Chinese Journal of Organic Chemistry >
Practical Synthesis of TJAB1099:An Effective Anti EV71 Inhibitor
Received date: 2017-04-01
Revised date: 2017-04-26
Online published: 2017-05-10
Supported by
Project supported by the State Key Laboratory of Medicinal Chemical Biology Open Fund (Nankai University) (No. 201602003), and the Science and Technology Planning Project of Tianjin City (Nos. 13ZCZDSY04200, 14ZCZDSY00039).
Enterovirus 71 (EV71) is the main pathogen caused Human Hand, Foot and Mouth Disease (HFMD) in China. It not only caused mild case, but also serious case. However, no effective commercialize drugs for the treatment of HFMD were available nowadays. TJAB1099 is an effective EV71 inhibitor which was designed based on the capsid protein VP1 of EV71. The preclinical study has revealed that it owns excellent druggability. Here an practical synthesis of TJAB1099, initiated with 2-amino-4-bromide pyridine is reported. The total synthetic steps are six and its total yield is 12%. The purity of TJAB1099 is more than 99%, and silic gel chromatography is not required in the whole process. This synthetic method has been examined by hectogram level starting feeding for several times, and the total yield and the content of impurities are stable. This method could meet the need of the inhibitor amount for the preclinical study, and it could lay the foundation of further large scale synthesis.
Key words： enterovirus 71; inhibitor; synthetic method
He Wanli , Zhao Yangyang , Mao Yonghong , Zhao Peipei , Wang Ying , Cai Yan . Practical Synthesis of TJAB1099:An Effective Anti EV71 Inhibitor[J]. Chinese Journal of Organic Chemistry, 2017 , 37(9) : 2361 -2368 . DOI: 10.6023/cjoc201704002
[1] (a) McMinn, P. C. FEMS Microbio. Rev. 2002, 26, 91.
(b) Shih, S. R.; Chen, S. J.; Hakimelahi, G. H.; Liu, H. J.; Tseng, C. T.; Shia, K. S. Med. Res. Rev. 2004, 24, 449.
[2] (a) Xu, W. B.; Tan, X. J. Disease Surveillance 2009, 24, 649.
(b) McMinn, P. C. Curr. Opin. Virol. 2012, 2, 199.
(c) Gui, J. J.; Liu, Z. F.; Hua, Q. H.; Dong, C. Z. Hereditas 2015, 37, 426(in Chinese). (桂娟娟, 刘志芳, 华启航, 董长征, 遗传, 2015, 37, 426.)
[3] (a) Chang, L.Y.; Lin, T. Y.; Hsu, K. H.; Huang, Y. C.; Lin, K. L.; Hsueh, C.; Shih, S. R.; Ning, H. C.; Hwang, M. S.; Wang, H. S.; Lee, C. Y. Lancet 1999, 354, 1682.
(b) Chan, K. P.; Goh, H. T.; Chong, C. Y.; Teo, E. S.; Lau, G.; Ling, A. E. Emerging Infect. Dis. 2003, 9, 78.
(c) Huang, K. Y.; Zhang, X.; Chung, P. H.; Tsao, K. C.; Lin, T. S.; Su, L. H., Chiu, C. H. Scand. J. Infect. Dis. 2008, 40, 571.
[4] (a) Tan, X.; Huang, X.; Zhu, S.; Chen, H.; Yu, Q.; Wang, H.; Huo, X.; Zhou, J.; Wu, Y.; Yan, D. PLos One 2011, 6, e25662.
(b) Zeng, D. B.; Ma, Y. Y.; Zhang, R.; Nie, Q. D.; Cui, Z. J.; Wang, Y. X.; Shang, L. Q.; Yin, Z. Bioorg. Med. Chem. 2016, 26, 1762.
[5] Li, R. C.; Liu, L. D.; Mo, Z. J.; Wang, X. Y.; Xia, J. L.; Liang, Z. L.; Zhang, Y.; Li, Y. P.; Mao, Q. Y.; Wang, J. J.; Jiang, L.; Dong, C. H.; Che, Y. C.; Huang, T.; Jiang, Z. W.; Xie, Z. P.; Wang, L. C.; Liao, Y.; Liang, Y.; Nong, Y.; Liu, J. S.; Zhao, H. L.; Na, R. X.; Guo, L.; Pu, J.; Yang, E.; Sun, L.; Cui, P. F.; Shi, H. J.; Wang, J. Z.; Li, Q. H. New Engl. J. Med. 2014, 370, 829.
[6] Guo, H.; Jia, Y. H. Guid. Chin. Med. 2009, 7, 66(in Chinese). (郭辉, 贾贻红, 中国医药指南, 2009, 7, 66.)
[7] Wang, X. X.; Peng, W.; Ren, J. S.; Hu, Z. Y.; Xu, J. W.; Lou, Z. Y.; Li, X. M.; Yin, W. D.; Shen, X. L.; Porta, C.; Walter, T. S.; Evans, G.; Axford, D.; Owen, R.; Rowlands, D.; Wang, J. Z.; Stuart, D. I.; Fry, E. E.; Rao, Z. H. J. Nat. Struct. Mol. Biol. 2012, 19, 424.
[8] De Colibus, L.; Wang, X. X.; Spyrou, J. A. B.; Kelly, J.; Ren, J. S.; Grimes, J.; Puerstinger, G.; Stonehouse, N.; Walter, T. S.; Hu, Z. Y.; Wang, J. Z.; Li, X. M.; Peng, W.; Rowlands, D. J. Fry, E. E.; Rao, Z. H.; Stuart, D. I. J. Nat. Struct. Mol. Biol. 2014, 21, 282.
[9] Rao, Z. H.; Yang, C.; Cai, Y.; Guo, Y.; Li, S.; Wang, Y.; Mao, Y. H.; Zhao, P. P.; He, W. L.; Zhao, Y. Y.; Liu, Y. H.; Meng, F. F. CN 201610315888.7, 2016.
[10] Lin, L. S.; Cui, M. X.; Hu, B.; Hao, J. L.; Chen, Z. X. WO 2014022528[Chem. Abstr. 2014, 160, 265016].
[11] Avis, T. J.; Boulanger, R. R.; Belanger, R. R. J. Chem. Ecol. 2000, 26, 987.
[12] Chern, J. H.; Lee, C. C.; Chang, C. S.; Lee, Y. C.; Tai, C. L.; Lin, Y. T.; Shia, K. S.; Lee, C. Y.; Shih, S. R. Bioorg. Med. Chem. Lett. 2004, 14, 5051.
/
| 〈 |
|
〉 |
