Exploratory Process Development and Kilogram-Scale Synthesis of a Novel Oxazolidinone Antibacterial Candidate

详细信息    查看全文

• 作者：Tao Yang ; Jia-Xiang Chen ; Yiwei Fu ; Kaixiao Chen ; Jinyun He ; Weiwei Ye ; Zitai Sang ; Youfu Luo
• 刊名：Organic Process Research & Development
• 出版年：2014
• 出版时间：April 18, 2014
• 年：2014
• 卷：18
• 期：4
• 页码：511-519
• 全文大小：368K
• 年卷期：v.18,no.4(April 18, 2014)
• ISSN：1520-586X

文摘

A concise, environmentally benign, and cost-effective route was developed for the large-scale preparation of 1, a novel oxazolidinone antibacterial candidate. The key intermediate 2-(1-(2-fluoro-4-nitrophenyl)-1H-pyrazol-4-yl)pyridine 7 was prepared with high purity by mild deamination of the regioisomeric mixture 21. The mixture was prepared from a nucleophilic SNAr reaction by selective C鈥揘 coupling of the secondary amine functionality of 4-(pyridin-2-yl)-1H-pyrazol-3-amine 14 with 1,2-difluoro-4-nitrobenzene 10 in optimized conditions with the primary amine group remaining intact. The gaseous nitrogen release rate and reaction mixture temperature of the deamination step can be well controlled by altering the feeding manner, thereby providing safety guarantees. The optimized synthetic strategy of 1 with an overall yield of 27.6%, including seven sequential transformations by only five solid鈥搇iquid isolations, significantly improved the product separation workup. The strategy bypassed time-consuming and laborious procedures for any intermediate involved as well as for the final API. This study presents a process enabling the rapid delivery of a multikilogram quantity of API with high purity.