A highly convergent synthesis of a fibrinogen receptor antagonist

Frederick W. Hartner, Raymond J. Cvetovich, Fuh Rong Tsay, Joseph S. Amato, Brenda Pipik, Edward J.J. Grabowski, Paul J. Reider

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Abstract

A practical multikilogram synthesis of 2(S)-[(p-toluenesulfonyl)amino]- 3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo[1,5- α][1,4]diazepin-2-yl]carbonyl]amino]propionic acid pentahydrate (1), an oral fibrinogen receptor antagonist, is described. The nine-step convergent process, which afforded 1 in 37% overall yield, included pyrazole 5a and N- tosylaminoalanine 16 as key fragments. Pyrazole 5a was obtained from pyrazole-3,5-dicarboxylic acid by esterification with MeOH, alkylation/cyclization with 3-bromopropylamine, and Michael addition with 4- vinylpyridine. N-Tosylaminoalanine 16 was prepared by tosylation of asparagine, Hofmann reaction, and benzyl esterification. Saponification of pyrazole 5a, coupling of the acid with N-tosylaminoalanine 16, and Pd- catalyzed hydrogenolysis and pyridine reduction completed the synthesis.

Original languageEnglish (US)
Pages (from-to)7751-7755
Number of pages5
JournalJournal of Organic Chemistry
Volume64
Issue number21
DOIs
StatePublished - Oct 15 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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    Hartner, F. W., Cvetovich, R. J., Tsay, F. R., Amato, J. S., Pipik, B., Grabowski, E. J. J., & Reider, P. J. (1999). A highly convergent synthesis of a fibrinogen receptor antagonist. Journal of Organic Chemistry, 64(21), 7751-7755. https://doi.org/10.1021/jo990644t