A Rapid, Large-Scale Synthesis of a Potent Cholecystokinin (CCK) 1R Receptor Agonist Jeffrey T. Kuethe,* Karla G. Childers, Guy R. Humphrey, Michel Journet, and Zhihui Peng Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, U.S.A. Abstract: The development of a scalable synthesis of a potent cholecystokinin (CCK) 1R receptor agonist is described. The focus on a rapid short-term delivery rather than longer-term development allowed for the preparation of multihundred gram quantities to support aggressive timelines and evaluate safety and pharmacological studies. Key improvements involved streamlining the preparation of imidazole acid 7 and discovery of a more efficient preparation of naphthyl piperazine fragment 23, including an improved preparation of 3-bromonaphthallic anhydride 16. Introduction Cholecystokinin (CCK) is a gastrointestinal hormone and neurotransmitter that induces satiety by direct stimulation of vagal afferents that signal to feeding centers in the brain. There are two G-protein-coupled seven transmembrane receptors associated with the physiological actions of CCK: CCK1R and CCK2R (also known as CCKA and CCKB receptors, respec- tively). CCK1R is predominately located in the periphery and is believed to be the primary mediator of satiety, while CCK2R is mostly expressed in the brain. Shown to inhibit food intake in many species including humans, 1 CCK1R agonists have been studied as satiety agents for the treatment of obesity. 2 Recently, Merck & Co., Inc. identified a number of potent and selective CCK1R agonists for the potential treatment of obesity, and compound 1 was selected for preclinical development to fully define safety and pharmacological properties. 3 In recent years, the increased pace of drug discovery has led to a corresponding increase in the pace of preclinical development. Key to the successful initiation of preclinical programs with well-defined and accelerated timelines is the ability of process chemists to deliver required amounts of development candidates in a timely manner. In the fast-paced environment of drug development, the development of a long-term manufacturing route is typically not required in the initial stages of a program, and rapid first deliveries of API that support safety assessment and pharma- cological studies may rely upon modifications to the existing route. Modifications that address liabilities such as low-yielding transformations, the use of potentially dangerous reagents and reaction conditions, and elimination of chromatography are examined and then implemented. The rapid development of a scalable synthesis of 1 aptly illustrates this approach. The original synthesis of 1 employed by the Medicinal chemistry group involved 13 chemical steps (longest linear sequence 10 steps) and required 6 chromatographic purifications including reverse phase chromatography of 1 (Schemes 1-3). 3 Fortunately, the synthesis was convergent and 1 was obtained from two key intermediates: imidazole acid 7 (Scheme 1) and naphthyl piperazine 13 (Scheme 2). The preparation of 7 began with the condensation of 2 with 3 in the presence of NaHMDS to give benzamidine 4. Direct reaction of 4 with ethyl bro- mopyruvate 5 in refluxing 1,4-dioxane afforded imidazole ester 6, which was purified by chromatography. Saponification of the ester then gave imidazole acid 7 in 50% overall yield. The synthesis of 13 started with 3-nitro-1,8-naphthoic anhydride 8 and involved the use of stoichiometric HgO to provide 3-ni- tronaphthoic acid 9 in 59% yield (Scheme 2). Conversion of 9 to the corresponding ester (95%) was followed by reduction of the nitro group to give naphthyl amine 10 (95%) as an unstable intermediate. Treatment of 10 with sodium nitrite in 48% HBr and subsequent heating to 95 °C in the presence of CuBr under standard Sandmeyer reaction conditions furnished bromide 11 in 70% yield. Cross-coupling of 11 with N-Boc-piperazine 12 under standard Buchwald cross-coupling conditions 4 and depro- tection of the product with TFA gave 13 in 50% yield. The overall yield of 13 was 19% from commercially available 8. The preparation of 1 from intermediates 7 and 13 in the initial route involved activation of 7 with MsCl in the presence of 1-methyl-imidazole followed by reaction with 12 to give 14, which was purified by silica gel chromatography. 5 Saponifica- tion of the methyl ester with LiOH provided 1 in 70% yield after purification by reverse phase chromatography. The initial * Author for correspondence. E-mail: jeffrey_kuethe@merck.com. 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U.; Bolene, S. B.; Soloshonok, V. A. J. Org. Chem. 2003, 68, 7104. Organic Process Research & Development 2008, 12, 1201–1208 10.1021/op800176e CCC: $40.75  2008 American Chemical Society Vol. 12, No. 6, 2008 / Organic Process Research & Development • 1201 Published on Web 10/28/2008