Analysis and Comparison of Synthesis Route of Small Molecule Kinase Inhibitors Tofacitinib

Research Article
Open access

Analysis and Comparison of Synthesis Route of Small Molecule Kinase Inhibitors Tofacitinib

Yujun Sun 1* , Hongyu Zhu 2
  • 1 School of Chemical Engineering and Technology, Tianjin University, Tianjin 300354, China    
  • 2 NUIST Reading Academy, Nanjing University of Information Science & Technology, Nanjing 210044, China    
  • *corresponding author 201883050012@nuist.edu.cn
Published on 28 April 2023 | https://doi.org/10.54254/2753-8818/4/20220553
TNS Vol.4
ISSN (Print): 2753-8826
ISSN (Online): 2753-8818
ISBN (Print): 978-1-915371-27-0
ISBN (Online): 978-1-915371-28-7

Abstract

Tofacitinib is one of the Janus activated kinase inhibitors, and the compound is characteristic of its high-throughput screening and lead optimization of its role as a JAK3 inhibitor in the cure of autoimmune diseases and organ transplant rejection. It can be used to the recovery of rheumatoid arthritis and psoriatic arthritis. In this article, we will introduce tofacitinib’s background and meaning, and then it’s function as a molecule kinase inhibitor. It has advantage on the remedy of inflammatory diseases. The initial synthesis procedure of tofacitinib is comparatively complicated and the cost is unaffordable. Thus, three synthesis routes are discussed, and the upsides and downsides of methods from aspects of atomic economy, reaction yield, purity and safety are analyzed. Tofacitinib’s mechanism and application are further introduced. Although the three synthesis routes of tofacitinib introduced in this paper still have many shortcomings, we put forward some improvement ideas for the future synthesis routes and put forward the possibility of its future application.

Keywords:

synthesis, tofacitinib, mechanism, application.

Sun,Y.;Zhu,H. (2023). Analysis and Comparison of Synthesis Route of Small Molecule Kinase Inhibitors Tofacitinib. Theoretical and Natural Science,4,220-228.
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References

[1]. Stober C. (2021). Pathogenesis of psoriatic arthritis. Best practice & research. Clinical rheumatology, 35(2), 101694.

[2]. Xie, Z., Yang, X., Duan, Y., Han, J., & Liao, C. (2021). Small-Molecule Kinase Inhibitors for the Treatment of Nononcologic Diseases. Journal of medicinal chemistry, 64(3), 1283–1345.

[3]. Patil, Y.S., Bonde, N.L., Kekan, A.S., Sathe, D.G., & Das, A. (2014). An Improved and Efficient Process for the Preparation of Tofacitinib Citrate. Organic Process Research & Development, 18, 1714-1720.

[4]. Su, W., Chen, Z., Liu, M., et al. (2022). Design, synthesis and structure-activity relationship studies of pyrido[2,3-d] pyrimidin-7-ones as potent Janus Kinase 3 (JAK3) covalent inhibitors. Bioorganic & medicinal chemistry letters, 64, 128680.

[5]. Maricán, A., Simirgiotis, M. J., & Santos, L. S. (2013). Asymmetric total synthesis of Tofacitinib. Tetrahedron Letters, 54(37), 5096-5098.

[6]. Mane, K. D., Kamble, R. B., & Suryavanshi, G. (2021). Short enantioselective total synthesis of (+)-tofacitinib. Tetrahedron Letters, 67, 152838.

[7]. Sandborn, W. J., Su, C., Sands, B. E., et al. (2017). OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med, 376(18), 1723-1736.

[8]. Guimarães, P. O., Quirk, D., Furtado, R. H., et al. (2021). Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. The New England journal of medicine, 385(5), 406–415.

[9]. Kim, D., Kobayashi, T., Voisin, B., et al. (2020). Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: a case report. Nature medicine, 26(2), 236–243.

[10]. Ruperto, N., Brunner, H. I., Synoverska, O., et al. (2021). Tofacitinib in juvenile idiopathic arthritis: a double-blind, placebo-controlled, withdrawal phase 3 randomised trial. Lancet (London, England), 398(10315), 1984–1996.

Cite this article

Sun,Y.;Zhu,H. (2023). Analysis and Comparison of Synthesis Route of Small Molecule Kinase Inhibitors Tofacitinib. Theoretical and Natural Science,4,220-228.

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The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

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About volume

Volume title: Proceedings of the 2nd International Conference on Biological Engineering and Medical Science (ICBioMed 2022), Part II

ISBN：978-1-915371-27-0(Print) / 978-1-915371-28-7(Online)
Editor：Gary Royle, Steven M. Lipkin
Conference website: http://www.icbiomed.org
Conference date: 7 November 2022
Series: Theoretical and Natural Science
Volume number: Vol.4
ISSN：2753-8818(Print) / 2753-8826(Online)

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References

[1]. Stober C. (2021). Pathogenesis of psoriatic arthritis. Best practice & research. Clinical rheumatology, 35(2), 101694.

[2]. Xie, Z., Yang, X., Duan, Y., Han, J., & Liao, C. (2021). Small-Molecule Kinase Inhibitors for the Treatment of Nononcologic Diseases. Journal of medicinal chemistry, 64(3), 1283–1345.

[3]. Patil, Y.S., Bonde, N.L., Kekan, A.S., Sathe, D.G., & Das, A. (2014). An Improved and Efficient Process for the Preparation of Tofacitinib Citrate. Organic Process Research & Development, 18, 1714-1720.

[4]. Su, W., Chen, Z., Liu, M., et al. (2022). Design, synthesis and structure-activity relationship studies of pyrido[2,3-d] pyrimidin-7-ones as potent Janus Kinase 3 (JAK3) covalent inhibitors. Bioorganic & medicinal chemistry letters, 64, 128680.

[5]. Maricán, A., Simirgiotis, M. J., & Santos, L. S. (2013). Asymmetric total synthesis of Tofacitinib. Tetrahedron Letters, 54(37), 5096-5098.

[6]. Mane, K. D., Kamble, R. B., & Suryavanshi, G. (2021). Short enantioselective total synthesis of (+)-tofacitinib. Tetrahedron Letters, 67, 152838.

[7]. Sandborn, W. J., Su, C., Sands, B. E., et al. (2017). OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain Investigators. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med, 376(18), 1723-1736.

[8]. Guimarães, P. O., Quirk, D., Furtado, R. H., et al. (2021). Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. The New England journal of medicine, 385(5), 406–415.

[9]. Kim, D., Kobayashi, T., Voisin, B., et al. (2020). Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: a case report. Nature medicine, 26(2), 236–243.

[10]. Ruperto, N., Brunner, H. I., Synoverska, O., et al. (2021). Tofacitinib in juvenile idiopathic arthritis: a double-blind, placebo-controlled, withdrawal phase 3 randomised trial. Lancet (London, England), 398(10315), 1984–1996.

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