CN111808083A - 3-pyrazoline isoflavone compound and preparation method and application thereof - Google Patents

3-pyrazoline isoflavone compound and preparation method and application thereof Download PDF

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CN111808083A
CN111808083A CN202010702207.9A CN202010702207A CN111808083A CN 111808083 A CN111808083 A CN 111808083A CN 202010702207 A CN202010702207 A CN 202010702207A CN 111808083 A CN111808083 A CN 111808083A
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pyrazoline
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CN111808083B (en
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张敏
黎峥
刘雄利
田民义
王慧娟
周英
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Guizhou University
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The method comprises the steps of adding various substituted dipyrazolone 1 and dihydrochromone 2 into an organic solvent, reacting under the catalysis of an organic secondary amine catalyst, separating to obtain an intermediate IA, protecting hydroxyl in the organic solvent through methanesulfonyl chloride under the catalysis of organic tertiary amine to obtain an intermediate IB, continuously carrying out elimination reaction under the catalysis of the organic tertiary amine without separating the intermediate IB, and obtaining the 3-pyrazoline isoflavone compound 3. And the novel skeleton compound has the effect of inhibiting activity on human lung adenocarcinoma cells. The method has the advantages of simple and easy operation, cheap and easily obtained raw material synthesis, capability of being carried out in various organic solvents, better air stability, wide applicability and good compatibility for various substituent groups.

Description

3-pyrazoline isoflavone compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of chemistry and pharmacy, in particular to a 3-pyrazoline isoflavone compound and a preparation method and application thereof.
Background
According to the active skeleton splicing principle of drug design, splicing two or more bioactive skeletons into a multi-skeleton molecule with potential bioactivity is an extremely important research field in organic chemistry and medicinal chemistry. (1) Pyrazoline skeletons are also ubiquitous in natural products and drug molecules. For example, the natural product molecules 4' -hydroxypyrazoline, 3-n-arylpyrazole, Withamnosine, Pyrazofurin and Edaravone share a pyrazoline molecular unit, and the compounds play an important role in relieving pain and realizing economic development. (2) The broad presence of the isoflavone backbone in natural products and synthetic drug molecules has attracted a wide range of interest to many chemists and medicinal chemistry teams, for example, fig. 8, where natural products or active small molecules of the isoflavones Daidzein, Genistein, Glycitein, Tectorigenin, Biochanin a and Genistein exhibit diverse biological activities. In view of the potential biological activity of the pyrazoline skeleton and the isoflavone skeleton. Therefore, pyrazoline is spliced to an isoflavone framework to synthesize a series of novel 3-pyrazoline isoflavone compounds with potential multi-active functional groups, so that a compound source can be provided for biological activity screening, and the pyrazoline isoflavone compound has important application value for drug screening and pharmaceutical industry (as shown in figure 8).
Disclosure of Invention
The purpose of the invention is: the 3-pyrazoline isoflavone compound is an important medical intermediate analogue and a drug molecule analogue, has important application value for drug screening and pharmaceutical industry, and has very economic and simple synthetic method.
The invention also discloses the application of the compounds in preparing the medicines for preventing and treating tumor diseases.
The invention is realized by the following steps: a3-pyrazoline isoflavone compound has a structure shown in the following general formula (I):
Figure BDA0002593359670000021
in the formula, R1Is methyl, methoxy, halogen or hydrogen; r2Is methyl or hydrogen; ar is a benzene ring, a chlorobenzene ring, a methyl-substituted benzene ring or a nitro-substituted benzene ring.
Adding various substituted pyrazolones 1 and dihydrochromone 2 into an organic solvent, carrying out Aldol reaction under the catalytic action of an organic secondary amine catalyst, separating to obtain an intermediate IA, then protecting hydroxyl in the organic solvent through methanesulfonyl chloride under the catalysis of organic tertiary amine to obtain an intermediate IB, wherein the intermediate IB does not need to be separated, and continues to carry out elimination reaction under the catalysis of the organic tertiary amine to obtain the 3-pyrazoline isoflavone compound 3.
The synthetic route is exemplified as follows:
Figure BDA0002593359670000022
wherein the substituents of the compounds in the synthetic route satisfy R1Is methyl, methoxy, halogen or hydrogen; r2Is methyl or hydrogen; ar is a benzene ring, a chlorobenzene ring, a methyl-substituted benzene ring or a nitro-substituted benzene ring.
The reaction mechanism is exemplified as follows:
Figure BDA0002593359670000023
the organic solvent is methanol, acetonitrile, toluene, dichloromethane or chloroform.
