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, and David Askin Department of Process Research, Merck Research Laboratories, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065 Received August 7, 2002 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 syn- thesis. 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 func- tional 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. J. Heterocyclic Chem., 40, 229 (2003). Introduction. Mutant ras proteins, the products of ras oncogenes, are involved in a significant proportion of human cancers [1]. The enzyme farnesyl-protein transferase (FPTase) cat- alyzes the farnesylation of the ras protein thereby activat- ing it; thus, FPTase inhibitors are currently the object of intense interest as novel and improved anticancer agents [2]. Piperazinone 1 has been identified as an effective FPTase inhibitor and has been found to be efficacious in animal models with a relatively high therapeutic index [3]. Phase I and phase II clinical studies of 1 in cancer patients have been completed [3c]. Results and Discussion. Retrosynthetic analysis of 1 can lead to an alkylation of piperazinone 3 with an electrophilic halomethylimidazole such as 2 (Scheme 1). The original preparation of 1 employed the same bond disconnection via a reductive amination of the imidazole-5-carboxaldehyde with 3; thus, both routes require a 1,5-disubstituted imidazole and a 1-arylpiperazin-2-one [4]. Originally this 1,5-substitution was achieved by selec- tive trityl and acetyl protection of commercially available 5-hydroxymethylimidazole at the 3- and hydroxyl posi- tions respectively followed by alkylation of the remaining 1-position and subsequent deprotection [4]. The starting material 5-hydroxymethylimidazole is expensive and diffi- cult to obtain in large (>100 g) quantities [5]. Since large quantities of 1 would be needed for safety assessment and clinical studies, we sought a more financially and atom economical route. Many methods for the preparation of imidazoles are known [6], but the convenient regioselective preparation of 1,5-substituted imidazoles can be more challenging. 1,5-Substituted imidazoles can be accessed by reaction of Gold’s reagent with an N-substituted glycine ester [7]. In Scheme 2 alkylation of glycine ethyl ester with commer- cially available 4-(bromomethyl)benzonitrile (4) gave 5 Mar-Apr 2003 229 Figure 1 Scheme 1 Scheme 2