AXL-MER 抑制剂肿瘤候选药物 PF-07265807 的商业开发路线

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2024-04-16 DOI:10.1021/acs.oprd.4c00049

Douglas J. Critcher, Christopher Paul Ashcroft, Alan J. Pettman, Matthew Badland, Robert Szpera, William Waddington

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摘要

本文介绍了我们为找到 PF-07265807 (ARRY-067) 的最有效结构，为商业化生产前的工艺开发做好准备而进行的路线考察工作。ARRY-067 包含氮杂吲唑（1H-吡唑并[3,4-b]吡啶）结构单元，这种结构单元在许多药物和生物活性制剂中都很常见。本文介绍了我们对这一具有挑战性的结构基团所采用的新方法，即通过加入肼引发噁唑啉开环级联，一步即可得到目标 3-丙氨醇取代的氮杂环唑。此外，还介绍了尿嘧啶羧酸偶联剂的改进合成方法。总体而言，新路线比原有路线缩短了六个步骤，最大程度地减少了保护基的操作，并避免了使用过渡金属催化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Commercial Route Development Toward PF-07265807, an AXL-MER Inhibitor Oncology Candidate

Our route scouting efforts toward finding the most efficient construction of PF-07265807 (ARRY-067) in readiness for process development prior to commercial manufacture are described. ARRY-067 contains the azaindazole (1H-pyrazolo [3,4-b]pyridine) building block that is common to many pharmaceuticals and bioactive agents. Herein, our novel approach to this challenging structural motif is described where an oxazoline ring-opening cyclization cascade triggered by the addition of hydrazine reveals the target 3-alaninol-substituted azaindazole in one step. An improved synthesis of the uracil carboxylic acid coupling partner is also described. Overall, the new route is six steps shorter than the enabling route, minimizes protecting group manipulations, and avoids the use of transition metal catalysis.

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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.