Development of a Practical and Efficient Synthesis of CP-945,598-01, a CB₁ Antagonist for the Treatment of Obesity

Abstract

Development of an efficient bond-forming sequence and optimization of reaction conditions are described for the synthesis of CP-945,598-01 (1 • HCl), a CB 1 antagonist in clinical studies for the treatment of obesity. Reordering of the bond-forming sequence provided a more efficient synthesis and avoided the use of phosphorous oxychloride. A telescoped reaction sequence (4 f 9) was developed to avoid a problematic isolation. Product isolations were developed so as to provide efficient throughput by minimizing solvent volumes and avoiding slow filtrations.

Excretion, Metabolism, and Pharmacokinetics of CP-945,598, a Selective Cannabinoid Receptor Antagonist, in Rats, Mice, and Dogs

“…1-(8-(2-Chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl)-4-(ethylamino)piperidine-4-carboxamide 598) is an orally active antagonist of the cannabinoid CB-1 receptor that progressed into phase 3 human clinical trials for the treatment of obesity (Griffith et al, 2009;Ragan et al, 2009;Hadcock et al, 2010). In vitro pharmacologic profiling indicated that it is a selective, high-affinity, and competitive CB-1 receptor antagonist that inhibits both basal and cannabinoid agonist-mediated CB-1 receptor signaling in vitro and in vivo (Hadcock et al, 2010).…”

Design of Experiments (DoE) and Process Optimization. A Review of Recent Publications

“…Researchers from Argonaut Technologies used DoE to optimize the preparation of oxazolidinone 103, beginning with the reduction of L-phenylalanine (101) to L-phenylalaninol (102) through borane generated from NaBH 4 and iodine (Scheme 9). 56 The product was treated with triphosgene to afford 103.…”

Self-optimisation of the final stage in the synthesis of EGFR kinase inhibitor AZD9291 using an automated flow reactor

“…1 The optimisation provided enough information about the reaction system to increase the yield by more than 25% on a 300 kg scale. DoE has been used to optimise reaction steps in the synthesis of many pharmaceutical products including vestipitant, 2 raltegravir, 3 otenebant, 4 denagliptin, 5 levovirin, 6 delafloxacin 7 and continuous processes towards doxercalciferol, 8 bendamustime, 9 pyrazinamide 10 and PARP-1 inhibitors. 11 However, there has been academic development in substituting DoE with evolutionary algorithms in automated reactors to find optimum conditions.…”