The organic secondary amine catalyst is diethylamine, tetrahydropyrrole, piperidine, tetrahydropyrrole derivatives or piperidine derivatives.
The organic tertiary amine catalyst is triethylamine, DABCO, DMAP, DBU, cinchona alkaloid or cinchona alkaloid derivatives.
Adding various substituted pyrazolones 1 and dihydrochromone 2 into an organic solvent, carrying out Aldol reaction under the catalytic action of an organic secondary amine catalyst at the reaction temperature of 25-40 ℃ for 5-24 h, separating to obtain an intermediate IA, protecting hydroxyl in the organic solvent through methanesulfonyl chloride under the catalysis of organic tertiary amine to obtain an intermediate IB, wherein the intermediate IB does not need to be separated, and continues to carry out elimination reaction under the catalysis of the organic tertiary amine, the reaction temperature is 25-40 ℃, and the reaction time is 5-48 h, so that the 3-pyrazoline isoflavone compound 3 is obtained.
Application of 3-pyrazoline isoflavone compound in preparing medicine for preventing and treating tumor diseases is provided.
By adopting the technical scheme, various substituted dipyrazolone 1 and dihydrochromone 2 are added into an organic solvent, Aldol reaction is carried out under the catalytic action of an organic secondary amine catalyst, an intermediate IA is obtained by separation, then hydroxyl is protected by methanesulfonyl chloride in the organic solvent under the catalysis of organic tertiary amine, an intermediate IB is obtained, the intermediate IB does not need to be separated, elimination reaction is continuously carried out under the catalysis of the organic tertiary amine, and a 3-pyrazoline isoflavone compound 3 is obtained. And the novel skeleton compound has the effect of inhibiting the activity of human lung adenocarcinoma cells (A549). The method has the advantages of simple and easy operation, cheap and easily obtained raw material synthesis, capability of being carried out in various organic solvents, better air stability, wide applicability and good compatibility for various substituent groups.
Drawings
FIGS. 1 and 2 are data of the spectrum of compound 3a according to an embodiment of the present invention;
FIGS. 3 and 4 are spectra data for compound 3b of the example of the present invention;
FIGS. 5 and 6 are data of the spectrum of compound 3c according to the example of the present invention;
FIG. 7 is a single crystal diagram of compound 3j according to an embodiment of the present invention.
FIG. 8 is an inventive design of the compounds of the present invention.
Detailed Description
The embodiment of the invention comprises the following steps:
Figure BDA0002593359670000031
pyrazolone 1a (0.50mmol) and dihydrochromone 2a (0.75mmol) were added to the reaction tube in sequence in MeOH (3.0mL) by addition of Et2Performing Aldol reaction at 25 deg.C for 24 hr under catalysis of NH (0.25mmol), separating by column chromatography (eluent: V (petroleum ether): V (ethyl acetate): 4:1) to obtain intermediate IA, and performing Et treatment3Under the catalysis of N (0.75mmoL), in DCM (10mL), protecting hydroxyl group with methanesulfonyl chloride (0.75mmoL), the reaction temperature is 25 ℃, the reaction time is 5h, obtaining intermediate IB, without separation, continuing to add Et3N (0.15mmoL), at 25 ℃ for 5h, after the TLC assay was essentially complete, and the crude product was directly purified by column chromatography (eluent: V (petroleum ether): V (ethyl acetate): 4:1) to give compound 3a, a white solid, m.p.: 128.1-128.5 ℃; the yield was 77%. The results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.30(s,3H),7.13-7.17(m,1H),7.31-7.37(m,3H),7.41(d,J＝8.4Hz,1H),7.60-7.64(m,1H),7.71-7.73(m,2H),8.11(s,1H),8.18-8.21(m,1H),11.91(br s,1H)；13C NMR(CDCl3,100MHz):14.3,91.9,116.9,117.8,120.6,121.7,124.6,125.0,125.2,127.8,133.4,137.5,144.0,151.7,154.6,178.5；HRMS(ESI-TOF)m/z:Calcd.for C19H14N2NaO3[M+Na]+:341.0897；Found:341.09004.
the compounds 3b to 3af can be obtained by the same production method of the compounds 3b to 3af as the compound 3a in the same charge ratio as the compound 3a, and the compounds 3b to 3af are shown in tables 1 to 3, but it is emphasized that the compounds of the present invention are not limited to those shown in tables 1 to 3.
