Toward the Development of a Manufacturing Process for Milvexian: Scale-Up Synthesis of the Side Chain

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.

Automated summary

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.