高极性杂环氨基环丙基构建块的可扩展路线的发展

IF 3.1 3区 化学 Q2 CHEMISTRY, APPLIED
Gabriel Schäfer*, Muhamed Ahmetovic, Tony Fleischer, Stefan Abele
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引用次数: 2

摘要

以环丙化起始原料1-氨基-1-环丙腈盐酸盐为原料,成功地开发了一条稳定、可扩展的关键杂环构建块1-(嘧啶-2-基)环丙-1-胺盐酸盐路线。成功的关键是通过脒中间体和稳定的2-氯六氟磷酸乙烯酰胺环化构建嘧啶环。在温和的条件下进行了环化反应,得到了收率高、纯度高的4-氯嘧啶衍生物。最终的加氢过程进行了优化:以Pd(OH)2/C为催化剂,NaOMe为碱,在甲醇中以1bar H2压力同时裂解Cbz基团和脱氯嘧啶环,同时抑制了嘧啶环的过还原至1.0%以下。用HCl酸化,过滤去除催化剂和NaCl,最终产物以高产率和纯度分离为实验稳定的灰白色固体。五步序列的总产率为57%。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Development of a Scalable Route for a Highly Polar Heterocyclic Aminocyclopropyl Building Block

Development of a Scalable Route for a Highly Polar Heterocyclic Aminocyclopropyl Building Block

A robust and scalable route toward key heterocyclic building block 1-(pyrimidin-2-yl)cyclopropan-1-amine hydrochloride from cyclopropanated starting material 1-amino-1-cyclopropanecarbonitrile hydrochloride was successfully developed. The key to success was the construction of a pyrimidine ring via cyclization from an amidine intermediate and a bench-stable 2-chloro vinamidinium hexafluorophosphate salt. The cyclization was performed under mild conditions, and the resulting 4-cloropyrimidine derivative was isolated in high yield and purity. The final hydrogenation was intensively optimized: A combination of Pd(OH)2/C as a catalyst and NaOMe as a base at 1 bar H2 pressure in MeOH simultaneously cleaved the Cbz group and dechlorinated the pyrimidine ring while at the same time suppressing the over-reduction of the pyrimidine ring to below 1.0%. After acidification with HCl, followed by removal of the catalyst and NaCl by filtration, the final product was isolated in high yield and purity as a bench-stable off-white solid. The overall yield of the five-step sequence was 57%.

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来源期刊
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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