Optimized synthesis process of tofacitinib citrate

LIU Li; LIU Zijin; TANG Jun; HE Guangwei; LIU Weizhong

doi:10.11665/j.issn.1000-5048.20220606

Journal of China Pharmaceutical University > 2022 > 53(6): 685-689. > DOI: 10.11665/j.issn.1000-5048.20220606

LIU Li, LIU Zijin, TANG Jun, HE Guangwei, LIU Weizhong. Optimized synthesis process of tofacitinib citrate[J]. Journal of China Pharmaceutical University, 2022, 53(6): 685-689. DOI: 10.11665/j.issn.1000-5048.20220606

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Optimized synthesis process of tofacitinib citrate

1.
Anhui Medical College, Hefei 230601
2.
School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012
3.
Hefei Industrial Pharmaceutical Institute Co., Ltd., Hefei 230601, China

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Received Date: September 19, 2022
Revised Date: December 05, 2022

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Abstract

In order to improve the yield and simplify the operation, the synthesizing process of JAK3 inhibitor tofacitinib citrate was improved based on the analysis of the methods previously published.Using 2, 4-dichloro-7H-pyrrolo [2, 3-d] pyrimidine and (3R, 4R)-1-benzyl-N, 4-dimethylpiperidin-3-amine dihydrochloride as starting materials, tofacitinib citrate was obtained through four steps of nucleophilic substitution, catalytic transfer hydrogenation, cyanide acetylation and citrate salt, and its crystal form was consistent with the original research.After optimization, the yield was better than those reported in literature, and the mild reaction conditions were suitable for industrial production.
- tofacitinib citrate,
- JAK3 inhibitor,
- synthesis,
- optimization

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[1]	. Prog Pharm Sci （药学进展），2011，35（10）：480.
[2]	Jiang JK，Kamran G，Francesca D，et al. Examining the chirality，conformation and selective kinase inhibition of 3-（（3R，4R）-4-methyl-3-（methyl（7H-pyrrolo［2，3-d］pyrimidin-4-yl）amino）piperidin-1-yl）-3-oxopropanenitrile（CP-690，550）［J］. J Med Chem，2008，51（24）：8012-8018.
[3]	Qiao JN，Wang TF，Zhang C. Design，synthesis and bioactivities of 4-（3-sulfonylbenzene）amino-6-formylpyrrole［2，3-d］pyrimidine derivatives［J］. J China Pharm Univ （中国药科大学学报），2017，48（5）：554-562.
[4]	Zhang ZK，Kuang CX. Synthesis of tofacitinib［J］. Chin J Pharm （中国医药工业杂志），2013，44（4）：321-323.
[5]	Burmester GR，Blanco R，Schoeman CC，et al. Tofacitinib（CP-690，550） in combination with methotrexate in patients with active rheumatoid arthritis with an inadequateresponse to tumour necrosis factor inhibitors：a randomised phase 3 trial［J］. Lancet，2013，381（9865）：451-460.
[6]	Ruggeri SG，Hawkins JM，Makowski TM，et al. Pyrrolo［ 2，3-d］pyrimidine derivatives：their intermediates and synthesis： WO2007012953［P］. 2007-01-02.
[7]	Dong L，Xu HB，He Y，et al. A preparation method of tofacitinib citrate （一种枸橼酸托法替布的制备方法）： CN 110724146 B［P］. 2019-11-04.
[8]	Shi JC，Chen HW，Zheng LK，et al. A purification method of tofacitinib citrate （一种枸橼酸托法替布的精制方法）： CN 108948020 B［P］. 2018-07-03.
[9]	Price KE，Lillie BM，Mclaughlin RW，et al. Mild and efficient DBU-catalyzed amidation of cyanoacetates［J］. Org Lett，2009，11（9）：2003-2006.
[10]	Zhang X. Study on separation and amplification of synthesis and purification of tofacitinib citrate（枸橼酸托法替尼的合成与精制分离及放大工艺研究）［D］. Hangzhou：Zhejiang University of Technology，2017.
[11]	Korhonen M，Niskanen H，Kiesvaara J，et al. Determination of optimal combination of surfactants in creams using rheology measurements［J］. Int J Pharm，2000，197（1/2）：143-151.

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