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Toward the Development of a Manufacturing Process for Milvexian: Scale-Up Synthesis of the Side Chain
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-04-03 , DOI: 10.1021/acs.oprd.2c00399 Simon Wagschal 1 , Diego Broggini 1 , Trung D.C. Cao 1 , Pascal Schleiss 1 , Kristian Paun 1 , Jessica Steiner 1 , Anna-Lena Merk 1 , Joachim Harsdorf 1 , Winfried Fiedler 1 , Stefan Schirling 1 , Sven Hock 1 , Tobias Strittmatter 1 , Jan Dijkmans 2 , Ivan Vervest 2 , Tim Van Hoegaerden 2 , Brecht Egle 2 , Matthew P. Mower 2 , Zhi Liu 3 , Zhiyong Cao 3 , Xiaoning He 3 , Lei Chen 4 , Lei Qin 4 , Hongyu Tan 4 , Jun Yan 4 , Nicolas Lucien Cunière 5 , Carolyn S. Wei 5 , Venkata Vuyyuru 6 , Rajaram Ayothiraman 6 , Sundaramurthy Rangaswamy 6 , Mohamed Jaleel 6 , Rajappa Vaidyanathan 6 , Martin D. Eastgate 5 , Richard Klep 2 , Cyril Benhaïm 2 , Ilse Vogels 2 , Koen Peeters 2 , Sébastien Lemaire 2
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-04-03 , DOI: 10.1021/acs.oprd.2c00399 Simon Wagschal 1 , Diego Broggini 1 , Trung D.C. Cao 1 , Pascal Schleiss 1 , Kristian Paun 1 , Jessica Steiner 1 , Anna-Lena Merk 1 , Joachim Harsdorf 1 , Winfried Fiedler 1 , Stefan Schirling 1 , Sven Hock 1 , Tobias Strittmatter 1 , Jan Dijkmans 2 , Ivan Vervest 2 , Tim Van Hoegaerden 2 , Brecht Egle 2 , Matthew P. Mower 2 , Zhi Liu 3 , Zhiyong Cao 3 , Xiaoning He 3 , Lei Chen 4 , Lei Qin 4 , Hongyu Tan 4 , Jun Yan 4 , Nicolas Lucien Cunière 5 , Carolyn S. Wei 5 , Venkata Vuyyuru 6 , Rajaram Ayothiraman 6 , Sundaramurthy Rangaswamy 6 , Mohamed Jaleel 6 , Rajappa Vaidyanathan 6 , Martin D. Eastgate 5 , Richard Klep 2 , Cyril Benhaïm 2 , Ilse Vogels 2 , Koen Peeters 2 , Sébastien Lemaire 2
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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.
中文翻译：
Milvexian 制造工艺的开发：侧链的放大合成
抗凝血剂在预防和治疗血栓性心血管疾病方面发挥着关键作用。因子 XIa (FXIa) 抑制剂有可能通过在患者易患血栓形成或出血事件高风险的各种情况下更安全的出血情况来改善现有抗凝剂的益处/风险情况。为了支持最近完成 II 期临床试验的 FXIa 抑制剂 milvexian (BMS-986177/JNJ-70033093) 的临床开发计划，我们改进了发现途径，以提供适量的关键中间体 1 用于临床供应。本文介绍了我们对 Suzuki 交叉偶联的优化，以及我们如何简化和改进 4-trimethylsilyl-1,2,3-triazole 6的分离在叠氮化-点击序列之后。除了简化氯化和脱甲基步骤的过程外，我们还证明了倒数第二个中间体7的重结晶是控制所需 4-氯-1,2,3-三唑1的纯度和颜色的关键，这可以分五步获得 70% 的收率。
更新日期：2023-04-03
中文翻译：
Milvexian 制造工艺的开发：侧链的放大合成
抗凝血剂在预防和治疗血栓性心血管疾病方面发挥着关键作用。因子 XIa (FXIa) 抑制剂有可能通过在患者易患血栓形成或出血事件高风险的各种情况下更安全的出血情况来改善现有抗凝剂的益处/风险情况。为了支持最近完成 II 期临床试验的 FXIa 抑制剂 milvexian (BMS-986177/JNJ-70033093) 的临床开发计划，我们改进了发现途径，以提供适量的关键中间体 1 用于临床供应。本文介绍了我们对 Suzuki 交叉偶联的优化，以及我们如何简化和改进 4-trimethylsilyl-1,2,3-triazole 6的分离在叠氮化-点击序列之后。除了简化氯化和脱甲基步骤的过程外，我们还证明了倒数第二个中间体7的重结晶是控制所需 4-氯-1,2,3-三唑1的纯度和颜色的关键，这可以分五步获得 70% 的收率。
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