Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination

被引：69

作者：

Bottecchia, Cecilia ^{[1
]}

Levesque, Francois ^{[1
]}

McMullen, Jonathan P. ^{[1
]}

Ji, Yining ^{[2
]}

Reibarkh, Mikhail ^{[2
]}

Peng, Feng ^{[1
]}

Tan, Lushi ^{[1
]}

Spencer, Glenn ^{[1
]}

Nappi, Jarod ^{[1
]}

Lehnherr, Dan ^{[1
]}

Narsimhan, Karthik ^{[1
]}

Wismer, Michael K. ^{[3
]}

Chen, Like ^{[4
]}

Lin, Yipeng ^{[4
]}

Dalby, Stephen M. ^{[1
]}

机构：

[1] Merck & Co Inc, Proc Res & Dev, Rahway, NJ 07065 USA

[2] Merck & Co Inc, Analyt Res & Dev, Rahway, NJ 07065 USA

[3] Merck & Co Inc, Sci Engn & Design, Kenilworth, NJ 07033 USA

[4] Shanghai SynTheAll Pharmaceut Co Ltd, Shanghai 201507, Peoples R China

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2022年 / 26卷 / 03期

关键词：

photochemistry; continuous flow; photobromination; scale-up; manufacturing route development; belzutifan; N-BROMOSUCCINIMIDE;

D O I：

10.1021/acs.oprd.1c00240

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

We report the development and scale-up of a continuous flow photochemical benzylic bromination en route to belzutifan (MK-6482), a small molecule for the treatment of renal cell carcinoma associated with Von Hippel-Lindau syndrome. Compared with the clinical supply route, the photochemical approach circumvents the need for azo radical initiators and proceeds at room temperature. Implementation of continuous flow technology allowed tight control of irradiation and residence time, resulting in a robust process with minimized byproduct formation. This method was selected for the manufacturing process for belzutifan and represents the first commercial continuous flow photochemical process in our company, laying the foundation for the utilization of photochemistry in the pharmaceutical industry.

引用

页码：516 / 524

页数：9

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