Table 1 shows the chemical structure of a 3-pyrazoline isoflavone compound
Figure BDA0002593359670000041
Table 2 shows the chemical structure of a 3-pyrazoline isoflavone compound
Figure BDA0002593359670000042
Table 3 shows the chemical structure of a 3-pyrazoline isoflavone compound
Figure BDA0002593359670000051
This example prepares compound 3b as a white solid, melting point: 108.6 to 109.2 ℃; the yield is 62%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.29(s,3H),2.36(s,3H),7.14-7.17(m,1H),7.30-7.35(m,3H),7.41-7.44(m,1H),7.72(d,J＝8.0Hz,2H),7.95(s,1H),8.08(s,1H),12.01(br s,1H)；13C NMR(CDCl3,100MHz):14.4,20.0,91.9,116.7,117.6,120.7,121.3,124.2,124.9,127.8,134.8,134.9,137.6,143.8,151.3,151.6,153.0,178.5；HRMS(ESI-TOF)m/z:Calcd.for C20H16N2NaO3[M+Na]+:355.1053；Found:355.1057.
this example prepares compound 3c as a white solid, melting point: 172.4-172.8 ℃; the yield is 56%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.33(s,3H),7.16-7.20(m,1H),7.25-7.28(m,1H),7.34-7.39(m,3H),7.54(d,J＝3.2Hz,1H),7.74(d,J＝7.6Hz,2H),8.15(s,1H)；13CNMR(CDCl3,100MHz):14.4,55.0,103.5,118.4,120.8,122.3,124.2,125.0,127.8,137.6,143.9,149.8,151.4,151.5,156.3,178.1；HRMS(ESI-TOF)m/z:Calcd.forC20H16N2NaO4[M+Na]+:371.1002；Found:371.0996.
this example prepares compound 3d as a white solid, melting point: 208.2 to 208.6 ℃; the yield is 47%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.15(s,3H),3.92(s,3H),7.10-7.12(m,1H),7.18(s,1H),7.23-7.27(m,1H),7.44-7.48(m,2H),7.45(d,J＝8.0Hz,2H),8.05(d,J＝8.8Hz,1H),8.35(s,1H)；13C NMR(CDCl3,100MHz):13.8,56.6,101.0,115.4,116.6,117.7,120.7,125.7,127.4,129.4,155.8,158.0,164.4,175.6；HRMS(ESI-TOF)m/z:Calcd.forC20H16N2NaO4[M+Na]+:371.1002；Found:371.1007.
this example prepares compound 3e as a white solid, melting point: 129.9-130.3 ℃; the yield is 67%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.16(s,3H),3.98(s,3H),7.24-7.28(m,1H),7.41-7.49(m,4H),7.66-7.69(m,1H),7.77(d,J＝7.6Hz,2H),8.48(s,1H),11.29(br s,1H)；13C NMR(CDCl3,100MHz):13.7,56.8,115.4,116.3,121.1,124.8,125.7,129.4,146.4,149.1,156.0；HRMS(ESI-TOF)m/z:Calcd.for C20H16N2NaO4[M+Na]+:371.1002；Found:371.1004.
this example prepares compound 3f as a white solid, melting point: 74.2-74.6 ℃; the yield is 75%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.34(s,3H),7.17-7.21(m,1H),7.34-7.43(m,3H),7.48-7.51(m,1H),7.73(d,J＝7.6Hz,2H),7.86-7.88(m,1H),8.18(s,1H),11.63(br s,1H)；13C NMR(CDCl3,100MHz):14.4,91.5,109.8(d,JCF＝24.1Hz),119.2(d,JCF＝7.4Hz),120.8,122.1(d,JCF＝25.3Hz),125.1,127.8,137.4,143.8,151.0,151.9,158.7(d,JCF＝246.4Hz),177.9；HRMS(ESI-TOF)m/z:Calcd.for C19H13FN2NaO3[M+Na]+:359.0802；Found:359.0800.
this example prepares compound 3g, white solid, melting point:97.3 to 97.7 ℃; the yield is 81%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.21(s,3H),7.10-7.13(m,1H),7.27-7.32(m,3H),7.47-7.50(m,1H),7.65(d,J＝7.6Hz,2H),8.02(s,1H),8.06(s,1H),11.68(brs,1H)；13C NMR(CDCl3,100MHz):14.3,91.4,118.7,120.5,122.8,124.3,125.0,127.7,128.4,130.5,133.6,152.8；HRMS(ESI-TOF)m/z:Calcd.For C19H13ClN2NaO3[M+Na]+:375.0507；Found:375.0512.
