CN110452230B - Chromone pyrazolone framework spliced dihydrochalcone compound and preparation method and application thereof - Google Patents

Chromone pyrazolone framework spliced dihydrochalcone compound and preparation method and application thereof Download PDF

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CN110452230B
CN110452230B CN201910817459.3A CN201910817459A CN110452230B CN 110452230 B CN110452230 B CN 110452230B CN 201910817459 A CN201910817459 A CN 201910817459A CN 110452230 B CN110452230 B CN 110452230B
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刘雄利
汪军鑫
周韦
常顺琴
田民义
周英
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Abstract

The invention discloses a chromone pyrazolone framework spliced dihydrochalcone compound, which comprises a potential bioactive chromone framework, a pyrazolone framework and a dihydrochalcone framework, can provide a compound source for bioactive screening, and has important application value for the screening of medicaments and the pharmaceutical industry. And the skeleton compound has inhibitory activity on human leukemia cells (K562). 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. And the skeleton compound has the function of inhibiting the tumor growth of human leukemia cells (K562).

Description

Chromone pyrazolone framework spliced dihydrochalcone compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of chemistry and pharmacy, in particular to a chromone pyrazolone framework spliced dihydrochalcone compound and a preparation method and application thereof.
Background
According to the active scaffold splicing and migration principle of drug design, splicing two or more scaffolds with biological activity into a multi-scaffold molecule with potential biological activity is an extremely important research field in organic chemistry and medicinal chemistry. (1) Chromone compounds are widely found in natural products and synthetic drug molecules. (2) Pyrazolones widely exist in natural products and synthetic drug molecules, attract the wide attention of many chemists and medicinal and chemical teams, and play an important role in pain relief and economic development. (3) Dihydrochalcones are also found in natural products and synthetic drug molecules. In view of the potential biological activity of the chromone, pyrazolone and dihydrochalcone skeletons. Therefore, the chromone pyrazolone skeleton is spliced into the dihydrochalcone compound to synthesize a series of new chromone pyrazolone skeleton spliced dihydrochalcone compounds with potential multi-active functional groups, which can provide a compound source for biological activity screening and has important application value for the screening of medicines and the pharmaceutical industry (as shown in figure 6).
Disclosure of Invention
The purpose of the invention is: the chromone pyrazolone framework spliced dihydrochalcone compound is an important medical intermediate analogue and a drug molecule analogue, has important application value for drug screening and pharmaceutical industry, and is very economical and simple in synthesis 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: a chromone pyrazolone framework splicing dihydrochalcone compound has a structure shown in the following general formula (I):
Figure BDA0002186712800000011
in the formula, Ar is fluorine, chlorine, bromine, nitro, methoxy or methyl substituted benzene ring; r is methyl or fluorine or chlorine or hydrogen.
A preparation method of a chromone pyrazolone framework spliced dihydrochalcone compound comprises the step of carrying out Michael/Michael cycloaddition reaction on various substituted pyrazolone-chromone synthons 1 and various substituted chalcones 2 in an organic solvent under the action of an organic tertiary amine catalyst to obtain a chromone pyrazolone framework spliced dihydrochalcone compound 3.
The synthetic route is exemplified as follows:
Figure BDA0002186712800000021
wherein, in the compound in the synthetic route, the substituent group of the compound satisfies the formula, Ar is fluorine, chlorine, bromine, nitro, methoxy or methyl substituted benzene ring; r is methyl or fluorine or chlorine or hydrogen.
The reaction mechanism is as follows:
Figure BDA0002186712800000022
the organic solvent is acetonitrile, toluene, dichloromethane or chloroform.
The organic tertiary amine catalyst is DABCO or triethylamine or DBU or chiral cinchona alkaloid or cinchona alkaloid derivatives.
The reaction temperature of various substituted pyrazolone-chromone synthons and various substituted chalcones in an organic solvent is between room temperature and 40 ℃, and the reaction time is between 2 and 10 days.
