TW343972B - Process for the preparation of an endothelin antagonist - Google Patents

Abstract

A process for the preparation of a compound of the structural formula I: (I) in which the * represents a chiral center; comprising the steps of: a) reacting the methyl 4-hydroxy-3-n-propylbenzoate with a base in an aprotic inert solvent to give a salt of methyl 4-hydroxy-3-n-propylbenzoate (formula) in which: M+ is Na+, K+, or Li+ ; b) acylating 1,3-benzodioxole with ethyl oxalyl chloride in the presence of a lewis acid and an organic solvent to give an ester (formula) c) hydrolyzing the ester with a base in a solvent to give an acid (formula) d) reacting the acid with a chlorinating agent in a solvent to give an acid chloride (formula) e) reacting the acid chloride with a chiral auxiliary, Rc, and an organic base to give a substituted ketoester derivative (formula) in which: Rc is (formulae) Ra is (C1 -C6)-alkyl, phenyl, or cyclohexyl; R13 is (C1 -C6)-alkyl, phenyl or cyclohexyl; R14 and R15 are independently: (C1 -C10)-alkyl, or R14 and R15 can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl; f) reducing the substituted ketoester derivative with a reducing agent to give a hydroxyl derivative (formula) g) halogenating the hydroxyl derivative with a halogenating agent in an organic solvent to give a halo derivative (formula) in which: X is Br, Cl, or I; h) alkylating the salt of methyl 4-hydroxy-3-n-propylbenzoate with the halo derivative, in an organic solvent to give a chiral auxiliary phenoxyphenylacetic acid derivative (formula) I) hydrolyzing the chiral auxiliary from the phenoxyphenylacetic acid derivative to give a phenoxyphenylacetic acid (formula) j) reacting the phenoxyphenylacetic acid with a chlorinating agent in a solvent to give an acid chloride (formula) k) reacting the acid chloride with a source of ammonia to give an amide (formula) l) alkylating the amide with 4-isopropylbenzenesulfonyl chloride in the presence of a base and a solvent to give a sulfonamide (formula) m) hydrolyzing the sulfonamide with an inorganic base in a solvent to give a salt of the acid (formula) n) neutralizing the salt with mineral acid to give a diacid (formula) o) reacting the diacid with two equivalents of α-methylbenzylamine in an organic solvent to give a diastereomeric salt (formula) p) breaking the salt with mineral acid to give an optically enriched acid (formula) q) reacting the optically enriched acid with a base in a solvent or mixture of solvents to give a dipotassium salt, the compound of formula I (formula).