CN112390804B - Cyclopentachromanone spliced spiro-oxoindole compound and preparation method and application thereof - Google Patents

Cyclopentachromanone spliced spiro-oxoindole compound and preparation method and application thereof Download PDF

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CN112390804B
CN112390804B CN201910747297.0A CN201910747297A CN112390804B CN 112390804 B CN112390804 B CN 112390804B CN 201910747297 A CN201910747297 A CN 201910747297A CN 112390804 B CN112390804 B CN 112390804B
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刘雄利
徐圣文
周韦
周豪杰
周彦佑
何学雯
周英
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Abstract

The invention discloses a cyclopentano-chromanone spliced spiro-oxoindole compound, which comprises a potential bioactive cyclopentano-chromanone skeleton and a latent spiro-oxoindole compound skeleton, can provide a compound source for bioactive screening, and has important application value for drug screening and 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

Cyclopentachromanone spliced spiro-oxoindole compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of chemistry and pharmacy, in particular to a cyclopentane chromanone spliced spiro-oxoindole 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) Spiro five-membered carbocyclic oxindoles are widely found in natural products and synthetic drug molecules, attracting a lot of attention from chemical workers and medicinal and chemical teams. (2) The cyclopentanochromenone backbone is also ubiquitous in natural products and drug molecules. For example, the natural product molecules Cryptosporioptide, Preussochloromones D, pseudobicuceol-I and Diaportenone B share a cyclopentanochromanone molecular unit, and the compounds play an important role in pain relief and economic development. The spiro five-membered carbocyclic oxoindole skeleton and the cyclopentanochromanone skeleton have potential biological activity. Therefore, the spiro pentabasic carbocyclic oxindole skeleton is spliced to the cyclopentano-chromanone skeleton to synthesize a series of novel potential multi-active functional group cyclopentano-chromanone spliced spiro oxindole compounds, which can provide a compound source for biological activity screening and have important application value for drug screening and pharmaceutical industry (as shown in figure 8).
Disclosure of Invention
The purpose of the invention is: the cyclopentane chromanone spliced spiro oxoindole 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 cyclopentane chromanone spliced spiro oxoindole compound has a structure shown in the following general formula (I):
Figure BDA0002165995320000021
in the formula, R1Is methyl or chlorine or hydrogen; r2Is methyl or fluorine or chlorine or hydrogen;ar is fluorine or chlorine or bromine or methyl or methoxy or a hydrogen substituted benzene ring.
A preparation method of a cyclopentano-chromanone spliced spiro-oxoindole compound comprises the step of carrying out Michael/Michael cycloaddition reaction on various substituted bifunctional oxoindole-chromone 3C synthons 1 and various substituted nitrostyrenes 2 in an organic solvent under the action of an organic micromolecule basic catalyst to obtain the cyclopentano-chromanone spliced spiro-oxoindole compound 3.
The synthetic route is exemplified as follows:
Figure BDA0002165995320000022
wherein the substituents of the compounds in the synthetic route satisfy the formula R1Is methyl or chlorine or hydrogen; r2Is methyl or fluoro or chloro or hydrogen; ar is fluorine or chlorine or bromine or methyl or methoxy or a hydrogen substituted benzene ring.
The reaction mechanism is as follows:
Figure BDA0002165995320000023
the organic solvent is acetonitrile, toluene, dichloromethane or chloroform.
The organic micromolecule basic catalyst is chiral thiourea or aromatic amide catalyst derived from 1, 2-diphenyldiamine, chiral thiourea or aromatic amide catalyst derived from cyclohexyldiamine, cinchona alkaloid or chiral thiourea or aromatic amide catalyst derived from cinchona alkaloid.
The organic small molecule basic catalyst is partially exemplified as follows (although it is emphasized that the organic small molecule basic catalyst of the present invention is not limited to the following representation):
Figure BDA0002165995320000031
the reaction temperature of various substituted bifunctional oxoindole-chromone synthons and various substituted nitrostyrenes in an organic solvent is between 10 ℃ below zero and 40 ℃, and the reaction time is between 2 and 10 days.
Application of cyclopentano-chromanone spliced spiro oxoindole compounds in preparing medicaments for preventing and treating tumor diseases.
By adopting the technical scheme, various substituted bifunctional oxoindole-chromone 3C synthons 1 and various substituted nitrostyrenes 2 are subjected to Michael/Michael cycloaddition reaction in an organic solvent under the action of an organic small-molecule basic catalyst to obtain the cyclopentanoperchromanone spliced spiro oxoindole compound 3, and the compound contains a potential bioactive cyclopentanoperchromanone skeleton and a spiro oxoindole compound 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 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;
FIG. 3 is liquid phase chromatogram data for Compound 3 a;
FIGS. 4 and 5 are spectra data of compound 3b according to the example of the present invention;
FIG. 6 is liquid phase chromatogram data for Compound 3 b;
FIG. 7 is a 3h single crystal diagram of a compound of an embodiment of the present invention;
FIG. 8 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: bifunctional oxoindole-chromone 3C synthon 1a (0.10mmol), nitrostyrene 2a (0.15mmol), chiral thiourea catalyst C2(20 mol%, 0.02mmol) and 1.0mL of diethyl ether are added in sequence into a reaction tube, after stirring reaction for 5 days at room temperature, TLC detection is carried out to complete the reaction, and the mixture is directly loaded to column chromatography [ eluent: v (petroleum ether): v (Ethyl acetate))＝6:1]Purification gave compound 3a, white solid, melting point: 106.9-107.5 ℃; the yield is 74%;>99％ee,>20:1dr,[α]D 20＝+61.69(c 0.24,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IA column(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝45.38min；τminor13.67 min). The results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.36(s,9H),3.89(d,J＝11.2Hz,1H),3.95(d,J＝12.4Hz,1H),5.78-5.82(m,1H),6.31-6.36(m,1H),6.81(d,J＝7.6Hz,2H),6.96-7.06(m,4H),7.10-7.12(m,1H),7.24-7.27(m,2H),7.42-7.44(m,1H),7.46-7.50(m,1H),7.53-7.55(m,1H),7.62-7.64(m,1H)；13C NMR(CDCl3,100MHz)δ:27.8,52.1,56.9,63.5,79.5,84.2,91.3,115.5,118.3,120.8,121.7,122.4,125.0,126.8,127.6,128.5,128.9,129.3,129.6,136.9,140.1,147.9,159.2,174.4,188.8；HRMS(ESI-TOF)m/z:Calcd.for C30H26N2NaO7[M+Na]+:549.1632；Found:549.1637.
table 1 shows the chemical structure of cyclopentano-chromanone spliced spiro-oxoindole compound
Figure BDA0002165995320000051
Table 2 shows the chemical structure of cyclopentano-chromanone spliced spiro-oxoindole compound
Figure BDA0002165995320000061
The process for producing the compounds 3b to 3v using the compound 3a in the same charge ratio as the compound 3a gave the compounds 3b to 3v with the reaction yields and dr values and ee 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.
This example prepares compound 3b as a white solid, melting point: 135.5-136.3 ℃; the yield is 83%;>99％ee,>20:1dr,[α]D 20＝+105.14(c 0.14,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IA column(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝34.21min；τminor11.66 min); the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:1.36(s,9H),2.12(s,3H),3.86-3.93(m,2H),5.76-5.79(m,1H),6.28-6.31(m,1H),6.68(d,J＝8.0Hz,2H),6.84(d,J＝7.5Hz,1H),6.95-7.01(m,2H),7.23-7.25(m,2H),7.40-7.42(m,1H),7.45-7.48(m,1H),7.55(d,J＝7.0Hz,1H),7.62(d,J＝6.3Hz,1H)；13C NMR(CDCl3,125MHz)δ:21.0,27.8,52.1,56.7,63.6,79.5,84.2,91.4,115.5,118.3,120.8,121.7,122.4,125.1,126.2,126.9,127.5,129.2,129.6,136.9,138.7,140.2,148.0,159.2,174.6,188.9；HRMS(ESI-TOF)m/z:Calcd.for C31H28N2NaO7[M+Na]+:563.1789；Found:563.1793.
this example prepares compound 3c as a white solid, melting point: 112.8 to 113.2 ℃; the yield is 60%;>99％ee,>20:1dr,[α]D 20＝+105.57(c 1.10,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IA column(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝30.22min；τminor11.28 min); the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.41(s,9H),1.77(s,3H),3.91(d,J＝11.2Hz,1H),4.45(d,J＝12.0Hz,1H),5.72-5.77(m,1H),6.17-6.21(m,1H),6.82(d,J＝6.8Hz,1H),6.97-7.03(m,4H),7.15-7.17(m,1H),7.20-7.24(m,1H),7.40-7.50(m,3H),7.55(d,J＝7.6Hz,1H),7.62-7.64(m,1H)；13C NMR(CDCl3,100MHz)δ:16.7,25.5,49.1,49.9,61.1,77.0,81.9,90.9,113.1,115.9,119.9,120.0,122.1,123.9,124.3,124.4,124.5,125.8,126.1,127.2,128.5,134.5,135.3,145.6,156.9,172.6,186.5；HRMS(ESI-TOF)m/z:Calcd.for C31H28N2NaO7[M+Na]+:563.1789；Found:563.1792.
this example prepares Compound 3d as a white solidMelting point: 107.5-108.2 ℃; the yield is 87%;>99％ee,14:1dr,[α]D 20＝+139.84(c 0.13,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IA column(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝42.92min；τminor13.80 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:1.37(s,9H),3.60(s,3H),3.86-3.91(m,2H),5.75-5.79(m,1H),6.24-6.28(m,1H),6.55(d,J＝9.0Hz,2H),6.73(d,J＝8.5Hz,2H),6.95-7.00(m,2H),7.22-7.23(m,2H),7.40(d,J＝5.5Hz,1H),7.45-7.48(m,1H),7.53(d,J＝7.0Hz,1H),7.62(d,J＝6.5Hz,1H)；13C NMR(CDCl3,125MHz)δ:27.9,52.0,55.1,56.4,63.5,79.5,84.2,91.6,113.9,115.5,118.3,120.8,121.1,121.7,122.4,125.0,126.8,127.5,128.9,129.5,136.9,140.1,147.9,159.2,159.9,174.7,188.9；HRMS(ESI-TOF)m/z:Calcd.for C31H28N2NaO8[M+Na]+:579.1738；Found:579.1734.
this example prepares compound 3e as a white solid, melting point: 197.8 to 198.1 ℃; the yield is 63%;>99％ee,>20:1dr,[α]D 20＝+85.50(c 0.73,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IA column(80/20hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝46.34min；τminor9.00 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.35(s,9H),3.47(s,3H),3.86-3.94(m,2H),5.73-5.77(m,1H),6.27-6.31(m,2H),6.40(d,J＝7.6Hz,1H),6.63(d,J＝7.6Hz,1H),6.92-7.01(m,3H),7.18-7.23(m,2H),7.41-7.47(m,2H),7.54(d,J＝6.8Hz,1H),7.61(d,J＝8.0Hz,1H)；13C NMR(CDCl3,100MHz)δ:26.8,51.0,54.0,55.7,62.5,78.5,83.3,90.3,111.4,114.2,114.5,117.3,118.8,120.7,121.4,124.0,125.8,126.5,128.5,129.8,135.9,139.2,146.9,158.2,158.4,173.5,187.9；HRMS(ESI-TOF)m/z:Calcd.for C31H28N2NaO8[M+Na]+:579.1738；Found:579.1744.
this example prepared compound 3f as a white solid, melting point: 92.5-93.0 ℃; the yield is 55%;>99％ee,>20:1dr,[α]D 20＝+61.00(c 0.14,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IA column(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝33.39min；τminor13.37 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:1.39(s,9H),3.87-3.91(m,2H),5.77-5.81(m,1H),6.25-6.29(m,1H),6.68(d,J＝8.5Hz,2H),6.98-7.02(m,2H),7.16-7.19(m,2H),7.25-7.28(m,2H),7.41(d,J＝5.0Hz,1H),7.46-7.49(m,1H),7.56(d,J＝7.5Hz,1H),7.63(d,J＝6.5Hz,1H)；13C NMR(CDCl3,125MHz)δ:27.9,52.1,56.2,63.4,79.4,84.6,91.1,115.6,118.4,120.7,121.7,122.5,123.3,125.2,126.9,127.1,128.5,129.3,129.9,131.7,137.1,140.1,147.8,159.1,174.4,188.6；HRMS(ESI-TOF)m/z:Calcd.forC30H25ClN2NaO7[M+Na]+:583.1242；Found:583.1245.
this example prepares compound 3g, white solid, melting point: 118.1-119.0 ℃; the yield is 63%;>99％ee,>20:1dr,[α]D 20＝+218.40(c 0.05,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝35.55min；τminor10.72 min); the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:1.38(s,9H),3.87-3.94(m,2H),5.77-5.80(m,1H),6.25-6.29(m,1H),6.72-6.76(m,2H),6.78-6.80(m,1H),6.96-7.01(m,2H),7.24-7.28(m,2H),7.41(d,J＝6.5Hz,1H),7.46-7.49(m,1H),7.54(d,J＝7.5Hz,1H),7.62(d,J＝7.5Hz,1H)；13C NMR(CDCl3,125MHz)δ:27.9,52.0,56.2,63.5,79.4,84.5,91.4,115.5,115.6(d,JCF＝21.3Hz),118.3,121.7,122.5,125.2,126.9,127.2,129.5(d,JCF＝7.2Hz),129.8,137.0,140.1,147.8,159.2,162.9(d,JCF＝246.3Hz),174.5,188.7；HRMS(ESI-TOF)m/z:Calcd.for C30H25FN2NaO7[M+Na]+:567.1538；Found:567.1542.
this example prepares compound 3h as a white solid, melting point: 95.5-96.2 ℃; the yield is 55%;>99％ee,20:1dr,[α]D 20＝+99.26(c 0.14,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(90/10hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝37.42min；τminor17.34 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.42(s,9H),2.27(s,3H),3.92(d,J＝11.6Hz,1H),4.00(d,J＝12.4Hz,1H),5.78-5.83(m,1H),6.34-6.39(m,1H),6.85-6.87(m,1H),6.97(d,J＝8.4Hz,1H),7.07-7.11(m,2H),7.15-7.19(m,1H),7.29-7.32(m,1H),7.33-7.36(m,2H),7.46-7.49(m,2H),7.58-7.61(m,1H)；13C NMR(CDCl3,100MHz)δ:20.5,28.0,52.2,56.9,63.5,79.6,84.3,91.2,115.5,118.2,120.6,121.8,125.2,126.5,127.6,127.7,128.6,129.0,129.5,129.7,132.1,138.1,140.2,148.0,157.3,174.5,189.2；HRMS(ESI-TOF)m/z:Calcd.for C31H28N2NaO7[M+Na]+:563.1789；Found:563.1793.
this example prepares compound 3i as a white solid, melting point: 128.7-129.3 ℃; the yield is 67%;>99％ee,15:1dr,[α]D 20＝+93.18(c 0.09,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝35.57min；τminor13.69 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.35(s,9H),3.58(s,3H),3.81(d,J＝11.2Hz,1H),3.86(d,J＝12.4Hz,1H),5.72-5.76(m,1H),6.19-6.24(m,1H),6.53(d,J＝8.8Hz,1H),6.70(d,J＝8.8Hz,1H),6.96-6.99(m,1H),7.17-7.18(m,1H),7.21-7.26(m,3H),7.36-7.39(m,1H),7.50-7.53(m,1H)；13C NMR(CDCl3,100MHz)δ:27.8,51.7,55.1,56.5,63.6,79.6,84.3,91.4,110.0,111.7,112.0,113.9,115.5,120.0,120.9,121.6,124.3,125.1,127.2,128.8,129.6,140.0,147.7,149.4,155.2,158.7,159.9,161.9,166.2,174.3；HRMS(ESI-TOF)m/z:Calcd.for C31H27FN2NaO8[M+Na]+:597.1644；Found:597.1647.
this example prepares compound 3j as a white solid, melting point: 108.8 to 109.2 ℃; the yield is 81%;>99％ee,7:1dr,[α]D 20＝+42.36(c 0.29,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝19.29min；τminor9.44 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,500MHz)δ:1.48(s,9H),3.96(d,J＝9.5Hz,1H),4.02(d,J＝10.5Hz,1H),5.86-5.89(m,1H),6.33-6.36(m,1H),6.83-6.90(m,4H),7.09-7.12(m,1H),7.29-7.32(m,1H),7.35-7.39(m,3H),7.51-7.52(m,1H),7.64-7.65(m,1H)；13C NMR(CDCl3,125MHz)δ:27.9,51.7,56.3,63.6,79.6,84.7,91.2,112.0(d,JCF＝20.0Hz),115.6,115.7,118.9(d,JCF＝16.3Hz),120.2,121.7,123.5,124.4,124.5(d,JCF＝20.3Hz),125.3,129.5,129.9,139.0,140.1,145.5,147.7,155.3,157.4(d,JCF＝202.3Hz),163.5(d,JCF＝236.3Hz),174.4,188.2；HRMS(ESI-TOF)m/z:Calcd.for C30H24F2N2NaO7[M+Na]+:585.1444；Found:585.1449.
this example prepares compound 3k as a white solid, melting point: 75.2-76.1 ℃; the yield is 50%;>99％ee,10:1dr,[α]D 20＝+67.04(c 0.18,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝26.37min；τminor11.69 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.37(s,9H),3.87(d,J＝11.6Hz,1H),3.94(d,J＝12.4Hz,1H),5.77-5.82(m,1H),6.28-6.33(m,1H),6.80(d,J＝7.2Hz,2H),6.99(d,J＝9.2Hz,1H),7.03-7.06(m,2H),7.10-7.14(m,1H),7.25-7.27(m,2H),7.41-7.44(m,2H),7.52-7.55(m,1H),7.59(d,J＝2.8Hz,1H)；13C NMR(CDCl3,100MHz)δ:26.8,50.6,55.9,62.8,78.8,83.4,90.2,114.5,119.1,120.3,120.7,124.1,125.2,126.1,126.6,126.9,127.5,128.0,128.1,128.8,128.1,128.8,135.8,139.1,146.8,156.6,173.4,186.8；HRMS(ESI-TOF)m/z:Calcd.for C30H25ClN2NaO7[M+Na]+:583.1242；Found:583.1247.
this example prepares compound 3l as a white solid, melting point: 88.7-89.2 ℃; the yield is 62%; the content of the solid is 96% ee,>20:1dr,[α]D 20＝+44.14(c 0.26,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝46.85min；τminor15.04 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.34(s,9H),2.34(s,3H),3.58(s,3H),3.81-3.87(m,2H),5.72-5.77(m,1H),6.21-6.26(m,1H),6.54(d,J＝8.8Hz,2H),6.72(d,J＝8.8Hz,2H),6.92-7.03(m,3H),7.18(s,1H),7.38(d,J＝8.4Hz,1H),7.42-7.46(m,1H),7.58-7.61(m,1H)；13C NMR(CDCl3,100MHz)δ:19.9,26.6,50.7,53.8,55.1,62.3,78.2,82.7,90.3,112.6,114.0,117.0,119.5,119.9,120.9,121.0,125.5,126.1,127.5,128.8,133.4,135.6,136.5,144.7,157.9,158.5,173.5,187.7；HRMS(ESI-TOF)m/z:Calcd.forC32H30N2NaO8[M+Na]+:593.1894；Found:593.1897.
this example prepares compound 3m as a white solid, melting point: 86.7-87.2 ℃; the yield is 53 percent;>99％ee,>20:1dr,[α]D 20＝+23.22(c 0.80,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(80/20hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝43.15min；τminor9.62 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.35(s,9H),2.36(s,3H),3.50(s,3H),3.85-3.93(m,2H),5.74-5.78(m,1H),6.26-6.32(m,2H),6.39(d,J＝7.6Hz,1H),6.63-6.65(m,1H),6.92-7.05(m,4H),7.22(s,1H),7.42(d,J＝8.0Hz,1H),7.44-7.49(m,1H),7.61-7.63(m,1H)；13C NMR(CDCl3,100MHz)δ:20.2,26.8,51.0,54.0,55.8,62.6,78.6,83.1,90.4,111.5,114.1,114.3,117.3,118.9,119.8,121.2,121.4,125.8,126.4,128.5,126.4,128.5,129.1,129.9,133.8,135.9,147.0,158.2,158.4,173.6,187.9；HRMS(ESI-TOF)m/z:Calcd.for C32H30N2NaO8[M+Na]+:593.1894；Found:593.1900.
this example prepares compound 3n as a white solid, melting point: 97.5-98.3 ℃; the yield is 48 percent; the content of the solid is 96% ee,>20:1dr,[α]D 20＝+175.00(c 0.07,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝39.38min；τminor10.69 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.43(s,9H),2.43(s,3H),3.91-3.97(m,2H),5.82-5.86(m,1H),6.30-6.34(m,1H),6.81(d,J＝8.4Hz,2H),7.02-7.14(m,5H),7.27(s,1H),7.48(d,J＝8.4Hz,1H),7.52-7.56(m,1H),7.67-7.70(m,1H)；13C NMR(CDCl3,100MHz)δ:21.4,27.9,52.0,56.2,63.6,79.5,84.5,91.2,115.5,118.4,120.8,122.3,122.6,127.0,127.1,128.1,128.8,129.1,130.5,135.1,137.1,137.8,147.9,159.2,174.6,188.8；HRMS(ESI-TOF)m/z:Calcd.for C31H27ClN2NaO7[M+Na]+:597.1399；Found:597.14002.
this example prepares compound 3o a white solid, melting point: 140.1-141.0 ℃; the yield is 52%;>99％ee,18:1dr,[α]D 20＝+214.58(c 0.05,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝40.04min；τminor10.70 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.43(s,9H),2.44(s,3H),3.91-3.96(m,2H),5.82-5.86(m,1H),6.29-6.34(m,1H),6.74-6.76(m,2H),7.02-7.07(m,2H),7.12-7.14(m,1H),7.23-7.25(m,1H),7.26-7.27(m,2H),7.36-7.41(m,1H),7.48(d,J＝8.4Hz,1H),7.52-7.58(m,2H),7.67-7.70(m,1H)；13C NMR(CDCl3,100MHz)δ:21.4,28.0,52.0,56.3,63.6,79.5,84.5,91.2,100.0,115.5,118.4,122.3,122.6,123.3,127.0,127.1,128.7,129.4,130.5,131.8,135.1,137.1,147.9,159.2,174.6,188.8；HRMS(ESI-TOF)m/z:Calcd.for C31H27BrN2NaO7[M+Na]+:641.0894；Found:641.0894.
this example prepares compound 3p as a white solid, melting point: 163.7-164.1 ℃; the yield is 54%;>99％ee,>20:1dr,[α]D 20＝+42.84(c 0.93,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝67.24min；τminor11.51 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.38(s,9H),2.37(s,3H),3.85-3.91(m,2H),5.73-5.77(m,1H),6.22-6.26(m,1H),6.69(d,J＝8.0Hz,1H),6.89-6.93(m,1H),6.96-7.01(m,3H),7.06(d,J＝8.4Hz,1H),7.19-7.21(m,1H),7.24-7.26(m,1H),7.45-7.50(m,2H),7.61-7.63(m,1H)；13C NMR(CDCl3,100MHz)δ:20.3,26.8,51.0,55.2,62.5,78.4,83.4,90.1,114.4,117.3,121.1,121.5,125.6,125.8,125.9,129.0,129.4,131.0,131.1,134.0,136.0,136.7,146.9,158.1,173.3,187.7；HRMS(ESI-TOF)m/z:Calcd.forC31H27BrN2NaO7[M+Na]+:641.0894；Found:641.0898.
this example prepares compound 3q as a white solid, melting point: 113.4-113.6 ℃; the yield is 74%;>99％ee,>20:1dr,[α]D 20＝+68.94(c 0.60,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(85/15hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝66.07min；τminor13.30 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.36(s,9H),3.85(d,J＝11.2Hz,1H),3.92(d,J＝12.0Hz,1H),5.75-5.79(m,1H),6.28-6.32(m,1H),6.83(d,J＝7.2Hz,2H),6.96-7.02(m,2H),7.06-7.09(m,2H),7.12-7.16(m,1H),7.21-7.24(m,1H),7.35(d,J＝8.0Hz,1H),7.46-7.50(m,1H),7.60-7.63(m,2H)；13C NMR(CDCl3,100MHz)δ:25.7,50.1,54.7,61.1,77.3,82.7,89.2,114.1,116.3,118.6,120.4,120.6,123.1,123.8,124.8,125.5,126.6,127.0,133.2,135.0,138.8,145.5,157.1,171.9,186.6；HRMS(ESI-TOF)m/z:Calcd.for C30H25ClN2NaO7[M+Na]+:583.1242；Found:583.1247.
this example prepares compound 3r as a white solid, melting point: 119.2-119.0 ℃; the yield is 76%;>99％ee,>20:1dr,[α]D 20＝+70.85(c 0.67,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(80/20hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝39.03min；τminor9.65 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.36(s,9H),2.14(s,3H),3.83(d,J＝11.2Hz,1H),3.88(d,J＝12.4Hz,1H),5.73-5.78(m,1H),6.24-6.29(m,1H),6.71(d,J＝7.6Hz,2H),6.87(d,J＝7.6Hz,2H),6.95-7.01(m,2H),7.18-7.22(m,1H),7.33(d,J＝8.0Hz,1H),7.45-7.49(m,1H),7.61(d,J＝10.0Hz,2H)；13C NMR(CDCl3,100MHz)δ:20.0,26.8,51.2,55.5,62.2,78.4,83.7,90.4,115.2,117.3,119.7,121.5,121.7,124.1,125.0,125.8,126.5,128.4,134.2,136.0,137.9,139.9,146.7,158.2,173.1,187.8；HRMS(ESI-TOF)m/z:Calcd.for C31H27ClN2NaO7[M+Na]+:597.1399；Found:597.14003.
this example prepares compound 3s as a white solid, melting point: 96.7-97.2 ℃; the yield is 51%;>99％ee,>20:1dr,[α]D 20＝+97.86(c 0.65,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(80/20hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝34.11min；τminor8.44 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.41(s,9H),1.83(s,3H),3.88(d,J＝11.6Hz,1H),4.43(d,J＝12.4Hz,1H),5.70-5.75(m,1H),6.14-6.19(m,1H),6.86-6.88(m,1H),6.97-7.04(m,4H),7.15-7.18(m,1H),7.35-7.40(m,2H),7.46-7.51(m,1H),7.61-7.64(m,2H)；13C NMR(CDCl3,100MHz)δ:18.5,26.9,50.4,51.5,62.2,78.3,83.9,92.3,115.3,117.4,121.5,122.2,123.7,125.4,125.6,125.8,127.0,127.7,130.1,134.4,136.0,136.6,146.8,158.4,173.6,187.8；HRMS(ESI-TOF)m/z:Calcd.for C31H27ClN2NaO7[M+Na]+:597.1399；Found:597.14005.
this example prepares compound 3t as a white solid, melting point: 97.3-98.0 ℃; the yield is 70%;>99％ee,>20:1dr,[α]D 20＝+74.25(c 0.66,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(80/20hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝51.80min；τminor12.33 min); the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.47(s,9H),3.71(s,3H),3.91-3.98(m,2H),5.83-5.87(m,1H),6.31-6.35(m,1H),6.68(d,J＝8.4Hz,2H),6.85(d,J＝8.4Hz,2H),7.05-7.10(m,2H),7.28-7.31(m,1H),7.42(d,J＝8.0Hz,1H),7.55-7.58(m,1H),7.71(d,J＝9.2Hz,2H)；13C NMR(CDCl3,100MHz)δ:26.8,51.2,54.1,55.3,62.2,78.3,83.8,90.6,113.1,115.2,117.3,119.7,119.8,121.5,121.6,124.1,125.0,125.8,127.8,134.2,136.0,139.9,146.7,158.2,159.0,173.2,187.8；HRMS(ESI-TOF)m/z:Calcd.forC31H27ClN2NaO8[M+Na]+:613.1348；Found:613.1352.
this example prepares compound 3u as a white solid, melting point: 105.8-106.1 ℃; the yield is 54%;>99％ee,>20:1dr,[α]D 20＝+63.51(c 0.60,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(80/20hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝61.62min；τminor12.75 min); the results of nuclear magnetic resonance and high-resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.37(s,9H),3.53(s,3H),3.83-3.91(m,2H),5.73-5.78(m,1H),6.25-6.29(m,1H),6.35(s,1H),6.39(d,J＝7.6Hz,1H),6.66-6.68(m,1H),6.95-7.02(m,3H),7.21-7.23(m,1H),7.33(d,J＝8.0Hz,1H),7.45-7.50(m,1H),7.60-7.65(m,2H)；13C NMR(CDCl3,100MHz)δ:26.8,51.2,54.0,55.7,62.2,78.4,83.9,90.4,111.7,114.1,115.3,117.4,118.9,119.7,121.5,121.6,124.1,124.9,125.8,128.7,129.5,134.3,136.1,140.1,146.7,158.2,158.5,173.0,187.7；HRMS(ESI-TOF)m/z:Calcd.forC31H27ClN2NaO8[M+Na]+:613.1348；Found:613.1345.
this example prepares compound 3v: white solid, melting point: 205.6-206.2 ℃; the yield is 49%;>99％ee,>20:1dr,[α]D 20＝+90.84(c 0.83,CH2Cl2)；The ee was determined by HPLC analysis using a Chiralpak IAcolumn(80/20hexane/i-PrOH；flow rate:1.0mL/min；λ＝254nm；τmajor＝41.55min；τminor9.39 min); the results of nuclear magnetic resonance and high resolution mass spectrometry are as follows:1H NMR(CDCl3,400MHz)δ:1.38(s,9H),3.84(d,J＝11.2Hz,1H),3.90(d,J＝12.4Hz,1H),5.74-5.79(m,1H),6.21-6.26(m,1H),6.75-6.84(m,4H),6.96-7.01(m,2H),7.21-7.24(m,1H),7.34(d,J＝8.0Hz,1H),7.46-7.50(m,1H),7.60-7.63(m,2H)；13C NMR(CDCl3,100MHz)δ:26.8,51.2,55.0,62.1,78.2,84.1,90.4,114.8(d,JCF＝22.3Hz),115.3,117.3,119.7,121.6(d,JCF＝11.0Hz),124.0,124.3,124.6,125.8,128.4,128.5,134.5,136.1,139.9,146.5,158.2,162.5(d,JCF＝248.0Hz),173.0,187.6；HRMS(ESI-TOF)m/z:Calcd.for C30H24ClFN2NaO7[M+Na]+:601.1148；Found:601.1149.
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 cyclopentane chromanone spliced spiro oxindole 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 by human leukemia cells (K562).
Pharmacological examples: cytotoxicity of Compounds de-Boc 3j, de-Boc 3v, de-Boc 3p and de-Boc 3r 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 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, a solution of the newly formulated compounds de-Boc 3j, de-Boc 3v, de-Boc 3p and de-Boc 3r in dimethylsulfoxide was added to each well in a concentration gradient such that the final concentration of the 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 de-Boc 3j, de-Boc 3v, de-Boc 3p and de-Boc 3r have half inhibitory concentration IC on K562 cells50Analyzed by the sps software (version 19). IC of compound de-Boc 3j on K562 tumor cells5032.1 mu mol/L; IC of compound de-Boc 3v against K562 tumor cells5037.7 mu mol/L; IC of compound de-Boc 3p on K562 tumor cells5040.8 mu mol/L; IC of compound de-Boc 3r on K562 tumor cells5036.1 mu mol/L; IC of positive control cisplatin on K562 tumor cells50It was 23.2. 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 cyclopentane chromanone spliced spiro oxindole compound shown in the formula (1) has strong 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 cyclopentane chromanone spliced spiro-oxoindole compound is characterized in that: the compound has a structure shown as a general formula (I):
Figure FDA0003482941870000011
in the formula, R1Is methyl or chlorine or hydrogen; r is2Is methyl, fluoro, chloro or hydrogen; ar is fluorine, chlorine, bromine, methyl, methoxy or hydrogen substituted benzene ring.
2. A preparation method of the cyclopentanochromanone spliced spiro-oxoindole compound as claimed in claim 1, wherein the synthetic route is as follows:
Figure FDA0003482941870000012
in the formula, R1Is methyl or chlorine or hydrogen; r2Is methyl, fluoro, chloro or hydrogen; ar is fluorine, chlorine, bromine, methyl, methoxy or hydrogen substituted benzene ring.
3. The application of the cyclopentanochromanone spliced spiro oxindole compound as claimed in claim 1 in preparing a medicament for preventing and treating leukemia.
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