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

被引：2

作者：

Wagschal, Simon ^{[1
]}

Broggini, Diego ^{[1
]}

Cao, Trung D. C. ^{[1
]}

Schleiss, Pascal ^{[1
]}

Paun, Kristian ^{[1
]}

Steiner, Jessica ^{[1
]}

Merk, Anna-Lena ^{[1
]}

Harsdorf, Joachim ^{[1
]}

Fiedler, Winfried ^{[1
]}

Schirling, Stefan ^{[1
]}

Hock, Sven ^{[1
]}

Strittmatter, Tobias ^{[1
]}

Dijkmans, Jan ^{[2
]}

Vervest, Ivan ^{[2
]}

Van Hoegaerden, Tim ^{[2
]}

Egle, Brecht ^{[2
]}

Mower, Matthew P. ^{[2
]}

Liu, Zhi ^{[3
]}

Cao, Zhiyong ^{[3
]}

He, Xiaoning ^{[3
]}

Chen, Lei ^{[4
]}

Qin, Lei ^{[4
]}

Tan, Hongyu ^{[4
]}

Yan, Jun ^{[4
]}

Cuniere, Nicolas Lucien ^{[4
,5
]}

Wei, Carolyn S. ^{[4
,5
,6
]}

Vuyyuru, Venkata ^{[7
]}

Ayothiraman, Rajaram ^{[7
]}

Rangaswamy, Sundaramurthy ^{[7
]}

Jaleel, Mohamed ^{[7
]}

Vaidyanathan, Rajappa ^{[7
,8
]}

Eastgate, Martin D. ^{[4
,5
]}

Klep, Richard ^{[2
]}

Benhaim, Cyril ^{[2
]}

Vogels, Ilse ^{[2
]}

Peeters, Koen ^{[2
]}

Lemaire, Sebastien ^{[2
]}

机构：

[1] Janssen Pharmaceut, Chem Proc Res & Dev, CH-8200 Schaffhausen, Switzerland

[2] Janssen Pharmaceut, Chem Proc Res & Dev, B-2340 Beerse, Belgium

[3] Janssen China R&D Ctr, Shanghai 200030, Peoples R China

[4] Changzhou SynTheAll Pharmaceut Co Ltd, Changzhou, Jiangsu, Peoples R China

[5] Bristol Myers Squibb, Chem Proc Dev, New Brunswick, NJ 08903 USA

[6] Amgen Inc, Proc Dev, Thousand Oaks, CA 91320 USA

[7] Biocon Bristol Myers Squibb Res & Dev Ctr, Chem Dev & API Supply, Bengaluru 560099, India

[8] SEAGEN INC, 22515 29th Dr SE, Bothell, WA 98021 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2023年 / 27卷 / 04期

关键词：

milvexian; Suzuki; click; azide; chlorination; factor XIa inhibitor; AZIDE; METHODOLOGY; THROMBOSIS;

D O I：

10.1021/acs.oprd.2c00399

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

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.

引用

页码：680 / 691

页数：12

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