Continuous Flow Photochemistry Enables Commercial Manufacturing of First-in-Class HIF-2α Inhibitor Belzutifan

By Medicine View

Recently, MSD and the flow chemistry team of Shanghai Syntheall Pharmaceutical Co., Ltd. published a paper titled “Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination” in the American Chemical Society (ACS) journal Organic Process Research & Development (OPR&D). OPR&D is one of the authoritative journals in the field of process chemistry, and the flow chemistry team of Shanghai Syntheall Pharmaceutical Co., Ltd. has co-published papers in this journal with several internationally renowned pharmaceutical companies.

Belzutifan (MK-6482), introduced in this paper, is an oral small-molecule First-in-class HIF-2α inhibitor. It received FDA approval for marketing in August this year for the treatment of von Hippel-Lindau (VHL)-related renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastoma, or pancreatic neuroendocrine tumors (pNET) in patients for whom immediate surgery is not required.

MK-6482 Original Intermittent Bromination Process Reaction Poses Scale-Up Safety and Batch Failure Risks

In the initial bromination process of the MK-6482 synthesis route, dichloromethane was used as the solvent, with dibromodimethylhydantoin (DBDMH) and azobisisobutyronitrile (AIBN) serving as the brominating agent and initiator, respectively, to trigger a radical reaction through heating. The reaction temperature for this process needs to reach 40°C (the boiling point of the solvent dichloromethane), and once initiated, it releases heat rapidly, making the reaction uncontrollable and posing significant safety risks for scale-up production.

At the same time, under the original intermittent process conditions, product 2 is unstable in the reaction solution and continues to form dibromo impurity 3. Moreover, the isolated intermediate solid 2 exhibits poor long-term stability. Applying this process to commercial production would affect the quality of the active pharmaceutical ingredient (API) and pose a risk of batch failure. Considering the drug lifecycle, it is necessary to redesign a safe, green, and stable process route.

Continuous Photochemical Technology Empowers Green Bromination Process, Maximizing Impurity Control While Achieving High Conversion Rates

Photochemical technology has been developed for decades, but due to issues related to light sources and photoreactors (such as the selection of light source types, photoreactor design, etc.) as well as certification and standardization challenges in a GMP environment, this technology is rarely applied in large-scale production within the pharmaceutical industry.

In this paper, considering the photosensitive characteristics of DBDMH, the research team attempted to use ultraviolet and blue light under intermittent conditions at room temperature to trigger the radical reaction between DBDMH and substrate 1, successfully obtaining the target brominated product 2. Using in-situ LED-NMR technology, they further verified that the bromination reaction is a photo-induced reaction with a certain induction period, and the bromination reaction stops immediately after the light is turned off. This result provides a theoretical basis for the development of photochemical processes.

The scale-up of MK-6482 photo-bromination reaction requires sufficient light flux and precise control of the irradiation time to ensure that the dibromo impurity is controlled within acceptable levels. Based on a plug flow reactor (PFR), it is possible to shorten the optical path and precisely control the irradiation time, achieving complete conversion of substrate 1 within a shorter residence time while effectively controlling the dibromo impurity. Additionally, using acetonitrile as the solvent successfully enables continuous bromination and subsequent steps. Based on these experimental results, the research team ultimately decided to proceed with the commercial production of MK-6482 using a continuous photo-bromination process.

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

After the process plan was determined, the research team began optimizing the original process route, significantly improving the stability and efficiency of the process. Based on the first-generation PFR photoreactor developed by the research team, a laboratory scale-up achieving a capacity of 17kg/day was realized; further upgrades to the reactor increased the capacity to 38kg/day.

Ultimately, the team successfully built a GMP-compliant continuous photochemical production line by connecting photoreactor units in series, achieving workshop production with a capacity of >100kg/day, and completed the commercial validation of the continuous photo-bromination process. By the time of manuscript submission, more than 1 ton of the target product had been stably produced.

The Significance of This Technological Breakthrough

Compared with the traditional radical thermal initiation bromination process, the photochemical process avoids the use of azo radical initiators and heating initiation conditions, while maximizing the control of impurity generation under the premise of achieving high conversion rates; the application of a novel continuous photoreactor breaks through the capacity bottleneck of photochemical reactions, enabling safe and green commercial production of bromination reactions.

It is worth mentioning that this is one of the few successful cases in the pharmaceutical industry where continuous photochemical technology has been applied to the commercial production of small-molecule new drugs. The adoption of technologies such as LED-NMR real-time detection, as well as the design, setup, and debugging of production equipment from laboratory scale to commercial scale in this research, have laid a solid foundation for the application of continuous photochemistry in the pharmaceutical industry.

References

[1] Manufacturing Process Development for Belzutifan, Part 2: A Continuous Flow Visible-Light-Induced Benzylic Bromination, Organic Process Research & Development Article ASAP, DOI: 10.1021/acs.oprd.1c00240

[2] MSD and Shanghai Syntheall Pharmaceutical Co., Ltd. jointly published: Continuous photochemical technology successfully applied to the commercial production of Belzutifan. Retrieved Dec 23, 2021, from https://mp.weixin.qq.com/s/aNbC73vfBQlW3ErN-Yblow

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