Journal
ORGANIC PROCESS RESEARCH & DEVELOPMENT
Volume 27, Issue 4, Pages 680-691Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.2c00399
Keywords
milvexian; Suzuki; click; azide; chlorination; factor XIa inhibitor
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Anticoagulants are important for preventing and treating cardiovascular diseases caused by blood clots. Factor XIa (FXIa) inhibitors offer the potential to improve the safety profile of existing anticoagulants in high-risk patients. This study discusses the optimization of the synthesis route for a FXIa inhibitor, including improvements in key intermediate isolation and streamlining of various chemical steps, resulting in a 70% yield of the desired product.
Anticoagulants play a critical role in the prevention and treatment of thrombotic-driven cardiovascular diseases. Factor XIa (FXIa) inhibitors have the potential to improve the benefit/risk profile of existing anticoagulants through a safer bleeding profile in a variety of conditions where patients are predisposed to a high risk of thrombotic or bleeding events. To support the clinical development program of milvexian (BMS-986177/JNJ-70033093), a FXIa inhibitor that recently completed phase II clinical trials, we improved the discovery route to deliver the suitable quantity of key intermediate 1 for clinical supply. This paper describes our optimization of the Suzuki cross-coupling and how we simplified and improved the isolation of 4-trimethylsilyl-1,2,3-triazole 6 after the azidation-click sequence. On top of streamlining the processes for the chlorination and demethylation steps, we demonstrated that the recrystallization of the penultimate intermediate 7 was key to control the purity and the color of the desired 4-chloro-1,2,3-triazole 1, which could be obtained in a 70% yield over five steps.
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