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。
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-1H-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.
作者
刘乐鹏
李广猛
陈玉龙
陈士肖
刘德福
戚郜飞
吴成军
孙铁民
LIU Lepeng;LI Guangmeng;CHEN Yulong;CHEN Shixiao;LIU Defu;QI Gaofei;WU Chengjun;SUN Tiemin(School of Pharmaceutical Engineering,Shenyang Pharmaceutical University,Shenyang 110016,China;Jiangsu Hausen Pharmaceutical Group Co.,Ltd.,Lianyungang 222069,China)
出处
《中国药物化学杂志》
CAS
2024年第1期61-66,共6页
Chinese Journal of Medicinal Chemistry
关键词
JAK抑制剂
克劳恩病
合成工艺
工艺优化
工业化
JAK inhibitor
Crohn disease
synthetic process
process optimization
industrialization
