CN114436918A - Cyclobut-1-enamine compound, preparation method thereof and application thereof in medicines - Google Patents

Cyclobut-1-enamine compound, preparation method thereof and application thereof in medicines Download PDF

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CN114436918A
CN114436918A CN202210171146.7A CN202210171146A CN114436918A CN 114436918 A CN114436918 A CN 114436918A CN 202210171146 A CN202210171146 A CN 202210171146A CN 114436918 A CN114436918 A CN 114436918A
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王晓娜
丁利霞
常俊标
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Abstract

The invention belongs to the field of organic chemical synthesis, and discloses a cyclobut-1-enamine compound, a preparation method thereof and application thereof in antiviral and antitumor drugs. The compound has a structure shown in a general formula (I), wherein, EWG is selected from alkyl or aryl substituted sulfonyl; r is selected from alkyl, alkoxy, halogen and nitro. The method heats the alkyne amide raw material to a molten state under the drive of heat, so that [2+2] is generated between molecules]Cycloaddition reaction to obtain polysubstituted cyclobutyl-1-enamine compound. The method has the advantages of easily obtained raw materials, simple steps, no catalyst, no solvent, high yield and the like. The compound has the activity of resisting SARS-CoV-2, 5637, Hela, SW480, Hep G2, A549 and MCF-7,has good application prospect in the aspect of treating novel coronavirus, bladder cancer, cervical cancer, colon cancer, liver cancer, lung cancer and breast cancer.
Figure 216091DEST_PATH_IMAGE002
（I）。

Description

Cyclobut-1-enamine compound, preparation method thereof and application thereof in medicines
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a cyclobut-1-enamine compound, a preparation method thereof and application thereof in antiviral and antitumor drugs.
Background
Functionalized cyclobut-1-enamines are an important building block and are found in many pharmaceutically active compounds and natural products. In addition, the cyclobut-1-enamine is also often used as a reaction substrate to construct other important organic functional group molecules, since the four-membered ring is endowed with good reactivity by tension. Therefore, the research on the synthesis method of the cyclobut-1-enamine compound is always a focus of the chemists.
The traditional construction of cyclobut-1-enamine compounds is carried out by Ficini [2+2]]By cycloaddition, i.e. by 2+2 reaction of alkynylamides with cyclic alkenones]Cycloaddition reactions produce cyclobut-1-enamines. In 2010, Hsung topic group reported alkyne amides and enones in CuCl for the first time2And AgSbF6Intermolecular Ficini [2+2] occurs under catalytic action]Cycloaddition reaction to synthesize cyclobut-1-enamine (org. Lett.,2010,12,3780-3783), and Cu (I), Ru (II), Rh (I) and other catalytic alkynylamides participating in [2+2]]Cycloaddition to form cyclobut-1-enamines, most of the methods are suitable only for alkynylamides having substituents at the alkynyl end, since these alkynylamides are relatively stable and highly active alkynylamides having no substituents at the end have almost no [2+2]]Generating cycloaddition product cyclobut-1-enamine; in addition, most of the reported methods use expensive heavy metal catalysts, and are not environment-friendly. Therefore, the method for constructing the cyclobut-1-enamine compound, which is efficient, environment-friendly and atom-economical, has important research significance, and particularly the method for constructing the cyclobut-1-enamine by the high-activity alkynylamide of which the tail end does not contain a substituent is still in a blank research state at present.
Disclosure of Invention
In order to overcome the technical defects, the invention aims to provide a polysubstituted cyclobut-1-enamine compound, a synthesis method thereof and application thereof in antiviral and antitumor drugs.
In order to achieve the purpose of the invention, the high-activity alkynylamide 1 without a substituent at the terminal is subjected to [2+2] cycloaddition reaction under the heating condition to obtain the cyclobut-1-enamine compound 2.
The specific technical scheme is as follows:
the cyclobut-1-enamine compound has a structural general formula as follows:
Figure BDA0003515798930000011
wherein, EWG is selected from sulfonyl, alkyl substituted sulfonyl or aryl substituted sulfonyl; r is selected from alkyl, alkoxy, halogen and nitro.
Preferably: EWG is selected from sulfonyl, C1-3 alkyl substituted sulfonyl or phenyl substituted sulfonyl; r is selected from halogen, C1-3 alkyl or C1-3 alkoxy, and is mono-substituted or di-substituted on a benzene ring.
The invention also provides a preparation method of the cyclobut-1-enamine compound, and the synthetic route is as follows:
Figure BDA0003515798930000021
the specific synthesis steps are as follows:
under the protection of nitrogen, adding the alkynylamide raw material 1 into a dry reaction bottle, heating the reaction bottle to a molten state, maintaining the molten state at the temperature until the reaction is completed, and carrying out column chromatography separation to obtain the cyclobut-1-enamine compound 2.
Further, in the above technical scheme, the synthetic route of the alkyne amide raw material 1 is as follows:
Figure BDA0003515798930000022
the specific synthesis steps are as follows:
under the protection of nitrogen, putting sulfonamide 3 and cesium carbonate into a round-bottom flask, adding anhydrous N, N-dimethylformamide, and stirring at room temperature; dissolving TMS-EBX iodide 4 in anhydrous dichloromethane, adding the obtained mixture into a reaction system at 0 ℃ in a dark condition, heating to room temperature, stirring until the reaction is complete, performing suction filtration, performing reduced pressure concentration to remove the solvent, and performing direct column chromatography separation to obtain the alkynylamide raw material 1.
In the step, the molar ratio of the sulfamide 3 to the cesium carbonate to the TMS-EBX iodide 4 is 1:1.3: 1.5; the volume ratio of the N, N-dimethylformamide to the dichloromethane solvent is 1: 2.5.
Further, in the above technical scheme, the synthetic route of the TMS-EBX iodide 4 is as follows:
Figure BDA0003515798930000023
the specific synthesis steps are as follows:
1) placing o-iodobenzoic acid 5 and sodium periodate in a round-bottom flask, adding glacial acetic acid aqueous solution (30% by volume), refluxing until the reaction is completed, adding ice water, cooling to room temperature in a dark place, filtering out white solid, and washing with ice water and glacial acetone to obtain the 1-hydroxy-1, 2-benzotriazole-3-one compound 6.
