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Development of a Scalable Route for a Highly Polar Heterocyclic Aminocyclopropyl Building Block
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-08-20 , DOI: 10.1021/acs.oprd.0c00358 Gabriel Schäfer 1 , Muhamed Ahmetovic 1 , Tony Fleischer 1 , Stefan Abele 1
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-08-20 , DOI: 10.1021/acs.oprd.0c00358 Gabriel Schäfer 1 , Muhamed Ahmetovic 1 , Tony Fleischer 1 , Stefan Abele 1
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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%.
中文翻译：
开发高极性杂环氨基环丙基构件的可扩展路线
从环丙烷化的原料1-氨基-1-环丙烷甲腈盐酸盐成功开发了一条通往关键杂环构件1-（嘧啶-2-基）环丙烷-1-胺盐酸盐的稳健且可扩展的途径。成功的关键是由from中间体和稳定的2-氯乙烯基ami六氟磷酸盐盐经环化反应构建嘧啶环。在温和的条件下进行环化，并以高收率和纯度分离得到的4-氯嘧啶衍生物。严格优化了最终的氢化反应：在1 bar H 2下，Pd（OH）2 / C作为催化剂和NaOMe作为碱的组合MeOH中的高压同时裂解Cbz基团并使嘧啶环脱氯，同时将嘧啶环的过度还原抑制到1.0％以下。用HCl酸化后，通过过滤除去催化剂和NaCl，最终产物以高收率和纯度分离为稳定的灰白色固体。五步序列的总产率为57％。
更新日期：2020-09-20
中文翻译：
开发高极性杂环氨基环丙基构件的可扩展路线
从环丙烷化的原料1-氨基-1-环丙烷甲腈盐酸盐成功开发了一条通往关键杂环构件1-（嘧啶-2-基）环丙烷-1-胺盐酸盐的稳健且可扩展的途径。成功的关键是由from中间体和稳定的2-氯乙烯基ami六氟磷酸盐盐经环化反应构建嘧啶环。在温和的条件下进行环化，并以高收率和纯度分离得到的4-氯嘧啶衍生物。严格优化了最终的氢化反应：在1 bar H 2下，Pd（OH）2 / C作为催化剂和NaOMe作为碱的组合MeOH中的高压同时裂解Cbz基团并使嘧啶环脱氯，同时将嘧啶环的过度还原抑制到1.0％以下。用HCl酸化后，通过过滤除去催化剂和NaCl，最终产物以高收率和纯度分离为稳定的灰白色固体。五步序列的总产率为57％。
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