this example prepares compound 3h as a white solid, melting point: 98.3-98.9 ℃; the yield is 70%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.13(s,3H),7.24-7.27(m,1H),7.45-7.49(m,2H),7.70-7.77(m,3H),7.98-8.01(m,1H),8.21(s,1H),8.47(s,1H),11.29(br s,1H)；13C NMR(DMSO-d6,100MHz):13.4,118.4,121.6,125.4,128.0,129.4,137.2,155.1,156.7；HRMS(ESI-TOF)m/z:Calcd.for C19H13BrN2NaO3[M+Na]+:419.0002；Found:419.0005.
this example prepares compound 3i as a white solid, melting point: 145.0 to 145.6 ℃; the yield is 57%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.29(s,3H),3.33(s,3H),7.14-7.18(m,2H),7.37-7.41(m,1H),7.46(d,J＝8.4Hz,1H),7.59(d,J＝8.4Hz,2H),7.65-7.69(m,1H),8.15(s,1H),8.23-8.25(m,1H),11.77(br s,1H)；13C NMR(CDCl3,100MHz):14.3,20.0,117.0,120.9,124.7,125.3,128.4,133.4,134.9,151.6,154.7,178.6；HRMS(ESI-TOF)m/z:Calcd.for C20H16N2NaO3[M+Na]+:355.1053；Found:355.1061.
this example prepares compound 3j as a white solid, melting point: 83.4-84.0 ℃; the yield is 64%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.13(s,3H),2.33(s,3H),2.45(s,3H),7.26(d,J＝8.4Hz,2H),7.58-7.66(m,4H),7.93(s,1H),8.40(s,1H),11.31(br s,1H)；13C NMR(DMSO-d6,100MHz):13.7,21.0,116.6,118.6,120.8,123.6,125.1,130.0,134.9,135.5,135.7,154.4,156.2,176.2；HRMS(ESI-TOF)m/z:Calcd.for C21H18N2NaO3[M+Na]+:369.1210；Found:369.1217.
this example prepares compound 3k as a white solid, melting point: 126.3-126.9 ℃; the yield is 77%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.06(s,3H),2.25(s,3H),3.80(s,3H),7.18(d,J＝8.4Hz,2H),7.34-7.37(m,1H),7.43(s,1H),7.55-7.60(m,3H),8.33(s,1H),11.23(br s,1H)；13C NMR(DMSO-d6,100MHz):13.8,21.0,56.2,105.4,115.9,120.5,123.9,124.5,129.8,134.9,150.9,156.1,157.1,175.9；HRMS(ESI-TOF)m/z:Calcd.forC21H18N2NaO4[M+Na]+:385.1159；Found:385.1164.
this example prepares compound 3l as a white solid, melting point: 199.6-200.0 ℃; the yield is 70%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.14(s,3H),2.33(s,3H),3.98(s,3H),7.26(d,J＝8.4Hz,2H),7.41-7.46(m,2H),7.62-7.68(m,3H),8.45(s,1H),11.17(brs,1H)；13C NMR(CDCl3,100MHz):13.8,21.0,56.8,115.4,116.3,121.4,124.8,125.7,129.8,134.9,146.4,149.1,155.8,176.1；HRMS(ESI-TOF)m/z:Calcd.for C21H18N2NaO4[M+Na]+:385.1159；Found:385.1155.
this example prepares compound 3m as a white solid, melting point: 138.2-138.8 ℃; the yield is 56%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):1.13(s,3H),2.33(s,3H),7.26(d,J＝8.4Hz,2H),7.62(d,J＝8.4Hz,2H),7.71-7.76(m,1H),7.79-7.82(m,2H),8.46(s,1H),11.24(br s,1H)；13C NMR(DMSO-d6,100MHz):13.6,21.0,110.4(d,JCF＝23.3Hz),116.1,121.8(d,JCF＝9.1Hz),122.7(d,JCF＝25.4Hz),125.0,125.1,129.8,134.9,152.6,156.6,159.4(d,JCF＝243.4Hz),175.5；HRMS(ESI-TOF)m/z:Calcd.for C20H15FN2NaO3[M+Na]+:373.0959；Found:373.0961.
