Kilo-Scale-Enabled Route toward PF-07907063, a Type II Brain Penetrant cMET Inhibitor

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-04-07 DOI:10.1021/acs.oprd.4c00441

Grace McKenna, Cole Cruz, Bryon Simmons, James T. Brewster, II, Anna M. Benz-Weeden, Thomas A. Brandt, Quinn A. Bumpers, Adam Cook, Mohamed Saad Abdullah Elsayed, Daniel Golec, Nicholas Lewandowski, Phong Nguyen, Robert W. Pipal, Pavel Savechenkov, Christina E. Wong, Eugene Tarlton, John J. Gaudino, Ronald J. Hinklin, Tony P. Tang

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Abstract

New synthetic methodologies that access complex saturated building blocks enable the synthesis of drug molecules with unique properties. Here, we report collaborative efforts between Pfizer’s Medicinal Chemistry, Medicinal Chemistry Synthesis Development, and Pharmaceutical Sciences Small Molecule (PSSM) groups for the development of kilogram-scale-enabled synthesis of a type II brain penetrant cMET inhibitor, PF-07907063. The chemistry presented herein demonstrates the importance of implementing a green chemistry approach for developing and applying new transformations throughout the drug development pipeline. Specifically, synthetic planning rooted in the 12 Principles of Green Chemistry led to advancements in deoxygenative photoredox-nickel dual catalysis and cross-electrophile nickel catalysis. The final route significantly lowered the process mass intensity (PMI), increased the yield of the final API, and allowed for the purification of key intermediates through crystallization versus purging impurities via column chromatography, among other improvements.

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一种II型脑渗透cMET抑制剂PF-07907063的kilo - scale激活途径

新的合成方法可以获得复杂的饱和构建块，从而合成具有独特性质的药物分子。在这里，我们报告了辉瑞药物化学、药物化学合成开发和药物科学小分子（PSSM）小组之间的合作努力，以开发一种II型脑渗透cMET抑制剂PF-07907063的公斤级合成。本文提出的化学证明了在整个药物开发管道中实施绿色化学方法开发和应用新转化的重要性。具体来说，基于绿色化学12原则的合成规划导致了脱氧光氧化还原-镍双催化和交叉亲电镍催化的进步。最终路线显著降低了过程质量强度（PMI），提高了最终API的收率，并允许通过结晶纯化关键中间体，而不是通过柱色谱净化杂质，以及其他改进。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.