CN110684032B - Pyrazolone or benzofuranone compound spliced by xanthone isoxazole skeleton and preparation method and application thereof - Google Patents

Pyrazolone or benzofuranone compound spliced by xanthone isoxazole skeleton and preparation method and application thereof Download PDF

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CN110684032B
CN110684032B CN201910744693.8A CN201910744693A CN110684032B CN 110684032 B CN110684032 B CN 110684032B CN 201910744693 A CN201910744693 A CN 201910744693A CN 110684032 B CN110684032 B CN 110684032B
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刘雄利
姚一鸣
常顺琴
左雄
周英
韦启迪
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Abstract

The invention discloses a xanthone isoxazole skeleton spliced pyrazolone or benzofuranone compound, which comprises a potential bioactive xanthone isoxazole skeleton and a spiro pyrazolone or spiro benzofuranone skeleton, can provide a compound source for bioactive screening, and has important application value for the screening of medicaments and the pharmaceutical industry. And the novel skeleton compound has an 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

Pyrazolone or benzofuranone compound spliced by xanthone isoxazole skeleton and preparation method and application thereof
Technical Field
The invention relates to the technical field of chemistry and pharmacy, in particular to a xanthone isoxazole skeleton spliced pyrazolone or benzofuranone 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) The xanthone skeleton is also ubiquitous in natural products and drug molecules. For example, the natural product molecules Ergochrome DD, Diversonol, Desoxydigersonol, Aplantin B and Isoochlioquinone A share one xanthone molecular unit, and the compounds play an important role in relieving pain and realizing economic development. (2) Spiro pyrazolones are widely found in natural products and synthetic drug molecules, and attract the extensive attention of many chemists and medicinal and chemical teams, for example, natural products or active small molecules, spirocyclic pyrazolone phosphodiesterase inhibitor and anti-inflammatory agent show obvious biological activity. (3) Spiro six-membered carbocyclic benzofuranone compounds are also widely found in natural products and synthetic drug molecules, for example, fig. 5, where natural products or active small molecules of spiro six-membered carbocyclic benzofuranones rosmeadia and ferrubitolide exhibit significant biological activity. (4) Isoxazolyl groups are also ubiquitous in natural products and drug molecules. For example, isoxazolyl groups are also ubiquitous in natural products and drug molecules. Such as many natural products and drugs (Cloxacilin V, muscimol VI, Isoxicam VII, leflunomide VIII, etc.).
The xanthone skeleton, the spiro pyrazolone skeleton, the spiro six-membered carbocyclic benzofuranone skeleton and the isoxazole group have potential biological activity. Therefore, the spiro pyrazolone and the spiro six-membered carbocyclic ring benzofuranone are spliced on the xanthone isoxazole skeleton to synthesize a series of novel xanthone isoxazole skeleton spliced pyrazolone or benzofuranone compounds with potential multi-active functional groups, so that a compound source can be provided for biological activity screening, and the application value of the compound source in the drug screening and pharmaceutical industry is important.
Disclosure of Invention
The purpose of the invention is: the pyrazolone or benzofuranone compound spliced by the xanthone isoxazole skeleton is an important medical intermediate analogue and a drug molecule analogue, has important application value to the 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 xanthone isoxazole skeleton splicing pyrazolone or benzofuranone compound has a structure shown in the following general formula (I):
Figure GDA0002287383380000021
in the formula, R1Is methyl or fluorine or hydrogen; ar is fluorine, chlorine, bromine, nitryl, a benzene ring or a thiophene ring substituted by methyl.
A preparation method of a xanthone isoxazole skeleton spliced pyrazolone or benzofuranone compound comprises the step of carrying out Michael/Michael cycloaddition reaction on various substituted bifunctional pyrazolone/benzofuranone-chromone synthons and various substituted nitroisoxazole olefins in an organic solvent under the action of an organic small molecular catalyst to obtain the xanthone isoxazole skeleton spliced pyrazolone or benzofuranone compound 3 or 5.
The synthetic route is exemplified as follows:
Figure GDA0002287383380000022
wherein the substituents of the compounds in the synthetic route satisfy R1Is methyl or fluorine or hydrogen; ar is fluorine, chlorine, bromine, nitryl, a benzene ring or a thiophene ring substituted by methyl.
The reaction mechanism is exemplified as follows:
Figure GDA0002287383380000031
the organic solvent is acetonitrile, toluene, dichloromethane or chloroform.
The organic small moleculeThe basic catalyst is DBU, DABCO, Et3N, DMAP, thiourea or aromatic amide derived from chiral difunctional cinchona-alkaloid, thiourea or aromatic amide derived from cyclohexyl diamine, thiourea or aromatic amide derived from 1, 2-diphenyl diamine.
The organic small molecule basic catalyst is partially exemplified as follows:
Figure GDA0002287383380000032
the reaction temperature of various substituted bifunctional pyrazolone/benzofuranone-chromone synthons and various substituted nitroisoxazole olefins in an organic solvent is-10 ℃ to 40 ℃, and the reaction time is 1 to 5 days.
The application of the xanthone isoxazole skeleton spliced pyrazolone or benzofuranone compound in preparing medicaments for preventing and treating tumor diseases.
By adopting the technical scheme, various substituted bifunctional pyrazolone/benzofuranone-chromone synthons and various substituted nitroisoxazole olefins are subjected to Michael/Michael cycloaddition reaction in an organic solvent under the action of an organic small-molecule catalyst to obtain the xanthone isoxazole skeleton spliced pyrazolone or benzofuranone compound 3 or 5, wherein the compound contains a potential bioactive xanthone isoxazole skeleton and a spiro pyrazolone or spiro benzofuranone skeleton, can provide a compound source for biological activity screening, and has important application value for the screening of medicaments and the pharmaceutical industry. And the novel skeleton compound has an 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 spectrum of compound 3a according to an embodiment of the present invention;
FIGS. 3 and 4 are data of the spectra of compound 5a according to the example of the invention;
FIG. 5 is a single crystal diagram of compounds 3r and 5q according to an embodiment of the present invention.
FIG. 6 is an inventive design of the compounds of the present invention.
