Preparation of N-(4,5-bis-(alkanesulfonyl)-2-alkyl-benzoyl)-guanidine salt used as sodium ion-proton antiporter inhibitor, by alkylsulfonylation of 4-substituted benzoate ester, reaction with guanidine and salification

摘要

Preparation of acid addition salts (A) of N-(4,5-bis-(alkanesulfonyl)-2-alkyl-benzoyl)-guanidines (I) involves: (a) esterifying a 2-alkyl-4-(halo or sulfonato)-5-alkylsulfonyl-benzoic acid (II); (b) converting the obtained ester (III) into the 4-alkylsulfonyl compound (IV) in presence of alkyl sulfinate; (c) converting (IV) into (I) by reaction with guanidine; and (d) converting (I) into (A) with acid. Preparation of acid addition salts (A) of benzoyl-guanidine derivatives of formula (I) involves: (a) converting a 4-substituted benzoic acid derivative of formula (II) into an ester of formula (III); (b) converting (III) into the 4-alkanesulfonyl ester of formula (IV) in presence of alkyl sulfinate; (c) converting (IV) into (I) by reaction with guanidine; and (d) converting (I) into (A) using a suitable acid. R1-R3 = 1-12C alkyl, and X = F, Cl, Br, alkylsulfonate, arylsulfonate or perfluoroalkyl-sulfonate (preferably Cl), and R4 = 1-10C alkyl.