Spiro butane indolone derivative as well as preparation method and application thereof

Abstract

The invention provides a spiro butane indolone derivative as well as a preparation method and application thereof, and belongs to the technical field of organic chemical synthesis. The series cyclization coupling reaction of the N-iodo aryl dicyclobutyl amide compound and the vinyl pyridine compound is realized by utilizing a photocatalytic system, and the method is used for constructing the spiro butane indolone derivative containing the pyridine structure. The spirobutane indolone derivative synthesized by the invention has an inhibition effect on H1975 human lung adenocarcinoma cells; the preparation method provided by the invention is mild in condition and simple and convenient to operate, has economical steps, provides a convenient synthesis way for the complex bioactive molecules, and has a good application prospect.

Description

Technical Field

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

[0002] Spiroindolones are an important class of spiroheterocyclic structures, found in numerous natural products and pharmaceutically active molecules, and possess significant biological activities (Bioorg. Med. Chem. 2015, 23, 7138; J. Am. Chem. Soc. 2008, 130, 17938; Angew. Chem., Int. Ed. 2004, 43, 1270). Studies have reported that compounds of this class, such as horsflinee, elacomine, and mitraphylline, exhibit antitumor, anti-inflammatory, antibacterial, and antiviral activities. Consequently, chemists have developed numerous efficient strategies for the synthesis of spiroindolones over the past few decades (J. Heterocycl. Chem. 2018, 55, 1783–1790; Tetrahedron. 2018, 74, 955–9614; Synlett. 2019, 30, 82–88). However, due to limitations in substrate synthesis, relatively few of these synthetic methods are suitable for the synthesis of spirobutane indolones. For example, nucleophilic substitution reactions of indolones with alkyl dihalides and 1,5-hydrogen shift reactions of aryl halides are only applicable to the preparation of some unsubstituted spirobutane indolones (Journal of Medicinal Chemistry, 2013, 56, 9275-9295; Journal of Medicinal Chemistry, 2013, 56, 9275-9295). Furthermore, intramolecular C-H arylation reactions of cyclobutanes are also limited to the synthesis of spirobenzocyclobutane indolones (Chem. Eur. J. 2013, 19, 119-16). In recent years, bicyclobutane (BCB) structures have become a star molecule for the preparation of functionalized strained ring molecules. Hari, Maji, Li Jinheng, Tang Kewen, Rong Liangce and other research groups have respectively used the radical cyclization strategy of aromatic bicyclobutylamides to achieve the synthesis of spirobutane indolones with functional groups such as carbonyl, sulfone, selenoether, and halogen (Chem. Sci. 2024, 15, 3182–3191; Org. Lett. 2024, 26, 6396-6401; Org. Lett. 2024, 26(10), 2073-2078; Org. Chem. Front. 2024, 11, 1982-1989; J. Org. Chem. 2024, 89, 15914-15923). Although some progress has been made, the functionalization types of spirobutane indolones still need to be expanded, and more novel and green synthetic methods need to be developed to further broaden the structural diversity of this type of skeleton. Summary of the Invention

[0003] Based on the above, the present invention aims to provide a spirobutane indole derivative, its preparation method, and application. This invention utilizes a photocatalytic system to achieve a tandem cyclization coupling reaction between an N-iodoaryl bicyclobutylamide compound and a vinyl pyridine compound, thereby constructing a spirobutane indole derivative containing a pyridine structure. Biological activity evaluation revealed that the spirobutane indole derivative prepared by this method exhibits inhibitory activity against H1975 human lung adenocarcinoma cells.

[0004] In order to achieve the above object, the present invention provides the following technical solutions:

[0005] One of the technical solutions of the present invention is a spirobutane indole derivative having the structure shown in Formula I:

[0006]

[0007] In Formula I, R 1 is hydrogen, alkoxy or alkyl, R 2 is an alkyl group or a benzyl group, R 3 is hydrogen or methyl.

[0008] In a preferred embodiment of the present invention, in Formula I, R 1 is hydrogen, methyl or methoxy, R 2 Methyl, benzyl, R 3 is hydrogen or methyl.

[0009] A second technical solution of the present invention is a method for preparing the above-mentioned spirobutane indole derivative, comprising dissolving an N-iodoaryl bicyclobutylamide compound and a vinyl pyridine compound in an organic solvent, adding a catalyst and an additive, and reacting under blue light catalysis to obtain the spirobutane indole derivative;

[0010] The structural formula of the N-iodoaryl bicyclobutylamide compound is:

[0011] The structural formula of the vinyl pyridine compound is

[0012] Among them, in the N-iodoaryl bicyclobutylamide compound and the vinyl pyridine compound, R 1 、R 2 、R 3 With the above R 1 、R 2 、R 3 same.

