A practical synthesis of fibrinogen receptor antagonist MK-383. selective functionalization of (S)-tyrosine

Abstract

A practical 4-step synthesis of fibrinogen receptor antagonist MK-383, N-( n-butanesulfonyl)-O-(4-(4-piperidinyl)-butyl)-(S)-tyrosine, is accomplished in 48% overall yield from (S)-tyrosine. Highlights include: (1) the dual use of 4-picoline as a masked form of piperidine, and as a nucleophile precursor for a 3-carbon homologation with 3-bromo-1-chloropropane; (2) the use of trimethylsilyl groups for temporary protection of phenolic and carboxylate oxygens of (S)-tyrosine that enable selective N-sulfonylation to be carried out in high yield; (3) the selective phenolic O-alkylation of the tyrosine derivative in high yield with no racemization using aqueous KOH/DMSO; and (4) the selective hydrogenation of the pyridine ring in the presence of the tyrosine ring using Pd/C in acetic acid.