Preparation of a clinically investigated ras farnesyl transferase inhibitor

Peter E. Maligres, Marjorie S. Waters, Steven A. Weissman, J. Christopher McWilliams, Stephanie Lewis, Jennifer Cowen, Robert A. Reamer, R. P. Volante, Paul J. Reider, David Askin

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

The synthesis of ras farnesyl-protein transferase inhibitor 1 is described on a multi-kilogram scale. Retrosynthetic analysis reveals chloromethylimidazole 2 and a piperazinone 3 as viable precursors. The 1,5-disubstituted imidazole system was regioselectively assembled via an improved Marckwald imidazole synthesis. A new imidazole dethionation procedure has been developed to convert the Marckwald mercaptoimidazole product to the desired imidazole. This methodology was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5-disubstituted imidazoles. A new Mitsunobu cyclization strategy was developed to prepare the arylpiperazinone fragment 3.

Original languageEnglish (US)
Pages (from-to)229-241
Number of pages13
JournalJournal of Heterocyclic Chemistry
Volume40
Issue number2
DOIs
StatePublished - Jan 1 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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    Maligres, P. E., Waters, M. S., Weissman, S. A., McWilliams, J. C., Lewis, S., Cowen, J., Reamer, R. A., Volante, R. P., Reider, P. J., & Askin, D. (2003). Preparation of a clinically investigated ras farnesyl transferase inhibitor. Journal of Heterocyclic Chemistry, 40(2), 229-241. https://doi.org/10.1002/jhet.5570400206