Application of a chromone pyrazolone framework spliced dihydrochalcone compound in preparation of a medicine for preventing and treating tumor diseases.
By adopting the technical scheme, various substituted pyrazolone-chromone synthons 1 and various substituted chalcones 2 are subjected to Michael/Michael cycloaddition reaction in an organic solvent under the action of an organic tertiary amine catalyst to obtain a chromone pyrazolone framework spliced dihydrochalcone compound 3, wherein the compound contains a potential bioactive chromone framework, a pyrazolone framework and a dihydrochalcone framework, can provide a compound source for bioactive screening, and has important application value for the screening of medicaments and the pharmaceutical industry. And the skeleton compound has inhibitory activity on human leukemia cells (K562). 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 spectra of compound 3a according to the example of the invention;
FIGS. 3 and 4 are data of the spectra of compound 3b according to the example of the present invention;
FIG. 5 is a single crystal diagram of compounds 3d and 3e of an embodiment of the present invention;
FIG. 6 shows the design concept and inventive step of the synthesized compound of the present invention.
Detailed Description
The embodiment of the invention comprises the following steps: pyrazolone-chromone synthon 1a (0.10mmol), chalcone 2a (0.12mmol), DABCO (10 mol%, 0.01mmol) and 2.0mL chloroform were added to a reaction tube in this order, stirred at room temperature for 4 days, then the reaction was detected by TLC for substantial completion, and directly loaded onto the column for purification by column chromatography (eluent: V (petroleum ether): V (ethyl acetate) ═ 4:1) to give compound 3a, a white solid, melting point: 202.3-203.1 ℃; the yield is 87%, and 10:1dr is adopted; the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.29-2.34(m,4H),2.93-2.98(m,1H),3.34(d,J＝13.6Hz,1H),3.65-3.72(m,1H),3.95-3.98(m,1H),7.07-7.10(m,1H),7.13-7.16(m,1H),7.21-7.32(m,8H),7.41-7.47(m,3H),7.57-7.59(m,2H),7.66-7.74(m,4H)；13C NMR(CDCl3,100MHz)δ:14.1,27.0,38.3,43.6,61.8,109.7(d,JCF＝24.3Hz),116.6,118.3,119.2,119.3,120.9(d,JCF＝25.1Hz),123.5,124.5,126.7,127.0,127.2,127.6,127.8,129.0,132.3,135.6,136.2,136.6,151.3,154.3,158.6(d,JCF＝247.2Hz),161.9,173.2,175.0,195.7；HRMS(ESI-TOF)m/z:Calcd.for C35H27FN2NaO4[M+Na]+:581.1847；Found:581.1853.
the process for producing the compounds 3b to 3t from the compound 3a in the same charge ratio as the compound 3a gave the compounds 3b to 3t with the reaction yields and dr values shown in tables 1 and 2, but it should be emphasized that the compounds of the present invention are not limited to those shown in tables 1 and 2.
Table 1 shows the chemical structure of a chromone pyrazolone skeleton-spliced dihydrochalcone compound
Figure BDA0002186712800000041
Table 2 shows the chemical structure of a chromone pyrazolone skeleton-spliced dihydrochalcone compound
Figure BDA0002186712800000051
This example prepares compound 3b as a white solid, melting point: 157.6-158.4 ℃; the yield is 80%, 9:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.28-2.33(m,4H),2.92-2.97(m,1H),3.34(d,J＝14.0Hz,1H),3.64-3.71(m,1H),3.95-3.98(m,1H),7.07-7.10(m,1H),7.14-7.32(m,8H),7.41-7.47(m,4H),7.57(d,J＝7.6Hz,2H),7.65(s,1H),7.71-7.74(m,2H),8.03(d,J＝2.4Hz,1H)；13C NMR(CDCl3,100MHz)δ:14.1,27.0,38.3,43.6,61.8,117.4,118.3,118.9,123.2,124.3,124.5,126.7,127.0,127.2,127.6,127.8,129.0,130.2,132.3,132.9,135.5,136.2,136.6,153.4,154.3,161.9,173.2,174.6,195.7；HRMS(ESI-TOF)m/z:Calcd.for C35H27ClN2NaO4[M+Na]+:597.1552；Found:597.1548.
