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Industrial process for the synthesis of 5- bis(carboxymethyl)amino -3-carboxymethyl-4-cyano-2-thiophene-carboxylic acid tetraesters and use for the synthesis of ranetic acid divalent salts and hydrates thereof
Industrial process for the synthesis of 5- bis(carboxymethyl)amino -3-carboxymethyl-4-cyano-2-thiophene-carboxylic acid tetraesters and use for the synthesis of ranetic acid divalent salts and hydrates thereof
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.
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