新型泛JAK抑制剂HS-10360的合成工艺研究
Study on synthetic process of a new JAK inhibitor HS-10360
刘乐鹏 1李广猛 2陈玉龙 2陈士肖 2刘德福 2戚郜飞 2吴成军 3孙铁民3
作者信息
- 1. 沈阳药科大学 制药工程学院,辽宁沈阳 110016;江苏豪森药业集团有限公司,江苏连云港 222069
- 2. 江苏豪森药业集团有限公司,江苏连云港 222069
- 3. 沈阳药科大学 制药工程学院,辽宁沈阳 110016
- 折叠
摘要
目的 设计并优化泛JAK抑制剂HS-10360的合成工艺.方法 以2,4-二氯噻吩[2,3-d]嘧啶为原料,依次与3-氨基-5-甲基-1H-吡唑和外向-3-氨基-9-Boc-9-氮杂双环[3.3.1]壬烷发生取代反应,再与Boc-肌氨酸缩合、脱除保护基,得到1-｛(1R,3S,5S)-3-(｛4-[(5-甲基-1H-吡唑-3-基)氨基]噻吩并[2,3-d]嘧啶-2-基｝氨基)-9-氮杂双环[3.3.1]壬-9-基｝-2-(甲基氨基)乙-1-酮(HS-10360).结果 与结论优化后的工艺路线短、反应条件温和,总收率为21.5％,终产品纯度为99.8％(HPLC法).经过中试及cGMP规模生产验证,本工艺稳定性好、产品质量高,适合工业化生产.
Abstract
As the oral small molecule targeted drugs with a novel mechanism,JAK inhibitors are widely used in tumors,ulcerative colitis and other fields.In this paper,a synthetic method for 1-｛(1R,3S,5S)-3-(｛ 4-[(5-methyl-1 H-pyrazol-3-yl)amino]thieno[2,3-d]pyrimidin-2-yl ｝ amino)-9-azabicyclo[3.3.1]non-9-yl}-2-(methylamino)ethan-1-one(HS-10360)as a second generation high potency JAK inhibitor was designed.As the raw material,2,4-dichlorothieno[2,3-d]pyrimidine was replaced with 3-amino-5-methyl-1H-pyrazole and exo-3-amino-9-Boc-9-azabicyclo[3.3.1]nonane respectively,and then condensed with Boc-sarcosine,deprotected and free to obtain HS-10360.This method has the advantages of short reaction route and mild reaction conditions,the overall yield was 21.5％and the purity of the final product was 99.8％.After key synthetic process optimization,pilot scale and cGMP scale production,it was confirmed that the synthetic process is stable,the quality of product is high,and it is suitable for industrial production.
关键词
JAK抑制剂/克劳恩病/合成工艺/工艺优化/工业化Key words
JAK inhibitor/Crohn disease/synthetic process/process optimization/industrialization引用本文复制引用
出版年
2024
NETL
NSTL
万方数据