this example prepares compound 3c as a white solid, melting point: 182.8-183.6 deg.C; the yield is 83 percent, and is 10:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.25(d,J＝14.0Hz,1H),2.32(s,3H),2.87-2.91(m,1H),3.32(d,J＝13.6Hz,1H),3.58-3.65(m,1H),3.90-3.94(m,1H),7.09-7.12(m,1H),7.18-7.39(m,10H),7.42-7.46(m,1H),7.49-7.54(m,1H),7.58-7.61(m,2H),7.65(s,1H),7.70-7.73(m,2H),8.06-8.08(m,1H)；13C NMR(CDCl3,100MHz)δ:14.0,27.1,38.2,42.9,61.5,117.0,117.1,118.3,120.8,122.3,124.2,124.6,124.9,127.0,127.7,127.9,130.3,130.8,132.5,132.7,135.4,135.7,136.2,154.1,155.1,161.8,173.1,175.6,195.4；HRMS(ESI-TOF)m/z:Calcd.for C35H27BrN2NaO4[M+Na]+:641.1046；Found:641.1051.
this example prepares compound 3d as a white solid, melting point: 140.5-141.3 ℃; the yield is 90 percent, and is 10:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.26(d,J＝13.6Hz,1H),2.32(s,3H),2.89-2.94(m,1H),3.33(d,J＝14.0Hz,1H),3.58-3.65(m,1H),3.90-3.94(m,1H),7.08-7.12(m,2H),7.19-7.33(m,7H),7.43-7.46(m,2H),7.49-7.54(m,1H),7.60(d,J＝7.6Hz,2H),7.67(d,J＝7.6Hz,2H),7.72-7.74(m,2H),8.06-8.08(m,1H)；13C NMR(CDCl3,100MHz)δ:14.0,27.1,38.4,43.1,61.5,117.0,117.1,118.3,121.3,122.4,124.2,124.6,124.9,127.0,127.7,127.9,128.7,129.9,132.1,132.5,132.7,135.4,136.2,139.2,154.1,155.1,161.7,173.1,175.6,195.3；HRMS(ESI-TOF)m/z:Calcd.for C35H27BrN2NaO4[M+Na]+:641.1046；Found:641.1047.
this example prepares compound 3e as a white solid, melting point: 213.9-214.6 ℃; the yield is 86 percent, and is 10:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.24(d,J＝14.0Hz,1H),2.32(s,3H),2.34(s,3H),2.86-2.91(m,1H),3.33(d,J＝13.6Hz,1H),3.58-3.65(m,1H),3.90-3.93(m,1H),7.08-7.13(m,2H),7.25-7.39(m,9H),7.42-7.46(m,1H),7.58-7.60(m,1H),7.62(s,1H),7.70-7.72(m,2H),7.85(d,J＝1.2Hz,1H)；13C NMR(CDCl3,100MHz)δ:14.0,20.0,27.2,38.3,42.9,61.5,116.7,116.9,118.3,120.8,122.0,124.2,124.6,127.0,127.6,127.9,130.3,130.8,132.5,133.9,134.2,135.4,135.8,136.2,153.4,154.0,161.9,173.2,175.7,195.5；HRMS(ESI-TOF)m/z:Calcd.for C36H29BrN2NaO4[M+Na]+:655.1203；Found:655.1207.
