Process for the preparation of an endothelin antagonist

A process for the preparation of a compound of the structural formula I:

• ##STR45## wherein the * represents a chiral center;
• comprising the steps of:
• a) reacting the methyl 4-hydroxy-3-n-propylbenzoate with a base in an aprotic solvent to give a salt of methyl 4-hydroxy-3-n-propylbenzoate ##STR46## wherein:
• M.sup.+ is Na.sup.+, K.sup.+, or Li.sup.+ ;
• b) acylating 1,3-benzodioxole with ethyl oxalyl chloride in the presence of a lewis acid and an organic solvent to give an ester ##STR47## c) hydrolyzing the ester with a base in a solvent to give an acid ##STR48## d) reacting the acid with a chlorinating agent in a solvent to give an acid chloride ##STR49## e) reacting the acid chloride with a chiral auxiliary, R.sup.c, and an organic base to give a substituted ketoester derivative ##STR50## wherein:
• R.sup.c is ##STR51## R.sup.a is (C.sub.1 -C.sub.6)-alkyl, phenyl, or cyclohexyl;
• R.sup.13 is (C.sub.1 -C.sub.6)-alkyl, phenyl or cyclohexyl;
• R.sup.14 and R.sup.15 are independently:
• (C.sub.1 -C.sub.10)-alkyl, or R.sup.14 and R.sup.15 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 ##STR52## g) halogenating the hydroxyl derivative with a halogenating agent in an organic solvent to give a halo derivative ##STR53## wherein:
• 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 ##STR54## i) hydrolyzing the chiral auxiliary from the phenoxyphenylacetic acid derivative with an inorganic base in an aqueous organic solvent mixture to give a phenoxyphenylacetic acid ##STR55## j) reacting the phenoxyphenylacetic acid with a chlorinating agent in a solvent to give an acid chloride ##STR56## k) reacting the acid chloride with a source of ammonia to give an amide ##STR57## l) alkylating the amide with 4-isopropylbenzenesulfonyl chloride in the presence of a base and a solvent to give a sulfonamide ##STR58## m) hydrolyzing the sulfonamide with an inorganic base in a solvent to give a salt of the acid ##STR59## n) neutralizing the salt with mineral acid to give a diacid ##STR60## o) reacting the diacid with two equivalents of .alpha.-methylbenzylamine in an organic solvent to give a diastereomeric salt ##STR61## p) breaking the salt with mineral acid to give an optically enriched acid ##STR62## 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 ##STR63##