[0013] In a preferred embodiment of the present invention, the catalyst is (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, tris(2-phenylpyridine)iridium, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile or tris(2,2'-bipyridine)ruthenium di(hexafluorophosphate);

[0014] The additive is triethylamine, 8-diazabicycloundec-7-ene or diisopropylamine;

[0015] The organic solvent is acetonitrile, N,N-dimethylformamide, dichloroethane, toluene or N,N-dimethylacetamide.

[0016] In a preferred embodiment of the present invention, the molar ratio of the N-iodinated aryl bicyclobutylamide compound to the vinyl pyridine compound is 1:2; the molar ratio of the N-iodinated aryl bicyclobutylamide compound to the catalyst is 1:0.01-0.2; the molar ratio of the N-iodinated aryl bicyclobutylamide compound to the additive is 1:10-15; the amount ratio of the N-iodinated aryl bicyclobutylamide compound to the organic solvent is 0.1 mmol:1-3 mlmL.

[0017] In a preferred embodiment of the present invention, the power of the blue light is 3 to 10 W, and the reaction time is 12 to 24 hours.

[0018] In a preferred embodiment of the present invention, after the reaction is completed, the step of separating and purifying the obtained product is further included.

[0019] The specific steps of separation and purification are: after the reaction is completed, the obtained reaction liquid is subjected to liquid phase extraction, and the extraction solvent 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, and the crude crystals are recrystallized and chromatographed on a 200-400 mesh silica gel column, and the eluent is a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1:1-10.

[0020] The third technical solution of the present invention is the use of the above-mentioned spirobutane indole derivative in the preparation of a drug for treating H1975 human lung adenocarcinoma.

[0021] The fourth technical solution of the present invention is a drug for treating H1975 human lung adenocarcinoma, the raw materials of which include the above-mentioned spirobutane indole derivative and pharmaceutically acceptable excipients.

[0022] The present invention discloses the following technical effects:

[0023] The present invention utilizes N-iodoaryl bicyclobutylamide compounds and vinylpyridine compounds to prepare spirobutane indole derivatives, thereby achieving inhibition of H1975 human lung adenocarcinoma cells.

[0024] The preparation method of the present invention has mild conditions, low cost, simple operation, high atom economy, and is environmentally friendly. It provides a convenient synthetic route for the complex bioactive molecule and has good industrial application prospects. DETAILED DESCRIPTION

[0025] 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 rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0026] It should be understood that the terms described herein are intended only to describe particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges herein, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. The intermediate value within any stated value or stated range, and each smaller range between any other stated value or intermediate value within the stated range, is also encompassed within the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0027] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice 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 any conflict with any incorporated document, the contents of this specification shall prevail.

[0028] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be exemplary only.

[0029] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0030] The preparation method of the spirobutane indole one derivative of the present invention comprises the following steps: dissolving an N-iodoaryl bicyclobutylamide compound and a vinyl pyridine compound in an organic solvent, adding a catalyst and an additive, and reacting under blue light catalysis. After the reaction is completed, the obtained reaction solution is subjected to liquid phase extraction; after the extraction, the supernatant is collected, dried over anhydrous sodium sulfate, and ethyl acetate is evaporated to obtain crude crystals. After recrystallization, the crude crystals are chromatographed on a 200-400 mesh silica gel column, and a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:1-10 is selected as the eluent to obtain the spirobutane indole one derivative.

[0031]

[0032] The N-iodoarylbicyclobutylamide compounds used in the examples can be synthesized according to the literature (Org. Chem. Front. 2024, 11, 1982-1989).

[0033] In the present invention, the additive is triethylamine, 8-diazabicycloundec-7-ene or diisopropylamine;

[0034] The organic solvent is acetonitrile, N,N-dimethylformamide, dichloroethane, toluene or N,N-dimethylacetamide;

[0035] The catalyst is (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, tris(2-phenylpyridine)iridium, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile or tris(2,2'-bipyridyl)ruthenium di(hexafluorophosphate).

[0036] The extraction agent used in the liquid phase extraction is ethyl acetate.

[0037] Unless otherwise specified, the technical solutions described in the present invention are all conventional solutions in the field, and the reagents or raw materials used, unless otherwise specified, are purchased from commercial channels or have been disclosed.

[0038] In the examples of the present invention, the anti-tumor activity of spirobutane indole derivatives on tumor cells was evaluated by in vitro cell proliferation and toxicity assay (CCK-8 method), and compounds with better activity on tumor cells were screened out.

[0039] The cells were observed under a microscope. When the cells adhered to the wall and grew to 80%-90%, the culture dish was disinfected and placed on a clean bench and washed twice with treated PBS buffer. The center area was blown with fresh culture medium and the cell suspension was transferred to a centrifuge tube. Then, 10 μL of the cell suspension was pipetted into a cell counting plate and the cells were counted on a cell counter. The cells were cultured in a 96-well plate at a seeding density of 5000 cells per well (cell suspension 50,000 cells / mL, 100 μL was added) and placed in a CO2 cell culture incubator for 24 h until the cells adhered. The compound to be tested was diluted with culture medium to the corresponding concentration (5 μmol / L, 10 μmol / L, 20 μmol / L, 40 μmol / L, 60 μmol / L, 80 μmol / L) and added to a 96-well plate seeded with H1975 cells. 100 μL was added to each well, 6 replicates were set, and the cells were cultured in a cell culture incubator. After 24 h, the cells were taken out and 100 μL CCK-8 reagent was added to each well and incubated for 2 h. The cells were detected by enzyme-labeled instrument and IC was calculated by GraphPad. 50 .