this example prepares compound 3f as a white solid, melting point: 189.9-190.5 ℃; the yield is 87%, and 8:1dr is adopted; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.28(d,J＝14.0Hz,1H),2.32(s,3H),2.88-2.93(m,1H),3.30(d,J＝14.0Hz,1H),3.58-3.65(m,1H),3.90-3.93(m,1H),7.08-7.12(m,2H),7.19(s,1H),7.23-7.34(m,7H),7.42-7.46(m,2H),7.59-7.61(m,2H),7.67-7.74(m,4H)；13C NMR(CDCl3,100MHz)δ:13.9,27.1,38.3,43.0,61.5,109.7(d,JCF＝24.3Hz),116.4,118.3,119.2(d,JCF＝8.1Hz),121.0(d,JCF＝26.0Hz),121.3,123.4,123.5,124.6,127.0,127.7,127.9,128.7,129.9,132.1,132.5,135.3,136.1,139.1,151.3,154.4,158.2(d,JCF＝236.3Hz),161.7,173.0,174.9,195.3；HRMS(ESI-TOF)m/z:Calcd.for C35H26BrFN2NaO4[M+Na]+:659.0952；Found:659.0957.
this example prepares compound 3g, white solid, melting point: 192.4-193.1 ℃; the yield is 80%, 9:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.28(d,J＝14.0Hz,1H),2.34(s,3H),2.90-2.95(m,1H),3.34(d,J＝14.0Hz,1H),3.59-3.66(m,1H),3.93-3.97(m,1H),6.89-6.93(m,2H),7.08-7.12(m,1H),7.22-7.33(m,6H),7.42-7.47(m,3H),7.50-7.54(m,1H),7.58-7.60(m,2H),7.66(s,1H),7.71-7.73(m,2H),8..06-8.09(m,1H)；13C NMR(CDCl3,100MHz)δ:14.1,27.0,38.5,42.9,61.7,114.1(d,JCF＝21.2Hz),117.1,118.3,122.4,124.2,124.6,124.9,127.0,127.6,127.9,130.6,132.5(d,JCF＝23.4Hz),135.5,136.2,154.1,155.1,161.7(d,JCF＝243.5Hz),161.9,173.2,175.7,195.6；HRMS(ESI-TOF)m/z:Calcd.for C35H27FN2NaO4[M+Na]+:581.1847；Found:581.1852.
this example prepares compound 3h as a white solid, melting point: 98.4-99.2℃(ii) a The yield is 89%, 9:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.30(d,J＝14.0Hz,1H),2.34(s,3H),2.90-2.95(m,1H),3.35(d,J＝14.0Hz,1H),3.60-3.67(m,1H),3.95-3.98(m,1H),6.83-6.87(m,1H),7.08-7.12(m,1H),7.18-7.21(m,2H),7.24-7.33(m,7H),7.43-7.46(m,1H),7.50-7.54(m,1H),7.58(s,1H),7.60(s,1H),7.67(s,1H),7.72-7.74(m,2H),8.06-8.09(m,1H)；13C NMR(CDCl3,100MHz)δ:14.0,27.0,38.4,43.2,61.6,113.7(d,JCF＝21.4Hz),115.9(d,JCF＝21.3Hz),117.0,117.1,118.3,122.4,124.2,124.5,124.9,127.0,127.7,127.9,128.6,129.9,132.5,132.7,135.4,136.2,154.1,155.1,161.4(d,JCF＝257.0Hz),161.7,173.1,175.6,195.4；HRMS(ESI-TOF)m/z:Calcd.for C35H27FN2NaO4[M+Na]+:581.1847；Found:581.1848.
this example prepares compound 3i as a white solid, melting point: 136.2-137.1 ℃; the yield is 83%, 6:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.28(d,J＝13.6Hz,1H),2.34(s,3H),2.87-2.92(m,1H),3.48(d,J＝13.6Hz,1H),3.64-3.71(m,1H),4.40-4.43(m,1H),6.98-7.12(m,3H),7.13-7.21(m,2H),7.25-7.33(m,5H),7.41-7.45(m,1H),7.48-7.52(m,1H),7.54-7.58(m,1H),7.62-7.65(m,3H),7.71-7.73(m,2H),8.05-8.08(m,1H)；13C NMR(CDCl3,100MHz)δ:13.7,26.1,28.7,37.6,61.2,114.4(d,JCF＝23.1Hz),117.0,118.2,122.4,123.0,123.7,124.2,124.4,124.9,127.0,127.6,127.9,128.2,128.3,129.8(d,JCF＝19.7Hz),132.6,135.4,136.3,154.1,155.1,160.5(d,JCF＝244.2Hz),162.4,173.0,175.6,195.3；HRMS(ESI-TOF)m/z:Calcd.for C35H27FN2NaO4[M+Na]+:581.1847；Found:581.1850.