2) Dissolving the 1-hydroxy-1, 2-benzotriazole-3-one compound 6 in dichloromethane, performing nitrogen protection, slowly adding trimethylsilyl trifluoromethanesulfonate at 0 ℃, heating to room temperature, and stirring; adding bis (trimethylsilyl) acetylene, stirring at room temperature until the reaction is complete, adding saturated sodium bicarbonate solution into the reaction system until the mixture is clear, adding dichloromethane to extract the water phase, and adding anhydrous Na into the organic phase2SO4Drying, and concentrating under reduced pressure to remove the solvent to obtain TMS-EBX iodide 4.
In the step, the molar ratio of the o-iodobenzoic acid 5 to the sodium periodate is 1:1.05, and the molar ratio of the 1-hydroxy-1, 2-benzotriazole-3-one 6 to the trimethylsilyl trifluoromethanesulfonate to the bis (trimethylsilyl) acetylene is 1:1.5: 1.1.
Further, in the technical scheme, the application of the cyclobut-1-enamine compound in antiviral and antitumor drugs shows the activity of resisting SARS-CoV-2, 5637, Hela, SW480, Hep G2, A549 and MCF-7, and the cyclobut-1-enamine compound can be applied to the preparation research of drugs for resisting novel coronaviruses, bladder cancer, cervical cancer, colon cancer, liver cancer, lung cancer and breast cancer.
Compared with the prior art, the cyclobut-1-enamine compound provided by the invention has the following advantages: 1. the compound has the activity of resisting SARS-CoV-2, 5637, Hela, SW480, Hep G2, A549 and MCF-7, is applied to the preparation of medicaments for resisting novel coronavirus, bladder cancer, cervical cancer, colon cancer, liver cancer, lung cancer and breast cancer, and has good application prospect. 2. The synthetic method has the advantages of easily available raw materials, no need of a catalyst and a solvent in the reaction process, simple post-treatment, environmental friendliness and wide substrate universality. 3. The reaction path is short, the product yield is high and reaches 76-91 percent, and the high-efficiency synthesis of a series of multi-substituted cyclobut-1-enamine compounds can be rapidly realized.
Drawings
FIG. 1 is a drawing of Compound 2a of the present invention1H NMR spectrum;
FIG. 2 is a drawing of Compound 2a of the present invention13C NMR spectrum;
FIG. 3 is a schematic representation of Compound 2c of the present invention1H NMR spectrum;
FIG. 4 is a drawing of Compound 2c of the present invention13C NMR spectrum;
FIG. 5 is a drawing of Compound 2e of the present invention1H NMR spectrum;
FIG. 6 is a drawing of Compound 2e of the present invention13C NMR spectrum;
FIG. 7 is a drawing of Compound 2f of the present invention1H NMR spectrum;
FIG. 8 is a drawing of Compound 2f of the present invention13C NMR spectrum;
FIG. 9 shows 2g of a compound of the present invention1H NMR spectrum;
FIG. 10 shows 2g of a compound of the present invention13C NMR spectrum;
FIG. 11 is a drawing of Compound 2i of the present invention1H NMR spectrum;
FIG. 12 is a drawing of Compound 2i of the present invention13C NMR spectrum;
FIG. 13 is a bar graph of the anti-SARS-CoV-2 activity of the positive control Redsivir;
FIG. 14 is a bar chart of the cytotoxicity of Compound 2a of the invention;
FIG. 15 is a bar graph of the anti-SARS-CoV-2 activity of Compound 2a of the present invention;
FIG. 16 is a bar graph of the cytotoxicity of Compound 2b of the invention;
FIG. 17 is a bar graph of the cytotoxicity of Compound 2c of the invention;
FIG. 18 is a bar graph of the cytotoxicity of Compound 2d of the invention;
FIG. 19 is a bar graph of the cytotoxicity of Compound 2e of the invention;
FIG. 20 is a bar graph of the anti-SARS-CoV-2 activity of Compound 2e of the present invention;
FIG. 21 is a bar graph of the cytotoxicity of Compound 2f of the invention;
FIG. 22 is a bar graph of the anti-SARS-CoV-2 activity of Compound 2f of the present invention;
FIG. 23 is a bar graph of the cytotoxicity of 2g of compound of the invention;
FIG. 24 is a bar graph of the anti-SARS-CoV-2 activity of compound 2g of the present invention;
FIG. 25 is a bar graph of the cytotoxicity of Compound 2h of the invention.
Detailed Description
The technical solution of the present invention is further described in detail by the following embodiments, but the scope of the present invention is not limited thereto. Unless otherwise specified, the technical means used in the following examples are conventional means well known to those skilled in the art.
Main instruments and chemical reagents
Nuclear magnetic resonance spectrometer: bruker AscendTM400, respectively; high resolution mass spectrometer: a Bruker MicroTOOF-Q II mass spectrometer; an infrared spectrometer: known micro Smart Fourier transform infrared spectrometer (Tianjin Hongkong science and technology Co., Ltd.); three-purpose ultraviolet analyzer: model ZF-6 (Shanghai Gapeng science and technology, Inc.); melting point apparatus for measurement: XT4A micro melting point tester (Beijing Cork. Instrument electro-optic Instrument).
The raw materials and solvents used in the implementation process of the invention are all purchased from commercial sources.
Example 1: synthesis of TMS-EBX iodide 4
Figure BDA0003515798930000041
The specific synthesis steps of TMS-EBX iodide 4 are as follows:
1) 5(7.44g,30mmol) of o-iodobenzoic acid and (6.74g,31.5mmol) of sodium periodate were dissolved in 30% (v: v) of an aqueous glacial acetic acid solution (50mL) and refluxed for 4.0h until the reaction was completed, ice water (30mL) was added to the reaction system, the reaction system was cooled to room temperature under exclusion of light, a white solid was filtered off, the filtered white solid was washed with ice water (60mL) and glacial acetone (60mL), and the washed white solid was dried under exclusion of light at room temperature to obtain 6(7.13g,27mmol) of 1-hydroxy-1, 2-benzotriazol-3-one compound with a yield of 90%.
2) Placing 1-hydroxy-1, 2-benzotriazole-3-one 6(5.28g,20mmol) in a round bottom flask under nitrogen protection, adding dichloromethane (30mL), slowly adding trimethylsilyl trifluoromethanesulfonate (5.44mL,30mmol) at 0 ℃, heating to room temperature, and stirring for 0.5 h; then adding bis (trimethylsilyl) acetylene (4.99mL,22mmol), and stirring at room temperature for 6.0h until the reaction is complete; adding saturated sodium bicarbonate into the reaction system until the solution is clear, adding dichloromethane for extraction, and using anhydrous Na for an organic phase2SO4Drying and removal of the solvent under reduced pressure gave TMS-EBX iodide 4(6.81g,19.8mmol) in 99% yield.
Example 2: synthesis of acetylenic amide starting materials 1a-1i
In particular, the compound structure is abbreviated as: ts represents a p-methylbenzenesulfonyl group, and Mbs represents a p-methoxybenzenesulfonyl group.
Figure BDA0003515798930000051
Taking the specific synthesis step of the alkynylamide 1a as an example, sequentially adding sulfonamide 3a (123.7mg,0.50mmol) and cesium carbonate (211.8mg,0.65mmol) into a 25mL round-bottom flask, plugging the opening of the flask with a well-closed flip-open rubber stopper, performing nitrogen protection, adding dried N, N-dimethylformamide (1.0mL), and stirring at room temperature for 0.5 h; dissolving TMS-EBX iodide 4(258.2mg,0.75mmol) in dichloromethane (2.5mL), slowly adding the mixture into the reaction system at 0 ℃ in the dark, heating to room temperature and stirring for 0.5 h; monitoring the reaction process by using a thin layer chromatography, after the reaction is finished, performing suction filtration on silica gel, removing the solvent under reduced pressure, and performing column chromatography separation on the obtained crude product by using petroleum ether/ethyl acetate (10: 1-4: 1) as an eluent to obtain a white solid raw material 1a (135.2mg,0.498mmol) with the yield of 99%.
Compounds 1 were prepared according to the methods described above in this example using the corresponding sulfonamides 3b-3i, respectively, to give compounds 1b-1 i.
Figure BDA0003515798930000052
Compound 1 a: white solid, 99% yield,1H NMR(400MHz,CDCl3)δ7.58(dt,J＝8.6Hz,2.0Hz,2H),7.33-7.31(m,3H),7.30-7.27(m,3H),7.26-7.24(m,1H),2.84(s,1H),2.44(s,3H)；13C NMR(100MHz,CDCl3)δ145.3,138.4,133.0,129.7,129.3,128.6,128.4,126.4,76.7,59.1,21.9.
Figure BDA0003515798930000053
compound 1 b: white solid, 90% yield,1H NMR(400MHz,CDCl3)δ7.59(dt,J＝8.6Hz,2.2Hz,2H),7.30-7.28(m,2H),7.11(s,4H),2.81(s,1H),2.45(s,3H),2.34(s,3H)；13C NMR(100MHz,CDCl3)δ145.2,138.8,135.8,133.1,129.9,129.7,128.4,126.4,76.9,58.7,21.9,21.3.
Figure BDA0003515798930000054
compound 1 c: white solid, 99% yield,1H NMR(400MHz,CDCl3)δ7.59(dt,J＝8.6Hz,2.2Hz,2H),7.29(d,J＝12.0Hz 2H),7.12(dt,J＝10.3Hz,3.5Hz,2H),6.82(dt,J＝10.3Hz,3.5Hz,2H),3.80(s,3H),2.80(s,1H),2.45(s,3H)；13C NMR(100MHz,CDCl3)δ159.7,145.2,133.0,131.0,129.7,128.5,128.1,114.4,77.1,58.4,55.7,21.9.
Figure BDA0003515798930000061
compound 1 d: white solidThe yield of the product was 88%,1H NMR(400MHz,CDCl3)δ7.58(d,J＝8.4Hz,2H),7.30(d,J＝8.0Hz,3H),7.24-7.19(m,2H),7.04-6.99(m,2H),2.84(s,1H),2.45(s,3H)；13C NMR(100MHz,CDCl3)δ162.4(C-F,1JC-F＝246.7Hz),145.5,134.3(C-F,4JC-F＝3.2Hz),132.7,129.8,128.5(C-F,3JC-F＝8.9Hz),128.4,116.3(C-F,2JC-F＝22.9Hz),76.6,59.2,21.9.
Figure BDA0003515798930000062
compound 1 e: white solid, 93% yield,1H NMR(400MHz,CDCl3)δ7.60(dt,J＝8.6Hz,2.2Hz,2H),7.30-7.28(m,2H),7.22-7.18(m,1H),7.14-7.08(m,2H),7.02-6.99(m,1H),2.82(s,1H),2.45(s,3H),2.32(s,3H)；13C NMR(100MHz,CDCl3)δ145.2,139.4,138.3,133.2,129.7,129.4,129.0,128.5,127.2,123.4,76.8,58.9,21.9,21.4.
Figure BDA0003515798930000063
compound 1 f: white solid, in 86% yield,1H NMR(400MHz,CDCl3)δ7.62(dt,J＝8.7Hz,2.1Hz,2H),7.30(d,J＝8.1Hz,2H),6.95(s,1H),6.85(s,2H),2.81(s,1H),2.45(s,3H),2.27(s,6H)；13C NMR(100MHz,CDCl3)δ145.1,139.1,138.2,133.3,130.4,129.6,128.5,124.2,77.0,58.8,21.9,21.3.
Figure BDA0003515798930000064
compound 1 g: white solid, in 91% yield,1H NMR(400MHz,CDCl3)δ7.61(d,J＝8.4Hz,2H),7.29(d,J＝8.0Hz,2H),7.23-7.19(m,1H),6.87-6.81(m,3H),3.76(s,3H),2.84(s,1H),2.44(s,3H)；13C NMR(100MHz,CDCl3)δ160.1,145.3,139.4,133.1,129.9,129.7,128.4,118.4,114.5,112.0,76.9,59.3,55.6,21.9.
Figure BDA0003515798930000065
compound 1 h: white solid, 72% yield,1H NMR(400MHz,CDCl3)δ7.60(dt,J＝8.6,2.2Hz,2H),7.32-7.27(m,5H),7.21(dt,J＝7.6,1.9Hz,1H),2.88(s,1H),2.45(s,3H)；13C NMR(100MHz,CDCl3)δ145.6,139.5,134.8,132.8,130.2,129.9,128.7,128.4,126.3,124.4,76.0,60.0,21.9.
Figure BDA0003515798930000071
compound 1 i: white solid, 95% yield,1H NMR(400MHz,CDCl3)δ7.63(dt,J＝9.9Hz,3.0Hz,2H),7.35-7.31(m,3H),7.28-7.25(m,2H),6.94(dt,J＝9.9Hz,3.1Hz,2H),3.88(s,3H),2.84(s,1H)；13C NMR(100MHz,CDCl3)δ164.1,138.5,130.7,129.3,128.6,127.6,126.5,114.2,76.9,59.1,55.9.
example 3: synthesis of Compounds 2a-2i
Figure BDA0003515798930000072
Taking the specific synthetic procedure of compound 2a as an example, the alkynylamide 1a (81.4mg,0.3mmol) was charged into a dry reaction flask under nitrogen, the reaction was warmed to its molten state (100 ℃) and maintained at that temperature, the progress of the reaction was monitored by thin layer chromatography, and the reaction was complete after 2.0 h. The crude product was isolated by column chromatography using petroleum ether/ethyl acetate (3.5:1) as eluent to give product 2a (70.8mg, 0.131mmol) as a white solid in 87% yield.
Compound 2 was prepared according to the above procedure in this example from the alkynylamide intermediates 1b to 1i prepared in example 2, respectively, to give compounds 2b to 2i (Ts represents p-methylbenzenesulfonyl, and Mbs represents p-methoxybenzenesulfonyl).
Figure BDA0003515798930000073
Compound 2 a: white solid, 87% yield, RfNot 0.25[ petroleum ether/ethyl acetate (2:1)]；mp＝86–89℃；1H NMR(400MHz,CDCl3)δ7.79(dt,J＝8.4Hz,2.0Hz,2H),7.50-7.38(m,5H),7.33-7.26(m,5H),7.24(s,1H),7.18-7.08(m,3H),6.76-6.73(m,2H),5.94(s,1H),4.91(s,1H),2.45(s,3H),2.42(s,3H)；13C NMR(100MHz,CDCl3)δ153.1,152.0,148.9,146.0,145.5,135.7,133.1,132.9,130.2,130.1,130.02,129.97,129.5,129.4,129.1,128.4,124.8,121.7,118.6,76.0,21.94,21.89；IR(neat)(cm-1)1769w,1695w,1552s,1486m,1320m,1173s,694s；HRMS(ESI):m/z calcd for C30H27N2O4S2[M+H]+543.1407,found 543.1411.
Figure BDA0003515798930000081
Compound 2 b: white solid, 81% yield, Rf0.37[ petroleum ether/ethyl acetate (2:1)]；mp＝100–101℃；1H NMR(400MHz,CDCl3)δ7.79(dt,J＝8.6Hz,2.1Hz,2H),7.48(dt,J＝8.7Hz,2.2Hz,2H),7.31(d,J＝8.0Hz,2H),7.24(s,1H),7.19(d,J＝8.3Hz,2H),7.11-7.06(m,3H),7.02-6.99(m,2H),6.64(dt,J＝8.8Hz,2.4Hz,2H),5.93(s,1H),4.87(s,1H),2.45(s,3H),2.42(s,3H),2.40(s,3H),2.32(s,3H)；13C NMR(100MHz,CDCl3)δ152.6,151.9,146.4,145.9,145.4,140.4,134.5,133.1,133.0,132.7,130.1,130.0,129.9,129.8,129.7,129.4,128.4,121.7,118.6,76.0,21.94,21.88,21.5,21.1；IR(neat)(cm-1)1695w,1554s,1450w,1320m,1172s,1137s,667s；HRMS(ESI):m/z calcd for C32H31N2O4S2[M+H]+571.1720,found 571.1716.
Figure BDA0003515798930000082
Compound 2 c: white solid, 76% yield, Rf0.13[ petroleum ether/ethyl acetate (2:1)]；mp＝95–97℃；1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.2Hz,2H),7.48(d,J＝8.4Hz,2H),7.32-7.27(m,3H),7.24(s,1H),7.05(s,2H),6.90-6.86(m,2H),6.82(dt,J＝9.9Hz,3.3Hz,2H),6.71(dt,J＝9.6Hz,2.9Hz,2H),5.96(s,1H),4.86(s,1H),3.84(s,3H),3.79(s,3H),2.45(s,3H),2.42(s,3H)；13C NMR(100MHz,CDCl3)δ160.6,157.1,151.99,151.95,145.9,145.4,142.1,133.1,132.8,131.4,130.0,129.9,129.4,128.4,127.9,123.0,118.5,114.4,114.3,76.0,55.63,55.58,21.93,21.87；IR(neat)(cm-1)1768w,1555s,1501s,1242s,1170s,1082m,668s；HRMS(ESI):m/z calcd for C32H31N2O6S2[M+H]+603.1618,found 603.1614.
Figure BDA0003515798930000083
Compound 2 d: white solid, 87% yield, Rf0.37[ petroleum ether/ethyl acetate (2:1)]；mp＝90–91℃；1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.2Hz,2H),7.50(d,J＝8.1Hz,2H),7.33-7.27(m,4H),7.16-7.05(m,4H),7.00-6.94(m,2H),6.73-6.68(m,2H),5.95(s,1H),4.89-4.87(m,1H),2.45(s,3H),2.43(s,3H)；13C NMR(100MHz,CDCl3)δ163.3(C-F,1JC-F＝250.1Hz),160.3(C-F,1JC-F＝242.2Hz),153.0,151.9,146.3,145.6,144.9(C-F,4JC-F＝2.9Hz),132.9,132.8,132.1(C-F,3JC-F＝9.1Hz),131.5(C-F,4JC-F＝3.2Hz),130.1,129.9,129.5,128.3,123.0(C-F,3JC-F＝8.0Hz),118.2,116.5(C-F,2JC-F＝23.0Hz),115.8(C-F,2JC-F＝22.3Hz),75.9,21.91,21.87；IR(neat)(cm-1)1695w,1558s,1498s,1219m,1082m,1017w,668s；HRMS(ESI):m/z calcd for C30H25F2N2O4S2[M+H]+579.1218,found 579.1221.
Figure BDA0003515798930000091
Compound 2 e: white solid, 91% yield, Rf0.40[ petroleum ether/ethyl acetate (2:1)]；mp＝77–78℃；1H NMR(400MHz,CDCl3)δ7.79(dt,J＝8.6Hz,2.1Hz,2H),7.50(dt,J＝8.7Hz,2.1Hz,2H),7.33-7.30(m,2H),7.27-7.26(m,2H),7.25-7.24(m,2H),7.18-7.14(m,1H),6.98-6.89(m,3H),6.54-6.51(m,2H),5.90(s,1H),4.90(s,1H),2.46(s,3H),2.43(s,3H),2.35(s,3H),2.31(s,3H)；13C NMR(100MHz,CDCl3)δ152.9,151.9,148.9,145.9,145.4,139.5,138.9,135.5,133.2,133.0,130.9,130.7,130.1,129.9,129.4,129.0,128.9,128.5,127.0,125.6,122.4,118.7,118.6,76.1,21.93,21.88,21.6,21.5；IR(neat)(cm-1)1769w,1595w,1551s,1370m,1172s,1136s,670s；HRMS(ESI):m/z calcd for C32H31N2O4S2[M+H]+571.1720,found 571.1718.
Figure BDA0003515798930000092
Compound 2 f: white solid, 87% yield, RfNot 0.50[ petroleum ether/ethyl acetate (2:1)]；mp＝132–134℃；1H NMR(400MHz,CDCl3)δ7.79(dt,J＝8.3,1.9Hz,2H),7.51(dt,J＝8.3,1.9Hz,2H),7.31(d,J＝8.0Hz,2H),7.27(s,1H),7.25(s,1H),7.06(s,1H),6.78-6.72(m,3H),6.30(s,2H),5.88(s,1H),4.89(s,1H),2.46(s,3H),2.43(s,3H),2.29(s,6H),2.26(s,6H)；13C NMR(100MHz,CDCl3)δ152.8,151.9,148.9,145.8,145.2,139.1,138.7,135.3,133.3,133.0,131.8,130.1,129.8,129.4,128.6,127.6,126.4,119.4,118.8,76.1,21.92,21.88,21.5,21.4；IR(neat)(cm-1)2920w,1594w,1553s,1318m,1147s,1082m,683s；HRMS(ESI):m/z calcd for C34H35N2O4S2[M+H]+599.2033,found599.2031.
Figure BDA0003515798930000093
Compound 2 g: white solid, 90% yield, RfNot 0.19[ petroleum ether/ethyl acetate (2:1)]；mp＝76–77℃；1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.3Hz,2H),7.53(d,J＝8.4Hz,2H),7.32(d,J＝8.0Hz,2H),7.29-7.27(m,2H),7.25-7.24(m,1H),7.19-7.15(m,1H),6.99(dd,J＝8.0Hz,2.1Hz,1H),6.74(s,1H),6.68-6.65(m,2H),6.31-6.29(m,2H),5.92(s,1H),4.94(s,1H),3.78(s,3H),3.76(s,3H),2.45(s,3H),2.42(s,3H)；13C NMR(100MHz,CDCl3) δ 160.3,160.1,153.3,152.0,150.3,146.0,145.4,136.5,133.2,133.1,130.0,129.9,129.81,129.76,129.5,128.5,122.0,118.7,116.0,113.8,110.5,107.6,76.1,55.7,55.4,21.92,21.88, wherein there is a carbon signal overlap at 129.9 ppm; IR (neat) (cm)-1)1700w,1551s,1449w,1370m,1135s,1040m,673s；HRMS(ESI):m/z calcd for C32H31N2O6S2[M+H]+603.1618,found 603.1622.
Figure BDA0003515798930000101
Compound 2 h: white solid, 91% yield, Rf0.35[ petroleum ether/ethyl acetate (2:1)]；mp＝82–83℃；1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.3Hz,2H),7.53(d,J＝8.2Hz,2H),7.46-7.43(m,1H),7.37-7.29(m,5H),7.20(t,J＝8.0Hz,1H),7.13-7.07(m,3H),6.66-6.63(m,1H),6.60(t,J＝2.0Hz,1H),5.91(s,1H),4.91(s,1H),2.47(s,3H),2.44(s,3H)；13C NMR(100MHz,CDCl3) δ 153.8,151.9,150.1,146.5,145.8,136.6,134.9,134.6,132.9,132.8,130.5,130.3,130.17,130.16,130.13,129.9,129.6,128.4,124.8,121.6,120.0,118.4,75.9,21.95,21.92, wherein there is a carbon signal overlap at 130.16 ppm; IR (near) (cm)-1)1696w,1550s,1288m,1175m,1081m,1021w,667s；HRMS(ESI):m/z calcd for C30H25Cl2N2O4S2[M+H]+611.0627,found 611.0628.
Figure BDA0003515798930000102
Compound 2 i: white solid, 82% yield, Rf0.12[ petroleum ether/ethyl acetate (2:1)]；mp＝94–97℃；1H NMR(400MHz,CDCl3)δ7.84(dt,J＝9.9Hz,2.8Hz,2H),7.52(dt,J＝10.0Hz,2.8Hz,2H),7.46-7.38(m,3H),7.30-7.26(m,2H),7.17-7.09(m,3H),6.98(dt,J＝9.4Hz,2.6Hz,2H),6.90(dt,J＝9.7Hz,2.8Hz,2H),6.79-6.77(m,2H),5.93(s,1H),4.91(s,1H),3.87(s,3H),3.84(s,3H)；13C NMR(100MHz,CDCl3) δ 164.5,164.3,153.3,152.2,148.9,135.7,132.2,130.6,130.11,130.07,129.3,129.1,127.3,124.8,121.8,118.2,114.5,114.0,76.1,55.9,55.8, where there is a carbon signal overlap at 129.1 ppm; IR (near) (cm)-1)1697w,1592m,1551s,1260s,1136s,1083s,832s；HRMS(ESI):m/z calcd for C30H27N2O6S2[M+H]+575.1305,found 575.1303.
Example 4: study of antiviral Activity of representative Compound synthesized in example 3 of the present invention
Preparing and storing a compound storage solution: DMSO dilution to 10mM or 20mM, -20 ℃ storage; after thawing the stock solution, it was diluted with cell culture medium DMEM/10% FBS/1% Pen/Strep.
4.1 test of antiviral Activity of Compound 2a-2i
TABLE 1 relative amount of mRNA of Envelope gene in viral genome of Compound 2a,2d-2h virus
Figure BDA0003515798930000111
The virus contained GFP, and the production of GFP, which is observed by fluorescence microscopy, represents viral replication, and compounds 2a to 2h of the present invention, except 2i, all showed inhibition of viral GFP production, i.e., antiviral activity, at a concentration of 5. mu.M. Then taking Reidesciclovir as an anti-SARS-CoV-2 positive control drug, and confirming the antiviral activity of the compound 2a-2h by utilizing qRT-PCR semi-quantitative detection of the expression of the virus Envelope gene, wherein the experimental steps are as follows:
1) day-1, cells Caco-2-N (6X 10 per well)4One) were plated in 24-well plates and 300 μ L of medium was added: DMEM/10% FBS/1% Pen/Strep;
2) on day 0, 200. mu.L of 5. mu.M compound solution was added; after incubation for 1h, 30 μ L of virus was added; infection (SARS-CoV-2 GFP/. DELTA.N trVLP); the final concentration of the compound was 5. mu.M;
3) after the cells are cultured for 24 hours, the liquid is changed to wash away free viruses; after the cells are continuously cultured for 24 hours, digesting the cells to extract RNA, and performing reverse transcription to obtain cDNA; qRT-PCR semi-quantitative detection of the expression of the virus Envelope gene;
4) the relative replication capacity of the viruses was calculated as shown in tables 1 and 2.
TABLE 2 relative amount of Envelope gene mRNA of viral genome by Compound 2c
Figure BDA0003515798930000121
Since compound 2b is highly cytotoxic, cell-dead, non-fluorescent, there is no data on the relative replicative capacity of the virus of compound 2b in the table. The relative quantity data of mRNA of an Envelope gene of a virus genome extracted under the action of compounds 2a-2h in the tables 1 and 2 show that the antiviral activity sequence of the compounds is 2e,2f >2a >2g >2d >2c >2h, namely the compounds 2a, 2e,2f and 2g which do not contain substituent groups on benzene rings or contain electron-donating substituent groups at benzene ring meta positions of the cyclobutyl-1-enamine 2 have better antiviral effect, and can be used for the next antiviral dose-dependent effect detection.
4.2 cytotoxicity assays of Compounds 2a-2h
The cytotoxicity of the compounds 2a-2h was measured using MTT colorimetry, the experimental procedure was as follows:
1) day-1, cells CaCo-2-N (8X 10 per well)3One) were plated in 96-well plates, and 100 μ L of medium was added: DMEM/10% FBS/1% Pen/Strep;
2) on day 0, 100 μ L of compound solution was added; the final concentration of compound was 25. mu.M, 5. mu.M, 1. mu.M, 0.2. mu.M, while a compound-free control was set;
3) after 48 hours of cell culture, 100. mu.L of the supernatant was discarded, 20. mu.L of MTT (5mg/mL) was added, and the cells were cultured at 37 ℃ for 4 hours;
4) discarding 100 μ L of supernatant, adding 100 μ L of DMSO, shaking in a shaker until formazen is dissolved;
5) detecting the absorbance at 595nm by using an enzyme-labeling instrument, wherein the reference wavelength is 630 nm;
6) the survival rate of the cells was calculated as shown in Table 3.
The survival rate of the cells CaCo-2-N under the action of the compounds 2a-2h in Table 3 is shown as follows: the compounds 2a, 2e,2f, 2g and 2h are relatively low in cytotoxicity, that is, the toxicity of the compound 2a without a substituent on the benzene ring and the compounds 2e,2f, 2g and 2h with a substituent at the meta-position of the benzene ring in the cyclobutyl-1-enamine 2 is lower than that of the compounds 2b, 2c and 2d with a substituent at the para-position of the benzene ring, and the cell survival rate is as high as more than 90% when the concentration of the compounds 2a, 2g and 2h is 25 μ M. However, as shown in Table 1, 2h compound had poor antiviral activity, 2a compound and 2g compound had better antiviral effect, and in order to calculate the half-toxic concentration CC of 2a compound and 2g compound50The cytotoxicity was further examined at final concentrations of 450. mu.M, 150. mu.M and 50. mu.M of Compound 2a and 2g according to the above experimental procedures, and the survival rate of the cells was calculated as shown in Table 4.
TABLE 3 cell viability at different concentrations of Compounds 2a-2h
Figure BDA0003515798930000131
TABLE 4 cell viability at high concentrations of Compounds 2a and 2g
Figure BDA0003515798930000132
4.3 testing of Compounds 2a, 2e,2f and 2g for antiviral dose-dependent Effect
TABLE 5 antiviral dose-dependent Effect of Compounds 2a, 2e,2f and 2g
Figure BDA0003515798930000141
The antiviral activity assay of compounds 2a, 2e,2f and 2g above gave better antiviral efficacy as tested for antiviral activity of compounds 2a-2h, followed by the antiviral dose-dependent effect assay of compounds 2a, 2e,2f and 2 g. The antiviral dose-dependent effect detection of the compounds 2a, 2e,2f and 2g is carried out by taking Reidsevir as an anti-SARS-CoV-2 positive control drug, diluting the compound concentration (5 mu M, 1 mu M, 0.2 mu M and 0.04 mu M) in a double ratio, and utilizing qRT-PCR semiquantitative detection of the expression of the virus Envelope gene, wherein the experimental steps are as follows:
1) day-1, cells Caco-2-N (6X 10 per well)4One) in 24-well plates, 300 μ L medium: DMEM/10% FBS/1% Pen/Strep;
2) on day 0, 200. mu.L of compound solution was added; after incubation for 1h, 30 μ L of virus was added; infection (SARS-CoV-2 GFP/. DELTA.N trVLP); the final concentration of the compound was 5. mu.M, 1. mu.M, 0.2. mu.M, 0.04. mu.M;
3) after the cells are cultured for 24 hours, the liquid is changed to wash away free viruses;
4) after the cells are continuously cultured for 24 hours, digesting the cells to extract RNA, and performing reverse transcription to obtain cDNA;
5) qRT-PCR semi-quantitative detection of the expression of the virus Envelope gene;
6) the relative replication capacity of the viruses was calculated as shown in tables 5 and 6.
TABLE 6 antiviral dose-dependent Effect of Reidesvir
Figure BDA0003515798930000151
Finally, according to the survival rate of the cells Caco-2-N under the action of the compounds 2a-2h with different concentrations detected and calculated by an MTT colorimetric method (tables 3 and 4), calculating the median toxicity concentration CC50(FIG. 14, FIG. 16, FIG. 17, FIG. 18, FIG. 19, FIG. 21, FIG. 23 and FIG. 25, respectively); based on the antiviral dose-dependent effect assays of compounds 2a, 2e,2f, 2g and Reidesciclovir (tables 5 and 6), different concentrations of compounds 2a, 2e,2f, 2g and Reidesciclovir against SARS-CoV-2 virus were calculatedThe inhibition ratio (FIG. 15, FIG. 20, FIG. 22, FIG. 24 and FIG. 13, respectively) of (A), and the half effective concentration EC was calculated50The value is obtained. The results are given in Table 7 below.
TABLE 7 Compounds 2a-2h and drug Retciclovir cytotoxicity (CC)50) And anti-SARS-CoV-2 activity (EC)50)
Compound (I) CC50(μM) EC50(μM)
2a 417.18 0.05
2b 4.21 -
2c 13.14 -
2d 16.43 -
2e >25 0.10
2f 19.21 0.14
2g >450 0.14
2h >25 -
Ruidexiwei (Ridexil) >125 0.04
In the table, the contents of the contents,*CC50representing the concentration of drug required to inhibit half of the cell growth,*EC50representing the drug concentration required to inhibit half of the SARS-CoV-2 virus.
The assay was performed using methods well known to those skilled in the art, using Caco-2-N cells to evaluate the inhibitory activity of the synthesized compounds 2a-2h of the present invention against SARS-CoV-2. Experimental results show that the compound 2a without substituent on benzene ring of the cyclobutyl-1-enamine 2 and the compound 2g with strong electron-donating substituent (methoxyl) at benzene ring meta position both have better anti-SARS-CoV-2 activity and lower cytotoxicity, and the compounds 2e and 2f have better anti-SARS-CoV-2 activity but slightly stronger cytotoxicity. FIG. 15, FIG. 20, FIG. 22 and FIG. 24 show that compounds 2a, 2e,2f, 2g dose-dependently inhibited the replication of the SARS-CoV-2 virus strain. The invention has good application prospect in the preparation and research of anti-SARS-CoV-2 medicine.
Example 5: research on antitumor Activity of representative Compound synthesized in example 3 of the present invention
The cell lines, cell culture reagents, experimental apparatus and sources used for the study of antitumor activity of compounds 2a-2i are shown in tables 8, 9 and 10.
TABLE 8 cell line types and sources
Figure BDA0003515798930000161
TABLE 9 cell culture reagents and manufacturers
Figure BDA0003515798930000171
TABLE 10 Experimental instruments and manufacturers
Figure BDA0003515798930000172
Anticancer cell Activity and cytotoxicity assays for Compounds 2a-2i
Counting cancer cells in logarithmic growth phase, and preparing to concentration of 5 × 104Mixing each/mL cell suspension, shaking, inoculating to 96-well plate, adding 100 μ L cell suspension per well, 37 deg.C, and 5% CO2Culturing for 4-8h under the culture condition; preparing culture solution containing compounds with different concentrations by using fresh culture medium, and culturing for 48 h; after 48h, the culture solution in the 96-well plate is thrown off, 100 mu L of 10% CCK8 solution is added into each well, the culture is continued for 1-4h, and then the absorbance is detected under the wavelength of 450 nm. Inhibition rate ═ [ (Ac-As)/(Ac-Ab)]X is 100%; as is the absorbance of the experimental wells (containing cells, culture medium, CCK-8 solution, compound culture solution treatment group); ac: absorbance of control wells (cells, medium, CCK-8 solution, compound free broth treated group); ab: blank wells absorbance (medium and CCK-8 solution, no cells and no compounds). IC of Compounds was calculated using GraphPad Prism 9.050。
TABLE 11 inhibitory Activity of Compounds 2a-2i on Hep G2, A549 and MCF-7
Figure BDA0003515798930000181
Firstly, the inhibitory activity of the compounds 2a-2i on 3 cancer cells Hep G2, A549 and MCF-7 is tested and the IC is calculated50(Table 11). As shown in Table 11, the structure includesCompounds 2c and 2i having p-methoxyphenyl group showed the strongest inhibitory activity against cancer cells. Based on the results of this preliminary screening, the cell lines (containing 11 kinds of cancer cells and 1 kind of normal cells) were expanded, and VCR (vincristine) was used as a positive control, and the activities of compounds 2C and 2i against human bladder cancer cell 5637, human glioblastoma cell a172, human malignant melanoma cell a375, human cervical cancer cell C33A, human colon cancer cell HCT 116 and SW480, human cervical cancer cell Hela, human pancreatic cancer cell CFPAC-1, human liver cancer cell Hep G2, human lung cancer cell a549 and human breast cancer cell MCF-7, and cytotoxicity against normal cell 293T (renal epithelial cell) were examined, and the results are shown in tables 12.1 and 12.2 below.
TABLE 12.1 inhibitory Activity of Compounds 2C and 2i against 5637, A172, A375, C33A, HCT 116 and Hela
Figure BDA0003515798930000182
TABLE 12.2 inhibitory Activity of Compounds 2c and 2i on CFPAC-1, SW480, Hep G2, A549, MCF-7 and 293T
Figure BDA0003515798930000183
This assay was performed using methods well known to those skilled in the art, and 12 cell lines (containing 11 cancer cells and 1 normal cell) were used to evaluate the antitumor activity and safety of the synthesized compounds 2a-2i of the present invention. The experimental result shows that the compounds 2c and 2i containing p-methoxyphenyl in the cyclobut-1-enamine structure have the strongest inhibitory activity on cancer cells. Compared with a positive control drug VCR, the compound 2c has good inhibitory activity on human bladder cancer cells 5637, human cervical cancer cells Hela, human colon cancer cells SW480, human liver cancer cells Hep G2, human lung cancer cells A549 and human breast cancer cells MCF-7, but has slightly strong cytotoxicity on normal cells 293T (renal epithelial cells); the compound 2i has good inhibitory activity on human bladder cancer cells 5637, human liver cancer cells Hep G2 and human breast cancer cells MCF-7, and low cytotoxicity on normal cells 293T (renal epithelial cells). The invention has good application prospect in the preparation and research of the anti-tumor medicine.

Claims (9)

1. A cyclobut-1-enamine compound characterized by the structural formula:
Figure FDA0003515798920000011
wherein, EWG is selected from sulfonyl, alkyl substituted sulfonyl or aryl substituted sulfonyl; r is selected from alkyl, alkoxy, halogen and nitro.
2. The cyclobut-1-enamine of claim 1 wherein the EWG is selected from the group consisting of sulfonyl, C1-3 alkyl substituted sulfonyl, and phenyl substituted sulfonyl; r is selected from C1-3 alkyl, C1-3 alkoxy or halogen, and is mono-substituted or di-substituted on a benzene ring.
3. The cyclobut-1-enamine according to claim 1 selected from the group consisting of,
Figure FDA0003515798920000012
4. a process for the preparation of cyclobut-1-enamine compounds according to claim 1 by:
Figure FDA0003515798920000013
under the protection of nitrogen, the alkyne amide raw material 1 is uniformly dispersed in a dry reactor, heated to a molten state, kept in the molten state until the reaction is complete, and subjected to column chromatography separation to obtain the cyclobut-1-enamine compound 2.
5. The process for producing cyclobut-1-enamine according to claim 4, wherein the starting alkynylamide 1 is obtained by:
Figure FDA0003515798920000021
under the protection of nitrogen, putting sulfonamide 3 and cesium carbonate into a reactor, adding anhydrous N, N-dimethylformamide, and stirring at room temperature; dissolving TMS-EBX iodide 4 in anhydrous dichloromethane, adding the obtained mixture into a reaction system at 0 ℃ in a dark condition, heating to room temperature, stirring until the reaction is complete, filtering through silica gel, removing the solvent under reduced pressure, and directly performing column chromatography separation to obtain the alkynylamide raw material 1.
6. The method for preparing cyclobutyl-1-enamine compounds according to claim 5, wherein the molar ratio of sulfonamide 3, cesium carbonate and TMS-EBX iodo-4 in said step is 1:1.3: 1.5; the volume ratio of the N, N-dimethylformamide to the dichloromethane solvent is 1: 2.5.
7. The method for preparing cyclobutyl-1-enamine compounds according to claim 5, wherein the starting material TMS-EBX iodo-4 is prepared by:
Figure FDA0003515798920000022
1) placing o-iodobenzoic acid 5 and sodium periodate in a reactor, adding glacial acetic acid aqueous solution, refluxing until the reaction is complete, adding ice water, cooling to room temperature in a dark place, filtering out solids, and washing to obtain a 1-hydroxy-1, 2-benzotriazole-3-one compound 6;
2) dissolving the 1-hydroxy-1, 2-benzotriazole-3-one compound 6 in dichloromethane, performing nitrogen protection, slowly adding trimethylsilyl trifluoromethanesulfonate at 0 ℃, heating to room temperature, and stirring; adding bis (trimethylsilyl) acetylene, and stirring at room temperature until the reaction is complete; and adding saturated sodium bicarbonate into the reaction system until the solution is in a clear state, extracting, drying and removing the solvent under reduced pressure to obtain TMS-EBX iodide 4.
8. The process for producing cyclobutane-1-enamine compounds according to claim 7, wherein the molar ratio of o-iodobenzoic acid 5 to sodium periodate in said step is 1: 1.05; the molar ratio of 1-hydroxy-1, 2-benzotriazol-3-one compound 6, trimethylsilyl trifluoromethanesulfonate and bis (trimethylsilyl) acetylene was 1:1.5: 1.1.
9. The use of cyclobut-1-enylamine compounds according to claim 1,2 or 3 in the preparation of antiviral and antitumor drugs, characterized in that they are used as active ingredients in the preparation of drugs for the treatment of novel coronaviruses, bladder cancer, cervical cancer, colon cancer, liver cancer, lung cancer or breast cancer.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114989048A (en) * 2022-07-19 2022-09-02 郑州大学 Cyclobut-1-enamine compound, preparation method thereof and application thereof in anti-II dengue virus drugs

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019209757A1 (en) * 2018-04-24 2019-10-31 Vertex Pharmaceuticals Incorporated Pteridinone compounds and uses thereof
CN112341423A (en) * 2020-11-06 2021-02-09 江西师范大学 Water-soluble alkyne amide condensing agent and preparation method and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019209757A1 (en) * 2018-04-24 2019-10-31 Vertex Pharmaceuticals Incorporated Pteridinone compounds and uses thereof
CN112341423A (en) * 2020-11-06 2021-02-09 江西师范大学 Water-soluble alkyne amide condensing agent and preparation method and application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HONGYAN LI 等: "Copper-Catalyzed Ficini [2 + 2] Cycloaddition of Ynamides", 《ORGANIC LETTERS》 *
周欣悦等: "近年来炔酰胺参与的成环反应研究进展", 《有机化学》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114989048A (en) * 2022-07-19 2022-09-02 郑州大学 Cyclobut-1-enamine compound, preparation method thereof and application thereof in anti-II dengue virus drugs
CN114989048B (en) * 2022-07-19 2023-05-23 郑州大学 Cyclobut-1-enamine compound, preparation method thereof and application thereof in anti-II-type dengue virus drugs

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