Continuous Photochemical Technology Successfully Applied in Commercial Production of HIF-2α Inhibitors

TextPharmaceutical Guanlan

Recently, Merck & Co (MSD) and the flow chemistry team of Hequan Pharmaceutical published a paper entitled "Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Light- Induced Benzylic Bromination" paper

Belzutifan (MK-6482) introduced in this paper is an oral small molecule First-in-class HIF-2α inhibitor, which was approved by the FDA in August this year for von Hippel-Lindau ( VHL) associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastoma or pancreatic neuroendocrine tumor (pNET)

The original batch bromination process of MK-6482 has the risk of scale-up safety and batch failure

The initial bromination process in the synthetic route of MK-6482 used dichloromethane as solvent, and dibromohydantoin (DBDMH) and azobisisobutyronitrile (AIBN) were used as bromination reagents and initiators, respectively, and radicals were induced by heating.

Meanwhile, under the original batch process conditions, the product 2 is unstable in the reaction solution, and will continue to generate dibromine impurities 3, and the isolated intermediate solid 2 has poor long-term stability

Continuous photochemical technology enables green bromination process and maximizes control of impurity generation under the premise of achieving high conversion rate

Photochemical technology has been developed for decades, but due to light source and photoreactor related issues (e.

In this paper, considering the photosensitivity of DBDMH, the research team tried to use ultraviolet light and blue light to excite the radical reaction between DBDMH and substrate 1 at room temperature under intermittent conditions, and successfully obtained the target brominated product 2

The production scale-up of MK-6482 photobromination requires sufficient luminous flux and precise control of illumination time to ensure that dibrominated impurities are controlled to acceptable levels

Establish a continuous photoreaction production line that meets GMP requirements, with a production capacity exceeding 100kg/day

After the process plan was determined, the research team started to optimize the original process route, which significantly improved the stability and efficiency of the process

In the end, the team successfully built a continuous photoreaction production line that meets the requirements of GMP by connecting photoreactor units in series, achieving workshop production with a capacity of >100kg/day, and completing the commercial verification of the continuous process of photobromination

The significance of this technological breakthrough

Compared with the traditional free radical thermally initiated bromination process, the photochemical process avoids the use of azo radical initiators and heating initiation conditions, and maximizes the control of impurity generation under the premise of achieving high conversion rates; through a new continuous photoreactor Its application breaks through the production capacity bottleneck of photoreaction and realizes safe and green commercial production of bromination reaction

It is worth mentioning that this is one of the few successful cases in the pharmaceutical industry where continuous photochemical technology is applied to the commercial production of new small molecule drugs

References

[1] Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination, Organic Process Research & Development Article ASAP, DOI: 10.

[2] Jointly published by MSD and Hequan Pharmaceutical: Continuous Photochemical Technology Successfully Applied in Belzutifan Commercial Production.