4-BROMO-3-METHYL-5-PROPOXYTHIOPHENE-2-CARBOXYLIC ACID 2,5-DIOXO-PYRROLIDIN-1-YL ESTER, ITS REGIO-SPECIFIC SYNTHESIS AND INTERMEDIATE THERETO

摘要

The present invention is directed to 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester, and intermediate, 3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester, thereto. The present invention is also directed to the regio-specific synthesis of 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester compound comprising the steps of iodinating 3-methyl-thiophene with an iodinating agent in the presence of a strong base in an non-protic polar or hydrocarbon solvent to yield 2-iodo-4-methylthiophene; Ullmann coupling the 2-iodo-4-methylthiophene with an alkali metal propoxide salt using a copper catalyst in propanol to yield 4-methyl-2-propoxythiophene; coupling the 4-methyl-2-propoxythiophene with CO2 using strong base in an non-protic polar or hydrocarbon solvent to yield 3 methyl-5-propoxy-thiophene-2-carboxylic acid; esterifying the 3 methyl-5-propoxy-thiophene-2-carboxylic acid with N hydroxysuccinimide in the presence of a coupling agent in an non-protic polar, hydrocarbon or halohydrocarbon solvent to yield 3-methyl-5-propoxythiophene-2-carboxylic acid 2,5 dioxo-pyrrolidin-1-yl ester; and brominating the 3-methyl-5-propoxythiophene-2-carboxylic acid 2,5 dioxo-pyrrolidin-1-yl ester with a brominating agent in an inert solvent to yield 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester.