Manufacturing Process Development for Belzutifan, Part 4: Nitrogen Flow Criticality for Transfer Hydrogenation Control

A scalable and efficient synthesis of hydroxyindanone 3, a key intermediate for belzutifan (MK-6482), is described. Mechanistic studies revealed the sensitivity of the reduction reaction toward the CO2 byproduct. Special effort was required to design a scale-insensitive process for the removal of CO2 with active nitrogen headspace sweeping, supported by process modeling and verification with process analytical technology data. Automated sampling facilitated data-rich experimentation via kinetic profiling, culminating in enhanced understanding and further robustness-based optimization for the reduction reaction. Herein we report the development of a one-pot through-process with direct isolation of 3 in high yield (>90%) and purity (>99 LCAP, >99 ee) at commercial scales. The newly developed process ensures process robustness and improves cycle times and process mass intensity.

Automated summary

This paper describes a scalable and efficient synthesis method for hydroxyindanone 3, a key intermediate for belzutifan (MK-6482). Mechanistic studies revealed the sensitivity of the reduction reaction towards the byproduct CO2. A scale-insensitive process for CO2 removal was designed using active nitrogen headspace sweeping, and further optimization was achieved through kinetic profiling and robustness-based optimization. The developed one-pot through-process allows for direct isolation of 3 in high yield and purity at commercial scales, improving process robustness and cycle times.