Stereoselective synthesis of a novel and bifunctional endothelin antagonist, IRL 3630

IRL 3630 (3), a single enantiomer of IRL 3461 with more potency was identified. Coupling reaction of the racemic fragment (1) with the chiral (L)-valinesulfonamide (2) under a biphasic solvent system (CH2Cl2---H2O) successfully led to the predominant formation of the desired isomer (3) with concomitant isomerization of 1. IRL 3630, N-butanesulfonyl-[N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-(D)-alanyl]-(L)-valineamide, is a highly potent and bifunctional (ETA+ETB) antagonist [Ki(ETA)=1.5 nM, Ki(ETB)=1.2 nM].