23. Jennison,C.P.R.; Mackay, D.; Watson, K.N. ; Taylor, N. J. J. Org.
Chem. 1986, 51, 3043.
24. Xu, F.; Hu, W.-X. J. Chem. Res. 2008, 212.
25. Hu, W.-X.; Xu, F. J. Chem. Res. 2006, 797.
26. Xu, F.; Yang, Z.-Z.; Hu, W.-X.; Xi, L.-M. Chin. J. Org. Chem. 2010, 2,
260.
27. Xu, F.; Yang, Z.-Z.; Zhang, S.-J.; Hu, W.-X. Synthetic Commun. 2011,
41, 3367.
28. Sharma, H.; Cheng, X.; Buolamwini, J. K. J. Chem. Inf. Model. 2012, 52,
515.
29. Sivan, S. K.; Manga, V. J. Mol. Model. 2012, 18, 569.
30. Xu, F.; Yang, Z.-Z.; Jiang, J.-R.; Pan, W.-G.; Yang, X.-L.; Wu, J.-Y.;
Zhu, Y.; Wang, J.; Shou, Q.-Y.; Wu, H.-G. Bioorg. Med. Chem. Lett.
2016, 26, 3042.
31.Synthesis of compound 233: To a mixture of 1 (20.5g, 76 mmol) in
acetonitrile (228 ml) was added 80% hydrazine hydrate (4.7g, 76mmol)
dropwise at 0 ℃. A red precipitate formed immediately. The mixture was
allowed to stir for 30 min at ambient temperature, filtered, washed with
toluene and dried to give 10.2 g of pure material. The mother liquid was
concentrated under reduced pressure and the residue treated with toluene,
filtered and dried to give an additional 3.3 g of pure material for a
combined yield of 87.3% of a red solid. m.p.135-137 ℃ ; IR νmax
Figure 5. Plot of actual predicted activities for training set and test set based
on CoMSIA model.
1
(KBr)/cm-1: 3336, 3225, 2929, 1652,, 1568, 1481, 1165, 1074; H NMR
(400MHz, DMSO-d6) δ: 9.75(s, 1H,NH), 6.17(s, 1H, CH), 4.60(s, 2H,
NH2), 2.37(s, 3H, CH3), 2.21(s, 3H, CH3); 13CNMR(100MHz, DMSO-d6)
δ: 162.9, 157.0, 149.9, 141.2, 108.3, 13.2, 12.0. Synthesis of compound
5d (Method A): The mixture of 3-(2-benzylidene hydrazinyl)-6-(3,5-
Acknowledgments
The authors are very grateful to the Marine Biological
Resources Exploitation and Utilisation of Science and
Technology Innovation Team of Taizhou (Document of CPC
Taizhou Municipal Committee Office of Zhejiang Province
NO.(2012) 58), the Scientific Project of Taizhou Vocational&
Technical College (2016ZJ08) and The Taizhou “211” Talent
Project Funding Scheme.
dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetra- zine (3a, 10 mmol)
and
chloroform (20 ml) was heated to reflux. Lead tetraacetate (5.0 g, 11.4
mmol) in chloroform (10 ml) was added and the color of the solution
was changed from wine red to yellow. After the starting 3a was
completely consumed (the reaction courses was monitored by TLC),
evaporation of the chloroform, the crude yellow compound 5d was
obtained and purified by preparative thin-layer chromatography over
silica gel PF 254 (2 mm, ethyl acetate). Yield: 41 %. mp 151-153℃; 1
NMR (400 MHz, CDCl3): 8.56 (m, 2H),7.63 (m, 3H), 6.26(s, 1H),
H
+
2.78(s, 3H), 2.42(s, 3H). EI-MS: m/z (%):293.2[(M+H)
, 100].
Compounds of 5a-g and 5m were synthesized in the same manner.
Synthesis of compound 5d (Method B): The mixture of N'-(6-(3,5-
dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazin-3-yl) benzohydrazide (4b, 10
mmol) and phosphoryl chloride (20 ml) was heated to 110℃ for 1 h.
References and notes
1. Falfushynska, H. I.; Gnatyshyna, L. L.; Stoliar, O. B. Comp. Biochem.
Physiol., Part C: Toxicol. Pharmacol. 2012, 155, 396.
2. Zhu, Y.-Q.; Cheng, J.; Zou, X.-M.; Hu, F.-Z.; Xiao, Y.-H.; Yang, H.-Z.
Chin. J. Org. Chem. 2008, 28, 1044.
3. Nhu, D.; Duffy, S.; Avery, V. M.; Hughes, A.; Baell, J. B. Bioorg. Med.
Chem. Lett. 2010, 20, 4496.
4. Pandey, V. K. Indian Drugs 1986, 23, 500.
5. Sharma, P.; Kumar, A.; Sahu, V.; Singh, J. Arkivoc (Gainesville, FL, US)
2008, 218.
6. Tabassum, S.; Parveen, M.; Ali, A.; Alam, M.; Ahmad, A.; Khan, A. U.;
Khan, R. A. J. Mol. Struct. 2012, 1020, 33.
7. Sauer, J. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 6, p
901.
