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

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.