this example prepares compound 3n as a white solid, melting point: 98.4-98.8 ℃; the yield is 50%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.12(s,3H),2.33(s,3H),7.26(d,J＝8.4Hz,2H),7.62(d,J＝8.4Hz,2H),7.79(d,J＝4.4Hz,1H),7.88-7.91(m,1H),8.07(s,1H),8.46(s,1H),11.06(br s,1H)；13C NMR(DMSO-d6,100MHz):14.0,21.0,121.5,124.8,125.0,129.8,130.4,134.5,154.7,156.7；HRMS(ESI-TOF)m/z:Calcd.For C20H15ClN2NaO3[M+Na]+:389.0663；Found:389.0664.
this example prepares compound 3o a white solid, melting point: 98.6-99.2 ℃; the yield is 59%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.11(s,3H),2.33(s,3H),7.26(d,J＝8.4Hz,2H),7.61(d,J＝8.4Hz,2H),7.72(d,J＝8.8Hz,1H),7.99-8.02(m,1H),8.21(d,J＝2.4Hz,1H),8.46(s,1H)；13C NMR(DMSO-d6,100MHz):13.6,21.0,118.3,121.7,125.4,128.0,129.8,137.2,155.1,156.7；HRMS(ESI-TOF)m/z:Calcd.For C20H15BrN2NaO3[M+Na]+:433.0158；Found:433.0154.
this example prepares compound 3p as a white solid, melting point: 176.5-176.9 ℃; the yield is 50%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.13(s,3H),7.50-7.55(m,3H),7.70(d,J＝8.0Hz,1H),7.79-7.86(m,3H),8.13-8.16(m,1H),8.43(s,1H),11.48(br s,1H)；13C NMR(DMSO-d6,100MHz):13.7(s,3H),116.5,118.9,121.9,123.9,125.9,126.0,134.7,156.1,156.5,176.2；HRMS(ESI-TOF)m/z:Calcd.for C19H13ClN2NaO3[M+Na]+:375.0507；Found:375.0511.
this example prepares compound 3q as a white solid, melting point: 223.5 to 223.9 ℃; the yield is 86%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.33(s,3H),2.42(s,3H),7.30(d,J＝8.8Hz,2H),7.37(d,J＝8.8Hz,1H),7.48-7.51(m,1H),7.72(d,J＝8.8Hz,2H),8.01(s,1H),8.14(s,1H),12.13(br s,1H)；13C NMR(CDCl3,100MHz):14.4,20.1,92.1,116.7,117.6,121.4,121.6,124.3,127.9,130.2,134.9,135.0,136.2,144.1,151.5,1151.6,153.1,178.6；HRMS(ESI-TOF)m/z:Calcd.forC20H15ClN2NaO3[M+Na]+:389.0663；Found:389.0667.
this example prepares compound 3r as a white solid, melting point: 202.9-203.3 ℃; the yield is 57%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.33(s,3H),3.85(s,3H),7.26-7.32(m,3H),7.40(d,J＝9.2Hz,1H),7.54(d,J＝2.8Hz,1H),7.72(d,J＝8.8Hz,2H),8.15(s,1H),12.13(br s,1H)；13C NMR(CDCl3,100MHz):14.4,55.0,92.1,103.5,117.1,118.4,121.6,122.3,124.3,127.9,130.2,136.2,144.2,149.8,151.5,156.4,178.1；HRMS(ESI-TOF)m/z:Calcd.for C20H15ClN2NaO4[M+Na]+:405.0613；Found:405.0618.
this example prepares compound 3s as a white solid, melting point: 210.6-211.0 ℃; the yield is 69%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.13(s,3H),3.98(s,3H),7.42-7.54(m,4H),7.66(d,J＝6.8Hz,1H),7.80(d,J＝8.4Hz,2H),8.46(s,1H),11.52(br s,1H)；13CNMR(CDCl3,100MHz):13.7,56.8,115.5,116.3,121.8,124.8,125.8,129.4,146.4,149.1,156.1；HRMS(ESI-TOF)m/z:Calcd.for C20H15ClN2NaO4[M+Na]+:405.0613；Found:405.0615.
this example prepares compound 3t as a white solid, melting point: 179.8-181.4 ℃; the yield is 54%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.12(s,3H),7.51(d,J＝8.8Hz,2H),7.71-7.83(m,5H),8.46(s,1H),11.51(br s,1H)；13C NMR(DMSO-d6,100MHz):13.6,110.3(d,JCF＝24.4Hz),115.9,121.7,121.8,122.8(d,JCF＝25.2Hz),125.0,125.1,129.4,129.5,130.1,152.6,156.8,159.5(d,JCF＝243.4Hz),175.4；HRMS(ESI-TOF)m/z:Calcd.forC19H12ClFN2NaO3[M+Na]+:393.0413；Found:393.0410.