this example prepares compound 3j as a white solid, melting point: 210.3-211.2 ℃; the yield is 79 percent, and 9:1dr is obtained; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.26(d,J＝13.6Hz,1H),2.33(s,3H),2.88-2.93(m,1H),3.31(d,J＝14.0Hz,1H),3.59-3.66(m,1H),3.93-3.96(m,1H),6.89-6.94(m,2H),7.09-7.12(m,1H),7.18-7.20(m,2H),7.25-7.33(m,4H),7.43-7.47(m,3H),7.59(d,J＝7.6Hz,2H),7.65(s,1H),7.71-7.73(m,2H),8.03(d,J＝2.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:14.0,27.1,38.4,42.9,61.7,114.1(d,JCF＝19.5Hz),117.2,118.2,118.9,123.2,124.5(d,JCF＝24.1Hz),127.0,127.6,127.9,130.2,130.6,132.3,132.5,132.9,135.4,136.2,153.4,154.3,161.2(d,JCF＝246.1Hz),161.8,173.1,174.6,195.6；HRMS(ESI-TOF)m/z:Calcd.for C35H26ClFN2NaO4[M+Na]+:615.1457；Found:615.1453.
this example prepares compound 3k as a white solid, melting point: 78.4-79.2 ℃; the yield is 88%, 7:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.11(s,3H),2.33(s,3H),2.87(d,J＝14.0Hz,1H),3.48(d,J＝13.6Hz,1H),3.92(d.J＝6.8Hz,2H),4.45-4.49(m,1H),6.75-6.78(m,1H),6.87-6.92(m,1H),6.98-7.04(m,1H),7.06-7.15(m,3H),7.23-7.27(m,2H),7.31-7.38(m,3H),7.45-7.51(m,3H),7.62-7.67(m,1H),7.77(s,1H),7.90-7.92(m,2H)；13C NMR(CDCl3,100MHz)δ:13.1,18.2,19.9,26.5,36.7,61.4,114.7(d,JCF＝24.3Hz),116.8,116.9,118.7,122.1,123.3,124.3,124.6,127.1,127.6,127.8,128.1,129.9,132.3,133.9,134.3,135.7,136.2,153.4,153.7,159.5(d,JCF＝237.1Hz),162.0,173.8,175.5,196.4；HRMS(ESI-TOF)m/z:Calcd.for C36H29FN2NaO4[M+Na]+:595.2004；Found:595.2001.
this example prepares compound 3l as a white solid, melting point: 197.4-198.1 ℃; the yield is 83%, 9:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.25(d,J＝14.0Hz,1H),2.33(s,3H),2.87-2.92(m,1H),3.33(d,J＝14.0Hz,1H),3.59-3.66(m,1H),3.92-3.95(m,1H),7.09-7.13(m,1H),7.19-7.21(m,3H),7.24-7.33(m,5H),7.42-7.46(m,3H),7.50-7.54(m,1H),7.59-7.61(m,2H),7.65(s,1H),7.71-7.73(m,2H),8.06-8.08(m,1H)；13C NMR(CDCl3,100MHz)δ:14.0,27.1,38.3,42.9,61.6,117.0,117.1,118.3,122.4,124.2,124.6,124.9,127.0,127.4,127.7,127.9,130.4,132.5,132.6,132.7,135.2,135.4,136.2,154.1,155.1,161.8,173.2,175.6,195.5；HRMS(ESI-TOF)m/z:Calcd.for C35H27ClN2NaO4[M+Na]+:597.1552；Found:597.1555.