8. Stanovnik, B.; Grošelj, U.; Svete, J. In Comprehensive Heterocyclic
Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor,
R. J. K., Eds.; Elsevier, 2008; Vol. 9, p 641.
9. Neunhoeffer, H. In Comprehensive Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Eds.; Pergamon: Frankfurt, 1984; Vol. 3, p 531.
10. Eremeev, A. V.; Tikhomirov, D. A.; Tyusheva, V. A.; Liepins, E. Khim.
Geterotsikl 1978, 753.
11. Rao, G.-W.; Guo, Y.-M.; Hu, W.-X. ChemMedChem 2012, 7, 973.
12. Rao, G.-W.; Wang, C.; Wang, J.; Zhao, Z.G.; Hu, W.-X. Bioorg. Med.
Chem. Lett. 2013, 23, 6474.
13. Rao, G.-W.; Hu, W.-X. Bioorg. Med. Chem. Lett. 2006, 16, 3702.
14. Rao, G.-W.; Hu, W.-X. Bioorg. Med. Chem. Lett. 2005, 15, 3174.
15. Sun, Y.Q.; Yuan,Q. Synth. Commun. 2003, 16, 2769.
16. Yang, Z.-Z.; Xu, F.; Ke, Z.-L.; Chen, H.Y.; Hu, W.-X.; Li, H.-B. J. Chem.
Res. 2013, 37, 586.
17. Bansal, R. K.; Sharma, S. K. J. J. Organomet. Chem.1978, 155, 293.
18. Cohen, V.I. J. Heterocylic Chem. 1978, 15, 1113.
19.Foti, F.; Grassi, G.; Liotta,C.; Risitano, F. Synlett 2007, 11, 1730.
20. Ito, S.; Kakehi, A.; Tanaka, Y.; Yoshida, K.; Matsuno, T. B. Chem. Soc.
Jpn. 1979, 52, 483.
Then the mixture was cooled to 0 ℃ and poured into ice water (100ml).
resulting in the formation of a yellow solid product. The solid was
filtered and washed thoroughly with water to yield the crude product that
was recrystallized from 95% ethanol to give a pure product. Compounds
of 5a, 5d-e and 5g-m were synthesized in the same manner. Synthesis of
compound 6a: The mixture of compound 5d (1.3 g, 4.6 mmol) and
ethyl acetatel (30 ml) was added to morpholine (0.4 g, 4.6 mmol). The
mixture was stirred at room temperature for 30min, then warmed up to
60 ℃. After the starting 5d was completely consumed (the reaction
courses was monitored by TLC), evaporation of ethyl acetatel, the crude
yellow compound 6a was obtained and purified by preparative thin-layer
chromatography over silica gel PF 254 (2 mm, ethyl acetate: petroleum
ether = 1 : 1). Yield: 75 %. mp 185-188℃; 1 H NMR (400 MHz, CDCl3):
8.43-8.45 (m, 2H), 7.60-7.67 (m, 3H), 3.92 (s, 4H), 3.83 (m, 4H). IR νmax
(KBr)/cm-1: 2955, 1560, 1438, 1123, 1037, 702. ESI-MS: m/z (%): 284.3
[(M+H) +, 100]. Anal. calcd (%) for C13H13N7O: C, 55.12; H, 4.63; N,
34.61; O, 5.65. Found: C, 55.17; H, 4.62; N, 34.55; O, 5.64. Compounds
of 6b-v were synthesized in the same manner. Data for other compounds
are provided in the Supplementary data.
32. Yan, Q. D.; Xu, J.; Chen, J. J. Chin. J. Syn. Chem. 2011, 19, 709.
33. Chavez, D. E.; Hiskey, M. A. J. Heterocyclic Chem. 1998, 35, 1329.
34. Chen, J.J.; Xu, F.; Yang, Z.Z. Huaxue Tongbao 2012, 75, 268.
35. Rusinov, G. L.; Ganebnykh, I. N.; Chupakhin, O. N. Russ. J. Org.
Chem. 1999, 35, 1350.
36. Chen, H.; Zheng, C.X.; Yang, Y.F.; Lin. T.T.;Yuan,D.; Xu, F. Chin. J.
Syn. Chem. 2012, 20, 475.
37. Crystal data of compound 5c: the crystal was obtained by slow
evaporation from 95% ethanol at room temperature. A yellow prism of
dimensions 0.40×0.38×0.31 mm3 was used for data collection on a
Rigaku AFC10 diffractometer with a Saturn724+ CCD detector using
graphite-monochromated MoKα radiation from
a rotating anode
graphite source (λ = 0.71073 Å) using the CrystalClear program.38 The
structures were solved with SHELXS97 and refined with the full ‑
21. Counotte-Potman, A.; van der Plas, H.C.; van Veldhuizen, B. J. Org.
Chem. 1981, 46, 2138.
39
matrix least‑squares procedure on F2 by SHELXL97
. All non‑
22. Stam, C.H.; Counotte-Potman, A.D.; van der Plas, H.C. J. Org. Chem.
1982, 47, 2856.
hydrogen atoms were located in a difference Fourier map and refined