this example prepares compound 3u as a white solid, melting point: 181.2-181.6 ℃; the yield is 60%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.05(s,3H),7.45(d,J＝9.2Hz,2H),7.70-7.74(m,3H),7.80-7.83(m,1H),7.99(s,1H),8.39(s,1H),11.40(br s,1H)；13CNMR(DMSO-d6,100MHz):13.6,121.5,124.8,125.0,129.4,130.4,134.5,154.7,156.8；HRMS(ESI-TOF)m/z:Calcd.for C19H12Cl2N2NaO3[M+Na]+:409.0117；Found:409.0117.
this example prepares compound 3v: white solid, melting point: 198.7-199.3 ℃; the yield is 55%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.32(s,3H),7.30(d,J＝8.4Hz,2H),7.37(d,J＝8.8Hz,1H),7.69-7.76(m,3H),8.15(s,1H),8.36(s,1H),11.74(br s,1H)；13CNMR(CDCl3,100MHz):14.4,91.7,118.2,118.3,118.9,121.6,122.9,127.8,127.9,130.4,136.1,136.6,144.1,151.4,151.8,153.4,177.4；HRMS(ESI-TOF)m/z:Calcd.forC19H12BrClN2NaO3[M+Na]+:452.9612；Found:452.9620.
this example prepares compound 3w: white solid, melting point: 198.2-198.8 ℃; the yield is 61%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.14(s,3H),7.48-7.56(m,4H),7.64-7.67(m,1H),7.71(d,J＝8.4Hz,1H),7.83-7.87(m,1H),8.15-8.17(m,1H),8.43(s,1H),10.99(br s,1H)；13C NMR(DMSO-d6,100MHz):14.0,118.8,123.9,125.9,126.0,126.4,128.2,128.3,130.4,130.5,130.7,134.6,156.1,176.4；HRMS(ESI-TOF)m/z:Calcd.for C19H13ClN2NaO3[M+Na]+:375.0507；Found:375.0510.
this example prepares compound 3x white solid, melting point: 224.1 to 224.7 ℃; the yield is 52%; nuclear magnetic resonance and magnetic resonanceThe results of resolution mass spectrometry and the like are as follows:1H NMR(DMSO-d6,400MHz):2.06(s,3H),2.39(s,3H),7.39-7.46(m,3H),7.53-7.61(m,3H),7.87(s,1H),8.33(s,1H),10.95(br s,1H)；13C NMR(DMSO-d6,100MHz):21.0,118.6,123.6,125.1,128.3,130.4,130.7,135.5,135.7,154.4,156.0；HRMS(ESI-TOF)m/z:Calcd.for C20H15ClN2NaO3[M+Na]+:389.0663；Found:389.0663.
this example prepares compound 3y as a white solid, melting point: 164.5-165.1 ℃; the yield is 76%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.07(s,3H),3.80(s,3H),7.34-7.37(m,1H),7.40-7.45(m,4H),7.56-7.61(m,2H),8.34(s,1H)；13C NMR(DMSO-d6,100MHz):14.0,56.2,105.4,116.1,120.5,123.9,124.5,128.3,130.4,130.5,130.6,131.7,150.9,155.9,157.1,175.9；HRMS(ESI-TOF)m/z:Calcd.for C20H15ClN2NaO4[M+Na]+:405.0613；Found:405.0618.
this example prepares compound 3z as a white solid, melting point: 197.3 to 197.9 ℃; the yield is 54%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.12(s,3H),7.49-7.50(m,3H),7.64-7.67(m,1H),7.72-7.78(m,1H),7.80-7.85(m,2H),8.45(s,1H),10.92(br s,1H)；13CNMR(DMSO-d6,100MHz):14.0,110.3(d,JCF＝24.3Hz),121.7,121.8,122.8(d,JCF＝26.1Hz),125.1,128.3,129.1,130.4,130.5,130.7,132.0,152.6,156.5,159.4(d,JCF＝243.3Hz)；HRMS(ESI-TOF)m/z:Calcd.for C19H12ClFN2NaO3[M+Na]+:393.0413；Found:393.0413.