this example prepares compound 3m as a white solid, melting point: 213.8-214.2 ℃; yield 84%, 7:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.26(d,J＝14.0Hz,1H),2.32(s,3H),2.86-2.91(m,1H),3.30(d,J＝14.0Hz,1H),3.58-3.65(m,1H),3.92-3.95(m,1H),7.09-7.13(m,1H),7.19-7.34(m,8H),7.42-7.47(m,4H),7.59-7.61(m,2H),7.66(s,1H),7.69-7.73(m,2H)；13C NMR(CDCl3,100MHz)δ:14.0,27.1,38.3,42.9,61.5,109.6(d,JCF＝25.0Hz),116.4,118.2,119.3,121.1(d,JCF＝24.5Hz),124.6,127.0,127.4,127.7,127.9,130.4,132.5,132.7,135.1,135.4,136.2,154.3,158.4(d,JCF＝253.2Hz),161.8,172.2,173.1,174.7,195.4；HRMS(ESI-TOF)m/z:Calcd.for C35H26ClFN2NaO4[M+Na]+:615.1457；Found:615.1458.
this example prepares compound 3n as a white solid, melting point: 200.4-201.2 ℃; the yield is 87%, and 8:1dr is adopted; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.25(d,J＝14.0Hz,1H),2.33(s,3H),2.34(s,3H),2.87-2.92(m,1H),3.34(d,J＝14.0Hz,1H),3.59-3.66(m,1H),3.91-3.95(m,1H),7.09-7.13(m,2H),7.19(s,1H),7.21(s,1H),7.25-7.33(m,5H),7.43(d,J＝8.4Hz,3H),7.58-7.63(m,3H),7.71-7.73(m,2H),7.85(s,1H)；13C NMR(CDCl3,100MHz)δ:14.0,19.9,27.2,38.3,42.9,61.6,116.7,116.9,118.3,122.0,124.2,124.6,127.0,127.4,127.6,127.9,130.4,132.5,132.6,133.9,134.3,135.2,135.4,136.2,153.4,154.0,161.9,173.2,175.7,195.5；HRMS(ESI-TOF)m/z:Calcd.for C36H29ClN2NaO4[M+Na]+:611.1708；Found:611.1714.
this example prepared compound 3o a white solid, melting point: 205.2-205.9 ℃; the yield is 91%, 10:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.24(d,J＝13.6Hz,1H),2.35(s,3H),2.97-3.02(m,1H),3.35(d,J＝13.6Hz,1H),3.65-3.72(m,1H),4.06-4.10(m,1H),7.10-7.13(m,1H),7.24-7.35(m,6H),7.40-7.48(m,2H),7.61(d,J＝8.0Hz,2H),7.65(s,1H),7.69-7.75(m,3H),7.86(d,J＝7.6Hz,1H),8.02-8.04(m,1H),8.41(s,1H)；13C NMR(CDCl3,100MHz)δ:14.0,27.2,38.2,43.0,61.2,109.8(d,JCF＝24.4Hz),116.1,118.1,119.3,121.1(d,JCF＝25.1Hz),121.8,123.4,123.7,124.7,127.0,127.8,127.9,128.1,132.7,135.0,135.6,136.0,138.9,147.0,151.3,154.3,158.5(d,JCF＝237.0Hz),161.3,172.8,174.9,194.9；HRMS(ESI-TOF)m/z:Calcd.for C35H26FN3NaO6[M+Na]+:626.1698；Found:626.1696.
