Citation: Shen Dadong, Zhu Jinlin, Wu Guofeng, Sheng Li, Gao Haoling, Wang Pu. Development of Synthesis of Phosphatidylinositol 3-Kinases Inhibitor Puquitinib Mesylate[J]. Chinese Journal of Organic Chemistry, ;2019, 39(9): 2676-2680. doi: 10.6023/cjoc201902020 shu

Development of Synthesis of Phosphatidylinositol 3-Kinases Inhibitor Puquitinib Mesylate

Shen Dadong ^a,, ,
Zhu Jinlin ^b ,
Wu Guofeng ^b ,
Sheng Li ^b ,
Gao Haoling ^b ,
Wang Pu ^a,,

a.
College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310032
b.
Research & Development Center, Zhejiang Medicine Co., Ltd., Shaoxing 312500

Corresponding author: Shen Dadong, shendadong@126.com Wang Pu, wangpu@zjut.edu.cn
Received Date: 20 February 2019
Revised Date: 25 March 2019
Available Online: 19 September 2019
Fund Project: the Significant New Drugs Development 2008ZX09101-048Project supported by the Significant New Drugs Development (No. 2008ZX09101-048)

Figures(4)

Puquitinib mesylate is a novel phosphatidylinositol 3-kinases (PI3K) inhibitor, which has been shown to be effective in the treatment of cancer. A convenient protocol for the synthesis of the compound at kilogram scale is described, using 2, 6-dichloropurine as starting material through amino-protection, S_N2 reaction with high regioselectivity, Buchwald-Hartwig coupling reaction, amino-deprotection and salt-forming reaction. The process is easy to operate and provides an effective way at kilogram scale produce with 48% yield in total.
- PI3K inhibitor,
- puquitinib,
- synthesis
1. [1]
  (a) Thomas, M.; Owen, C. Curr. Opin. Pharmacol. 2008, 8, 267.
  (b) Marone, R.; Cmiljanovic, V.; Giese, B.; Wymann, M. P. Biochim. Biophys. Acta, Proteins Proteomics 2008, 1784, 159.
  (c) Shuttleworth, S.; Silva, F.; Tomassi, C.; Cecil, A.; Hill, T.; Rogers, H.; Townsend, P. Prog. Med. Chem. 2009, 48, 81.
2. [2]
  (a) Vlahos, C. J.; Matter, W. F.; Hui, K. Y.; Brown, R. F. J. Biol. Chem. 1994, 269, 5241.
  (b) Walker, E. H.; Pacold, M. E.; Perisic, O.; Stephens, L.; Hawkins, P.; Wymann, M. Williams, R. L. Mol. Cell. 2000, 6, 909.
3. [3]
  (a) Ameriks, M. K.; Venable, J. D. Curr. Top. Med. Chem. 2009, 9, 738.
  (b) Welker, M. E.; Kulik, G. Bioorg. Med. Chem. 2013, 21, 4063.
  (c) Wei, M.-M.; Wang, X.; Song, Z.-L.; Jiao, M.-K.; Ding, J.; Meng, L.-H.; Zhang, A. Med. Res. Rev. 2015, 35, 720.
  (d) Musiol R. Expert Opin. Drug Discovery 2017, 12, 583.
4. [4]
  Xie, C.-Y.; Xu, Y.; Lou, L.-G. Cancer Res. 2011, 71, 4245.
5. [5]
  Wang, K.-F.; Yang, H.; Jiang, W.-Q.; Li, S.; Cai, Y.-C. Int. J. Mol. Med. 2015, 36, 1556. doi: 10.3892/ijmm.2015.2378
6. [6]
  Xie, C. Y.; He, Y.; Zhen, M. Y.; Wang, Y. L.; Xu, Y. P.; Lou, L. G. Cancer Sci. 2017, 108, 1476. doi: 10.1111/cas.13263
7. [7]
  Yang, H.; Wang, Y.; Zhan, J.; Xia, Y.; Sun, P.; Bi, X.-W.; Liu, P.-P.; Li, Z.-M.; Li, S.; Zou, B.-Y.; Jiang, W.-Q. Oncotarget 2015, 6, 44049.
8. [8]
  Ding, Y.; Zhan, Q.; Wu, Y.-H.; Zou, B.-Y.; Li, Z.-M.; Li, S.; Jiang, W.-Q. J. Sun Yat-Sen Univ. Med. Sci. 2015, 36, 414 (in Chinese).
9. [9]
  Wu, Z.-G. WO 2006133611, 2006.
10. [10]
  (a) Murray, J. M.; Sweeney, Z. K.; Chan, B. K.; Balazs, M.; Bradley, E.; Castanedo, G.; Chabot, C.; Chantry, D.; Flagella, M.; Goldstein, D. M.; Kondru, R.; Lesnick, J.; Li, J.; Lucas, M. C.; Nonomiya, J.; Pang, J.; Price, S.; Salphati, L.; Safina, B.; Savy, P. P. A.; Seward, E. M.; Ultsch, M.; Sutherlin, D. P. J. Med. Chem. 2012, 55, 7686.
  (b) Kenny, J. R.; Krintel, S. L.; Li, J.; Lesnick, J.; Lucas, M. C.; Lewis, C.; Mukadam, S.; Murray, J.; Nadin, A. J.; Nonomiya, J.; Padilla, F.; Palmer, W. S.; Pang, J.; Pegg, N.; Price, S.; Reif, K.; Salphati, L.; Savy, P. A.; Seward, E. M.; Shuttleworth, S.; Sohal, S.; Sweeney, Z. K.; Tay, S.; Tivitmahaisoon, P.; Waszkowycz, B.; Wei, B.; Yue, Q.; Zhang, C.; Sutherlin, D. P. J. Med. Chem. 2012, 55, 5887.
11. [11]
  Blanchard, S.; Soh, C. K.; Lee, C. P.; Poulsen, A.; Bonday, Z.; Goh, K. L.; Goh, K. C.; Goh, M. K.; Pasha, M. K.; Wang, H. S.; Williams, M.; Wood, J. M.; Ethirajulu, K.; Dymock, B. W. Bioorg. Med. Chem. Lett. 2012, 22, 2880. doi: 10.1016/j.bmcl.2012.02.058
12. [12]
  Fiorini, M. T.; Abell, C. Tetrahedron Lett. 1998, 39, 1827 doi: 10.1016/S0040-4039(98)00098-7
13. [13]
  Beletskaya, I. P.; Cheprakov, A. V. Organometallics 2012, 31, 7753 doi: 10.1021/om300683c
14. [14]
  Burger, M. T.; Knapp, M.; Wagman, A.; Ni, Z. J.; Hendrickson, T.; Atallah, G.; Zhang, Y.; Frazier, K.; Verhagen, J.; Pfister, K.; Ng, S.; Smith, A.; Bartulis, S.; Merrit, H.; Weismann, M.; Xin, X.; Haznedar, J.; Voliva, C. F.; Iwanowicz, E.; Pecchi, S. ACS Med. Chem. Lett. 2011, 2, 34. doi: 10.1021/ml1001932
15. [15]
  Giordanetto, F.; Wållberg, A.; Cassel, J.; Ghosal, S.; Kossenjans, M.; Yuan, Z. Q.; Wang, X.; Liang, L. Bioorg. Med. Chem. Lett. 2012, 22, 6665. doi: 10.1016/j.bmcl.2012.08.101
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