this example prepares compound 3aa white solid, melting point: 98.2-98.8 ℃; the yield is 51%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.12(s,3H),7.49(s,3H),7.65-7.67(m,1H),7.79(d,J＝9.2Hz,1H),7.88-7.90(m,1H),8.08(s,1H),8.45(s,1H),10.91(br s,1H)；13CNMR(DMSO-d6,100MHz):14.0,121.5,124.8,125.0,128.4,129.1,130.4,130.5,130.6,130.7,132.0,134.5,154.7,156.4,167.4；HRMS(ESI-TOF)m/z:Calcd.ForC19H12Cl2N2NaO3[M+Na]+:409.0117；Found:409.0121.
this example prepares compound 3ab as a white solid, melting point: 185.4 to 185.8 ℃; the yield is 54%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(DMSO-d6,400MHz):2.11(s,3H),7.49(s,3H),7.64-7.68(m,1H),7.73(d,J＝9.2Hz,1H),7.99-8.02(m,1H),8.21(s,1H),8.45(s,1H),10.92(brs,1H)；13CNMR(DMSO-d6,100MHz):14.0,118.3,121.7,125.4,128.0,128.4,129.1,130.4,132.0,137.2,155.1,156.4,167.4,191.0；HRMS(ESI-TOF)m/z:Calcd.For C19H12BrClN2NaO3[M+Na]+:452.9612；Found:452.9612.
this example prepares compound 3ac white solid, melting point: 210.5-210.9 ℃; the yield is 60%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.17(s,3H),3.89(s,3H),7.43-7.46(m,1H),7.50(d,J＝2.8Hz,1H),7.67(d,J＝9.2Hz,1H),8.10(d,J＝9.6Hz,2H),8.35(d,J＝9.2Hz,2H),8.44(s,1H)；13C NMR(CDCl3,100MHz):13.7,56.2,105.4,115.1,120.5,123.9,124.6,125.5,143.8,150.9,156.5,157.1,175.9；HRMS(ESI-TOF)m/z:Calcd.forC20H15N3NaO6[M+Na]+:416.0853；Found:416.0852.
this example prepares compound 3ad as a white solid, melting point: 90.4-90.6 ℃; the yield is 51%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.04(s,3H),2.38(s,3H),7.22-7.26(m,1H),7.45-7.49(m,2H),7.68-7.80(m,5H),11.10(br s,1H)；13C NMR(CDCl3,100MHz):19.8,26.8,110.3(d,JCF＝24.4Hz),113.1,121.2(d,JCF＝8.2Hz),122.4(d,JCF＝26.3Hz),124.1,125.5,129.4,130.1,152.2,159.8(d,JCF＝242.3Hz),160.4,174.9；HRMS(ESI-TOF)m/z:Calcd.for C20H15FN2NaO3[M+Na]+:373.0959；Found:373.0962.
this example prepared compound 3ae as a white solid, melting point: 252.0-252.4 ℃; the yield is 76%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.03(s,3H),2.33(s,3H),2.37(s,3H),7.25(d,J＝8.4Hz,2H),7.65-7.75(m,5H),10.91(br s,1H)；13C NMR(CDCl3,100MHz):19.7,20.9,110.3(d,JCF＝24.2Hz),113.2,121.2(d,JCF＝8.3Hz),122.3(d,JCF＝25.3Hz),124.1,129.7,134.7,152.2,158.1,160.5,166.3,175.4；HRMS(ESI-TOF)m/z:Calcd.forC21H17FN2NaO3[M+Na]+:387.1115；Found:387.1118.
this example prepares compound 3af as a white solid, melting point: 243.5-243.9 ℃; the yield is 50%; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz):2.04(s,3H),2.37(s,3H),7.51(d,J＝8.8Hz,2H),7.68-7.78(m,3H),7.83(d,J＝8.8Hz,2H),11.39(br s,1H)；13C NMR(CDCl3,100MHz):13.3,19.7,110.3(d,JCF＝23.4Hz),113.0,121.2(d,JCF＝8.2Hz),122.4(d,JCF＝25.3Hz),124.1,129.3,152.2,159.8(d,JCF＝244.2Hz),166.4,175.4；HRMS(ESI-TOF)m/z:Calcd.for C20H14ClFN2NaO3[M+Na]+:407.0569；Found:407.0571.
the compound of formula (1) of the invention has important biological activity, and the cytotoxicity test of A549 (human lung adenocarcinoma cells) in vitro shows that: the 3-pyrazoline isoflavone compound with the structure shown in the formula (1) has an inhibiting effect on the growth of tumor cells, and can be possibly developed into a new tumor prevention and treatment drug. It is emphasized, however, that the compounds of the invention are not limited to the cytotoxicity indicated for A549 (human lung adenocarcinoma cells).
