A Highly Convergent Synthesis of a Fibrinogen Receptor Antagonist

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-a][1,4]diazepin-2-yl]carbonyl]amino]propionic acid pentahydrate (1), an oral fibrinogen receptor antagonist, is described. The nine-step convergent process...

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Bibliographic Details
Published inJournal of organic chemistry Vol. 64; no. 21; pp. 7751 - 7755
Main Authors Hartner, Frederick W, Cvetovich, Raymond J, Tsay, Fuh-Rong, Amato, Joseph S, Pipik, Brenda, Grabowski, Edward J. J, Reider, Paul J
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 15.10.1999
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Organic
Physical Sciences
Science & Technology
PEPTIDE MIMETICS
DESIGN
GLYCOPROTEIN IIB/IIIA INHIBITORS
4-VINYLPYRIDINE
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Summary: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-a][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.
Bibliography:ark:/67375/TPS-T8H08Z6X-M
istex:12AF72D10B259D55AB2BD80220864F7AA843F3F8
ISSN:0022-3263
1520-6904
DOI:10.1021/jo990644t