Detailed Description
The embodiment of the invention comprises the following steps: bifunctional pyrazolone-chromone synthon 1a (0.10mmol), nitroisoxazole alkene 2a (0.12mmol), catalyst DBU (10 mol%, 0.01mmol) and 2.0mL dichloromethane are sequentially added into a reaction tube, the mixture is stirred and reacted for 3 days at room temperature, TLC detection is carried out to basically complete the reaction, and the mixture is directly loaded and purified by column chromatography (eluent: V (petroleum ether): V (ethyl acetate) ═ 6:1) to obtain a compound 3a, a white solid, a melting point: 197.3 to 198.1 ℃; the yield is 82 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.04-2.09(m,1H),2.18(s,3H),2.47(s,3H),2.63-2.66(m,1H),3.59-3.61(m,1H),4.19-4.24(m,1H),4.73-4.77(m,1H),5.93-5.95(m,1H),6.85(d,J＝7.0Hz,1H),7.07-7.16(m,5H),7.21-7.24(m,1H),7.38-7.41(m,2H),7.48-7.51(m,1H),7.69(d,J＝6.5Hz,2H),7.89-7.91(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,28.1,40.2,41.6,47.9,56.0,80.0,118.0,119.4,120.5,122.2,125.8,127.1,128.9,129.3,132.8,134.8,136.3,137.1,155.7,160.2,170.9,173.2,191.9；HRMS(ESI-TOF)m/z:Calcd.for C32H25ClN4NaO6[M+Na]+:619.1355；Found:619.1358.
the preparation methods of the compounds 3b to 3v and the compounds 5a to 5r were the same as the preparation method of the compound 3a, and the compounds 3b to 3v and the compounds 5a to 5r were obtained at the same charge ratio as the compound 3a, and the reaction yields and dr values are shown in tables 1 to 4, but it should be emphasized that the compounds of the present invention are not limited to those shown in tables 1 to 4.
Table 1 shows the chemical structure of a xanthone isoxazole skeleton-spliced pyrazolone compound
Figure GDA0002287383380000051
Table 2 shows the chemical structure of a xanthone isoxazole skeleton-spliced pyrazolone compound
Figure GDA0002287383380000061
Table 3 shows the chemical structure of a preparation method of xanthone isoxazole skeleton spliced benzofuranone compounds
Figure GDA0002287383380000062
Table 4 shows the chemical structure of a preparation method of xanthone isoxazole skeleton spliced benzofuranone compounds
Figure GDA0002287383380000071
This example prepares compound 3b as a white solid, melting point: 215.1 to 216.3 ℃; the yield is 85%;>20:1 dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.04-2.09(m,1H),2.19(s,3H),2.47(s,3H),2.64-2.67(m,1H),3.55-3.58(m,1H),4.20-4.25(m,1H),4.74-4.77(m,1H),5.92-5.93(m,1H),6.85(d,J＝7.0Hz,1H),6.99-7.02(m,1H),7.07-7.10(m,1H),7.16-7.24(m,2H),7.29-7.31(m,2H),7.38-7.41(m,2H),7.48-7.51(m,1H),7.68(d,J＝6.0Hz,2H),7.89-7.91(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,13.6,28.0,40.2,41.6,47.9,55.9,80.0,118.0,119.7,120.5,122.2,123.4,124.4,125.9,127.1,128.9,130.6,132.1,136.3,136.4,137.0,155.7,160.1,160.2,170.8,173.2,191.9；HRMS(ESI-TOF)m/z:Calcd.for C32H25BrN4NaO6[M+Na]+:663.0850；Found:663.0851.
this example prepares compound 3c as a white solid, melting point: 203.3 to 204.2 ℃; the yield is 82%, 9:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.05-2.10(m,1H),2.19(s,3H),2.35(s,3H),2.54-2.57(m,1H),4.17-4.22(m,1H),4.21-4.27(m,1H),4.88(d,J＝10.0Hz,1H),5.83-5.85(m,1H),6.76(d,J＝7.0Hz,1H),6.89-6.91(m,1H),6.95-7.00(m,2H),7.12-7.15(m,1H),7.30-7.33(m,3H),7.38-7.41(m,1H),7.44-7.46(m,1H),7.66-7.67(m,2H),7.81-7.83(m,1H)；13C NMR(CDCl3,125MHz)δ:10.6,13.3,27.6,39.6,40.5,45.3,54.9,78.4,116.9,118.4,118.5,119.6,121.1,123.2,124.7,126.0,127.2,127.7,127.8,127.9,129.2,132.5,132.8,135.2,136.2,154.6,159.3,160.0,169.7,172.6,191.0；HRMS(ESI-TOF)m/z:Calcd.for C32H25BrN4NaO6[M+Na]+:663.0850；Found:663.0846.
this example prepares compound 3d as a white solid, melting point: 198.6-199.2 deg.c; the yield is 84 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:1.94-1.97(m,1H),2.01(s,3H),2.07(s,3H),2.33(s,3H),2.53-2.56(m,1H),3.43-3.47(m,1H),4.13-4.18(m,1H),4.69-4.71(m,1H),5.83-5.85(m,1H),6.76(d,J＝6.5Hz,1H),6.83(d,J＝6.0Hz,2H),6.88-6.90(m,2H),6.97-7.00(m,1H),7.10-7.12(m,1H),7.27-7.30(m,2H),7.38-7.41(m,1H),7.58-7.59(m,2H),7.81-7.82(m,1H)；13C NMR(CDCl3,125MHz)δ:10.5,12.5,20.2,27.0,39.2,40.7,47.7,55.0,79.1,116.9,118.5,119.5,121.1,124.6,126.0,127.7,127.8,128.5,132.9,135.2,136.2,154.5,159.2,159.4,170.3,172.5,191.1；HRMS(ESI-TOF)m/z:Calcd.for C33H28N4NaO6[M+Na]+:599.1901；Found:599.1907.
this example prepares compound 3e as a white solid, melting point: 173.2-174.1 ℃; yield 84%, 18:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.03-2.07(m,1H),2.17(s,3H),2.33(s,3H),2.46(s,3H),2.62-2.65(m,1H),3.58-3.61(m,1H),4.14-4.19(m,1H),4.68-4.72(m,1H),5.91-5.93(m,1H),6.75(d,J＝7.0Hz,1H),7.09-7.14(m,4H),7.21-7.23(m,1H),7.28-7.30(m,1H),7.38-7.41(m,2H),7.68-7.70(m,3H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,20.4,28.1,40.4,41.6,47.7,56.1,80.0,117.7,119.4,120.1,125.8,126.6,128.9,129.2,131.7,132.8,134.8,137.1,137.4,155.7,158.3,160.2,171.0,173.3,192.1；HRMS(ESI-TOF)m/z:Calcd.for C33H27ClN4NaO6[M+Na]+:633.1511；Found:633.1517.
this example prepares compound 3f as a white solid, melting point: 148.6-150.1 ℃; the yield is 83 percent, and is 19:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.03-2.07(m,1H),2.17(s,3H),2.33(s,3H),2.44(s,3H),2.62-2.66(m,1H),3.58-3.61(m,1H),4.15-4.20(m,1H),4.70-4.74(m,1H),5.91-5.92(m,1H),6.74(d,J＝7.0Hz,1H),6.80-6.83(m,2H),7.16-7.22(m,3H),7.28-7.30(m,1H),7.37-7.40(m,2H),7.68(d,J＝6.5Hz,3H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,20.4,28.1,40.6,41.7,51.0,56.2,79.8,116.0(d,JCF＝17.5Hz),117.7,119.4,120.1,125.8,126.6,128.9,130.1,131.7,137.4,155.7,158.3,160.3,162.5(d,JCF＝206.3Hz),171.2,173.3,192.2；HRMS(ESI-TOF)m/z:Calcd.for C33H27FN4NaO6[M+Na]+:617.1807；Found:617.1812.
this example prepares compound 3g, white solid, melting point: 201.6-202.3 ℃; the yield is 80 percent,>20:1 dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.03-2.08(m,1H),2.18(s,3H),2.33(s,3H),2.45(s,3H),2.63-2.66(m,1H),3.60-3.62(m,1H),4.16-4.21(m,1H),4.69-4.73(m,1H),5.91-5.93(m,1H),6.74(d,J＝7.0Hz,1H),6.84-6.86(m,1H),6.90-6.92(m,1H),7.00-7.02(m,1H),7.09-7.12(m,1H),7.20-7.22(m,1H),7.28-7.30(m,1H),7.37-7.40(m,2H),7.69(d,J＝6.5Hz,3H)；13C NMR(CDCl3,125MHz)δ:11.6,13.6,20.4,28.1,40.4,41.6,48.1,56.0,80.0,115.9(d,JCF＝17.5Hz),117.7,119.5,120.1,125.8,126.6,128.9,130.7,131.7,136.7(d,JCF＝6.3Hz),137.1,137.4,155.7,158.3,160.2,162.5(d,JCF′＝206.3Hz),170.9,173.2,192.1；HRMS(ESI-TOF)m/z:Calcd.for C33H27FN4NaO6[M+Na]+:617.1807；Found:617.1814.
this example prepares compound 3h as a white solid, melting point: 138.8-139.5 ℃; the yield is 89 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.02-2.05(m,1H),2.18(s,3H),2.33(s,3H),2.46(s,3H),2.63-2.66(m,1H),3.55-3.58(m,1H),4.16-4.20(m,1H),4.69-4.73(m,1H),5.90-5.92(m,1H),6.74(d,J＝7.5Hz,1H),6.98-7.01(m,1H),7.16-7.23(m,2H),7.27-7.30(m,3H),7.38-7.41(m,2H),7.67(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.6,20.4,28.0,40.2,41.6,48.1,56.0,79.8,117.7,119.7,120.1,125.9,126.6,128.9,130.6,131.8,132.1,136.5,137.0,137.4,155.7,158.3,160.2,170.9,173.2,192.1；HRMS(ESI-TOF)m/z:Calcd.for C33H27BrN4NaO6[M+Na]+:677.1006；Found:677.1012.
this example prepares compound 3i as a white solid, melting point: 181.6 to 183.1 ℃; the yield of the product is 87%,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.11-2.15(m,1H),2.24(s,3H),2.33(s,3H),2.48(s,3H),2.63-2.66(m,1H),4.19-4.24(m,1H),4.36(d,J＝10.0Hz,1H),4.84-4.87(m,1H),5.87-5.89(m,1H),6.74(d,J＝7.0Hz,1H),6.99-7.01(m,1H),7.23-7.25(m,2H),7.28-7.30(m,1H),7.40-7.43(m,2H),7.51(d,J＝7.5Hz,1H),7.68-7.69(m,1H),7.75(d,J＝7.0Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.7,13.8,20.4,28.6,40.2,41.5,50.9,55.9,79.6,117.7,119.3,120.1,125.9,126.6,127.9,129.0,129.6,129.9,130.9,131.8,134.2,135.2,137.1,137.4,155.7,158.3,160.8,170.6,173.4,192.0；HRMS(ESI-TOF)m/z:Calcd.for C33H26Cl2N4NaO6[M+Na]+:667.1122；Found:667.1125.
this example prepares compound 3j as a white solid, melting point: 175.6 to 176.2 ℃; yield 83%, 13:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.03-2.07(m,1H),2.16(s,3H),2.17(s,3H),2.32(s,3H),2.43(s,3H),2.61-2.64(m,1H),3.55-3.57(m,1H),4.17-4.22(m,1H),4.72-4.73(m,1H),5.92-5.94(m,1H),6.74(d,J＝7.0Hz,1H),6.89(d,J＝7.0Hz,2H),7.03-7.05(m,2H),7.19-7.21(m,1H),7.27-7.29(m,1H),7.37-7.39(m,2H),7.68-7.71(m,3H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,20.4,21.0,28.2,40.6,41.7,56.2,80.0,117.7,119.5,120.1,125.6,126.6,128.8,129.6,131.1,131.6,137.3,138.5,155.6,158.4,160.6,171.6,173.6,192.4；HRMS(ESI-TOF)m/z:Calcd.for C34H30N4NaO6[M+Na]+:613.2058；Found:613.2058.
this example prepares compound 3k as a white solid, melting point: 230.6-231.5 ℃; the yield of the product is 81 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.03-2.07(m,1H),2.10(s,3H),2.16(s,3H),2.33(s,3H),2.42(s,3H),2.62-2.65(m,1H),3.50-3.52(m,1H),4.19-4.24(m,1H),4.72-4.74(m,1H),5.91-5.93(m,1H),6.75(d,J＝7.0Hz,1H),6.92(d,J＝6.5Hz,2H),6.97-6.99(m,2H),7.19-7.21(m,1H),7.28-7.30(m,1H),7.36-7.39(m,2H),7.68(d,J＝6.5Hz,3H)；13C NMR(CDCl3,125MHz)δ:11.6,13.6,20.4,21.2,28.1,40.5,41.7,50.9,56.0,80.1,117.7,119.5,120.1,125.6,126.7,128.7,128.8,129.5,131.6,134.0,137.2,137.3,138.7,155.5,158.4,160.5,171.5,173.6,192.4；HRMS(ESI-TOF)m/z:Calcd.for C34H30N4NaO6[M+Na]+:613.2058；Found:613.2054.
this example prepares compound 3l as a white solid, melting point: 153.3-155.1 ℃; the yield is 85 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.05-2.09(m,1H),2.17(s,3H),2.41(s,3H),2.63-2.66(m,1H),3.57-3.59(m,1H),4.22-4.27(m,1H),4.76-4.80(m,1H),5.96-5.97(m,1H),6.83-6.86(m,1H),7.10-7.17(m,5H),7.19-7.23(m,2H),7.37-7.39(m,2H),7.54-7.56(m,1H),7.68(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,28.0,40.4,41.6,48.8,56.0,80.5,112.1(d,JCF＝20.5Hz),119.5,119.7(d,JCF′＝6.3Hz),123.8(d,JCF′＝20.1Hz),125.7,128.9,129.0,134.0,137.2,155.6,156.5,157.6(d,JCF′＝201.3Hz),160.3,171.1,173.4,191.3；HRMS(ESI-TOF)m/z:Calcd.for C32H25FN4NaO6[M+Na]+:603.1650；Found:603.1653.
this example prepares compound 3m as a white solid, melting point: 186.3-187.1 ℃; the yield is 90 percent,>20:1 dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:1.93-1.98(m,1H),2.07(s,3H),2.36(s,3H),2.53-2.56(m,1H),3.48-3.51(m,1H),4.07-4.13(m,1H),4.61-4.65(m,1H),5.82-5.84(m,1H),6.73-6.75(m,1H),6.99-7.03(m,4H),7.09-7.13(m,2H),7.28-7.31(m,2H),7.43-7.45(m,1H),7.59(d,J＝7.0Hz,2H)；13C NMR(CDCl3,125MHz)δ:10.6,12.5,26.9,39.2,40.5,46.8,54.9,79.2,111.0(d,JCF′＝20.3Hz),118.4,118.7,119.9,122.8(d,JCF′＝20.0Hz),124.8,127.9,128.3,131.6,133.8,136.0,154.7,155.3,156.6(d,JCF′＝201.3Hz),159.1,169.7,172.2,190.1；HRMS(ESI-TOF)m/z:Calcd.for C32H24ClFN4NaO6[M+Na]+:637.1261；Found:637.1265.
this example prepares compound 3n as a white solid, melting point: 167.1-168.3 ℃; the yield is 85 percent, and is 15:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.03-2.08(m,1H),2.17(s,3H),2.45(s,3H),2.63-2.66(m,1H),3.58-3.62(m,1H),4.19-4.24(m,1H),4.73-4.77(m,1H),5.91-5.93(m,1H),6.81-6.85(m,3H),7.16-7.23(m,4H),7.37-7.40(m,2H),7.54-7.56(m,1H),7.68(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,27.9,40.2,41.6,47.5,56.0,80.2,112.1(d,JCF′＝20.0Hz),116.1(d,JCF′＝17.5Hz),119.4,119.7,119.8,120.9,121.0,123.8(d,JCF＝20.0Hz),125.9,128.9,129.9,137.1,155.7,157.6(d,JCF＝201.3Hz),158.4,160.2,162.6(d,JCF＝206.3Hz),170.9,173.3,191.2；HRMS(ESI-TOF)m/z:Calcd.for C32H24F2N4NaO6[M+Na]+:621.1556；Found:621.1557.
this example prepares compound 3o a white solid, melting point: 195.6-196.8 ℃; the yield is 91 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.04-2.08(m,1H),2.18(s,3H),2.45(s,3H),2.63-2.67(m,1H),3.59-3.62(m,1H),4.19-4.24(m,1H),4.72-4.76(m,1H),5.92-5.94(m,1H),6.83-6.87(m,2H),6.89-6.90(m,1H),7.00-7.02(m,1H),7.09-7.13(m,1H),7.19-7.23(m,2H),7.38-7.40(m,2H),7.54-7.56(m,1H),7.68(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,28.0,40.3,41.5,48.1,55.9,80.0,112.1(d,JCF＝18.8Hz),116.1(d,JCF＝16.3Hz),119.5,119.7(d,JCF＝6.3Hz),120.9,121.0,123.9(d,JCF＝21.3Hz),125.9,128.9,130.8,136.5,136.6,137.0,155.7,156.4,157.6(d,JCF＝201.3Hz),160.1,170.7,173.2,191.1；HRMS(ESI-TOF)m/z:Calcd.for C32H24F2N4NaO6[M+Na]+:621.1556；Found:621.1558.
this example prepares compound 3p as a white solid, melting point: 182.4-183.5 ℃; the yield is 82 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.03-2.08(m,1H),2.18(s,3H),2.46(s,3H),2.63-2.67(m,1H),3.54-3.58(m,1H),4.19-4.23(m,1H),4.72-4.76(m,1H),5.91-5.93(m,1H),6.83-6.85(m,1H),6.98-7.01(m,1H),7.16-7.23(m,3H),7.27-7.33(m,1H),7.32-7.34(m,1H),7.37-7.40(m,2H),7.53-7.55(m,1H),7.67(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.6,27.9,40.2,41.5,48.1,55.8,80.1,112.0(d,JCF＝20.1Hz),119.7,119.8,123.9,125.9,128.9(d,JCF＝20.0Hz),132.2,136.3,137.0,155.7,156.4,157.6(d,JCF＝201.3Hz),160.0,170.6,173.1,191.1；HRMS(ESI-TOF)m/z:Calcd.for C32H24BrFN4NaO6[M+Na]+:681.0755；Found:681.0755.
this example prepares compound 3q as a white solid, melting point: 181.6 to 182.5 ℃; the yield is 89 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.03-2.07(m,1H),2.16(s,3H),2.17(s,3H),2.43(s,3H),2.61-2.64(m,1H),3.55-3.56(m,1H),4.20-4.25(m,1H),4.75-4.78(m,1H),5.93-5.95(m,1H),6.83-6.85(m,1H),6.90(d,J＝7.0Hz,2H),7.03-7.05(m,2H),7.19-7.22(m,2H),7.37-7.40(m,2H),7.54-7.56(m,1H),7.70(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.5,21.0,28.1,40.3,41.6,56.0,60.3,80.4,112.0(d,JCF＝18.8Hz),119.5,119.7(d,JCF＝6.3Hz),123.7(d,JCF＝20.3Hz),125.7,128.8,129.7,130.9,137.3,138.6,155.6,156.5,157.5(d,JCF＝201.3Hz),160.5,171.3,173.5,191.4；HRMS(ESI-TOF)m/z:Calcd.for C33H27FN4NaO6[M+Na]+:617.1807；Found:617.1809.
this example prepares compound 3r as a white solid, melting point: 187.6-188.3 ℃; the yield is 85 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:1.93-1.98(m,1H),2.00(s,3H),2.06(s,3H),2.32(s,3H),2.53-2.56(m,1H),3.42-3.44(m,1H),4.12-4.17(m,1H),4.65-4.69(m,1H),5.82-5.84(m,1H),6.73-6.76(m,1H),6.81-6.85(m,2H),6.87-6.90(m,2H),7.09-7.13(m,2H),7.27-7.30(m,2H),7.44-7.46(m,1H),7.58(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:10.5,12.5,20.1,26.9,39.3,40.6,47.8,54.9,79.3,111.0(d,JCF＝18.8Hz),118.5,118.7(d,JCF＝6.3Hz),119.9(d,JCF＝5.0Hz),122.6(d,JCF＝21.3Hz),124.7,127.8,128.6,132.8,136.1,154.5,155.5,156.7(d,JCF＝201.3Hz),159.4,170.1,172.5,190.4；HRMS(ESI-TOF)m/z:Calcd.for C33H27FN4NaO6[M+Na]+:617.1807；Found:617.1813.
this example prepares compound 3s as a white solid, melting point: 140.1-141.3 ℃; the yield is 86 percent, and 8:1dr is obtained; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.04-2.09(m,1H),2.19(s,3H),2.34(s,3H),2.54-2.57(m,1H),4.17-4.21(m,1H),4.25(d,J＝10.0Hz,1H),4.85-4.87(m,1H),5.82-5.84(m,1H),6.74-6.77(m,1H),6.89-6.92(m,1H),6.95-6.98(m,1H),7.10-7.15(m,2H),7.30-7.33(m,3H),7.43-7.47(m,2H),7.66(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:10.6,13.2,27.5,39.5,40.4,45.4,52.4,54.8,78.8,111.1(d,JCF＝20.1Hz),118.4,120.0,122.7(d,JCF＝21.3Hz),123.2,124.8,127.2,127.7,127.9,129.2,132.5,132.7,154.6,156.5(d,JCF＝202.5Hz),157.4,159.9,169.5,172.5,190.3；HRMS(ESI-TOF)m/z:Calcd.for C33H27FN4NaO6[M+Na]+:617.1807；Found:617.1811.
this example prepared compound 3t a white solid, melting point: 180.5-181.7 ℃; the yield is 85 percent, and the ratio is 7:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.12-2.16(m,1H),2.24(s,3H),2.28(s,3H),2.63-2.66(m,1H),4.22-4.27(m,1H),4.36(d,J＝10.0Hz,1H),4.87-4.94(m,1H),5.87-5.89(m,1H),6.83-6.85(m,1H),7.00-7.02(m,1H),7.20-7.26(m,3H),7.41-7.43(m,2H),7.49(d,J＝7.0Hz,1H),7.54-7.56(m,1H),7.75(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.7,13.8,28.4,41.4,42.6,55.8,60.5,79.9,112.1(d,JCF＝20.5Hz),119.3,119.7,123.8(d,JCF＝20.7Hz),126.0,128.0,129.0,129.5,129.9,130.7,134.2,135.3,155.8,156.4,157.6(d,JCF′＝202.6Hz),160.7,170.3,173.4,191.1；HRMS(ESI-TOF)m/z:Calcd.for C32H23Cl2FN4NaO6[M+Na]+:671.0871；Found:671.0877.
this example prepares compound 3u as a white solid, melting point: 153.3-155.1 ℃; the yield is 90%, 12:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.11(s,3H),2.13(s,3H),2.23(s,3H),2.43(s,3H),2.60-2.63(m,1H),3.84(d,J＝9.5Hz,1H),4.28-4.34(m,1H),4.83-4.86(m,1H),5.99-6.02(m,1H),6.71(d,J＝6.5Hz,1H),6.77(s,1H),6.83-6.86(m,1H),7.19-7.25(m,2H),7.28-7.29(m,2H),7.40-7.43(m,2H),7.55-7.57(m,1H),7.77(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.6,19.2,20.8,28.8,40.8,41.6,56.0,80.5,112.0(d,JCF＝20.0Hz),119.5,119.7,123.8(d,JCF＝22.3Hz),125.7,126.6,127.6,128.9,129.4,131.8,137.4,138.0,155.7,157.2(d,JCF＝201.3Hz),160.4,171.3,174.0,191.6；HRMS(ESI-TOF)m/z:Calcd.for C34H29FN4NaO6[M+Na]+:631.1963；Found:631.1965.
this example prepares compound 3v a white solid, melting point: 131.0-132.3 ℃; the yield is 90 percent, and is 17:1 dr; nuclear magnetic resonanceAnd the results of high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.01-2.06(m,1H),2.20(s,3H),2.48(s,3H),2.64-2.67(m,1H),3.91-3.93(m,1H),4.15-4.20(m,1H),4.72-4.74(m,1H),5.91-5.93(m,1H),6.74-6.75(m,1H),6.83-6.86(m,1H),6.89(d,J＝2.5Hz,1H),7.02(d,J＝4.0Hz,1H),7.19-7.24(m,2H),7.38-7.41(m,2H),7.53-7.55(m,1H),7.76(d,J＝6.5Hz,2H)；13C NMR(CDCl3,125MHz)δ:11.6,13.4,27.9,39.6,41.4,50.9,56.3,79.8,112.1(d,JCF＝20.1Hz),119.4,119.7,123.9(d,JCF＝20.0Hz),125.6,125.7,126.3,127.4,128.9,135.7,155.7,156.4,157.6(d,JCF＝201.3Hz),160.2,170.8,173.2,191.1；HRMS(ESI-TOF)m/z:Calcd.for C30H23FN4NaO6S[M+Na]+:609.1215；Found:609.1211.
this example prepares compound 5a as a white solid, melting point: 270.0 to 273.5 ℃; the yield is 75 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.21-2.25(m,1H),2.43(s,3H),2.80-2.84(m,1H),3.74-3.76(m,1H),4.00-4.05(m,1H),4.84-4.86(m,1H),5.80-5.82(m,1H),6.83-6.87(m,2H),7.00-7.10(m,5H),7.20-7.21(m,2H),7.29(s,1H),7.36-7.38(m,1H),7.48-7.51(m,1H),7.91(d,J＝6.5Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,32.0,41.2,43.3,51.1,80.2,110.8,118.0,120.5,122.2,122.8,124.5,127.1,128.3,129.1,129.5,134.0,136.3,152.3,155.6,160.2,171.2,177.0,191.7；HRMS(ESI-TOF)m/z:Calcd.for C30H22N2NaO7[M+Na]+:545.1319；Found:545.1323.
this example prepares compound 5b as a white solid, melting point:>300.0 ℃; the yield is 61 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.12(s,3H),2.19-2.23(m,1H),2.44(s,3H),2.79-2.82(m,1H),3.72-3.74(m,1H),3.98-4.02(m,1H),4.82-4.84(m,1H),5.77-5.79(m,1H),6.78(s,3H),6.78-6.86(m,3H),7.06-7.09(m,1H),7.19-7.22(m,2H),7.36-7.37(m,1H),7.47-7.50(m,1H),7.89-7.91(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,20.9,32.0,41.4,43.3,51.2,80.3,110.8,118.0,120.5,122.2,122.8,124.4,127.1,129.3,129.4,130.9,136.2,138.0,152.3,155.6,160.2,171.4,177.0,191.7；HRMS(ESI-TOF)m/z:Calcd.for C31H24N2NaO7[M+Na]+:559.1476；Found:559.1477.
this example prepares compound 5c as a white solid, melting point:>300.0 ℃; the yield is 70%, 12:1 dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.39-2.44(m,1H),2.47(s,3H),2.69-2.72(m,1H),3.48-3.53(m,1H),3.94(d,J＝11.0Hz,1H),4.86-4.90(m,1H),5.36-5.40(m,1H),6.74(s,2H),6.87(d,J＝7.0Hz,1H),6.95(s,2H),7.01(d,J＝6.5Hz,1H),7.11-7.13(m,1H),7.33-7.36(m,1H),7.39-7.42(m,1H),7.51-7.53(m,1H),7.88(d,J＝6.0Hz,1H),7.93(d,J＝5.5Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,31.9,42.2,44.5,50.2,52.8,80.3,111.9,117.9,120.6,122.6,124.7,125.0,127.0,127.4,128.7,130.3,132.2,134.5,136.5,152.8,155.5,160.0,170.5,176.6,190.3；HRMS(ESI-TOF)m/z:Calcd.for C30H21ClN2NaO7[M+Na]+:579.0929；Found:579.0934.
this example prepares compound 5d as a white solid, melting point: 196.1 to 200.8 ℃; the yield is 69%, 10:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.27-2.32(m,1H),2.48(s,3H),2.77-2.80(m,1H),3.98-7.03(m,1H),4.59(d,J＝10.0Hz,1H),4.91-4.95(m,1H),5.71-5.72(m,1H),6.85(d,J＝7.0Hz,1H),6.90(d,J＝7.0Hz,1H),7.01(s,1H),7.07-7.13(m,2H),7.15-7.18(m,1H),7.23-7.26(m,1H),7.47-7.50(m,3H),7.89(d,J＝6.5Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.7,32.4,41.6,43.2,44.8,51.1,79.9,110.6,117.9,122.3,124.0,124.3,127.1,128.0,128.5,129.7,129.9,134.8,136.3,151.9,155.7,160.1,170.5,177.2,191.5；HRMS(ESI-TOF)m/z:Calcd.for C30H20Cl2N2NaO7[M+Na]+:613.0540；Found:613.0546.
this example prepares compound 5e as a white solid, melting point:>300.0 ℃; the yield is 75%, 7:1 dr; nuclear magnetic resonance and high resolution mass spectrometryThe results are as follows:1H NMR(CDCl3,500MHz)δ:2.25-2.30(m,1H),2.46(s,3H),2.77-2.80(m,1H),4.00-4.05(m,1H),5.02-5.06(m,1H),5.14(d,J＝10.0Hz,1H),5.84-5.88(m,1H),6.83(d,J＝6.5Hz,1H),6.87(d,J＝7.0Hz,1H),7.09-7.11(m,1H),7.16-7.18(m,1H),7.23-7.29(m,3H),7.47-7.52(m,3H),7.77(d,J＝6.5Hz,1H),7.91-7.92(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,32.2,41.0,43.2,51.5,79.8,110.6,117.9,122.3,123.1,125.3,125.5,127.2,129.4,130.0,133.5,136.3,149.7,151.9,155.7,160.1,170.3,177.0,191.3；HRMS(ESI-TOF)m/z:Calcd.for C30H21N3NaO9[M+Na]+:590.1170；Found:590.1174.
this example prepares compound 5f as a white solid, melting point: 177.5-180.1 ℃; the yield is 68 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.17-2.21(m,1H),2.49(s,3H),2.81-2.84(m,1H),3.95-3.99(m,1H),4.05-4.06(m,1H),4.80-4.81(m,1H),5.74-5.76(m,1H),6.68-6.70(m,1H),6.83-6.86(m,2H),6.89-6.90(m,1H),6.93-6.94(m,1H),7.07-7.09(m,1H),7.23-7.29(m,2H),7.37(d,J＝6.0Hz,1H),7.48-7.51(m,1H),7.89-7.90(m,1H)；13C NMR(CDCl3,125MHz)δ:11.7,31.7,43.1,51.6,79.8,110.9,118.0,120.5,122.2,122.7,124.8,125.4,126.1,127.1,129.8,136.3,152.6,155.7,160.1,171.0,176.8,191.5；HRMS(ESI-TOF)m/z:Calcd.for C28H20N2NaO7S[M+Na]+:551.0883；Found:551.0889.
this example prepares compound 5g as a white solid, melting point:>300.0 ℃; the yield is 69 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.20-2.25(m,1H),2.42(s,3H),2.80-2.83(m,1H),3.75(d,J＝9.5Hz,1H),3.99-4.03(m,1H),4.82-4.86(m,1H),5.79-5.81(m,1H),6.82-6.86(m,2H),6.98-7.03(m,5H),7.19-7.23(m,3H),7.36-7.37(m,1H),7.53-7.55(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,31.9,41.4,43.3,51.1,80.5,110.8,112.1(d,JCF＝18.8Hz),119.7,119.8,122.8,123.8(d,JCF＝21.3Hz),124.5,128.4,129.0,129.5,133.9,152.3,155.6,156.4,157.6(d,JCF＝18.8Hz),171.1,177.0,191.0；HRMS(ESI-TOF)m/z:Calcd.for C30H21FN2NaO7[M+Na]+:563.1225；Found:563.1229.
this example prepared compound 5h as a white solid, melting point: 261.8-265.0 deg.C; the yield is 80%, and 10:1dr is adopted; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.28-2.33(m,1H),2.44(s,3H),2.78-2.81(m,1H),4.01-4.06(m,1H),4.63(d,J＝10.5Hz,1H),4.95-4.99(m,1H),5.73-5.75(m,1H),6.84-6.86(m,2H),6.98(d,J＝3.0Hz,2H),7.11-7.14(m,1H),7.15(d,J＝6.5Hz,1H),7.19-7.23(m,2H),7.50-7.52(m,2H),7.54-7.56(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,32.3,41.6,43.1,45.3,51.0,80.1,110.4,112.1(d,JCF＝20.3Hz),123.7(d,JCF＝20.1Hz),124.0,124.2,127.4,127.6,127.7,129.5,129.7,134.0,151.9,155.6,156.4,157.6(d,JCF＝21.3Hz),170.6,177.3,190.9；HRMS(ESI-TOF)m/z:Calcd.for C30H20ClFN2NaO7[M+Na]+:597.0835；Found:597.0841.
this example prepares compound 5i as a white solid, melting point:>300.0 ℃; the yield is 73 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.28-2.33(s,1H),2.43(s,3H),2.77-2.80(m,1H),4.01-4.06(m,1H),4.63(d,J＝10.0Hz,1H),4.96-4.98(m,1H),5.73-5.75(m,1H),6.85-6.86(m,2H),6.98(s,2H),7.10-7.16(m,2H),7.19-7.23(m,2H),7.51-7.56(m,3H)；13C NMR(CDCl3,125MHz)δ:11.6,32.4,41.7,43.2,45.4,51.1,80.1,110.4,112.1(d,JCF＝18.8Hz),123.8(d,JCF＝21.3Hz),124.0,124.2,127.5,127.7,129.6,129.8,132.5,152.0,155.6,157.6(d,JCF＝201.3Hz),158.4,170.6,177.4,190.9；HRMS(ESI-TOF)m/z:Calcd.for C30H20ClFN2NaO7[M+Na]+:597.0835；Found:597.0831.