this example prepares compound 3p as a white solid, melting point: 79.4-80.2 ℃; the yield is 87%, and 5:1dr is adopted; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.33(s,6H),2.91-2.96(m,1H),3.36(d,J＝14.0Hz,1H),3.62-3.67(m,1H),3.71(s,3H),3.92-3.96(m,1H),6.67-6.70(m,1H),7.04-7.15(m,4H),7.23-7.32(m,5H),7.41-7.47(m,2H),7.57-7.59(m,2H),7.65(s,1H),7.72-7.75(m,2H),7.85(s,1H)；13C NMR(CDCl3,100MHz)δ:14.1,19.9,27.0,38.4,43.6,54.2,61.9,112.0,114.8,116.8,116.9,118.4,118.6,121.4,122.0,124.2,124.4,127.0,127.2,127.6,127.8,128.1,129.9,132.3,133.8,134.2,135.6,136.3,138.3,153.4,154.1,158.3,162.0,166.7,173.3,175.7,195.8；HRMS(ESI-TOF)m/z:Calcd.for C37H32N2NaO5[M+Na]+:607.2203；Found:607.2207.
this example prepares compound 3q as a white solid, melting point: 203.2 to 203.9 ℃; the yield is 78%, 8:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.20(s,3H),2.27(d,J＝14.0Hz,1H),2.32(s,3H),2.34(s,3H),2.88-2.93(m,1H),3.35(d,J＝14.0Hz,1H),3.62-3.69(m,1H),3.90-3.94(m,1H),7.02(d,J＝8.0Hz,2H),7.07-7.12(m,2H),7.19(s,1H),7.24-7.36(m,6H),7.41-7.44(m,1H),7.59(d,J＝8.8Hz,2H),7.63(s,1H),7.72-7.74(m,2H),7.85(s,1H)；13C NMR(CDCl3,100MHz)δ:14.0,20.0,20.1,27.1,38.3,43.2,61.9,116.8,118.3,122.0,124.2,124.4,127.0,127.6,127.8,127.9,128.9,132.2,133.5,133.8,134.1,135.6,136.3,153.4,154.0,162.2,173.4,175.7,195.9；HRMS(ESI-TOF)m/z:Calcd.for C37H32N2NaO4[M+Na]+:591.2254；Found:591.2257.
this example prepares compound 3r as a white solid, melting point: 73.5-74.3℃(ii) a The yield is 86 percent, and is 10:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.32(d,J＝14.0Hz,1H),2.35(s,3H),3.10-3.15(m,1H),3.38(d,J＝13.6Hz,1H),3.49-3.56(m,1H),3.79-3.83(m,1H),6.82-6.85(m,1H),7.05-7.08(m,1H),7.12-7.15(m,2H),7.18-7.25(m,6H),7.26-7.30(m,1H),7.36(d,J＝6.8Hz,2H),7.43-7.47(m,1H),7.52(d,J＝16.0Hz,3H),7.66(s,1H),8.06-8.09(m,1H)；13C NMR(CDCl3,100MHz)δ:14.2,26.7,42.7,44.4,61.8,117.1,118.4,124.2,124.5,124.9,126.3,126.9,127.2,127.5,127.8,129.1,130.7,132.4,132.6,135.9,140.2,154.2,155.1,161.6,173.0,175.7,200.2；HRMS(ESI-TOF)m/z:Calcd.for C35H27BrN2NaO4[M+Na]+:641.1046；Found:641.1048.
this example prepares compound 3s as a white solid, melting point: 135.6 to 136.2 ℃; yield 78%, 7:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.09(s,3H),2.81(d,J＝13.6Hz,1H),3.43(d,J＝13.6Hz,1H),3.77-3.84(m,1H),3.90-4.01(m,2H),7.02-7.08(m,3H),7.10-7.16(m,3H),7.22-7.28(m,5H),7.31(d,J＝7.6Hz,1H),7.42-7.49(m,3H),7.68-7.72(m,1H),7.80(s,1H),7.84-7.85(m,1H)；13C NMR(CDCl3,100MHz)δ:13.8,26.5,37.4,44.0,61.6,109.8(d,JCF＝24.4Hz),116.6,118.7,119.3,121.0(d,JCF＝25.0Hz),124.7,125.3,126.8,127.2,127.6,127.8,128.9,132.2,134.0,136.1,137.3,138.1,151.3,154.0,158.5(d,JCF＝256.2Hz),161.7,173.8,195.6；HRMS(ESI-TOF)m/z:Calcd.for C35H26ClFN2NaO4[M+Na]+:615.1457；Found:615.1461.
this example prepares compound 3t as a white solid, melting point: 115.3 to 115.9 ℃; the yield is 85%, 9:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:2.30(d,J＝14.0Hz,1H),2.33(s,3H),2.89-2.94(m,1H),3.20(d,J＝13.6Hz,1H),3.59-3.66(m,1H),3.92-3.96(m,1H),6.94-6.98(m,2H),7.07-7.11(m,1H),7.13-7.17(m,1H),7.21-7.28(m,6H),7.44-7.47(m,2H),7.57-7.59(m,2H),7.66(s,1H),7.68-7.71(m,1H),7.73-7.77(m,2H)；13C NMR(CDCl3,100MHz)δ:14.1,27.0,38.3,43.7,61.8,109.7(d,JCF＝24.2Hz),114.7(d,JCF＝21.4Hz),116.6,118.2,119.2,119.3,120.9(d,JCF＝26.1Hz),124.5,126.8,127.3,127.8,129.0,129.7,129.8(d,JCF＝26.3Hz),132.0,136.2,136.5,151.3,154.3,158.5(d,JCF＝246.4Hz),161.9,164.8(d,JCF＝253.3Hz),173.2,175.0,194.2；HRMS(ESI-TOF)m/z:Calcd.for C35H26F2N2NaO4[M+Na]+:599.1753；Found:599.1758.
the compound of formula (1) of the invention has important biological activity, and the cytotoxicity test on human leukemia cells (K562) tumor cells in vitro shows that: the chromone pyrazolone skeleton splicing dihydrochalcone 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 medicine. It is emphasized, however, that the compounds of the invention are not limited to the cytotoxicity indicated by human leukemia cells (K562).
Pharmacological examples: cytotoxicity of Compounds 3b,3g,3l and 3s on K562 cells
K562 (human chronic myelogenous leukemia 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, with 5% CO at 37 ℃2Incubate 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, newly prepared solutions of compound 3b,3g,3L and 3s in dimethylsulfoxide were added to each well in a concentration gradient such that the final concentration of compound in the wells was 5. mu. mol/L, 10. mu. mol/L, 20. mu. mol/L, 40. mu. mol/L and 80. 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 compounds 3b,3g,3l and 3s have a half inhibitory concentration IC on K562 cells50Analyzed by the sps software (version 19). IC of Compound 3b on K562 tumor cells5037.4 mu mol/L; compound 3g vs. K562IC of tumor cells5044.0 mu mol/L; IC of compound 3l on K562 tumor cells5034.7 mu mol/L; IC of compound 3s on K562 tumor cells5041.2 mu mol/L; IC of positive control cisplatin on K562 tumor cells50It was 23.1. mu. mol/L.
And (4) experimental conclusion: k562 cells are an effective tool and an evaluation index for testing the cytotoxicity of compounds on tumor cells. The experiment shows that the chromone pyrazolone framework splicing dihydrochalcone compound shown in the formula (1) has stronger cytotoxicity on K562 cells, can be possibly developed into a new drug with an anti-tumor effect, and is worthy of further research.

Claims (3)

1. A chromone pyrazolone framework splicing dihydrochalcone compound is characterized in that: the compound has a structure shown as a general formula (I):
Figure FDA0003480765820000011
in the formula, Ar is a benzene ring substituted by fluorine, chlorine, bromine, nitryl, methoxyl or methyl; r is methyl, fluorine, chlorine or hydrogen.
2. A method for preparing the chromone pyrazolone skeleton-spliced dihydrochalcones compound according to claim 1, wherein the synthetic route is as follows:
Figure FDA0003480765820000012
in the formula, Ar is a benzene ring substituted by fluorine, chlorine, bromine, nitryl, methoxyl or methyl; r is methyl, fluorine, chlorine or hydrogen.
3. The use of the chromone pyrazolone backbone-conjugated dihydrochalcones compound according to claim 1 for preparing a medicament for preventing and treating leukemia.
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