Development of a Scalable Asymmetric Process for the Synthesis of Selective PDE4B Inhibitor Nerandomilast (BI 1015550)

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED Organic Process Research & Development Pub Date : 2024-09-05 DOI:10.1021/acs.oprd.4c00309

Rogelio P. Frutos, Thomas G. Tampone, Frank Gerstmann, Dirk Weber, Tobias Brodmann, Robert Hagenkötter, Jocelyn Abella, Bing-Shiou Yang, Jason Mulder, Sonia Rodriguez, Heewon Lee, Joe Gao, Jinhua J. Song

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Abstract

A robust and scalable synthesis process for Nerandomilast (1, BI 1015550), a selective PDE4B inhibitor with potential therapeutic properties for the treatment of respiratory diseases, was developed and implemented at a pilot plant on a multikilogram scale. Key aspects of the process include the efficient synthesis of intermediate (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (4) by means of a regioselective S_NAr reaction between (1-aminocyclobutyl)methanol (6) and 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (5), a new convergent synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (3) by means of a Suzuki coupling, and a highly enantioselective sulfide oxidation to give chiral nonracemic (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (2).

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开发用于合成选择性 PDE4B 抑制剂 Nerandomilast（BI 1015550）的可扩展不对称工艺

我们开发了一种稳健且可扩展的合成奈兰多吉司特（Nerandomilast，1，BI 1015550）工艺，这是一种选择性 PDE4B 抑制剂，具有治疗呼吸系统疾病的潜在疗效。该工艺的主要方面包括通过 (1-aminocyclobutyl)methanol (6) 与 2,4-二氯-6,7-二氢噻吩并[3,2-d]嘧啶-4-基)氨基环丁基)甲醇 (5) 之间的区域选择性 SNAr 反应，高效合成中间体 (1-((2-氯-6,7-二氢噻吩并[3,2-d]嘧啶-4-基)氨基)环丁基)甲醇 (4)、嘧啶 (5)，通过铃木偶联合成 5-氯-2-(哌啶-4-基)嘧啶 (3)，以及通过高度对映选择性硫化物氧化反应得到手性非外消旋 (R)-2-氯-4-((1-(羟甲基)环丁基)氨基)-6,7-二氢噻吩并[3,2-d]嘧啶 5-氧化物 (2)。

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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.