetoxymethyl, pivaloyloxymethyl, methoxymethyl, p-nitrophenyl or 3,5-dinitrophenyl;
- which comprises mixing the compound of the formula:
- ##STR17## in which R.sub.2 is trichloroethoxycarbonyl, tertiary butoxy carbonyl, benzoylmethoxycarbonyl, trimethylsilyl, p-methoxybenzyloxy, 2-nitrophenylsulfenyl, 2,4-dinitrophenylsulfenyl, chloroacetyl, or o-nitrophenylthio;
- and R.sub.1, A, X and R.sub.4 are as above defined,
- with an approximately equimolar amount of the acylating agent having the formula ##STR18## where R.sub.11 and R.sub.10 are as defined above and with a molecular excess of the silylating agent which is N-(trimethylsilyl)acetamide, N-(tripropylsilyl)acetamide, N-(tributylsilyl)acetamide, N-(triphenylsilyl)acetamide or N-(tribenzylsilyl)acetamide, N,O-bis(trimethylsilyl)acetamide, N,O-bis(triphenylsilyl)acetamide, N,O-bis(tribenzylsilyl)acetamide, N-(trimethylsilyl)trifluoroacetamide, N-(tributylsilyl)trifluoroacetamide, N-(trimethylsilyl)benzoamide, N-(trimethylsilyl)diphenylurea, N-(trimethylsilyl)ethylcarbamate, N-triphenylsuccinimide or N-(trimethylsilyl)phthalimide, N-(trimethylsilyl)benzene sulfonamide, N-trimethylsilyl urethane, N-trimethylsilyl phthalimide, monosilyltrifluoroacetamide or bis(ethoxycarbonylamino)dimethyl silane in an inert solvent at a temperature of between about 25.degree. C and about 70.degree. C. for a duration of 3-65 hours, and then optionally adding loweralkanol or loweralkylthiol, alkyl having 1-6 carbon atoms benzylalcohol, 2.5N HCl or aqueous sodium bicarbonate;
- and recovering the product.
The process for preparing the compound ##STR19## in which A is acetoxy or carbamoyloxy, and R.sub.11 is phenyl, 2-thienyl, 3-thienyl, 2-furyl, or 3furyl, and R.sub.5 is H, methoxymethyl, benzyl, or benzhydryl, which comprises mixing approximately equimolar amounts of ##STR20## in which R.sub.2 is trichloroethoxycarbonyl, t-butoxycarbonyl, chloroacetyl, or 2-nitrophenylsulfenyl, and A and R.sub.5 are defined above;
- and ##STR21## together with a molecular excess of N-trimethylsilyl urethane, bis-trimethylsilyltrifluoroacetamide, N-trimethylsilyl phthalimide, N-trimethylsilylethyl carbamate, N-trimethyllsilylbenzene sulfonamide, or monosilyltrifluoroacetamide, in an inert solvent which is acetonitrile, chloroform, dichloromethane, or methylene chloride, at a temperature between 25.degree. C. and about 70.degree. C., for about 3 - 65 hours, then optionally adding loweralkanol, benzyl alcohol, 2.5N HCl or aqueous sodium bicarbonate, and recovering the product.
Dependencies are inferred from the claim text.