当前位置: X-MOL 学术Org. Process Res. Dev. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Development of a Scalable Route for a Highly Polar Heterocyclic Aminocyclopropyl Building Block
Organic Process Research & Development ( IF 3.4 ) Pub Date : 2020-08-20 , DOI: 10.1021/acs.oprd.0c00358
Gabriel Schäfer 1 , Muhamed Ahmetovic 1 , Tony Fleischer 1 , Stefan Abele 1
Affiliation  

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
down
wechat
bug