Development and Optimization of a Scalable Enzymatic Cascade-Carbamate Formation Telescope Process for the Synthesis of CDK2 Selective Candidate Tegtociclib (PF-07104091)

IF 3.5 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2025-10-07 DOI:10.1021/acs.oprd.5c00268

Kaitlyn Gray, Thomas A. Brandt, Robert David Bright, Michael Burns, Yiqing Feng, Michael Herr, Elaa Hilou, Sarah Karasik, Shawn Lacasse, Melissa Lee, Lesly Mejia, Mark A. Olivier, Angela L. A. Puchlopek-Dermenci, Sergei Tcyrulnikov, Carlos Alberto Martinez, Sebastien Monfette, Asaad Nematalla, Rachel Ruest, Ariana Vargas, Nancy Walsh-Sayles, Gerald A. Weisenburger

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Abstract

PF-07104091 (tegtociclib) is a cyclin-dependent kinase 2 (CDK2) selective inhibitor under investigation as an oncology treatment with breast cancer as the leading indication. In this report, we detail the development and optimization of a selective enzyme cascade-carbamate formation telescoped sequence for the synthesis of PF-07104091. The newly developed process enables exquisite stereochemical control and efficient processing, affording crude active pharmaceutical ingredient (API) in good yield and high purity while demonstrating reduced process mass intensity (PMI) and cycle time. This optimized highly efficient and sustainable process was demonstrated during pilot plant scale production of >450 kg of PF-07104091.

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CDK2选择性候选药物Tegtociclib的可扩展酶级联-氨基甲酸酯形成望远镜工艺的开发与优化

PF-07104091 （tegtociclib）是一种细胞周期蛋白依赖性激酶2 （CDK2）选择性抑制剂，正在研究以乳腺癌为主要适应症的肿瘤治疗。在本报告中，我们详细介绍了选择性酶级联氨基甲酸酯形成伸缩序列的开发和优化，用于合成PF-07104091。新开发的工艺实现了精细的立体化学控制和高效的加工，提供了收率高、纯度高的粗活性药物成分（API），同时降低了工艺质量强度（PMI）和周期时间。这种优化的高效和可持续的过程在中试工厂规模生产>；450公斤PF-07104091中得到了验证。

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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.