CN111196791B - Chiral gamma-butyrolactone derivative and synthesis method and application thereof - Google Patents

Chiral gamma-butyrolactone derivative and synthesis method and application thereof Download PDF

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CN111196791B
CN111196791B CN202010067182.XA CN202010067182A CN111196791B CN 111196791 B CN111196791 B CN 111196791B CN 202010067182 A CN202010067182 A CN 202010067182A CN 111196791 B CN111196791 B CN 111196791B
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substituted phenyl
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butyrolactone derivative
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胡文浩
杨晓涵
刘俊文
张丹
张梦楚
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Sun Yat Sen University
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Abstract

The invention discloses a chiral gamma-butyrolactone derivative and a synthesis method and application thereof. The structure is shown as formula (1); wherein Ar is1、Ar2And Ar3Each independently is phenyl, halophenyl, nitro-substituted phenyl, C1～4Alkyl-substituted phenyl, C1～4Alkoxy-substituted phenyl, C1～4Haloalkyl substituted phenyl, naphthyl or halonaphthyl. The derivative has a novel structure, has a good effect of resisting cancer cells, particularly has a good inhibiting effect on human breast cancer cells (MCF-7) and human lung adenocarcinoma cells (A549), shows a good effect of resisting breast cancer and lung cancer cells, and can be prepared into a breast cancer and lung cancer resisting medicament for application; in addition, the preparation method of the compound is simple, the compound which is cheap and easy to obtain is used as a raw material, and the compound has the beneficial effects of mild reaction conditions, few reaction steps, fast reaction, few generated wastes, simplicity and safety in operation, high atom economy, high selectivity, high yield and the like.
Figure DDA0002376324340000011

Description

Chiral gamma-butyrolactone derivative and synthesis method and application thereof
Technical Field
The invention belongs to the field of synthetic medicine and chemical industry, and mainly relates to an optically active gamma-butyrolactone derivative, and a synthetic method and application thereof.
Background
Gamma-butyrolactone is the basic skeleton of many natural products, and more than 10% of natural compound molecules contain the structure of gamma-butyrolactone, and is widely used in various fields such as materials, agriculture, biology, medicine, and the like. The gamma-butyrolactone derivative with optical activity has the functions of sterilization, anti-inflammation, antianaphylaxis, antivirus, anticancer, rheumatism prevention, disinsection and weeding, and at the same time, many complex natural products can be conveniently synthesized by the gamma-butyrolactone derivative, and the effective synthesis of the gamma-butyrolactone structure is always an important research direction of synthetic methodology and natural product synthetic chemistry. The synthesis of a plurality of optically active gamma-butyrolactone derivatives reported at present has a plurality of defects, most of the defects are harsh, or the used raw materials are unstable or difficult to obtain, the synthesis process has a plurality of steps, the yield is low, and the operation is very inconvenient.
Therefore, it is necessary to provide a kind of optically active γ -butyrolactone derivatives with novel structure and a simple preparation method with mild reaction conditions, which is helpful for promoting the research and application of γ -butyrolactone derivatives.
Disclosure of Invention
The present invention is directed to chiral gamma-butyrolactone derivatives that address the deficiencies and drawbacks of the prior art. The chiral gamma-butyrolactone derivative disclosed by the invention is novel in structure, has a good effect of resisting cancer cells, particularly has a good inhibition effect on human breast cancer cells (MCF-7) and human lung adenocarcinoma cells (A549), shows a good effect of resisting breast cancer and lung cancer cells, and can be prepared into a medicine for resisting breast cancer and lung cancer for application.
Another object of the present invention is to provide a method for preparing the chiral gamma-butyrolactone derivative.
Still another object of the present invention is to provide the use of the chiral gamma-butyrolactone derivative.
The above object of the present invention is achieved by the following scheme:
a chiral gamma-butyrolactone derivative has a structure shown in formula (1):
Figure BDA0002376324320000011
wherein Ar is1、Ar2And Ar3Each independently is phenyl, halophenyl, nitro-substituted phenyl, C1～4Alkyl-substituted phenyl, C1～4Alkoxy-substituted phenyl, C1～4Haloalkyl substituted phenyl, naphthyl or halonaphthyl.
Preferably, Ar is1、Ar2And Ar3Each independently is phenyl, halophenyl, nitro-substituted phenyl, methyl-substituted phenyl, ethyl-substituted phenyl, methoxy-substituted phenyl, ethoxy-substituted phenyl, trifluoromethyl-substituted phenyl, trifluoroethyl-substituted phenyl, naphthyl, or halonaphthyl.
Preferably, A isr1、Ar2And Ar3Each independently is phenyl, halophenyl, nitro-substituted phenyl, naphthyl, or halonaphthyl.
Preferably, Ar is1、Ar2And Ar3Each independently phenyl, bromophenyl, chlorophenyl, fluorophenyl, nitro-substituted phenyl or naphthyl.
Preferably, Ar is1、Ar2And Ar3Each independently is phenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3, 4-dichlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-nitro-phenyl, 2-nitro-phenyl or naphthyl.
More preferably, Ar is1Is phenyl or 4-bromophenyl.
More preferably, Ar is2Is phenyl, 4-fluorophenyl or 4-bromophenyl.
More preferably, Ar is3Is phenyl, 4-chlorophenyl, 4-bromophenyl, 3, 4-dichlorophenyl, 2-nitro-phenyl, 4-nitro-phenyl or naphthyl.
More preferably, the chiral gamma-butyrolactone derivative has the structure shown in one of the formulae:
Figure BDA0002376324320000021
the invention also provides a preparation method of the chiral gamma-butyrolactone derivative, which comprises the steps of reacting the 3-aryl cyclopropene carboxylic acid shown in the formula (2) and the imine shown in the formula (3) serving as raw materials under the action of a catalyst to obtain the chiral gamma-butyrolactone derivative shown in the formula (1);
wherein the structures of formula (2) and formula (3) are:
Figure BDA0002376324320000031
preferably, the catalyst is bis [ (α, α, α ', α' -tetramethyl-1, 3-benzenedipropionic acid) rhodium ] and chiral phosphoric acid.
Preferably, the chiral phosphoric acid has the structure:
Figure BDA0002376324320000032
wherein Ar is 4-CF3C6H4。
Preferably, the reaction molar ratio of the 3-aryl cyclopropene carboxylic acid, the imine, the bis [ (alpha, alpha' -tetramethyl-1, 3-benzenedipropionic acid) rhodium ] and the chiral phosphoric acid is 1.8-2.0: 1.0-1.2: 0.04-0.1: 0.1-0.2; more preferably, the reaction molar ratio is 1.8:1.0:0.04: 0.1.
Preferably, the temperature of the reaction is-20 ℃ to 40 ℃; more preferably, the reaction temperature is 25 ℃.
Preferably, the reaction time is 24-96 h; more preferably, the reaction time is 96 h.
Preferably, the reaction is carried out in toluene, tetrahydrofuran, chlorobenzene, dichloromethane, chloroform or ethyl acetate organic solvents; more preferably, the reaction is carried out in tetrahydrofuran.
The application of the chiral gamma-butyrolactone derivative or the pharmaceutically acceptable salt thereof in preparing the anti-cancer medicine is also within the protection scope of the invention.
Preferably, the anti-cancer drug is a drug for resisting human breast cancer cells and human lung adenocarcinoma cells.
Compared with the prior art, the invention has the following beneficial effects:
the optically active gamma-butyrolactone derivative disclosed by the invention is novel in structure, has a good anti-cancer cell effect, particularly has a good inhibition effect on human breast cancer cells (MCF-7) and human lung adenocarcinoma cells (A549), shows a good anti-breast cancer and lung cancer cell effect, and can be prepared into anti-breast cancer and lung cancer medicaments for application.
Meanwhile, the preparation method of the compound is simple, the compound which is cheap and easy to obtain is used as a raw material, and the compound has the beneficial effects of mild reaction conditions, few reaction steps, fast reaction, few generated wastes, simplicity and safety in operation, high atom economy, high selectivity, high yield and the like.
The compound is simple to prepare, low in cost, has a good inhibition effect on breast cancer and lung cancer cells, and has a great application prospect in the aspect of preparing medicaments for treating breast cancer and lung cancer.
Drawings
FIG. 1 shows the product obtained in example 11H NMR scheme.
FIG. 2 shows the product obtained in example 113Schematic C NMR.
FIG. 3 shows the product obtained in example 21H NMR scheme.
FIG. 4 shows the product obtained in example 213Schematic C NMR.
FIG. 5 shows the product obtained in example 31H NMR scheme.
FIG. 6 shows the product obtained in example 313Schematic C NMR.
FIG. 7 shows the product obtained in example 41H NMR scheme.
FIG. 8 shows the product obtained in example 413Schematic C NMR.
FIG. 9 shows the results of example 51H NMR scheme.
FIG. 10 shows the results of example 513Schematic C NMR.
FIG. 11 shows the results of example 61H NMR scheme.
FIG. 12 shows the results obtained in example 613Schematic C NMR.
FIG. 13 shows the product obtained in example 71H NMR scheme.
FIG. 14 shows the results of example 713Schematic C NMR.
FIG. 15 shows the results of example 81H NMR scheme.
FIG. 16 shows the results of example 813Schematic C NMR.
FIG. 17 shows the results of example 91H NMR scheme.
FIG. 18 shows the results of example 913Schematic C NMR.
FIG. 19 shows the results of example 101H NMR scheme.
FIG. 20 shows the results of example 1013Schematic C NMR.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
EXAMPLE 1 preparation of Compound 3bl
Figure BDA0002376324320000051
Adding Rh to the solution2(esp)2(0.008mmol), chiral phosphoric acid (0.02mmol), 3-p-bromophenylcyclopropenoic carboxylic acid (0.36mmol) and p-bromobenzylidene aniline (0.2mmol) were dissolved in a test tube containing 2.5mL of tetrahydrofuran, stirred at a specific temperature (25 ℃) and reacted for 96 hours, and after the imine reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether: 1:10-1:3) to give the pure product. The yield was 91%, dr>95:5，er:93:7。
1H NMR(500MHz,CDCl3)δ7.65–7.61(m,2H),7.55–7.49(m,4H),7.38–7.33(m,3H),7.12–7.06(m,2H),6.73(dd,J1＝J2＝7.4Hz,1H),6.55–6.50(m,2H),5.19(dd,J＝6.4,1.8Hz,1H),5.19(dd,J＝6.4,1.8Hz,1H),4.53(d,J＝6.1Hz,1H),4.53(d,J＝6.1Hz,1H),4.49(s,1H),4.49(s,1H).13C NMR(125MHz,CDCl3)δ170.6,146.2,144.9,137.5,132.4,132.1,132.0,129.3,129.0,128.7,127.8,124.2,122.5,119.1,114.4,82.8,60.9.HRMS(ESI)m/z:calcd.for C23H17NO2Br2(M+Na)+519.9518,found 519.9524.
EXAMPLE 2 preparation of Compound 3aq
Figure BDA0002376324320000052
Adding Rh to the solution2(esp)2(0.008mmol), chiral phosphoric acid (0.02mmol), 3-phenylcyclopropene carboxylic acid (0.36mmol) and p-fluorobenzylidene p-chloroaniline (0.2mmol) were dissolved in a test tube containing 2.5mL of tetrahydrofuran, stirred at a specific temperature (25 ℃) and reacted for 96 hours, and after the imine reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether: 1:10-1:3) to give the pure product. The yield was 80%, dr:94:6, er:95: 5.
1H NMR(500MHz,CDCl3)δ7.76(dd,J1＝J2＝6.6,3.0Hz,2H),7.46–7.37(m,5H),7.32(d,J＝1.8Hz,1H),7.10(dd,J1＝J2＝8.5Hz,2H),7.05–7.01(m,2H),6.47–6.42(m,2H),5.17(dd,J＝6.9,1.7Hz,1H),4.57(d,J＝3.9Hz,1H),4.46(dd,J＝6.8,4.2Hz,1H).13C NMR(125MHz,CDCl3)δ170.8,162.7(d,J＝247.9Hz),144.9,144.4,133.8(d,J＝3.2Hz),133.2,129.9,129.1,129.0,128.92,128.88,128.8,127.1,123.7,116.4,116.2,115.5,82.8,61.2.HRMS(ESI)m/z:calcd.for C23H17NO2FClNa(M+Na)+416.0824,found416.0814.
EXAMPLE 3 preparation of Compound 3al
Figure BDA0002376324320000061
Adding Rh to the solution2(esp)2(0.008mmol), chiral phosphoric acid (0.02mmol), 3-phenylcyclopropene carboxylic acid (0.36mmol) and benzylidene p-bromoaniline (0.2mmol) are dissolved in a test tube containing 2.5mL of tetrahydrofuran, stirred at a specific temperature (25 ℃), reacted for 96 hours, and after the imine reaction is completed, the solvent is removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether: 1:10-1:3) to give the pure product. The yield was 89%, dr:95:5, er:94.5: 5.5.
1H NMR(400MHz,CDCl3)δ7.75(dd,J1＝J2＝6.4,2.7Hz,2H),7.49–7.28(m,9H),7.15(d,J＝8.7Hz,2H),6.41(d,J＝8.7Hz,2H),5.19(dd,J＝7.1,1.2Hz,1H),4.61(d,J＝3.5Hz,1H),4.44(dd,J＝6.9,4.1Hz,1H).13C NMR(100MHz,CDCl3)δ170.9,145.6,144.8,138.0,133.0,131.9,129.7,129.3,129.1,128.8,127.21,127.15,116.0,110.6,83.0,61.9.HRMS(ESI)m/z:calcd.for C23H18NO2BrNa(M+Na)+442.0413,found 442.0408.
EXAMPLE 4 preparation of Compound 3aj
Figure BDA0002376324320000062
Adding Rh to the solution2(esp)2(0.008mmol), chiral phosphoric acid (0.02mmol), 3-phenylcyclopropene carboxylic acid (0.36mmol) and substituted imine (0.2mmol) were dissolved in a test tube containing 2.5mL of tetrahydrofuran, stirred at a specific temperature (25 ℃) and reacted for 96 hours, and after the imine reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether: 1:10-1:3) to give the pure product. The yield was 91%, dr:88:12, er:94: 6.
1H NMR(500MHz,CDCl3)δ8.23(d,J＝8.5Hz,1H),7.94(d,J＝8.2Hz,1H),7.82(d,J＝8.2Hz,1H),7.71–7.62(m,4H),7.60–7.54(m,1H),7.45(dd,J1＝J2＝7.7Hz,1H),7.41–7.33(m,4H),7.07(dd,J1＝J2＝7.8Hz,2H),6.69(dd,J1＝J2＝7.3Hz,1H),6.52(d,J＝8.0Hz,2H),5.83–5.77(m,1H),5.67–5.62(m,1H),4.30(d,J＝5.1Hz,1H).13C NMR(125MHz,CDCl3)δ170.9,146.1,144.2,134.2,133.3,132.3,130.8,129.7,129.3,129.1,129.0,128.7,127.1,127.0,125.9,125.7,124.7,121.7,118.6,113.9,81.5,55.2.HRMS(ESI)m/z:calcd.for C27H21NO2Na(M+Na)+414.1465,found 414.1468.
EXAMPLE 5 preparation of Compound 3ah
Figure BDA0002376324320000071
Adding Rh to the solution2(esp)2(0.008mmol), chiral phosphoric acid (0.02mmol), 3-phenylcyclopropene carboxylic acid (0.36mmol) and 3, 4-dichlorobenzylideneaniline (0.2mmol) were dissolved in a test tube containing 2.5mL of tetrahydrofuran, stirred at a specific temperature (25 ℃) and reacted for 96 hours, and after the imine reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether: 1:10-1:3) to give the pure product. The yield was 84%, dr:93:7, er:97: 3.
1H NMR(500MHz,CDCl3)δ7.76(dd,J＝6.6,3.0Hz,2H),7.61(d,J＝1.9Hz,1H),7.47(d,J＝8.3Hz,1H),7.43–7.38(m,3H),7.36(d,J＝1.7Hz,1H),7.33(dd,J＝8.3,2.0Hz,1H),7.11(dd,J1＝J2＝7.9Hz,2H),6.75(dd,J1＝J2＝7.3Hz,1H),6.52(d,J＝7.8Hz,2H),5.21(dd,J＝6.2,1.7Hz,1H),4.56–4.51(m,1H),4.48(d,J＝4.5Hz,1H).13C NMR(125MHz,CDCl3)δ170.8,146.0,144.2,139.1,133.44,133.41,132.7,131.1,129.9,129.4,129.2,128.9,128.8,127.2,126.7,119.2,114.3,82.5,60.4.HRMS(ESI)m/z:calcd.forC23H17NO2Cl2Na(M+Na)+432.0529,found 432.0525.
EXAMPLE 6 preparation of Compound 3ag
Figure BDA0002376324320000072
Figure BDA0002376324320000081
Adding Rh to the solution2(esp)2(0.008mmol), chiral phosphoric acid (0.02mmol), 3-phenylcyclopropene carboxylic acid (0.36mmol) and o-nitrobenzylideneaniline (0.2mmol) were dissolved in a test tube containing 2.5mL of tetrahydrofuran, stirred at a specific temperature (25 ℃) and reacted for 96 hours, and after the imine reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to give the crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether: 1:10-1:3) to give the pure product. The yield is94％，dr>95:5，er:98:2。
1H NMR(500MHz,CDCl3)δ8.09(d,J＝8.0Hz,1H),7.86–7.79(m,2H),7.77(d,J＝7.7Hz,1H),7.65(d,J＝1.5Hz,1H),7.59(dd,J1＝J2＝7.5Hz,1H),7.48(dd,J1＝J2＝7.7Hz,1H),7.45–7.35(m,3H),7.10–7.04(m,2H),6.68(dd,J1＝J2＝7.3Hz,1H),6.46(d,J＝8.0Hz,2H),5.67(d,J＝2.4Hz,1H),5.59–5.49(m,1H),4.53(d,J＝5.4Hz,1H).13C NMR(125MHz,CDCl3)δ171.5,148.7,145.8,145.2,135.3,134.2,133.0,129.8,129.6,129.5,129.1,129.0,128.8,127.2,125.3,119.0,113.7,82.4,53.7.HRMS(ESI)m/z:calcd.for C23H18NO4Na(M+Na)+409.1159,found 409.1159.
EXAMPLE 7 preparation of Compound 3ae
Figure BDA0002376324320000082
Adding Rh to the solution2(esp)2(0.008mmol), chiral phosphoric acid (0.02mmol), 3-phenylcyclopropene carboxylic acid (0.36mmol) and p-nitrobenzylideneaniline (0.2mmol) were dissolved in a test tube containing 2.5mL of tetrahydrofuran, stirred at a specific temperature (25 ℃) and reacted for 96 hours, and after the imine reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether: 1:10-1:3) to give the pure product. The yield was 91%, dr:92:8, er:97: 3.
1H NMR(500MHz,CDCl3)δ8.24(d,J＝8.5Hz,2H),7.75(dd,J＝6.5,2.6Hz,2H),7.68(d,J＝8.6Hz,2H),7.44–7.36(m,4H),7.10(dd,J1＝J2＝7.8Hz,2H),6.74(dd,J1＝J2＝7.3Hz,1H),6.51(d,J＝8.4Hz,2H),5.30(dd,J＝5.8,1.7Hz,1H),4.80–4.73(m,1H),4.55(d,J＝3.9Hz,1H).13C NMR(125MHz,CDCl3)δ170.7,148.0,146.1,145.7,144.0,133.6,130.0,129.4,128.81,128.75,128.3,127.2,124.3,119.4,114.3,82.3,60.4.HRMS(ESI)m/z:calcd.for C23H18NO4Na(M+Na)+409.1159,found 409.1153.
EXAMPLE 8 preparation of Compound 3ac
Figure BDA0002376324320000091
Adding Rh to the solution2(esp)2(0.008mmol), chiral phosphoric acid (0.02mmol), 3-phenylcyclopropene carboxylic acid (0.36mmol) and p-fluorobenzylideneaniline (0.2mmol) were dissolved in a test tube containing 2.5mL of tetrahydrofuran, stirred at a specific temperature (25 ℃) and reacted for 96 hours, and after the imine reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether: 1:10-1:3) to give the pure product. The yield was 92%, dr:89:11, er:95: 5.
1H NMR(500MHz,CDCl3)δ7.80–7.73(m,2H),7.48–7.44(m,2H),7.42–7.37(m,3H),7.34(d,J＝1.8Hz,1H),7.14–7.05(m,4H),6.72(dd,J1＝J2＝7.3Hz,1H),6.54(d,J＝7.7Hz,2H),5.21(dd,J＝6.3,1.6Hz,1H),4.60–4.49(m,2H).13C NMR(125MHz,CDCl3)δ170.9,162.7(d,J＝247.4Hz),146.4,144.7,134.2(d,J＝3.2Hz),133.1,129.8,129.2,129.04,129.01,128.9,128.8,127.2,119.0,116.2,116.1,114.4,82.9,61.0.HRMS(ESI)m/z:calcd.for C23H18NO2FNa(M+Na)+382.1214,found 382.1205.
EXAMPLE 9 preparation of Compound 3ab
Figure BDA0002376324320000092
Adding Rh to the solution2(esp)2(0.008mmol), chiral phosphoric acid (0.02mmol), 3-phenylcyclopropene carboxylic acid (0.36mmol) and p-chlorobenzylideneaniline (0.2mmol) were dissolved in a test tube containing 2.5mL of tetrahydrofuran, stirred at a specific temperature (25 ℃) and reacted for 96 hours, and after the imine reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether: 1:10-1:3) to give the pure product. Yield 87%, dr>95:5，er:96:4。
1H NMR(500MHz,CDCl3)δ7.79–7.72(m,2H),7.44–7.33(m,8H),7.12–7.06(m,2H),6.72(dd,J1＝J2＝7.3Hz,1H),6.55–6.50(m,2H),5.19(dd,J＝6.4,1.6Hz,1H),4.58–4.45(m,2H).13C NMR(125MHz,CDCl3)δ170.9,146.3,144.6,137.1,134.3,133.2,129.8,129.4,129.3,129.0,128.8,128.7,127.2,119.0,114.4,82.8,61.0.HRMS(ESI)m/z:calcd.for C23H18NO2ClNa(M+Na)+398.0918,found 398.0913.
EXAMPLE 10 preparation of Compound 3aa
Figure BDA0002376324320000101
Adding Rh to the solution2(esp)2(0.008mmol), chiral phosphoric acid (0.02mmol), 3-phenylcyclopropene carboxylic acid (0.36mmol) and p-chlorobenzylideneaniline (0.2mmol) were dissolved in a test tube containing 2.5mL of tetrahydrofuran, stirred at a specific temperature (25 ℃) and reacted for 96 hours, and after the imine reaction was completed, the solvent was removed by rotary evaporation under reduced pressure to give a crude product. The crude product was subjected to column chromatography (ethyl acetate: petroleum ether: 1:10-1:3) to give the pure product. The yield was 90%, dr:90:10, er:95: 5.
1H NMR(500MHz,CDCl3)δ7.85–7.74(m,2H),7.62–7.50(m,2H),7.46–7.35(m,6H),7.12(dd,J1＝J2＝7.1Hz,2H),6.76(dd,J1＝J2＝7.3Hz,1H),6.55(d,J＝7.5Hz,2H),5.23(d,J＝6.0Hz,1H),4.59–4.45(m,2H).13C NMR(125MHz,CDCl3)δ170.9,146.2,144.5,137.6,133.2,132.3,129.8,129.3,129.01,128.98,128.8,127.2,122.5,119.0,114.4,82.7,61.1.HRMS(ESI)m/z:calcd.for C23H18NO2BrNa(M+Na)+442.0413,found442.0415.
Example 11
And (3) activity test:
1. the CCK-8 method was used to determine the inhibitory effect of the compounds on the proliferation of human breast cancer cells (MCF-7).
The specific test process is as follows:
(1) preparing MCF-7 cell strain into single cell suspension, inoculating 100uL into 96-well culture plate, wherein the concentration of the single cell suspension is 6000 cells/well, and CO2Incubator (37 ℃, 5% CO)295% air) overnight;
(2) the compounds were dissolved in DMSO respectively to prepare 3.3mM stock solution, and 0.3uL of the stock solution was added to each well of the cells to give a final concentration of 10 uM. Control group was added 0.3uL DMSO to give a final concentration of 0.3%, CO2Culturing in an incubator for 48 hours; wherein MCF-7 cells are DMEM medium (10% containing newborn calf serum, 1% double antibody)
(3) Adding 10uL of CCK-8 reagent into each hole of cells after culturing for 48 hours, incubating for 2 hours at 37 ℃, measuring absorbance A at 450nm by using a Biotek multifunctional enzyme-labeling instrument, and calculating the inhibition rate of the cells on the growth of tumor cells;
(4) the inhibition rate is calculated by the method of [1- (A drug treatment group-A blank control)/(A non-drug treatment group-A blank control) ] x 100%, and A is absorbance.
2. The CCK-8 method is adopted to measure the proliferation inhibition effect of the compound on human lung adenocarcinoma cells (A549).
The specific test process is as follows:
(1) preparing A549 cell strain into single cell suspension, inoculating 100uL into 96-well culture plate, wherein the concentration of the single cell suspension is 6000 cells/well, and CO2Incubator (37 ℃, 5% CO)295% air) overnight;
(2) the compounds were dissolved in DMSO respectively to prepare 3.3mM stock solution, and 0.3uL of the stock solution was added to each well of the cells to give a final concentration of 10 uM. Control group was added 0.3uL DMSO to give a final concentration of 0.3%, CO2Culturing in an incubator for 48 hours; wherein, the A549 cells adopt 1640 culture medium (10% containing newborn calf serum and 1% double antibody)
(3) Adding 10uL of CCK-8 reagent into each hole of cells after culturing for 48 hours, incubating for 1 hour at 37 ℃, measuring absorbance A at 450nm by using a Biotek multifunctional enzyme-labeling instrument, and calculating the inhibition rate of the cells on the growth of tumor cells;
(4) the inhibition rate is calculated by the method of [1- (A drug treatment group-A blank control)/(A non-drug treatment group-A blank control) ] x 100%, and A is absorbance.
Table 1 shows the results of the inhibition of proliferation of human breast cancer cells (MCF-7) and human lung adenocarcinoma cells (A549) by the compounds.
TABLE 1 test results of the inhibition rate of MCF-7 and A549 cells by the compounds
Sample number Sample numbering MCF-7 inhibition ratio% (10uM) A549 inhibition rate% (10uM)
1 3bl 12 30
2 3aq 74 67
3 3al 74 66
4 3aj 35 52
5 3ah 69 69
6 3ag 7 21
7 3ae 8 19
8 3ac 15 23
9 3ab 72 69
10 3aa 76 78
From the detection results in the table, the above compound shows better inhibition effect on human breast cancer cells (MCF-7) and human lung adenocarcinoma cells (A549) at a concentration of 10uM, especially compounds 3aq, 3al, 3ah, 3ab and 3aa show better inhibition effect on human breast cancer cells (MCF-7) and human lung adenocarcinoma cells (A549) at the same time, and the inhibition rate is higher than 66%. The results show that the compound prepared by the invention can be developed and prepared into the medicines for treating breast cancer and lung cancer.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.

Claims (7)

1. A chiral gamma-butyrolactone derivative is characterized in that the structure is shown as formula (1):
Figure FDA0003477272760000011
wherein Ar is1、Ar2And Ar3Each independently is phenyl, halophenyl, nitro-substituted phenyl, C1～4Alkyl-substituted phenyl, C1～4Alkoxy-substituted phenyl, C1～4Haloalkyl substituted phenyl, naphthyl or halonaphthyl.
2. The chiral gamma-butyrolactone derivative of claim 1, wherein Ar is1、Ar2And Ar3Each independently is phenyl, halophenyl, nitro-substituted phenyl, methyl-substituted phenyl, ethyl-substituted phenyl, methoxy-substituted phenyl, ethoxy-substituted phenyl, trifluoromethyl-substituted phenyl, trifluoroethyl-substituted phenyl, naphthyl, or halonaphthyl.
3. The chiral gamma-butyrolactone derivative of claim 2, wherein Ar is1、Ar2And Ar3Each independently is phenyl, halophenyl, nitro-substituted phenyl, naphthyl, or halonaphthyl.
4. The chiral gamma-butyrolactone derivative of claim 3, wherein said Ar1、Ar2And Ar3Each independently phenyl, bromophenyl, chlorophenyl, fluorophenyl, nitro-substituted phenyl or naphthyl.
5. The chiral gamma-butyrolactone derivative of claim 4, wherein Ar1、Ar2And Ar3Each independently is phenyl, 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 3, 4-dichlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-nitro-phenyl, 2-nitro-phenyl or naphthyl.
6. The process for preparing a chiral γ -butyrolactone derivative according to any one of claims 1 to 5, wherein the 3-arylcyclopropene carboxylic acid of formula (2) and the imine of formula (3) are reacted with each other in the presence of a catalyst to obtain the chiral γ -butyrolactone derivative of formula (1);
wherein the structures of formula (2) and formula (3) are:
Figure FDA0003477272760000012
a substituent Ar of the formulae (2) and (3)1、Ar2、Ar3Claims 1 to 5 having the same meaning as in the corresponding claims;
the catalyst is bis [ (alpha, alpha' -tetramethyl-1, 3-benzenedipropionic acid) rhodium]And chiral phosphoric acid; the structure of the chiral phosphoric acid is as follows:
Figure FDA0003477272760000021
wherein Ar is 4-CF3C6H4。
7. The use of the chiral γ -butyrolactone derivative of any one of claims 1 to 5, or its pharmaceutically acceptable salt, in the preparation of an anticancer drug, wherein the anticancer drug is a drug against human breast cancer cells and human lung adenocarcinoma cells.
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