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US 4,465,632 AGranted
Process for preparing 1-6-and 2-substituted-1-carba-2-penem-3-carboxylic acids
AssigneeMerck & Co., Inc.
InventorsBurton G. Christensen, David H. Shih
Life of this patent
Estimating the term…
Abstract
Disclosed are 1-, 6- and 2-substituted-1-carba-2-penem-3-carboxylic acids of the following structure: ##STR1## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are, inter alia, independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl. Such compounds as well as their pharmaceutically acceptable salt, ester and amide derivatives are useful as antibiotics. Also disclosed are processes for the preparation of such compounds, pharmaceutical compositions comprising such compounds and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
Claims2
A process for preparing a compound having the structure:
- ##STR188## and the pharmaceutically acceptable salts thereof:
- wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen, and substituted and unsubstituted:
- alkyl having 1-6 carbon atoms, aralkyl, alkenyl and alkynyl having 2-6 carbon atoms, aryl and aralkyl having 6-10 ring carbon atoms and 1-6 carbon atoms in the alkyl chain, cycloalkyl and cycloalkylalkyl having 3 to 6 ring carbon atoms and 1-6 carbon atoms in the alkyl moiety;
- wherein the substituents on R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are selected from chloro, bromo, fluoro, hydroxyl, amino, mono-, di- and trialkyl substituted amino (each alkyl having 1-6 carbon atoms) alkoxyl having 1-6 carbon atoms, guanidino, cyano, amidino, and carboxyl;
- comprising treating a compound of the formula:
- ##STR189## wherein R is a readily removable protecting group selected from acetyl, bromo-t-butoxycarbonyl, benzyloxycarbonyl, formyl, trifluoroacetyl, trimethylsilyl, t-butyldimethylsilyl with a glyoxalate ester wherein the ester moiety is a pharmaceutically acceptable ester moiety or a readily removable blocking group, R.sup.5, selected from benzyl, p-nitrobenzyl, o-nitrobenzyl, pivaloyloxymethyl, bromo-t-butyl to provide a compound having the structure:
- ##STR190## followed by halogenating with a reagent selected from SOCl.sub.2, POCl.sub.3, oxalyl chloride to provide a compound having the structure;
- ##STR191## wherein X is chloro followed by treating with triphenylphosphine in a solvent to yield:
- ##STR192## followed by deblocking and oxidation to yield:
- ##STR193## followed by treating with oxalyl chloride to yield:
- ##STR194## followed by treating with thiophenol to yield:
- ##STR195## followed by treating with a Grignard reagent R.sup.3 -Mg-halo to obtain ##STR196## and followed by heating at 100.degree.-160.degree. C. in a solvent selected from the group consisting of benzene, toluene, dioxane, xylene, or dimethylformamide to yield ##STR197## followed by deblocking.
9 more elements
A process for preparing a compound having the structure:
- ##STR198## and the pharmaceutically acceptable salts thereof:
- wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen, and substituted and unsubstituted:
- alkyl having 1-6 carbon atoms, aralkyl, alkenyl and alkynyl having 2-6 carbon atoms, aryl and aralkyl having 6-10 ring carbon atoms and 1-6 carbon atoms in the alkyl chain, cycloakyl and cycloalkylalkyl having 3 to 6 ring carbon atoms and 1-6 carbon atoms in the alkyl moiety;
- wherein the substituents on R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are selected from chloro, bromo, fluoro, hydroxyl, amino, mono- di- and trialkyl substituted amino (each alkyl having 1-6 carbon atoms) alkoxyl having 1-6 carbon atoms, guanidino, cyano, amidino, and carboxyl;
- comprising treating a compound of the formula:
- ##STR199## with chlorosulphonyl isocyanate to yield:
- ##STR200## followed by hydrolysis and reduction to yield:
- ##STR201## followed by hydrolysis to yield:
- ##STR202## followed by reaction with 2,2-dimethoxypropane in the presence of a catalyst to yield:
- ##STR203## followed by alkylation and hydrolysis to obtain ##STR204## followed by establishing O-protecting group R to obtain:
- ##STR205## wherein R is a readily removable protecting group selected from acetyl, bromo-t-butoxycarbonyl, benzyloxycarbonyl, formyl, trifluoroacetyl, trimethylsilyl, t-butyldimethylsilyl and treating the above O-protected intermediate with a glyoxalate ester wherein the ester moiety is a pharmaceutically acceptable ester moiety or a readily removable blocking group, R.sup.5, selected from benzyl, p-nitrobenzyl, o-nitrobenzyl, pivaloyloxymethyl, bromo-t-butyl to provide a compound having the structure:
- ##STR206## followed by halogenating with a reagent selected from SOCl.sub.2, POCl.sub.3, oxalyl chloride to provide a compound having the structure:
- ##STR207## wherein X is chloro followed by treating with triphenylphosphine in a solvent to yield:
- ##STR208## followed by deblocking and oxidation to yield:
- ##STR209## followed by treating with oxalyl chloride to yield:
- ##STR210## followed by treating with thiophenol to yield:
- ##STR211## followed by treating with a Grignard reagent R.sup.3 -Mg-halo and heating at 100.degree.-160.degree. C. in a solvent selected from the group consisting of benzene, toluene, dioxane, xylene, or dimethylformamide;
- followed by deblocking.
15 more elements
Dependencies are inferred from the claim text.