CN113307815B - Trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compound and preparation method and application thereof - Google Patents

Trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compound and preparation method and application thereof Download PDF

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CN113307815B
CN113307815B CN202110647863.8A CN202110647863A CN113307815B CN 113307815 B CN113307815 B CN 113307815B CN 202110647863 A CN202110647863 A CN 202110647863A CN 113307815 B CN113307815 B CN 113307815B
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张敏
卢玉
刘雄利
田民义
王慧娟
周英
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Abstract

The invention discloses a trifluoromethyl spliced double-spiro-chromanone skeleton pyrrole oxindole compound, which is prepared by reacting raw materials in an organic solvent under the catalysis of an organic small molecule tertiary amine catalyst, wherein the trifluoromethyl spliced double-spiro-chromanone skeleton pyrrole oxindole compound 3 comprises a potential biological activity spiro-chromanone skeleton, a spiro-pyrrole oxindole skeleton and a trifluoromethyl group, can provide a compound source for biological activity screening, and has important application value for the screening and pharmaceutical industry of medicines. And the skeleton compound has an inhibitory activity on human leukemia cells (K562). The invention has simple and easy operation, cheap and easily obtained raw material synthesis, can be carried out in various organic solvents, has better air stability and wide applicability, and has good compatibility for various substituents.

Description

Trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of chemistry and pharmacy, in particular to a trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compound, a preparation method and application thereof.
Background
According to the active skeleton splicing principle of drug design, splicing two or more bioactive skeletons into a multi-skeleton molecule with potential bioactivity is an extremely important research field in organic chemistry and medicinal chemistry. (1) Chromanone backbones are also prevalent in natural products and drug molecules. For example, the natural product molecules elaeocarpine, tephrosin and 12 a-hydroxy-a-topicarol share a chromanone backbone unit, which compounds play a major role in the relief of pain, economic development. (2) The widespread presence of pyrrole spiro oxindoles in natural product and synthetic drug molecules has attracted a great deal of attention from many chemists and pharmaceutical chemistry teams, for example, the natural product active small molecule pyrrole spiro oxindoles pteropodine and alstonine exhibit significant biological activity. In addition, trifluoromethyl is also an important pharmacophore group, and the introduction of trifluoromethyl into one molecule tends to significantly alter the biological properties of the molecule (J.Med.Chem.2008, 51,4359;Chem.Soc.Rev.2008,37,320;J.Med.Chem.2015,58,8315). In view of the potential biological activity of spiro chromanone and spiro pyrrole oxindole backbones and trifluoromethyl. Therefore, the trifluoromethyl group and the spiro-chromanone skeleton are spliced to the spiro-pyrrole oxindole skeleton to synthesize a series of new trifluoromethyl spliced double-spiro-chromanone skeleton pyrrole oxindole compounds with potential multi-active functional groups, which can provide compound sources for biological activity screening and has important application value for the drug screening and pharmaceutical industry (shown in figure 8).
Disclosure of Invention
The purpose of the invention is that: provides trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compounds, and a preparation method and application thereof, which are important medical intermediate analogues and medical molecule analogues, have important application values for the medicine screening and pharmaceutical industry, and the synthesis method is very economic and simple.
The invention also discovers the application of the compounds in preparing medicines for preventing and treating tumor K562 (human chronic myelogenous leukemia) cells.
The invention is realized in the following way: trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compound has the structure shown in the following general formula (I):
wherein R is 1 Methyl, ethyl, or benzyl; r is R 2 Fluorine, methoxy, methyl or hydrogen; r is R 3 Fluorine, chlorine, methyl or hydrogen; ar is methoxy, methyl, fluorine or hydrogen substituted benzene ring.
The preparation method of the trifluoromethyl spliced double-spiro-chromanone framework pyrrole oxindole compound comprises the steps of taking various substituted 3-trifluoromethyl methylene imine substituted oxindole 1 as a 1, 3-dipole and various substituted 3-alkene chromone 2, and carrying out [3+2] cycloaddition reaction in an organic solvent under the catalysis of an organic small molecule tertiary amine catalyst to obtain the trifluoromethyl spliced double-spiro-chromanone framework pyrrole oxindole compound 3.
The synthetic route is exemplified as follows:
wherein the substituents of the compounds in the synthetic route satisfy the formula, R 1 Methyl, ethyl, or benzyl; r is R 2 Fluorine, methoxy, methyl or hydrogen; r is R 3 Fluorine, chlorine, methyl or hydrogen; ar is methoxy, methyl, fluorine or hydrogen substituted benzene ring.
The reaction mechanism is as follows:
the organic solvent is methanol, toluene, ethyl acetate, methylene dichloride, chloroform or acetonitrile.
The organic small molecule tertiary amine catalyst is a DABCO or triethylamine or DBU or DMAP or cinchona alkaloid derived alkaline catalyst or a cyclohexyl diamine derived catalyst.
Examples of cinchona-derived basic catalysts or cyclohexyldiamine-derived catalysts are the following:
the reaction temperature in the organic solvent is room temperature, and the reaction time is 1-2 days, with various substituted 3-trifluoromethyl methylene imine substituted oxindole 1 as 1, 3-dipole and various substituted 3-alkene chromone 2.
The application of trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compounds in preparing medicaments for preventing and treating tumor K562 (human chronic myelogenous leukemia) cells.
By adopting the technical scheme, various substituted 3-trifluoromethyl methylene imine substituted oxindole 1 is used as a 1, 3-dipole, and various substituted 3-alkene chromone 2 are subjected to [3+2] cycloaddition reaction in an organic solvent under the catalysis of an organic small molecule tertiary amine catalyst, so that trifluoromethyl spliced double-spiro-chromane skeleton pyrrole oxindole compound 3 is obtained, the compound contains a potential biological activity spiro-chromane skeleton, a spiro-pyrrole oxindole skeleton and a trifluoromethyl group, a compound source can be provided for biological activity screening, and the compound has important application value for the medicine screening and pharmaceutical industry. And the skeleton compound has an inhibitory activity on human leukemia cells (K562). The invention has simple and easy operation, cheap and easily obtained raw material synthesis, can be carried out in various organic solvents, has better air stability and wide applicability, and has good compatibility for various substituents.
Drawings
FIGS. 1-3 are data of compound 3a spectra of examples of the present invention;
FIGS. 4-6 are data of compound 3b spectra of examples of the present invention;
FIG. 7 is a single crystal plot of compounds 3e and 3v of the examples of the present invention;
FIG. 8 shows the design concept and the inventive concept of the synthesized compounds of the present invention.
Detailed Description
Embodiments of the invention: 3-trifluoromethyl methylene imine substituted oxindole 1a (0.30 mmol), 3-alkene chromone 2a (0.20 mmol), small molecule catalyst DABCO (0.2 eq,0.04 mmol) and 1.5mL DCM are sequentially added into a reaction tube, stirring reaction is carried out at room temperature for 30h, TLC detection is basically complete, and the compound 3a is directly obtained by column chromatography (eluent: V (petroleum ether): V (ethyl acetate) =5:1) purification, white solid, melting point: 181.0-182.1 deg.C, yield 87%,18:1dr. Nuclear magnetic resonance and high resolutionThe results of the spectrum test and the like are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.58(br s,1H),3.16(s,3H),3.46(d,J＝12.4Hz,1H),4.76(d,J＝12.4Hz,1H),5.04(d,J＝10.4Hz,1H),5.12-5.15(m,1H),6.47-6.53(m,2H),6.73-6.77(m,2H),6.99-7.03(m,2H),7.15-7.19(m,1H),7.27-7.30(m,1H),7.33-7.37(m,2H),7.49-7.51(m,2H),7.57-7.59(m,1H)； 13 C NMR(CDCl 3 ,100MHz)δ:26.2,46.7,59.8,61.9(q,J C,F ＝31.1Hz),70.1,71.5,107.6,116.4,121.2,122.5,124.2(q,J C,F ＝271.0Hz),126.2,127.9,128.0,128.7,129.6,135.4,143.2,160.8,178.2,190.6； 19 F NMR(CDCl 3 ,375MHz)δ:-74.3；HRMS(ESI-TOF)m/z:Calcd.for C 27 H 21 F 3 N 2 NaO 3 [M+Na] + :501.1396；Found:501.1392.
the compounds 3b to 3x were prepared by the same method as the compound 3a in the same feed ratio as the compound 3a, and the compounds 3b to 3x were obtained 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 trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compound
Table 2 shows the chemical structure of trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compound
Compound 3b was prepared as a pale yellow solid, melting point: 282.3-282.9 ℃, yield is 85%,12:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.44(br s,1H),3.05(s,3H),3.37(d,J＝12.4Hz,1H),4.66(d,J＝12.8Hz,1H),4.94(d,J＝10.0Hz,1H),5.00-5.05(m,1H),6.29-6.32(m,1H),6.44(d,J＝8.0Hz,1H),6.58-6.63(m,1H),6.69-6.73(m,2H),7.08-7.13(m,1H),7.18-7.28(m,3H),7.38-7.41(m,2H),7.54-7.56(m,1H)； 13 C NMR(CDCl 3 ,100MHz)δ:25.3,45.1,58.8,60.9(q,J C,F ＝31.0Hz),69.0,70.3,107.1,113.5(d,J C,F ＝25.5Hz),114.8(d,J C,F ＝24.2Hz),115.4,119.6,120.4,122.9,124.1(q,J C,F ＝270.5Hz),125.7,126.9,127.0,127.3,127.4,127.8,128.4,129.9,132.7,134.6,138.1,157.8(d,J C,F ＝241.4Hz),159.7,177.0,189.3； 19 F NMR(CDCl 3 ,375MHz)δ:-74.4,-120.2；HRMS(ESI-TOF)m/z:Calcd.for C 27 H 20 F 4 N 2 NaO 3 [M+Na] + :519.1302；Found:519.1306.
compound 3c was prepared as a pale yellow solid, melting point: 90.7-91.2 ℃, 89 percent of yield,>20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:1.23-1.27(m,3H),2.51(br s,1H),3.44(d,J＝12.4Hz,1H),3.46-3.53(m,1H),3.84-3.93(m,1H),4.76(d,J＝12.4Hz,1H),5.02(d,J＝10.4Hz,1H),5.10-5.15(m,1H),6.41-6.44(m,1H),6.48(d,J＝8.0Hz,1H),6.64-6.69(m,1H),6.75-6.82(m,2H),7.14-7.18(m,1H),7.25-7.27(m,1H),7.29-7.35(m,2H),7.45-7.47(m,2H),7.66-7.68(m,1H)； 13 C NMR(CDCl 3 ,100MHz)δ:12.0,34.8,46.2,59.6,61.7(q,J C,F ＝30.5Hz),70.1,71.6,108.3(d,J C,F ＝8.3Hz),114.8(d,J C,F ＝26.2Hz),115.8(d,J C,F ＝24.4Hz),116.5,120.6,121.5,124.0,124.3(q,J C,F ＝270.5Hz),126.8,128.0,128.5,128.6,128.8,129.5,133.9,135.6,138.2,138.3,158.7(d,J C,F ＝240.5Hz),160.8,177.5,190.5； 19 F NMR(CDCl 3 ,375MHz)δ:-74.4,-120.5；HRMS(ESI-TOF)m/z:Calcd.for C 28 H 22 F 4 N 2 NaO 3 [M+Na] + :533.1459；Found:533.1460.
compound 3d was prepared as a pale yellow solid, melting point: 187.0-187.9 ℃, 91 percent of yield,>20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.40(br s,1H),3.36(d,J＝12.4Hz,1H),4.65(d,J＝12.4Hz,1H),4.97(d,J＝10.0Hz,1H),5.01-5.06(m,1H),5.13-5.23(m,2H),6.47(d,J＝8.4Hz,1H),6.53-6.57(m,1H),6.67-6.71(m,1H),6.75-6.77(m,1H),6.86-6.88(m,1H),7.10-7.26(m,9H),7.38-7.40(m,2H),7.50-7.53(m,1H)； 13 C NMR(CDCl 3 ,100MHz)δ:45.3,46.1,60.0,61.7(q,J C,F ＝30.1Hz),69.5,71.4,114.9,116.6,120.6,121.5,123.4,124.2(q,J C,F ＝270.1Hz),125.1,126.7,127.3,128.0,128.5,128.8,129.7,132.0,133.8,135.8,137.1,138.6,160.6,179.1,190.4； 19 F NMR(CDCl 3 ,375MHz)δ:-74.3；HRMS(ESI-TOF)m/z:Calcd.for C 33 H 24 ClF 3 N 2 NaO 3 [M+Na] + :611.1320；Found:611.1316.
compound 3e was prepared as a pale yellow solid, melting point: 181.0-181.6 ℃, the yield is 90 percent,>20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:1.24-1.27(m,3H),2.06(s,3H),2.47(br s,1H),3.42(d,J＝12.4Hz,1H),3.47-3.54(m,1H),3.84-3.93(m,1H),4.71(d,J＝12.4Hz,1H),5.03(d,J＝10.4Hz,1H),5.13-5.20(m,1H),6.39-6.44(m,2H),6.72-6.78(m,3H),7.09-7.13(m,1H),7.24-7.28(m,1H),7.31-7.35(m,2H),7.50-7.52(m,2H),7.64-7.66(m,1H)； 13 C NMR(CDCl 3 ,100MHz)δ:10.0,18.5,32.5,44.2,57.0,59.9(q,J C,F ＝30.2Hz),68.2,69.7,105.5,114.4,118.8,124.2,124.4(q,J C,F ＝270.4Hz),124.8,125.1,125.6,125.8,126.6,127.5,129.8,132.2,133.1,137.8,158.7,175.3,189.0； 19 F NMR(CDCl 3 ,375MHz)δ:-74.3；HRMS(ESI-TOF)m/z:Calcd.for C 29 H 25 F 3 N 2 NaO 3 [M+Na] + :529.1709；Found:529.1714.
compound 3f was prepared as a pale yellow solid, melting point: 197.8-198.5 ℃, yield 78%,19:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.09(s,3H),2.44(br s,1H),3.06(s,3H),3.33(d,J＝12.4Hz,1H),4.57(d,J＝12.4Hz,1H),4.90(d,J＝10.4Hz,1H),4.94-4.99(m,2H),6.31-6.34(m,2H),6.60-6.69(m,2H),6.91-6.97(m,3H),7.35(s,1H),7.39(s,2H)； 13 C NMR(CDCl 3 ,100MHz)δ:19.20,25.3,44.5,58.6,61.0(q,J C,F ＝30.3Hz),69.1,70.3,107.1(d,J C,F ＝8.1Hz),113.5(d,J C,F ＝26.2Hz),114.7(d,J C,F ＝21.4Hz),115.2,119.2,122.9,124.4(q,J C,F ＝270.4Hz),125.7,126.3,127.2(d,J C,F ＝7.5Hz),128.7,130.0,135.8,138.1,157.8,157.9(d,J C,F ＝240.4Hz),161.7(d,J C,F ＝246.2Hz),176.9,189.5； 19 F NMR(CDCl 3 ,375MHz)δ:-74.4,-114.0,-120.3；HRMS(ESI-TOF)m/z:Calcd.for C 28 H 21 F 5 N 2 NaO 3 [M+Na] + :551.1365；Found:551.1365.
this example prepares compound 3g as a pale yellow solid, melting point: 201.0-201.7 deg.C, yield 81%,>20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:1.99(s,3H),2.09(s,3H),3.06(s,3H),3.31(d,J＝12.4Hz,1H),4.52(d,J＝12.4Hz,1H),4.91(d,J＝10.0Hz,1H),4.97-5.02(m,1H),6.26-6.31(m,2H),6.66(s,1H),6.68(d,J＝8.0Hz,1H),6.86-6.88(m,1H),6.93-6.97(m,2H),7.36(s,1H),7.43(s,2H)； 13 C NMR(CDCl 3 ,100MHz)δ:19.2,19.6,25.2,44.6,58.0,61.2(q,J C,F ＝30.1Hz),69.5,70.6,106.4,114.6(d,J C,F ＝21.3Hz),115.3,119.5,124.3(q,J C,F ＝270.2Hz),124.9,126.0(d,J C,F ＝18.3Hz),128.6,129.2,129.5,131.0,135.5,139.8,157.9,161.3(d,J C,F ＝246.2Hz),176.7,190.2； 19 F NMR(CDCl 3 ,375MHz)δ:-74.3,-114.3；HRMS(ESI-TOF)m/z:Calcd.for C 29 H 24 F 4 N 2 NaO 3 [M+Na] + :547.1615；Found:547.1613.
the compound was prepared as a pale yellow solid, melting point: 214.8-215.9 ℃, yield 80%,18:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.45(br s,1H),3.09(s,3H),3.36(d,J＝12.4Hz,1H),4.64(d,J＝12.4Hz,1H),4.90(d,J＝10.4Hz,1H),4.98-5.05(m,1H),6.39-6.45(m,2H),6.67-6.71(m,1H),6.78-6.83(m,1H),6.87-6.98(m,3H),7.17-7.27(m,4H)； 13 C NMR(CDCl 3 ,100MHz)δ:24.1,44.1,57.2,59.8(q,J C,F ＝30.4Hz),68.0,69.6,105.7,110.6(d,J C,F ＝24.3Hz),113.0(d,J C,F ＝21.2Hz),116.0(d,J C,F ＝8.1Hz),119.0,120.5,121.0(d,J C,F ＝25.3Hz),121.7,123.9(d,J C,F ＝23.2Hz),124.2(q,J C,F ＝270.3Hz),127.8,128.2,128.3,134.4(d,J C,F ＝7.7Hz),141.1,154.6(d,J C,F ＝241.3Hz),155.0,161.0(d,J C,F ＝245.1Hz),175.7,187.9；HRMS(ESI-TOF)m/z:Calcd.for C 27 H 19 F 5 N 2 NaO 3 [M+Na] + :537.1208；Found:537.1212.
compound 3i was prepared as a pale yellow solid, melting point: 216.9-218.7 deg.C, 78% yield,>20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.03(s,3H),2.41(br s,1H),3.08(s,3H),3.35(d,J＝12.4Hz,1H),4.59(d,J＝12.8Hz,1H),4.90(d,J＝10.0Hz,1H),5.00-5.05(m,1H),6.33-6.39(m,2H),6.65(s,1H),6.73(d,J＝8.0Hz,1H),6.77-6.82(m,1H),6.88-6.93(m,1H),7.21-7.24(m,4H)； 13 C NMR(CDCl 3 ,100MHz)δ:19.6,25.2,45.0,57.9,61.0(q,J C,F ＝30.2Hz),69.3,70.8,106.6,111.4(d,J C,F ＝24.4Hz),114.1(d,J C,F ＝21.5Hz),117.1,117.2,120.3,122.0(d,J C,F ＝25.3Hz),124.6,124.7(q,J C,F ＝270.1Hz),126.0,128.9,129.2,129.3,131.3,135.7,135.8,139.8,155.9(d,J C,F ＝240.4Hz),156.0,161.8(d,J C,F ＝246.1Hz),176.6,189.3；HRMS(ESI-TOF)m/z:Calcd.for C 28 H 21 F 5 N 2 NaO 3 [M+Na] + :551.1365；Found:551.1369.
compound 3j was prepared as a pale yellow solid, melting point: 170.4-171.2 ℃ and the yield is 79 percent,>20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:1.16-1.20(m,3H),2.43(br s,1H),3.35(d,J＝12.4Hz,1H),3.39-3.45(m,1H),3.64(s,3H),3.77-3.86(m,1H),4.62(d,J＝12.4Hz,1H),4.92(d,J＝10.4Hz,1H),4.99-5.02(m,1H),6.33(d,J＝7.2Hz,1H),6.36-6.40(m,1H),6.59-6.73(m,3H),6.89-6.93(m,1H),7.01(d,J＝8.0Hz,1H),7.19-7.24(m,3H)； 13 C NMR(CDCl 3 ,100MHz)δ:11.0,33.8,44.8,54.8,58.4,59.4,61.0(q,J C,F ＝30.4Hz),69.0,70.6,106.8,107.4(d,J C,F ＝8.2Hz),113.7(d,J C,F ＝26.2Hz),114.0,114.2,114.8(d,J C,F ＝24.4Hz),116.9,119.3,124.4(q,J C,F ＝270.4Hz),125.6,127.3,127.4,129.2(d,J C,F ＝8.1Hz),135.6(d,J C,F ＝7.5Hz),137.3,153.1,154.6,157.7(d,J C,F ＝240.3Hz),161.7(d,J C,F ＝245.0Hz),170.2,176.3,189.4；HRMS(ESI-TOF)m/z:Calcd.for C 29 H 23 F 5 N 2 NaO 4 [M+Na] + :581.1470；Found:581.1471.
compound 3k was prepared as a pale yellow solid, melting point: 180.1-181.7 deg.c, 75% yield,>20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.09(s,3H),2.49(br s,1H),3.15(s,3H),3.41(d,J＝12.4Hz,1H),3.70(s,3H),4.62(d,J＝12.4Hz,1H),4.99(d,J＝10.0Hz,1H),5.07-5.12(m,1H),6.39(d,J＝8.8Hz,2H),6.75-6.80(m,3H),6.94-7.02(m,2H),7.06(d,J＝7.1Hz,1H),7.26-7.30(m,2H)； 13 C NMR(CDCl 3 ,100MHz)δ:18.3,23.9,43.7,53.3,56.8,59.6(q,J C,F ＝30.5Hz),68.0,69.2,105.1,105.2,112.5,112.7,115.5,118.2,122.6(d,J C,F ＝21.3Hz),123.6,124.5(q,J C,F ＝270.3Hz),127.4,127.8(d,J C,F ＝8.2Hz),129.5,134.5,138.5,151.5,153.2,158.2(d,J C,F ＝252.0Hz),161.7,175.3,188.6； 19 F NMR(CDCl 3 ,375MHz)δ:-70.1,-112.6；HRMS(ESI-TOF)m/z:Calcd.for C 29 H 24 F 4 N 2 NaO 4 [M+Na] + :563.1564；Found:563.1566.
compound 3l was prepared as a pale yellow solid, melting point: 167.1-168.5 ℃, yield 80%,20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:1.24-1.28(m,3H),2.08(s,3H),2.47(br s,1H),3.41(d,J＝12.0Hz,1H),3.48-3.55(m,1H),3.71(s,3H),3.84-3.93(m,1H),4.65(d,J＝12.4Hz,1H),5.01(d,J＝10.0Hz,1H),5.10-5.14(m,1H),6.36(d,J＝9.2Hz,1H),6.42(d,J＝7.6Hz,1H),6.73-6.78(m,3H),6.95-7.00(m,1H),7.08(d,J＝3.2Hz,1H),7.28-7.31(m,3H)； 13 C NMR(CDCl 3 ,100MHz)δ:11.1,19.6,33.6,45.0,54.7,58.0,61.0(q,J C,F ＝30.6Hz),69.4,70.8,106.7(d,J C,F ＝8.2Hz),113.8(d,J C,F ＝20.4Hz),116.8,119.6,123.9,124.3(q,J C,F ＝270.1Hz),125.1,125.8,126.1,128.7,129.2,130.7,136.0,138.9,152.8,154.6,161.6(d,J C,F ＝245.1Hz),176.2,190.0；HRMS(ESI-TOF)m/z:Calcd.for C 30 H 26 F 4 N 2 NaO 4 [M+Na] + :577.1721；Found:577.1717.
compound 3m was prepared as a pale yellow solid, melting point: 183.7-184.5 ℃, yield 78%,20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.17(s,3H),2.54(br s,1H),3.13(s,3H),3.43(d,J＝12.4Hz,1H),4.65(d,J＝12.4Hz,1H),4.98(d,J＝10.0Hz,1H),5.04-5.08(m,1H),6.39-6.42(m,2H),6.78-6.76(m,2H),6.95-7.01(m,2H),7.27-7.33(m,3H),7.43(s,1H)； 13 C NMR(CDCl 3 ,100MHz)δ:20.2,26.4,45.9,59.7,61.9(q,J C,F ＝30.3Hz),70.1,71.2,108.1(d,J C,F ＝8.3Hz),114.5(d,J C,F ＝25.1Hz),115.1(d,J C,F ＝21.2Hz),115.8(d,J C,F ＝23.3Hz),116.3,120.2,123.9,124.2(q,J C,F ＝270.2Hz),126.6,127.4,128.1,128.2,130.2(d,J C,F ＝8.2Hz),131.1,136.5(d,J C,F ＝8.2Hz),136.9,139.2,158.8,158.9(d,J C,F ＝240.2Hz),162.8(d,J C,F ＝245.2Hz),177.8,190.4；HRMS(ESI-TOF)m/z:Calcd.for C 28 H 21 F 5 N 2 NaO 3 [M+Na] + :551.1365；Found:551.1369.
compound 3n was prepared as a pale yellow solid, melting point: 193.8-194.8 ℃, yield 80%,12:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.00(s,3H),2.09(s,3H),2.38(br s,1H),3.07(s,3H),3.31(d,J＝12.4Hz,1H),4.52(d,J＝12.4Hz,1H),4.92(d,J＝10.0Hz,1H),4.97-5.03(m,1H),6.26-6.32(m,2H),6.66(s,1H),6.69(d,J＝8.0Hz,1H),6.86-6.89(m,1H),6.93-6.97(m,2H),7.36(s,1H),7.43(s,2H)； 13 C NMR(CDCl 3 ,100MHz)δ:19.2,19.6,25.2,44.6,58.0,61.2(q,J C,F ＝30.4Hz),69.5,70.6,106.4,114.6(d,J C,F ＝21.3Hz),115.3,119.6,124.3(q,J C,F ＝270.2Hz),124.9,126.1(d,J C,F ＝18.8Hz),128.6,129.2,129.5,131.0,135.5,139.8,157.9,161.3(d,J C,F ＝245.3Hz),176.7,190.2； 19 F NMR(CDCl 3 ,375MHz)δ:-74.3,-114.3；HRMS(ESI-TOF)m/z:Calcd.for C 29 H 24 F 4 N 2 NaO 3 [M+Na] + :547.1615；Found:547.1618.
compound 3o was prepared as a pale yellow solid, melting point: 81.7-82.5 ℃, the yield is 71%,>20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.06(s,3H),3.07(s,3H),3.33(d,J＝12.4Hz,1H),4.60(d,J＝12.4Hz,1H),4.91(d,J＝10.0Hz,1H),4.94-5.00(m,1H),6.32(d,J＝8.8Hz,1H),6.39(d,J＝8.0Hz,1H),6.64-6.68(m,1H),6.88-6.97(m,5H),7.27(s,1H),7.39(s,2H)； 13 C NMR(CDCl 3 ,100MHz)δ:19.2,25.2,44.8,58.6,61.0(q,J C,F ＝30.3Hz),69.2,70.4,114.6(d,J C,F ＝25.1Hz),115.2,119.3,121.4,124.1(q,J C,F ＝270.5Hz),125.1,125.4,126.3,128.6,128.9,129.0,130.0,130.1,135.6,142.2,157.9,161.3(d,J C,F ＝245.0Hz),177.1,189.8； 19 F NMR(CDCl 3 ,375MHz)δ:-74.3,-114.2；HRMS(ESI-TOF)m/z:Calcd.for C 28 H 22 F 4 N 2 NaO 4 [M+Na] + :549.1408；Found:549.1412.
compound 3p was prepared as a pale yellow solid, melting point: 63.9-64.5 ℃, yield 78%,17:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.05(s,3H),3.05(s,3H),3.36(d,J＝12.4Hz,1H),3.70(s,3H),4.62(d,J＝12.4Hz,1H),4.88(d,J＝10.4Hz,1H),4.93-5.00(m,1H),6.32-6.38(m,2H),6.65-6.69(m,1H),6.78(d,J＝8.8Hz,2H),6.87-6.94(m,3H),7.24(s,1H),7.30-7.32(m,2H)； 13 C NMR(CDCl 3 ,100MHz)δ:19.2,25.2,44.8,54.2,58.9,60.8(q,J C,F ＝30.5Hz),69.1,70.4,106.4,113.0,115.1,119.3,121.4,124.5(q,J C,F ＝271.1Hz),124.9,125.1,125.8,126.3,128.4,129.5,135.4,142.1,157.9,158.1,177.2,189.9； 19 F NMR(CDCl 3 ,375MHz)δ:-74.3；HRMS(ESI-TOF)m/z:Calcd.for C 29 H 25 F 3 N 2 NaO 4 [M+Na] + :545.1659；Found:545.1661.
compound 3q was prepared as a pale yellow solid, melting point: 72.4-73.8 ℃, yield 77%,12:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.13(s,3H),2.53(br s,1H),3.46(d,J＝12.4Hz,1H),3.78(s,3H),4.57(d,J＝16.0Hz,1H),4.76(d,J＝12.8Hz,1H),5.00(d,J＝10.0Hz,1H),5.06-5.10(m,1H),5.12(d,J＝10.0Hz,1H),6.25(d,J＝8.8Hz,1H),6.37(d,J＝7.6Hz,1H),6.64-6.68(m,1H),6.85-6.92(m,4H),6.96-6.98(m,1H),7.28-7.38(m,6H),7.42-7.44(m,2H)； 13 C NMR(CDCl 3 ,100MHz)δ:19.2,43.1,45.1,54.2,58.4,60.9(q,J C,F ＝30.3Hz),69.2,70.8,107.8,113.1,115.3,119.4,121.4,124.5(q,J C,F ＝270.3Hz),125.2,125.4,126.4,126.7,127.7,128.0,128.4,129.6,134.3,135.5,141.6,157.9,158.1,177.1,190.3； 19 F NMR(CDCl 3 ,375MHz)δ:-74.1；HRMS(ESI-TOF)m/z:Calcd.for C 35 H 29 F 3 N 2 NaO 4 [M+Na] + :621.1972；Found:621.1970.
compound 3r was prepared as a pale yellow solid, melting point: 84.3-85.5 ℃, yield 82%,20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.08(s,3H),2.47(br s,1H),3.03(s,3H),3.36(d,J＝12.4Hz,1H),3.69(s,3H),4.60(d,J＝12.4Hz,1H),4.87(d,J＝10.4Hz,1H),4.92-4.97(m,1H),6.28-6.35(m,2H),6.59-6.64(m,1H),6.68-6.71(m,1H),6.77(d,J＝8.8Hz,2H),6.90-6.92(m,1H),7.29-7.32(m,3H)； 13 C NMR(CDCl 3 ,100MHz)δ:20.2,26.3,45.6,55.2,59.9,62.0(q,J C,F ＝30.4Hz),70.1,71.3,108.0(d,J C,F ＝8.2Hz),114.1,114.5(d,J C,F ＝25.2Hz),115.6(d,J C,F ＝24.1Hz),116.2,120.3,124.4(q,J C,F ＝271.4Hz),125.7,126.8,127.3,128.5,128.6,130.5,130.9,136.7,139.1,158.8,158.9(d,J C,F ＝240.4Hz),159.2,178.1,190.6； 19 F NMR(CDCl 3 ,375MHz)δ:-74.4,-120.4；HRMS(ESI-TOF)m/z:Calcd.for C 29 H 24 F 4 N 2 NaO 4 [M+Na] + :563.1564；Found:563.1565.
compound 3s was prepared as a pale yellow solid, melting point: 65.6-66.8 ℃, yield 84%,19:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:1.22-1.26(m,3H),2.19(s,3H),3.42(d,J＝12.4Hz,1H),3.46-3.51(m,1H),3.77(s,3H),3.83-3.92(m,1H),4.63(d,J＝12.4Hz,1H),4.97(d,J＝10.4Hz,1H),5.03-5.09(m,1H),6.34(d,J＝8.8Hz,1H),6.42(d,J＝8.8Hz,1H),6.86(d,J＝8.8Hz,2H),6.92-6.98(m,3H),7.40(s,1H),7.45-7.48(m,2H)； 13 C NMR(CDCl 3 ,100MHz)δ:12.0,20.2,34.8,45.3,55.2,59.4,62.0(q,J C,F ＝30.4Hz),70.0,71.6,108.6,114.1,116.2,117.7,120.5,124.5(q,J C,F ＝270.5Hz),125.9,127.0,127.5,127.9,128.4,129.2,129.9,131.0,136.6,140.8,158.8,159.2,177.3,190.9； 19 F NMR(CDCl 3 ,375MHz)δ:-74.3；HRMS(ESI-TOF)m/z:Calcd.for C 30 H 26 ClF 3 N 2 NaO 4 [M+Na] + :593.1425；Found:593.1425.
compound 3t, a pale yellow solid, melting point: 166.0-166.9 ℃, yield is 85%,>20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.24(s,3H),3.07(s,3H),3.35(d,J＝12.4Hz,1H),4.65(d,J＝12.4Hz,1H),4.88(d,J＝10.0Hz,1H),4.98-5.05(m,1H),6.39-6.42(m,2H),6.68-6.72(m,1H),6.77-6.82(m,1H),6.90-6.97(m,2H),7.06(d,J＝8.0Hz,2H),7.13-7.16(m,1H),7.25-7.29(m,2H)； 13 C NMR(CDCl 3 ,100MHz)δ:20.0,25.2,45.2,58.5,60.7(q,J C,F ＝30.6Hz),69.0,70.8,106.6,111.6(d,J C,F ＝22.2Hz),117.0(d,J C,F ＝7.4Hz),120.1,120.2,121.6,121.9(d,J C,F ＝25.2Hz),124.3(q,J C,F ＝271.3Hz),125.2,125.4,128.5,128.8,129.7,136.7,142.2,155.8(d,J C,F ＝241.2Hz),156.1,177.0,189.1； 19 F NMR(CDCl 3 ,375MHz)δ:-74.3,-121.5；HRMS(ESI-TOF)m/z:Calcd.for C 28 H 22 F 4 N 2 NaO 3 [M+Na] + :533.1459；Found:533.1462.
compound 3u was prepared as a pale yellow solid, melting point: 63.7-64.2 ℃, yield 86%,10:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.31(s,3H),2.53(br s,1H),3.44(d,J＝12.8Hz,1H),4.57(d,J＝15.6Hz,1H),4.78(d,J＝12.8Hz,1H),4.99(d,J＝10.4Hz,1H),5.12-5.17(m,2H),6.24-6.27(m,1H),6.42(d,J＝7.6Hz,1H),6.68-6.72(m,1H),6.76-6.81(m,1H),6.88-6.95(m,2H),7.14(d,J＝7.6Hz,2H),7.29-7.39(m,8H)； 13 C NMR(CDCl 3 ,100MHz)δ:19.6,42.7,44.9,57.7,60.4(q,J C,F ＝30.5Hz),68.7,70.6,107.5,111.3(d,J C,F ＝23.3Hz),116.6(d,J C,F ＝8.1Hz),119.8,121.2,121.5(d,J C,F ＝25.0Hz),124.2(q,J C,F ＝270.4Hz),124.6,124.8,126.2,126.3,127.2,127.9,128.1,128.3,129.5,133.9,136.3,141.2,155.4(d,J C,F ＝240.3Hz),156.6,176.5,189.0； 19 F NMR(CDCl 3 ,375MHz)δ:-74.2,-121.3；HRMS(ESI-TOF)m/z:Calcd.for C 34 H 26 F 4 N 2 NaO 3 [M+Na] + :609.1772；Found:609.1774.
compound 3v was prepared as a pale yellow solid, melting point: 187.4-188.1 deg.c, yield 70%,>20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.05(s,3H),2.24(s,3H),2.41(br s,1H),3.06(s,3H),3.33(d,J＝12.4Hz,1H),4.60(d,J＝12.4Hz,1H),4.87(d,J＝10.0Hz,1H),5.00-5.05(m,1H),6.31(d,J＝7.6Hz,1H),6.36-6.39(m,1H),6.68-6.81(m,3H),7.06(d,J＝8.0Hz,2H),7.18-7.20(m,1H),7.28-7.30(m,2H)； 13 C NMR(CDCl 3 ,100MHz)δ:19.7,20.0,25.2,45.0,58.2,60.9(q,J C,F ＝30.4Hz),69.2,70.9,106.5,111.4(d,J C,F ＝24.3Hz),117.0(d,J C,F ＝8.1Hz),120.3,120.4,121.8(d,J C,F ＝25.1Hz),124.1(q,J C,F ＝270.3Hz),125.0,126.0,128.5,128.8,129.8,131.2,136.7,139.8,156.0,156.3(d,J C,F ＝241.2Hz),176.8,189.4； 19 F NMR(CDCl 3 ,375MHz)δ:-74.3,-121.9；HRMS(ESI-TOF)m/z:Calcd.for C 29 H 24 F 4 N 2 NaO 3 [M+Na] + :547.1615；Found:547.1617.
compound 3w was prepared as a pale yellow solid, melting point: 46.7-47.3 ℃, yield 75%,10:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:2.04(s,3H),2.23(s,3H),2.47(br s,1H),3.04(s,3H),3.35(d,J＝12.4Hz,1H),4.64(d,J＝12.4Hz,1H),4.90(d,J＝10.4Hz,1H),4.96-5.02(m,1H),6.32-6.37(m,2H),6.65-6.69(m,1H),6.86-6.94(m,3H),7.05(d,J＝8.0Hz,2H),7.24-7.27(m,3H)； 13 C NMR(CDCl 3 ,100MHz)δ:19.2,20.0,25.2,45.2,59.0,60.7(q,J C,F ＝31.0Hz),69.0,70.3,106.4,112.9,115.1,119.3,121.4,124.0(q,J C,F ＝270.2Hz),125.2,125.8,126.3,126.8,127.8,128.4,129.5,129.9,135.4,136.6,142.1,157.8,166.7,177.3,189.7； 19 F NMR(CDCl 3 ,375MHz)δ:-74.2；HRMS(ESI-TOF)m/z:Calcd.for C 29 H 25 F 3 N 2 NaO 3 [M+Na] + :529.1709；Found:529.1714.
compound 3x was prepared as a pale yellow solid, melting point: 129.1-129.6 deg.C, yield 79%,20:1dr; results of nuclear magnetic resonance and high resolution mass spectrometry are as follows: 1 H NMR(CDCl 3 ,400MHz)δ:1.23-1.26(m,3H),2.08(s,3H),2.16(s,3H),2.31(s,3H),2.45(br s,1H),3.40(d,J＝12.4Hz,1H),3.45-3.54(m,1H),3.83-3.92(m,1H),4.65(d,J＝12.4Hz,1H),4.98(d,J＝10.4Hz,1H),5.09-5.14(m,1H),6.31(d,J＝8.4Hz,1H),6.39(d,J＝7.6Hz,1H),6.74(d,J＝8.4Hz,1H),6.76(s,1H),6.91-6.93(m,1H),7.12(d,J＝8.0Hz,2H),7.37-7.41(m,2H),7.44(s,1H)； 13 C NMR(CDCl 3 ,100MHz)δ:10.7,18.8,19.2,19.7,33.2,44.5,57.8,60.8(q,J C,F ＝30.5Hz),68.9,70.4,106.1,114.8,119.2,124.7(q,J C,F ＝270.6Hz),125.0,125.8,128.0,128.9,129.9,130.4,134.9,136.1,138.5,157.5,176.0,189.9； 19 F NMR(CDCl 3 ,375MHz)δ:-74.2；HRMS(ESI-TOF)m/z:Calcd.for C 31 H 29 F 3 N 2 NaO 3 [M+Na] + :557.2022；Found:557.2017.
the compound of the formula (1) has important biological activity, and cytotoxicity test of human leukemia cells (K562) tumor cells in vitro shows that: the trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole 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 novel tumor prevention and treatment drug. It is emphasized that the compounds of the invention are not limited to cytotoxicity expressed by human leukemia cells (K562).
Pharmacological examples: cytotoxicity of Compounds 3f,3v and 3w on K562 cells
K562 (human chronic myelogenous leukemia cells) were 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 at 37℃with 5% CO 2 Culturing in a humid air incubator for 24 hours.
Cell viability was determined using the modified MTT method. After 24 hours incubation of the cells, newly formulated solutions of compounds 3f,3v and 3w in dimethyl sulfoxide were added to each well in concentration gradients such that the final concentrations of compounds in the wells were 6. Mu. Mol/L, 12. Mu. Mol/L, 25. Mu. Mol/L, 50. Mu. Mol/L and 100. Mu. Mol/L, respectively. After 48 hours, 10. Mu.L of MTT (5 mg/mL) phosphate buffer was added to each well, and after further incubation at 37℃for 4 hours, centrifugation was performed for 5 minutes to remove unconverted MTT, and 150. Mu.L of dimethyl sulfoxide was added to each well. OD was measured at 490nm using a microplate reader by dissolving reduced MTT crystal formazan (formazan). Wherein compounds 3f,3v and 3w semi-inhibitory concentration IC against K562 cells 50 Analysis was performed by spss software (version 19). IC of Compound 3f on K562 tumor cells 50 65.10 mu mol/L; IC of Compound 3v against K562 tumor cells 50 75.32. Mu. Mol/L; IC of Compound 3w against K562 tumor cells 50 37.30. Mu. Mol/L; while positive control cisplatin versus K562 tumor cell IC 50 21.32. Mu. Mol/L.
Conclusion of experiment: k562 cells are an effective tool and evaluation index for testing compounds for cytotoxicity against tumor cells. The experiment shows that the trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compound shown in the formula (1) has stronger cytotoxicity to K562 cells, is likely to develop into a new medicament for preventing and treating tumor K562 cells (human chronic myelogenous leukemia), and is worthy of further intensive research.

Claims (3)

1. A trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compound is characterized in that: the compound has a structure shown in a general formula (I):
wherein R is 1 Methyl, ethyl or benzyl; r is R 2 Fluorine, methoxy, methyl or hydrogen; r is R 3 Fluorine, chlorine, methyl or hydrogen; ar is methoxy, methyl, fluorine or hydrogen substituted benzene ring.
2. A method for preparing trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compound according to claim 1, which is characterized in that the synthetic route is as follows:
wherein R is 1 Methyl, ethyl or benzyl; r is R 2 Fluorine, methoxy, methyl or hydrogen; r is R 3 Fluorine, chlorine, methyl or hydrogen; ar is methoxy, methyl, fluorine or hydrogen substituted benzene ring.
3. The use of a trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compound according to claim 1 for preparing a medicament for preventing and treating human chronic myelogenous leukemia cells.
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