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Tetrahydronaphthofuranone spiro pyrrolidone compound and preparation method thereof

A compound and alkyl technology, applied in the field of compounds containing hydrogenated naphthofuran structures and their preparation, can solve problems such as single reaction mode, and achieve the effects of good application prospect, excellent reaction yield and few side reactions

Pending Publication Date: 2020-12-04
PINGDINGSHAN UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the previous reaction mode is relatively simple, starting from the addition of the benzylic position, and then ending with the nucleophilic attack on the aldehyde group by another component in the molecule.

Method used

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  • Tetrahydronaphthofuranone spiro pyrrolidone compound and preparation method thereof
  • Tetrahydronaphthofuranone spiro pyrrolidone compound and preparation method thereof
  • Tetrahydronaphthofuranone spiro pyrrolidone compound and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] Add ortho-pyrrolidone-substituted benzaldehyde 1a (0.2mmol), 2(5H)-furanone (1.5equiv), 1,8-diazabicycloundec-7-ene (DBU , 20mol%), and dimethyl sulfoxide (2 mL) was added, and the reaction tube was sealed with a rubber stopper. The reaction test tube was placed in an oil bath at 60° C. and heated with stirring for about 4 hours. During the reaction, TLC was used to detect that the reaction was complete. Then the solvent was spin-dried, and the pure tetrahydronaphthofuranone spiropyrrolidone compound 3a was separated by silica gel column chromatography.

[0031] Compound 3a, yield: 90%. 1 H NMR (500MHz, CDCl 3 )δ7.10(s,1H),6.75(s,1H),5.39(d,J=9.0Hz,1H),4.96(d,J=12.0Hz,1H),4.76(d,J=12.5Hz, 1H), 3.54(dtt, J=20.5, 14.0, 7.0Hz, 2H), 3.42(dd, J=20.0, 10.0Hz, 1H), 3.34(d, J=18.0Hz, 1H), 2.78(d, J =18.5Hz,1H),2.51(dd,J=18.0,9.5Hz,1H),2.46(s,3H),2.31(s,3H),2.17(dd,J=17.5,11.0Hz,1H),1.12 (t,J=7.0Hz,3H); 13 C NMR (125MHz, CDCl 3 )δ180.6,173.9,173.6,140.8,139.2,...

Embodiment 2

[0034]

[0035] Compound 3b, yield: 75%; 6: 1dr. Major isomer: 1 H NMR (500MHz, CDCl 3 )δ7.01(dd, J=9.0,2.0Hz,1H),6.71(dd,J=9.5,2.5Hz,1H),5.37(d,J=9.0Hz,1H),4.95(d,J=11.5 Hz, 1H), 4.82–4.78(m, 1H), 3.55(dd, J=9.0, 7.5Hz, 2H), 3.47(q, J=9.5Hz, 1H), 3.28(d, J=18.0Hz, 1H ),2.85(d,J=18.5Hz,1H),2.56(dd,J=17.5,9.5Hz,1H),2.51(s,3H),2.15(dd,J=18.0,7.0Hz,1H),1.12 (t,J=7.0Hz,3H); 13 C NMR (125MHz, CDCl 3 )δ180.0, 173.4, 173.3, 162.4 (d, J C-F =247.9Hz), 144.1(d, J C-F =8.1Hz), 133.2(d, J C-F =7.3Hz), 132.4(d, J C-F =3.3Hz), 118.9(d, J C-F =20.4Hz), 109.9(d, J C-F =22.8Hz), 83.7, 67.0, 50.5 (d, J C-F =1.6Hz), 41.4, 41.3, 34.7, 31.0, 19.6 (d, J C-F =1.4Hz), 12.6.Minor isomer: 1 H NMR (500MHz, CDCl 3 )δ6.93(dd, J=9.0,2.0Hz,1H),6.53(dd,J=9.0,2.5Hz,1H),5.38(d,J=9.0Hz,1H),4.82–4.78(m,1H ), 3.71(qd, J=7.5, 2.0Hz, 2H), 3.47(q, J=9.5Hz, 1H), 3.13(d, J=20.0Hz, 1H), 2.75(d, J=18.5Hz, 1H ),2.47(s,3H),1.28(t,J=7.0Hz,3H); 13 C NMR (125MHz, CDCl 3 )δ179.9, 175.2, 174.7, 162.6 (d, ...

Embodiment 3

[0037]

[0038] Compound 3c, yield: 80%. 1 H NMR (500MHz, CDCl 3 )δ7.29(s,1H),6.98(d,J=1.5Hz,1H),5.37(d,J=9.0Hz,1H),4.94(d,J=12.5Hz,1H),4.80(d, J=12.5Hz, 1H), 3.54(dtt, J=20.5, 14.0, 7.0Hz, 2H), 3.46(dd, J=20.0 9.5Hz, 1H), 3.32(d, J=18.0Hz, 1H), 2.85 (d, J=18.0Hz, 1H), 2.56(dd, J=17.5, 9.5Hz, 1H), 2.50(s, 3H), 2.15(dd, J=17.5, 11.0Hz, 1H), 1.14(t, J=7.0Hz,3H); 13 C NMR (125MHz, CDCl 3 )δ179.9,173.3,143.1,135.0,134.9,132.8,131.9,123.0,83.6,67.1,50.3,41.5,41.3,34.7,30.9,19.3,12.7.HRMS(pos.ESI):m / z[M+H] + for C 18 h 19 ClNO 5 calcd: 364.0946, found: 364.0955.

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Abstract

The invention provides a tetrahydronaphthofuranone spiro pyrrolidone compound and a preparation method thereof. According to the method, a metal-free organic catalytic cascade reaction is adopted, andvarious ortho-pyrrolidone substituted benzaldehyde and 2(5H) furanone are used as reaction substrates. The reaction yield can reach medium to excellent, the chemical selectivity and diastereoselectivity are excellent, the reaction atom economy is high, the reaction condition is mild, and the application range of a substrate is wide. The method is simple and convenient to operate, low in cost, fewin side reaction, high in product purity, convenient to separate and purify and suitable for large-scale preparation. Moreover, the obtained product has a very good application prospect in the fieldof biological medicines.

Description

technical field [0001] The invention relates to the field of organic chemistry, in particular to a compound containing a hydrogenated naphthofuran structure and a preparation method thereof. Background technique [0002] Tetrahydronaphthofuranone structures widely exist in natural products and drug molecules, and have a series of important physiological and pharmaceutical activities, such as the natural product etoposide (etoposide), which has important anti-tumor activity, and can be used as a pure natural plant source. Hanagokenol A, a potent antibiotic; xestoquinone, with important antimalarial activity ((a) Yoshikawa, K.; Kokudo, N.; Tanaka, M.; Nakano, T.; Shibata , H.; Aragaki, N.; Higuchi, T.; Hashimoto, T. Chem. Pharm. Bull. 2008, 56, 89–92. (b) Yao, S.; Tang, C.P.; Ke, C.Q.; Y. J. Nat. Prod. 2008, 71, 1242–1246. (c) Cao, S.; Foster, C.; Brisson, M.; Lazo, J. S.; (d) Laurent, D.; Jullian, V.; Parenty, A.; Knibiehler, M.; Dorin, D.; F.; Maurel, S.; Doerig, C.; Meij...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107A61P35/00A61P33/06
CPCA61P33/06A61P35/00C07D491/107
Inventor 刘丹丹廖秉华周宜荣
Owner PINGDINGSHAN UNIVERSITY