From Chiral Resolution to Diastereoselective Ellman Chemistry to Biocatalysis: Route Evolution for the Efficient Synthesis of the Tetrahydrobenzoazepine Core of BTK Inhibitor BIIB091

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2023-07-18 DOI:10.1021/acs.oprd.3c00133

Chaomin Li*, Shujun Wang, Jianxin Yang, Cuicui Yuan, Dong Wang, Deju Shang and Erin M. O’Brien,

引用次数: 0

Abstract

Two improved routes to BIIB091 key tetrahydrobenzoazepine core (1) were developed to support tox and early clinical demands. The first improved route takes advantage of a diastereoselective Ellman’s sulfinimine reduction as the key step of chiral amine synthesis. This route was successfully scaled up to support API manufacturing for early clinical trials. The second improved route uses an amine transaminase (ATA) biocatalysis reaction of an N-Boc ketone (15) precursor, which was prepared by applying a trifluoroacetamide-protecting group for effective azepine ring construction and protecting group swap. The ATA route is demonstrated at a subkilogram scale and has the potential to become a late clinical and commercial route due to its significant improvements in synthetic efficiency, overall yield, and process greenness.

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从手性拆分到非对映选择性Ellman化学再到生物催化:BTK抑制剂BIIB091高效合成四氢苯并氮卓核心的途径进化

开发了两条通往BIIB091关键四氢苯氮卓核心(1)的改进路线，以支持毒素和早期临床需求。第一种改进的途径利用非对映选择性埃尔曼亚胺还原作为手性胺合成的关键步骤。这条路线成功地扩大了规模，以支持早期临床试验的原料药生产。第二种改进途径是利用氨基转氨酶(ATA)生物催化N-Boc酮(15)前体反应，利用三氟乙酰胺保护基团进行有效的氮平环构建和保护基团交换制备。ATA路线在亚千克规模上进行了演示，由于其在合成效率、总体产量和工艺绿色方面的显着提高，因此有可能成为后期临床和商业路线。

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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.

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