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An Asymmetric Reductive Amination Synthesis of Ritlecitinib Using (S)-α-Methylbenzylamine as Chiral Auxiliary

文献类型：期刊论文

作者Dong, Hongkun3,4; Bonku, Emmanuel Mintah4; Zhang, Yuxuan3,4; Yang, Xingbang3,4; Abduahadi, Safomuddin2,4; Zhu, Fuqiang1; Jiang, Xiangrui2,4; Yang, Peng3; Qin, Hongjian1,4; Shen, Jingshan2,4
刊名CHEMISTRY-A EUROPEAN JOURNAL
出版日期2025-05-12
页码10
关键词asymmetric reductive amination chiral auxiliary intramolecular amide formation ritlecitinib delta-lactam
ISSN号0947-6539
DOI10.1002/chem.202501218
英文摘要We present a new synthesis of ritlecitinib, employing asymmetric reductive amination via a chiral auxiliary group combined with intramolecular amide formation. This method employs a titanium(IV) ethoxide/sodium tetrahydroborate (Ti(OEt)(4)/NaBH4) reductive system to achieve a one-pot condensation-reduction of the ketone-amino acid derivative with (S)-alpha-methylbenzylamine, resulting in an 85% yield of the di-amino acid derivative with a diastereomeric ratio of 86:14. The incorporation of a chiral auxiliary substantially enhances the diastereopurity. Subsequently, acetic acid-mediated cyclization then forms the delta-lactam in 60% yield. This lactam is converted to ritlecitinib via a five-step sequence in 62% overall yield. This approach effectively circumvents the use of precious metal catalysts or hazardous reagents for constructing the chiral piperidine moiety, which were essential components in prior synthetic route.
WOS关键词JANUS KINASE INHIBITORS ; SCALE-UP
资助项目Special Foundation of Chinese Academy of Sciences for strategic pilot technology ; [XDA12050411]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001484934100001
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/317863]  
专题新药研究国家重点实验室
通讯作者Yang, Peng; Qin, Hongjian
作者单位1.Topharman Shanghai Co Ltd, Zhangjiang Hitech Pk, 388 Jialilue Rd, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Shenyang Pharmaceut Univ, Wuya Coll Innovat, Shenyang 110016, Peoples R China
4.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Dong, Hongkun,Bonku, Emmanuel Mintah,Zhang, Yuxuan,et al. An Asymmetric Reductive Amination Synthesis of Ritlecitinib Using (S)-α-Methylbenzylamine as Chiral Auxiliary[J]. CHEMISTRY-A EUROPEAN JOURNAL,2025:10.
APA Dong, Hongkun.,Bonku, Emmanuel Mintah.,Zhang, Yuxuan.,Yang, Xingbang.,Abduahadi, Safomuddin.,...&Shen, Jingshan.(2025).An Asymmetric Reductive Amination Synthesis of Ritlecitinib Using (S)-α-Methylbenzylamine as Chiral Auxiliary.CHEMISTRY-A EUROPEAN JOURNAL,10.
MLA Dong, Hongkun,et al."An Asymmetric Reductive Amination Synthesis of Ritlecitinib Using (S)-α-Methylbenzylamine as Chiral Auxiliary".CHEMISTRY-A EUROPEAN JOURNAL (2025):10.

入库方式： OAI收割

来源：上海药物研究所

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