A practical synthesis of fibrinogen receptor antagonist MK-383. Selective functionalization of (S)-tyrosine
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.
Chung,Zhao,Hughes,Grabowski
p. 5767 - 5776
(2007/10/02)
Process for preparing fibrinogen receptor antagonists
The invention is a highly efficient synthesis for making compounds of the formula: STR1 wherein: R1 is a six member saturated or unsaturated heterocyclic ring containing one or two heterocyclic atoms wherein the heteroatoms are N; or NR6, wherein R6 is H or C1-10 alkyl; m is an integer from two to six; and R4 is aryl, C1-10 alkyl, or C4-10 aralkyl.
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(2008/06/13)
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