this example prepares compound 5j as a white solid, melting point:>300.0 ℃; the yield is 69%, and 15:1dr is adopted; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.24-2.29(m,1H),2.46(s,3H),2.85-2.88(m,1H),3.92(d,J＝10.5Hz,1H),3.97-4.02(m,1H),4.81-4.85(m,1H),5.82-5.85(m,1H),6.84-6.87(m,2H),7.22-7.32(m,5H),7.46(d,J＝6.0Hz,1H),7.54-7.56(m,1H),7.61-7.70(m,1H),7.93(d,J＝7.0Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,31.6,40.9,43.1,51.1,80.2,111.1,112.2(d,JCF＝20.1Hz),119.7,119.8,122.7,123.5,123.9(d,JCF＝20.5Hz),125.1,128.0,130.2,136.1,152.1,155.8,156.2,157.4(d,JCF＝201.3Hz),170.0,176.4,190.5；HRMS(ESI-TOF)m/z:Calcd.for C30H20FN3NaO9[M+Na]+:608.1076；Found:608.1079.
this example prepared compound 5k a white solid, melting point: 201.2 to 205.3 ℃; the yield is 65%, 12:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.26-2.31(m,1H),2.48(s,3H),2.77-2.80(m,1H),3.98-4.03(m,1H),4.58(d,J＝10.5Hz,1H),4.91-4.95(m,1H),5.70-5.72(m,1H),6.84-6.86(m,1H),6.90(d,J＝7.0Hz,1H),7.01(s,1H),7.11-7.13(m,1H),7.15-7.18(m,1H),7.20-7.26(m,2H),7.46-7.49(m,2H),7.53-7.55(m,1H)；13C NMR(CDCl3,125MHz)δ:11.7,32.3,41.5,43.1,44.8,51.0,80.1,110.7,112.2(d,JCF＝17.5Hz),123.9(d,JCF＝20.7Hz),124.4,127.4,128.0,128.4,129.7,130.0,134.9(d,JCF＝8.8Hz),151.9,155.8,156.3,157.6(d,JCF＝201.3Hz),170.3,177.2,190.7；HRMS(ESI-TOF)m/z:Calcd.for C30H19Cl2FN2NaO7[M+Na]+:631.0446；Found:631.0446.
this example prepares compound 5l as a white solid, melting point: 160.2-165.8 ℃; the yield of the product is 76%,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.11(s,3H),2.18-2.22(m,1H),2.43(s,3H),2.78-2.81(m,1H),3.71-3.73(m,1H),3.96-4.01(m,1H),4.81-4.83(m,1H),5.76-5.78(m,1H),6.78(s,3H),6.83-6.85(m,2H),7.18-7.22(m,3H),7.35-7.36(m,1H),7.53-7.54(m,1H)；13C NMR(CDCl3,125MHz)δ:11.6,20.9,31.9,41.4,43.3,51.1,80.5,110.8,112.1(d,JCF＝20.1Hz),122.8,123.7(d,JCF＝20.1Hz),124.5,129.1,129.5,130.8,138.0,152.3,155.6,157.6(d,JCF＝202.5Hz),158.4,171.2,177.0,191.0；HRMS(ESI-TOF)m/z:Calcd.for C31H23FN2NaO7[M+Na]+:577.1382；Found:577.1387.
this example prepares compound 5m as a white solid, melting point: 263.2-265.1 ℃; the yield of the product is 67 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.34-2.39(m,1H),2.47(s,3H),2.70-2.73(m,1H),3.45-3.50(m,1H),4.28(d,J＝10.5Hz,1H),4.85-4.89(m,1H),5.30-5.31(m,1H),6.52(d,J＝2.5Hz,1H),6.62-6.64(m,1H),6.87-6.89(m,1H),6.93(d,J＝5.0Hz,1H),7.08(d,J＝7.0Hz,1H),7.22-7.26(m,1H),7.35-7.38(m,1H),7.44-7.47(m,1H),7.56-7.58(m,1H),7.86(d,J＝6.0Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,31.7,44.3,46.6,50.9,52.8,80.2,111.9,112.4(d,JCF＝18.8Hz),119.7,119.8,124.0(d,JCF＝21.3Hz),124.8,125.2,126.4,127.8,130.5,135.5,153.3,155.5,156.3,157.6(d,JCF＝202.5Hz),170.2,176.6,189.7；HRMS(ESI-TOF)m/z:Calcd.for C28H19FN2NaO7S[M+Na]+:569.0789；Found:569.0786.
this example prepares compound 5n as a white solid, melting point: 258.8 to 261.1 ℃; yield 74%, 17:1 dr; the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.34(s,3H),2.37-2.42(m,1H),2.47(s,3H),2.68-2.71(m,1H),3.44-3.51(m,1H),3.93(d,J＝10.5Hz,1H),4.81-4.85(m,1H),5.32-5.38(m,1H),6.73(s,2H),6.76(d,J＝7.0Hz,1H),6.93-6.95(m,2H),7.00(d,J＝6.5Hz,1H),7.31-7.35(m,2H),7.39-7.42(m,1H),7.70(s,1H),7.88(d,J＝6.5Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,20.5,31.9,42.2,44.5,50.2,52.8,80.3,111.9,117.7,120.2,124.7,125.0,126.9,127.1,128.7,130.2,132.2,134.5,137.5,152.8,155.5,158.1,170.6,176.6,190.6；HRMS(ESI-TOF)m/z:Calcd.for C31H23ClN2NaO7[M+Na]+:593.1086；Found:593.1087.
this example prepared compound 5o a white solid, melting point:>300.0 ℃; yield 67%, 9:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.27-2.31(m,1H),2.33(s,3H),2.44(s,3H),2.77-2.80(m,1H),3.99-4.04(m,1H),4.62(d,J＝10.0Hz,1H),4.92-4.95(m,1H),5.68-5.74(m,1H),6.76(d,J＝7.0Hz,1H),6.86(d,J＝6.5Hz,1H),6.98(d,J＝3.5Hz,2H),7.10-7.13(m,1H),7.15(d,J＝6.5Hz,1H),7.19-7.22(m,1H),7.29-7.31(m,1H),7.51-7.53(m,2H),7.69(s,1H)；13C NMR(CDCl3,125MHz)δ:11.6,20.4,32.6,42.1,43.3,45.4,51.2,79.9,110.4,117.7,124.0,124.2,126.7,127.5,127.6,127.9,129.5,129.7,129.8,137.3,152.0,155.6,158.3,170.9,177.4,191.9；HRMS(ESI-TOF)m/z:Calcd.for C31H23ClN2NaO7[M+Na]+:593.1086；Found:593.1091.