Figure BDA0002593359670000121
Pharmacological examples: cytotoxicity of Compounds 3u,3v and 3u-0,3v-0 on A549 cells
A549 (human lung adenocarcinoma cells) was cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100U/mL penicillin and 100U/mL streptomycin. Cells were added to 96 wells at a concentration of 5000 cells per well and 5% CO at 37 deg.C2Incubate in a humidified air incubator for 24 hours.
The cell viability was determined by the modified MTT method. After 24 hours incubation of the cells, solutions of the newly formulated compounds 3u,3v and 3u-0,3v-0 in dimethylsulfoxide were added to each well in a concentration gradient such that the final concentration of the compounds in the wells was 10, 20, 40, 80 and 100. mu. mol/L, respectively. After 48 hours, 10. mu.L of MTT (5mg/mL) in phosphate buffer was added to each well, and after further incubation at 37 ℃ for 4 hours, the unconverted MTT was removed by centrifugation for 5 minutes, and 150. mu.L of dimethyl sulfoxide was added to each well. The OD value was measured at 490nm wavelength with a microplate reader by dissolving reduced MTT crystal formazan (formazan). Wherein the compound compounds 3u,3v and 3u-0,3v-0 have half-inhibitory concentration IC on A549 cells50Analyzed by the sps software (version 19). IC of compound 3u on A549 tumor cells5048.12 mu mol/L; IC of compound 3v on A549 tumor cells5037.71 mu mol/L; IC of compound 3u-0 on A549 tumor cells50Is composed of>100.00 mu mol/L; IC of compound 3v-0 on A549 tumor cells50Is composed of>100.00 mu mol/L; while the IC of positive control cisplatin on A549 tumor cells50It was 23.12. mu. mol/L.
And (4) experimental conclusion: the experiment shows that the 3-pyrazoline group can enhance the activity of the anti-tumor A549 cells of isoflavone skeletons. A549 cells are effective tools and evaluation indexes for testing cytotoxicity of compounds on tumor cells. The experiment shows that the 3-pyrazoline isoflavone compound shown in the formula (1) has stronger cytotoxicity to A549 cells and is likely to be developed into a new medicament with an anti-tumor effect.
From the pharmacological examples, we can see that the 3-pyrazoline isoflavone compound has the potential of being developed into an anti-tumor medicament, and is worthy of continuing further research.

Claims (7)

1. A3-pyrazoline isoflavone compound is characterized in that: the compound has a structure shown as a general formula (I):
Figure FDA0002593359660000011
in the formula, R1Is methyl, methoxy, halogen or hydrogen; r2Is methyl or hydrogen; ar is a benzene ring, a chlorobenzene ring, a methyl-substituted benzene ring or a nitro-substituted benzene ring.
2. A method for preparing 3-pyrazoline isoflavonoids according to claim 1, characterized in that: adding various substituted pyrazolones 1 and dihydrochromone 2 into an organic solvent, carrying out Aldol reaction under the catalytic action of an organic secondary amine catalyst, separating to obtain an intermediate IA, then protecting hydroxyl in the organic solvent through methanesulfonyl chloride under the catalysis of organic tertiary amine to obtain an intermediate IB, wherein the intermediate IB does not need to be separated, and continues to carry out elimination reaction under the catalysis of the organic tertiary amine to obtain a 3-pyrazoline isoflavone compound 3, which has the following formula:
Figure FDA0002593359660000012
3. the method for producing 3-pyrazoline isoflavones according to claim 2, characterized in that: the organic solvent is methanol, acetonitrile, toluene, dichloromethane or chloroform.
4. The method for producing 3-pyrazoline isoflavones according to claim 2, characterized in that: the organic secondary amine catalyst is diethylamine, tetrahydropyrrole, piperidine, tetrahydropyrrole derivatives or piperidine derivatives.
5. The method for producing 3-pyrazoline isoflavones according to claim 2, characterized in that: the organic tertiary amine catalyst is triethylamine, DABCO, DMAP, DBU, cinchona alkaloid or cinchona alkaloid derivatives.
6. The method for producing 3-pyrazoline isoflavones according to claim 2, characterized in that: the Aldol reaction is carried out at the reaction temperature of 25-40 ℃ for 5-24 h; the reaction temperature of the intermediate IB for elimination reaction under the catalysis of the organic tertiary amine is 25-40 ℃, and the reaction time is 5-48 h.
7. The use of the 3-pyrazoline isoflavones of claim 1 in the preparation of a medicament for the prevention or treatment of a neoplastic disease.
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