Process for preparing 1-6-and 2-substituted-1-carba-2-penem-3-carboxylic acids

Claim 2

A process for preparing a compound having the structure: ##STR188## and the pharmaceutically acceptable salts thereof: wherein R 1 , R 2 , R 3 and R 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 1 , R 2 , R 3 and R 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 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 2 , POCl 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 3 -Mg-halo to obtain ##STR196## and followed by heating at 100°-160° C. in a solvent selected from the group consisting of benzene, toluene, dioxane, xylene, or dimethylformamide to yield ##STR197## followed by deblocking.

Claim 3

A process for preparing a compound having the structure: ##STR198## and the pharmaceutically acceptable salts thereof: wherein R 1 , R 2 , R 3 and R 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 1 , R 2 , R 3 and R 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 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 2 , POCl 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 3 -Mg-halo and heating at 100°-160° C. in a solvent selected from the group consisting of benzene, toluene, dioxane, xylene, or dimethylformamide; followed by deblocking.

Claim 4

A process for preparing a compound having the structure: ##STR198## and the pharmaceutically acceptable salts thereof: wherein R 1 , R 2 , R 3 and R 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 1 , R 2 , R 3 and R 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 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 2 , POCl 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 3 -Mg-halo and heating at 100°-160° C. in a solvent selected from the group consisting of benzene, toluene, dioxane, xylene, or dimethylformamide; followed by deblocking.