this example prepares compound 5p as a white solid, melting point:>300.0 ℃; the yield is 65 percent,>20:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.33(s,3H),2.36-2.41(m,1H),2.45(s,3H),2.68-2.71(m,1H),3.45-3.50(m,1H),3.89(d,J＝11.0Hz,1H),4.82-4.86(m,1H),5.33-5.37(m,1H),6.73(s,1H),6.76(d,J＝7.0Hz,1H),6.84(s,1H),6.92(s,1H),7.00(d,J＝6.5Hz,1H),7.19(d,J＝6.5Hz,1H),7.30-7.32(m,1H),7.35-7.37(m,1H),7.40-7.42(m,1H),7.70(s,1H),7.90(d,J＝6.0Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,20.5,31.9,42.1,44.5,50.5,52.7,80.2,111.8,117.7,120.2,122.4,124.7,125.1,126.9,127.0,129.8,130.3,131.7,132.2,132.5,135.9,137.5,152.8,155.5,158.1,170.4,176.5,190.6；HRMS(ESI-TOF)m/z:Calcd.for C31H23BrN2NaO7[M+Na]+:637.0581；Found:637.0578.
this example prepares compound 5q as a white solid, melting point: 193.5-200.4 ℃; the yield is 76%, 12:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.26-2.30(m,1H),2.32(s,3H),2.48(s,3H),2.76-2.79(m,1H),3.95-4.00(m,1H),4.58(d,J＝10.5Hz,1H),4.87-4.91(m,1H),5.69-5.71(m,1H),6.74(d,J＝7.0Hz,1H),6.89(d,J＝6.5Hz,1H),7.00(s,1H),7.10-7.12(m,1H),7.15-7.17(m,1H),7.23-7.25(m,1H),7.29-7.30(m,1H),7.47-7.50(m,2H),7.68(s,1H)；13C NMR(CDCl3,125MHz)δ:11.7,20.4,32.5,41.7,43.2,44.8,51.1,79.9,110.6,117.7,124.0,124.3,126.7,128.0,128.5,129.6,129.9,131.4,131.8,137.4,151.9,155.7,158.2,170.6,177.2,191.7；HRMS(ESI-TOF)m/z:Calcd.for C31H22Cl2N2NaO7[M+Na]+:627.0696；Found:627.0697.
this example prepares compound 5r as a white solid, melting point:>300.0 ℃; the yield is 80%, 18:1 dr; the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:2.13(s,3H),2.34(s,3H),2.37-2.42(m,1H),2.43(s,3H),2.66-2.69(m,1H),3.45-3.50(m,1H),3.90(d,J＝6.0Hz,1H),4.83-4.86(m,1H),5.36-5.40(m,1H),6.65(s,2H),6.73-6.75(m,2H),6.77(d,J＝7.0Hz,1H),6.96(d,J＝6.5Hz,1H),7.31-7.34(m,2H),7.36-7.39(m,1H),7.71(s,1H),7.89(d,J＝6.0Hz,1H)；13C NMR(CDCl3,125MHz)δ:11.6,20.5,21.0,32.0,42.4,44.6,50.6,52.9,80.4,111.6,117.7,120.2,124.5,125.1,126.9,127.6,129.1,129.9,130.5,132.0,137.4,138.1,152.9,155.4,158.2,171.1,176.9,190.8；HRMS(ESI-TOF)m/z:Calcd.for C32H26N2NaO7[M+Na]+:573.1632；Found:573.1637.
the compound of formula (1) of the present invention has important biological activity, and cytotoxicity test in vitro against human leukemia cells (K562) shows that: the xanthone isoxazole skeleton spliced pyrazolone or benzofuranone compound with the structure shown in the formula (1) has an inhibition 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 by human leukemia cells (K562).
Pharmacological examples: cytotoxicity of Compounds 3i,3m and 5m on K562 cells
K562 (human chronic myelogenous leukemia cells) was cultured in RPMI-1640 medium containing 10% fetal bovine serum, 100U/mL penicillin and 100Ustreptomycin/mL. 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, newly prepared solutions of compounds 3i,3m and 5m in dimethylsulfoxide were added to each well in a concentration gradient such that the final concentrations of the compounds in the wells were 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 with a microplate reader using dissolved and reduced MTT crystal formazan (formazan). Wherein the compound 3i,3m and 5m have half inhibitory concentration IC on K562 cells50Analyzed by the sps software (version 19). IC of Compound 3i on K562 tumor cells5042.31 mu mol/L; IC of compound 3m on K562 tumor cells5036.27 mu mol/L; IC of compound 5m on K562 tumor cells5039.40 mu mol/L; IC of positive control cisplatin on K562 tumor cells50It was 23.01. 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 xanthone isoxazole skeleton spliced pyrazolone or benzofuranone compound shown in the formula (1) has stronger cytotoxicity on K562 cells and is likely to be developed into a new medicine with an anti-tumor effect.
From the pharmacological examples, the xanthone isoxazole skeleton spliced pyrazolone or benzofuranone compounds have the potential of being developed into antitumor drugs and are worthy of further research.

Claims (3)

1. A xanthone isoxazole skeleton spliced pyrazolone or benzofuranone compound is characterized in that: the compound has a structure shown as a general formula (I):
Figure FDA0003480768820000011
in the formula, R1Is methyl, fluoro or hydrogen; ar is fluorine, chlorine, bromine, nitro or methyl substituted benzene ring or thiophene ring.
2. The preparation method of the xanthone isoxazole skeleton-spliced pyrazolone or benzofuranone compound as claimed in claim 1, characterized in that the synthetic route is as follows:
Figure FDA0003480768820000012
3. an application of the xanthone isoxazole skeleton-spliced pyrazolone or benzofuranone compound in the preparation of drugs for preventing and treating leukemia according to claim 1.
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CN110092793A (en) * 2019-02-28 2019-08-06 贵州大学 Mountain ketone element skeleton and isoxazole loop coil Oxoindole splicing derivative and preparation method and application

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* Cited by examiner, † Cited by third party
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CN110092793A (en) * 2019-02-28 2019-08-06 贵州大学 Mountain ketone element skeleton and isoxazole loop coil Oxoindole splicing derivative and preparation method and application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
An expedient approach for the synthesis of dispiropyrrolidine bisoxindoles,spiropyrrolidine oxindoles and spiroindane-1,3-diones through 1,3-dipolar cycloaddition reactions;Neelakandan Vidhya Lakshmi;《Tetrahedron Letters》;20091221;第51卷;1064-1068页 *
通过1，3－偶极环加成反应合成3－吡咯螺环氧化吲哚的研究进展;周英;《山地农业生物学报》;20151231;第34卷(第2期);009-013页 *

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