Preparation of dialkylaminothiophenecarboxylic acid derivative as intermediate for renalic acid involves reacting aminothiophenecarboxylic acid with carboxyalkyl bromide in presence of quaternary ammonium compound of eight to ten carbons

摘要

Preparation of 3-alkoxycarbonylmethyl-4-cyano-5-(N,N-bis(carboxyalkyl))aminothiophene-2-carboxylic acid derivatives (I) involves reaction of 3-alkoxycarbonylmethyl-4-cyano-5-amino-thiophene-2-carboxylic acid (II) with alkoxycarbonylalkyl bromide in presence of quaternary ammonium compound and potassium carbonate at reflux of an organic solvent, followed by filtration, cooling and drying. Preparation of 3-alkoxycarbonylmethyl-4-cyano-5-(N,N-bis(carboxyalkyl))aminothiophene-2-carboxylic acid derivatives of formula (I) involves: (1) reacting 3-alkoxycarbonylmethyl-4-cyano-5-amino-thiophene-2-carboxylic acid of formula (II) with alkoxycarbonyl alkyl bromide of formula Br-CH2-C(O)OR' (III) in the presence of 8-10C type quaternary ammonium compound of formula R1R2R3R4-N+X- and potassium carbonate at reflux of an organic solvent; (2) filtrating the reaction mixture; (3) concentrating the mixture by distillation; (4) adding a co-solvent; (5) cooling and filtering the reaction mixture; and (6) drying to form a powder. R and R' = linear or branched 1-6C alkyl; R1 = 1-6C alkyl; R2 - R4 = 8-10C alkyl; and X = halo. Independent claims are included for the following: (1) synthesis of ranelic acid, its strontium, calcium or magnesium salt or hydrate of the salt from (I); and (2) new methyl 5-(bis(2-methoxy-2-oxoethyl)amino)-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate and methyl 5-(bis(2-ethoxy-2-oxoethyl)amino)-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate.