A 3-geminalcoholactam derivative and its preparation method and application

Abstract

The present invention provides a 3-gem-difluoroalkenyl lactam derivative and a preparation method and application thereof, belonging to the technical field of organic chemical synthesis. The 3-gem-difluoroalkenyl lactam derivative of the present invention has a structure shown in formula I. The method of the present invention uses zinc powder as a reducing agent and water as a proton source to quickly construct a molecular skeleton of the 3-gem-difluoroalkenyl lactam derivative through continuous reduction dechlorination and defluorination reactions. The method of the present invention has low cost, simple operation, high atom economy, and good industrial application prospects.

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical synthesis, and in particular to a 3-geminalfluoroalkenyl lactam derivative and a preparation method and application thereof. Background Art

[0002] As a common type of fluorinated olefin compounds, geminal difluoroolefins are similar to compounds such as ketones, aldehydes and esters in terms of spatial structure and electronic effects. They are electronic isosteres of carbonyl groups and have received extensive attention in the field of drug design and development. For example, diaryl-substituted geminal difluoroolefins can inhibit the polymerization of tubulin and have high cytotoxicity to HCT116 cells (J. Med. Chem, 2009, 52, 4538). In addition, the practical drug seleracetam with geminal difluoroolefin structure has significant therapeutic effects on the treatment of epilepsy (Epilepsia, 2009, 50, 702). It is worth noting that geminal difluoroolefin molecules are also often used as bioisomers of carbonyl groups to improve metabolic stability and target specificity. For example, when the carbonyl group in artemisinin is converted into geminal difluoroolefins, the drug activity of the artemisinin analog is nearly doubled (J. Med. Chem. 2018, 61, 5822).

[0003] Traditional synthesis methods for geminal difluoroolefin compounds include classic Wittig, Horner-Wadsworth-Emmons or Julia Kocienski reactions, or by reacting diazo compounds with difluorocarbene precursors or difluoromethyl sulfone reagents. However, these methods have harsh reaction conditions and limited product structural diversity. With the rapid development of modern synthetic chemistry, more convenient and efficient methods have been reported. Among them, the selective defluorination reaction of trifluoromethyl olefins (Adv. Synth. Catal. 2022, 364, 234) is the most common method. However, although great progress has been made in the current methods for accurately constructing geminal difluoroolefin compounds, there are still limitations such as: 1) long steps and low efficiency; 2) poor selectivity; 3) insufficient synthesis of structural diversity, which makes it difficult to support its application in the field of new drug research and development. Therefore, it is of great theoretical and practical significance to develop novel synthesis methods and construct geminal difluoroolefin molecules with diverse structures. Summary of the invention

[0004] Based on the above, the purpose of the present invention is to provide a 3-gem-difluoroalkenyl lactam derivative and a preparation method and application thereof. The method of the present invention uses zinc powder as a reducing agent and water as a proton source to quickly construct a molecular skeleton of a 3-gem-difluoroalkenyl lactam derivative through continuous reduction dechlorination and defluorination reactions. It is found that the gem-difluoroalkene derivative prepared by the method of the present invention has an inhibitory effect on breast cancer cells MDA-MB-231.

[0005] In order to achieve the above-mentioned object, the present invention provides the following technical solution: a 3-geminal difluoroalkenyl lactam derivative having a structure shown in Formula I:

[0006]

[0007] Wherein, R is phenyl, 1-naphthyl, 4-methoxyphenyl, 6-Cl-3-pyridyl or 4-methoxybenzoyl; n is 5, 6 or 7.

[0008] Preferably, the 3-geminalfluoroalkenyl lactam derivative is selected from one of the following structural formulas:

[0009]

[0010] The present invention also provides a method for preparing the 3-gem-difluoroalkenyl lactam derivative described in the above technical scheme, wherein a 1-chloro-2,2,2-trifluoroethyl lactam compound is reacted with water and a reducing agent in an organic solvent in an oil bath to prepare the 3-gem-difluoroalkenyl lactam derivative.

[0011] Preferably, the structural formula of the 1-chloro-2,2,2-trifluoroethylene lactam compound is as shown in Formula II:

[0012]

[0013] Wherein, R is phenyl, 1-naphthyl, 4-methoxyphenyl, 6-Cl-3-pyridyl or 4-methoxybenzoyl; n is 5, 6 or 7.

[0014] Preferably, the reducing agent is Zn powder; and the molar ratio of the 1-chloro-2,2,2-trifluoroethylene lactam compound to the reducing agent is 1:(1.5-4.0).

[0015] Preferably, the molar ratio of the 1-chloro-2,2,2-trifluoroethylene lactam compound to the water is 1:(5-30).

[0016] Preferably, the reaction is carried out under an inert atmosphere; the reaction temperature is 80 to 110° C., and the reaction time is 12 to 36 hours.

[0017] The present invention also provides an antibacterial active drug, the raw materials of which include the 3-geminaldifluoroalkenyl lactam derivative.

[0018] The present invention also provides an anti-tumor active drug, the raw materials of which include the 3-geminaldifluoroalkenyl lactam derivative.

[0019] The present invention also provides an antiviral active drug, the raw materials of which include the 3-geminaldifluoroalkenyl lactam derivative.

[0020] Beneficial technical effects:

[0021] The present invention provides a rapid synthesis method of 3-geminal difluoroalkenyl lactam derivatives, which has low cost, simple operation and high atom economy. The geminal difluoroalkenyl derivatives prepared by the method have certain anti-tumor activity and good application prospects. DETAILED DESCRIPTION

[0022] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0023] It should be understood that the terms described in the present invention are only for describing a particular embodiment and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. The intermediate value in any stated value or stated range, and each smaller range between any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0024] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0025] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to the skilled artisan. The present invention description and examples are exemplary only.

[0026] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0027] The present invention provides a 3-geminal difluoroalkenyl lactam derivative having a structure shown in Formula I:

[0028]

[0029] Wherein, R is phenyl, 1-naphthyl, 4-methoxyphenyl, 6-Cl-3-pyridyl or 4-methoxybenzoyl; n is 5, 6 or 7.

[0030] In some embodiments, the 3-geminalfluoroalkenyl lactam derivative is selected from one of the following structural formulas:

[0031]

[0032]

[0033] The present invention also provides a method for preparing the 3-gem-difluoroalkenyl lactam derivative described in the above technical scheme, wherein a 1-chloro-2,2,2-trifluoroethyl lactam compound is reacted with water and a reducing agent in an organic solvent in an oil bath to prepare the 3-gem-difluoroalkenyl lactam derivative.

[0034] In some embodiments, the structural formula of the 1-chloro-2,2,2-trifluoroethylene lactam compound is as shown in Formula II:

[0035]

[0036] Wherein, R is phenyl, 1-naphthyl, 4-methoxyphenyl, 6-Cl-3-pyridyl or 4-methoxybenzoyl; n is 5, 6 or 7.

[0037] When the structural formula of the 1-chloro-2,2,2-trifluoroethylene lactam compound is as shown in Formula II, the reaction equation of the 3-gem-difluoroalkenyl lactam derivative is as follows:

[0038]

[0039] In some embodiments, the organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, ethanol or dimethyl sulfoxide; the usage ratio of the 1-chloro-2,2,2-trifluoroethylene lactam compound to the organic solvent is 0.3 mmol: 1 to 3 mL.

[0040] In some embodiments, the reducing agent is Zn powder; and the molar ratio of the 1-chloro-2,2,2-trifluoroethylene lactam compound to the reducing agent is 1:(1.5-4.0).

[0041] In some embodiments, the molar ratio of the 1-chloro-2,2,2-trifluoroethylene lactam compound to the water is 1:(5-30).

[0042] In some embodiments, the reaction is carried out under an inert atmosphere; the reaction temperature is 80 to 110° C., and the reaction time is 12 to 36 hours.

[0043] In some embodiments, after the reaction is completed, the steps of separation and purification are also included.

[0044] In some embodiments, the separation may be performed by liquid extraction; and the purification may be performed by column chromatography.

[0045] In some embodiments, the extractant used in the liquid phase extraction is ethyl acetate. After extraction, the upper layer liquid is collected, dried with anhydrous sodium sulfate, and the ethyl acetate is evaporated to obtain crude crystals. After recrystallization, the crude crystals are chromatographed on a 200-400 mesh silica gel column. The eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:2 to 10.

[0046] In the method of the present invention, zinc powder is used as a reducing agent to firstly perform two consecutive single-electron reductions to obtain a dechlorinated product; then, two consecutive single-electron reductions and defluorination are performed to obtain a 3-geminaldifluoroalkenyl lactam product.

[0047] In order to better understand the present invention, the content of the present invention is further explained below in conjunction with the embodiments, but the content of the present invention is not limited to the following embodiments.

[0048] Example 1

[0049] To a 25 mL Shrek tube, weighed 1-chloro-2,2,2-trifluoroethylene lactam compound (0.3 mmol), zinc powder (0.9 mmol), water (1.5 mmol) and N,N-dimethylformamide (2 mL) were added in sequence, nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain a white solid with a yield of 93%.

[0050] The reaction equation is as follows:

[0051]

[0052] The structural characterization data of the obtained target product are shown below:

[0053] 1H NMR (400MHz, DMSO-d6) δ7.65(d,J=8.8Hz,2H),7.38(t,J=8.0Hz,2H),7.15(t,J=7.9Hz,1H),4.73(ddd,J=26.7,9 .2,2.4Hz,1H),3.88-3.76(m,2H),3.49(q,J=9.5Hz,1H),2.42-2.32(m,1H),1.93(ddd,J=20.6,11.8,9.2Hz,1H);

[0054] 13 C NMR (100MHz, DMSO-d6) δ 172.5, 156.6 (dd, J = 283.0Hz), 139.5, 128.7, 124.1, 119.4, 78.6 (dd, J = 8.0Hz), 46.1, 38.3 (d, J = 5.6Hz), 25.1; 19 F NMR(376MHz, DMSO-d6)δ-87.62(d,J=44.1Hz),-89.91(d,J=44.1Hz)

[0055] HRMS(ESI)m / z calcd for C 12 H 12 ONF2 + [M+H] + 224.0881, found 224.0878.

[0056] The structure of the target compound is inferred from the above characterization data as follows:

[0057]

[0058] The compound has an inhibitory effect on MDA-MB-231 breast cancer cells, IC 50 >80μM.

[0059] Example 2

[0060] To a 25 mL Shrek tube, weighed 1-chloro-2,2,2-trifluoroethylene lactam compound (0.3 mmol), zinc powder (0.9 mmol), water (1.5 mmol) and N,N-dimethylformamide (2 mL) were added in sequence, nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain a white solid with a yield of 92%.

[0061] The reaction equation is as follows:

[0062]

[0063] The structural characterization data of the obtained target product are shown below:

[0064] 1 H NMR (400MHz, CDCl3) δ7.94-7.88(m,1H),7.85(d,J=8.2Hz,1H),7.70(d,J=8.1Hz,1H),7.56-7.47(m,3H),7.37(d,J=7.2Hz,1H),4.57(dd,J=25 .4,8.4Hz,1H),3.92(q,J=9.5Hz,1H),3.78(t,J=9.2Hz,1H),3.59(q,J=9.0Hz,1H),2.64(dt,J=14.3,7.6Hz,1H),2.23(dt,J=21.0,9.7Hz,1H).

[0065] 13 C NMR(100MHz, CDCl3) δ173.92,157.8(dd,J=286.1,286.0Hz),135.4,134.7,129.6,128.7,128.7 ,126.9,126.5,125.7,124.7,122.6,77.6(dd,J=18.5,18.3Hz),49.9,37.9(d,J=5.5Hz),27.5.

[0066] 19 F NMR (377MHz, Chloroform-d) δ -85.21 (d, J = 39.9Hz), -87.61 (d, J = 39.9Hz).

[0067] HRMS(ESI)m / z calcd for C 16 H 14 ONF2 + [M+H] + 274.1038, found 274.1032.

[0068] The structure of the target compound is inferred from the above characterization data as follows:

[0069]

[0070] The compound has an inhibitory effect on MDA-MB-231 breast cancer cells, IC 50 >80μM.

[0071] Example 3

[0072] To a 25 mL Shrek tube, weighed 1-chloro-2,2,2-trifluoroethylene lactam compound (0.3 mmol), zinc powder (0.9 mmol), water (1.5 mmol) and N,N-dimethylformamide (2 mL) were added in sequence, nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain a white solid with a yield of 93%.

[0073] The reaction equation is as follows:

[0074]

[0075] The structural characterization data of the obtained target product are shown below:

[0076] 1 H NMR (400MHz, CDCl3) δ7.52-7.47(m,2H),6.93-6.87(m,2H),4.44(ddd,J=25.3,8.5,1.8Hz,1H),3.83(dd,J=9.7,6.7Hz,1H),3.80(s,3H),3. 75(td,J=9.3,2.1Hz,1H), 3.42(dtd,J=10.2,8.6,1.4Hz,1H), 2.48(dddd,J=12.4,8.5,6.6,1.8Hz,1H), 1.97(ddd,J=21.2,12.5,9.4Hz,1H).

[0077] 13 C NMR(100MHz,DMSO-d6)δ171.9,156.6(dd,J=282.7,282.4Hz),155.9,132.7,1 21.2, 113.8, 78.7 (dd, J = 25.1, 17.2Hz), 55.2, 46.4, δ 38.1 (d, J = 5.6Hz), 25.2.

[0078] 19 F NMR (376MHz, DMSO) δ -87.67 (d, J = 44.3Hz), -89.87 (d, J = 44.3Hz).

[0079] HRMS(ESI)m / z calcd for C13 H 14 O2NF2 + [M+H] + 254.0987, found 254.0983.

[0080] The structure of the target compound is inferred from the above characterization data as follows:

[0081]

[0082] The compound has an inhibitory effect on MDA-MB-231 breast cancer cells, IC 50 >80μM.

[0083] Example 4

[0084] To a 25 mL Shrek tube, weighed 1-chloro-2,2,2-trifluoroethylene lactam compound (0.3 mmol), zinc powder (0.9 mmol), water (1.5 mmol) and N,N-dimethylformamide (2 mL) were added in sequence, nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain a white solid with a yield of 93%.

[0085] The reaction equation is as follows:

[0086]

[0087] The structural characterization data of the obtained target product are shown below:

[0088] 1 HNMR (400MHz, DMSO-d6) δ8.70(d,J=2.8Hz,1H),8.22(dd,J=8.8,2.9Hz,1H),7.56(d,J=8.8Hz,1H),4.74(ddd,J=26.7, 9.3,2.2Hz,1H),3.89-3.77(m,2H),3.54(q,J=9.3Hz,1H),2.42(dddd,J=12.1,8.8,5.8,3.1Hz,1H),2.02-1.91(m,1H).

[0089] 13C NMR(100MHz,DMSO-d6)δ173.3,156.6(dd,J=283.2,283.2Hz),144.5,140.3,1 35.6, 129.7, 124.1, 78.2 (dd, J = 25.7, 17.0Hz), 45.6, 38.0 (d, J = 5.7Hz), 25.1.

[0090] 19 F NMR (376MHz, DMSO) δ -87.30 (d, J = 43.5Hz), -89.61 (d, J = 43.4Hz).

[0091] HRMS(ESI)m / z calcd for C 11 H 10 ON2ClF2 + [M+H] + 259.0444, found 259.0441.

[0092] The structure of the target compound is inferred from the above characterization data as follows:

[0093]

[0094] The compound has an inhibitory effect on MDA-MB-231 breast cancer cells, IC 50 >80μM.

[0095] Example 5

[0096] To a 25 mL Shrek tube, weighed 1-chloro-2,2,2-trifluoroethylene lactam compound (0.3 mmol), zinc powder (0.9 mmol), water (1.5 mmol) and N,N-dimethylformamide (2 mL) were added in sequence, nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain a white solid with a yield of 93%.

[0097] The reaction equation is as follows:

[0098]

[0099] The structural characterization data of the obtained target product are shown below:

[0100] 1HNMR (400MHz, CDCl3) δ7.62(d,J=7.4Hz,2H),6.90(d,J=7.4Hz,2H),4.37(dd,J=24.7,7.6Hz,1H),4.00(t,J =9.6Hz,1H),3.85(s,3H),3.84-3.79(m,1H),3.40(t,J=10.5Hz,1H),2.53-2.41(m,1H),2.02-1.90(m,1H);

[0101] 13 C NMR (100MHz, CDCl3) δ173.5, 170.0, 163.2, 157.9 (t, J = 289.2Hz), 131.9, 125.9, 113.3, 76.4 (dd, J = 27.6, 18.9Hz), 55.5, 44.7, 39.8 (d, J = 5.3Hz), 25.6.

[0102] 19 F NMR (376MHz, Chloroform-d) δ -84.65 (dd, J = 37.2, 3.3Hz), -86.67 (dd, J = 37.1, 3.4Hz).

[0103] HRMS(ESI)m / z calcd for C 14 H 14 O3NF2 + [M+H] + 282.0936, found 282.0932.

[0104] The structure of the target compound is inferred from the above characterization data as follows:

[0105]

[0106] The compound has an inhibitory effect on MDA-MB-231 breast cancer cells, IC 50 >80μM.

[0107] Example 6

[0108] To a 25 mL Shrek tube, weighed 1-chloro-2,2,2-trifluoroethylene lactam compound (0.3 mmol), zinc powder (0.9 mmol), water (1.5 mmol) and N,N-dimethylformamide (2 mL) were added in sequence, nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain a white solid with a yield of 93%.

[0109] The reaction equation is as follows:

[0110]

[0111] The structural characterization data of the obtained target product are shown below:

[0112] 1 H NMR (400MHz, CDCl3) δ7.50-7.42(m,2H),7.39-7.29(m,2H),7.26-7.20(m,2H ),6.94-6.88(m,2H),4.56-4.36(m,3H),4.14-4.08(m,2H),3.80(s,3H),3.7 2-3.57(m,2H),3.33(dt,J=13.4,6.3Hz,3H),2.17(dt,J=10.8,5.3Hz,1H),2 .05-1.97(m,2H),1.81(ddt,J=19.0,10.1,5.2Hz,1H),1.43(t,J=7.1Hz,3H);

[0113] 13 C NMR (100MHz, DMSO) δ169.0,161.5,159.4,156.5,156.2(dd,J=281.5,281.6Hz),141.3,139.9,138.5,133.1,132.5,126.9,126.8 ,126.4,126.1,113.5,79.9(dd,J=24.5,17.5Hz),60.7,55.6,55.0,50.84(d,J=16.3Hz),37.4(d,J=4.8),27.7,21.6,21.2,14.2.

[0114] 19F NMR (376MHz, DMSO-d6) δ -87.30 (d, J = 43.6Hz), -89.61 (d, J = 43.4Hz).

[0115] HRMS(ESI)m / z calcd for C 29 H 29 O5N4F2 + [M+H] + 551.2101, found 551.2094.

[0116] The structure of the target compound is inferred from the above characterization data as follows:

[0117]

[0118] The compound has an inhibitory effect on MDA-MB-231 breast cancer cells, IC 50 =70.25μM.

[0119] Example 7

[0120] To a 25 mL Shrek tube, weighed 1-chloro-2,2,2-trifluoroethylene lactam compound (0.3 mmol), zinc powder (0.9 mmol), water (1.5 mmol) and N,N-dimethylformamide (2 mL) were added in sequence, nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain a white solid with a yield of 93%.

[0121] The reaction equation is as follows:

[0122]

[0123] The structural characterization data of the obtained target product are shown below:

[0124] 1H NMR (400MHz, CDCl3) δ7.32(t,J=7.7Hz,2H),7.26-7.20(m,2H),7.20-7.11(m,4H),6.86(dq,J=7.4,3.8Hz,1H),4.74(d dd,J=26.3,9.3,1.9Hz,1H),3.35(q,J=9.5Hz,1H),3.07(td,J=13.1,8.3Hz,1H),2.79-2.65(m,1H),2.26-2.09(m,2H).

[0125] 13 C NMR(100MHz, CDCl3)δ172.0,155.4(t,J=285.8Hz),142.4,142.1,135.7,129.3,129.1,128 .1,127.4,127.0,126.8,125.7,77.8(dd,J=26.2,17.4Hz),37.3,37.2(d,J=5.6Hz),29.9.

[0126] 19 F NMR (376MHz, CDCl3) δ -87.63 (d, J = 44.4Hz), -88.90 (d, J = 44.4Hz).

[0127] HRMS(ESI)m / z calcd for C 18 H 16 ONF2 + [M+H] + 300.1194, found 300.1189.

[0128] The structure of the target compound is inferred from the above characterization data as follows:

[0129]

[0130] The compound has an inhibitory effect on MDA-MB-231 breast cancer cells, IC 50 >80μM.

[0131] Example 8

[0132] To a 25 mL Shrek tube, weighed 1-chloro-2,2,2-trifluoroethylene lactam compound (0.3 mmol), zinc powder (0.9 mmol), deuterated water (9 mmol) and N,N-dimethylformamide (2 mL) were added in sequence, nitrogen was replaced, nitrogen was filled, and the mixture was placed in an oil bath at 100°C for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain a white solid with a yield of 93%.

[0133] The reaction equation is as follows:

[0134]

[0135] The structural characterization data of the obtained target product are shown below:

[0136] 1 HNMR (400MHz, Chloroform-d) δ 7.78-7.44 (m, 2H), 7.07-6.67 (m, 2H), 3.92 (d, J = 55.5Hz, 5H), 2.45 (d, J = 11.2Hz, 1H), 1.95 (d, J = 9.3Hz, 1H).

[0137] 13 C NMR (100MHz, DMSO) δ173.5, 169.2, 162.3, 156.7 (dd, J = 283.7, 283.8Hz), 131.5, 126.2, 113.0, 77.7 (m), 55.4, 44.4, 38.5 (m), 24.5.

[0138] 19 F NMR (376MHz, Chloroform-d) δ -84.83 (d, J = 37.7Hz), -86.88 (d, J = 37.6Hz).

[0139] HRMS(ESI)m / z calcd for C 14 H 12 D2O3NF2 + [M+H] + 284.1062, found 284.1056.

[0140] The structure of the target compound is inferred from the above characterization data as follows:

[0141]

[0142] The compound has an inhibitory effect on MDA-MB-231 breast cancer cells, IC 50 >80μM.

[0143] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A 3-geminalfluoroalkenyl lactam derivative, characterized in that: The structural formula is:

2. A method for preparing the 3-geminalfluoroalkenyl lactam derivative according to claim 1, characterized in that: The 1-chloro-2,2,2-trifluoroethylene lactam compound is reacted with water and a reducing agent in an organic solvent in an oil bath to prepare the 3-gem-difluoroalkenyl lactam derivative; The structural formula of the 1-chloro-2,2,2-trifluoroethylene lactam compound is:

3. The preparation method according to claim 2, characterized in that: The reducing agent is Zn powder; the molar ratio of the 1-chloro-2,2,2-trifluoroethylene lactam compound to the reducing agent is 1:(1.5-4.0).

4. The preparation method according to claim 2, characterized in that: The molar ratio of the 1-chloro-2,2,2-trifluoroethylene lactam compound to the water is 1:(5-30).

5. The preparation method according to claim 2, characterized in that: The reaction is carried out under an inert atmosphere; the reaction temperature is 80 to 110° C., and the reaction time is 12 to 36 hours.

6. An anti-tumor active drug, characterized in that: The raw material comprises the 3-geminalfluoroalkenyl lactam derivative according to claim 1.

Images