An Asymmetric Reductive Amination Synthesis of Ritlecitinib Using (<i>S</i>)‐<i>α</i>‐Methylbenzylamine as Chiral Auxiliary

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)-α-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 δ-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.

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Publication Details

Journal
Chemistry - A European Journal
Published
2025-04-30
DOI
https://doi.org/10.1002/chem.202501218
Primary Topic
Asymmetric Hydrogenation and Catalysis
Type
article
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article

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

Jingshan Shen, Xingbang Yang, Peng Yang, Hongjian Qin et al.
Chemistry - A European Journal
Asymmetric Hydrogenation and Catalysis
article

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

Jingshan Shen, Xingbang Yang, Peng Yang, Hongjian Qin, Emmanuel Mintah Bonku, Xiangrui Jiang, Fuqiang Zhu, Safomuddin Abduahadi, Yuxuan Zhang, Hongkun Dong
article en

Abstract

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)-α-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 δ-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.

Chemistry - A European JournalVol. 31(33)
Shenyang Pharmaceutical University (CN), Chinese Academy of Sciences (CN), Danaher (United States) (US), Xinjiang Technical Institute of Physics & Chemistry (CN), Shanghai Institute of Materia Medica (CN), Shanghai Zhangjiang Laboratory (CN), University of Chinese Academy of Sciences (CN), State Key Laboratory of Drug Research
Openalex Percentile: Top 92%
Asymmetric Hydrogenation and Catalysis
DOISourceOpenAlex
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