USE OF 4-BROMO-3-METHYL-5-PROPOXYTHIOPHENE-2-CARBOXYLIC ACID 2,5-DIOXO-PYRROLIDIN-1-YL ESTER FOR PREPARING THE TRYPTASE INHIBITOR [4-(5-AMINOMETHYL-2-FLUORO-PHENYL)-PIPERIDIN-1-YL]-(4-BROMO-3-METHYL-5-PROPOXY-THIOPHEN-2-YL)-METHANONE

摘要

This invention is directed to a five step regio-specific synthesis of 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid compound of formula 16 comprising the steps of acetalating 3-methyl-thiophene-2-carbaldehyde in an alcohol solvent; iodinating the acetalated 3-methyl-thiophene-2-carbaldehyde in an non-protic polar or hydrocarbon solvent to yield the corresponding iodinated and acetalated 3-methyl-thiophene-2-carbaldehyde product; treating the iodinated and acetalated product with water to yield the corresponding 5-iodo-3-methyl-thiophene-2-carbaldehyde; oxidizing the 5-iodo-3-methyl-thiophene-2-carbaldehyde to the corresponding 5-iodo-3-methyl-thiophene-2-carboxylic acid in ketone solvent; Ullmann coupling of the 5-iodo-3-methyl-thiophene-2-carboxylic acid with alkali metal propoxide salt using a copper catalyst in propanol to yield 3-methyl-5-propoxy-thiophene-2-carboxylic acid; esterifying 3-methyl-5-propoxy-thiophene-2-carboxylic acid to yield the corresponding alkyl 3-methyl-5-propoxy-thiophene-2-carboxylate; brominating the 3-methyl-5-propoxy-thiophene-2-carboxylic acid to yield the corresponding alkyl 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylate; and basic hydrolyzing the alkyl 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylate with base to yield 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid.