Preparation of a clinically investigated ras farnesyl transferase inhibitor

✍ Scribed by 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

• Publisher: Journal of Heterocyclic Chemistry
• Year: 2003
• Tongue: English
• Weight: 128 KB
• Volume: 40
• Category: Article
• ISSN: 0022-152X
• DOI: 10.1002/jhet.5570400206

✦ Synopsis

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 mercaptoim‐idazole 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 cycliza‐tion strategy was developed to prepare the arylpiperazinone fragment 3.