[0040] In order to better understand the present invention, the content of the present invention is further illustrated below in conjunction with the examples, but the content of the present invention is not limited to the following examples.

[0041] Example 1

[0042] To a 25 mL Shrek tube, weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol) and acetonitrile (3 ml mL) were added in sequence. Under nitrogen conditions, the mixture was placed under 3 W blue light and reacted for 16 hours. After the reaction, the mixture was extracted with ethyl acetate (15 mL × 3). The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated in vacuo, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-2 / 1) to obtain a yellow liquid with a yield of 82%.

[0043] The reaction equation is as follows:

[0044]

[0045] The structural characterization data of the obtained target product are shown below:

[0046] 1H NMR(400MHz,Chloroform-d)δ8.57–8.44(m,1H),7.67–7.44(m,1H),7.30(s,0 .3H),7.18–7.13(m,1.7H),7.11–7.05(m,1H),7.04–6.98(m,1H),6.69–6.53( m,1H),3.12(d,J=2.8Hz,3H),2.93–2.83(m,0.7H),2.80–2.67(m,2.3H),2.60 –2.50(m,2H),2.34(d,J=4.4Hz,3H),2.30–2.23(m,0.7H),2.10–1.91(m,3.3H)

[0047] 13 C NMR(100MHz,Chloroform-d)δ181.4,179.3,161.9,161.8,149.2(2C),140.7(2C),136.4(2C),135.1,133.6,132.1(2C),128.1,127.8 ,123.7,122.9(2C),122.8,121.1(2C),107.5,107.3,45.0(2C),37.6,37.4,37.2,36.6,35.8(2C),30.3,29.0,26.3,26.2,21.2(2C).

[0048] HRMS(ESI)m / z calcd for C 20 H 23 N2O1[M+H] + 307.1805, found 307.1797.

[0049] The structure of the target compound is inferred from the above characterization data as follows:

[0050]

[0051] The compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC 50 It is 57.07μM.

[0052] Example 2

[0053] To a 25 mL Shrek tube, weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol) and acetonitrile (3 ml mL) were added in sequence. Under nitrogen conditions, the mixture was placed under 3 W blue light and reacted for 16 hours. After the reaction, the mixture was extracted with ethyl acetate (15 mL × 3). The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated in vacuo, and separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-2 / 1) to obtain a yellow liquid with a yield of 84%.

[0054] The reaction equation is as follows:

[0055]

[0056] The structural characterization data of the obtained target product are shown below:

[0057] 1 H NMR(400MHz,Chloroform-d)δ8.50(t,J=5.3Hz,1H),7.65–7.48(m,1H),7.18–7.12(m,1H ),7.11–7.05(m,1.5H),6.95(d,J=2.5Hz,0.5H),6.77–6.71(m,1H),6.64(t,J=8.8Hz,1H ),3.80(d,3H),3.13(d,J=3.0Hz,3H),2.95–2.83(m,0.5H),2.80–2.74(m,2H),2.72–2.6 5(m,0.5H),2.61–2.52(m,1H),2.40–2.32(m,1H),2.31–2.23(m,1H),2.08–1.93(m,3H).

[0058] 13 C NMR(100MHz,Chloroform-d)δ181.1,179.0,161.9(2C),156.3(2C),149.4(2C),136.8(2C),136.61–136.4(3C),134.9,122.9(2C) ),121.1(2C),112.1,111.5,110.5,110.1,107.9(2C),56.0(2C),45.5(2C),37.8,37.4,37.3,36.6,35.9,30.3,29.1,26.5,26.3.

[0059] HRMS(ESI)m / z calcd for C 20 H 23 N2O2[M+H] + 323.1754, found 323.1748.

[0060] The structure of the target compound is inferred from the above characterization data as follows:

[0061]

[0062] The compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC 50 It is 61.01μM.

[0063] Example 3

[0064] To a 25 mL Shrek tube, weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol) and acetonitrile (0.3 mL) were added in sequence. Under nitrogen conditions, the mixture was placed under 3 W blue light and fully reacted for 16 hours. After the reaction, it was extracted with ethyl acetate (15 mL × 3), and 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 / 1-2 / 1) to obtain a yellow liquid with a yield of 81%.

[0065] The reaction equation is as follows:

[0066]

[0067] The structural characterization data of the obtained target product are shown below:

[0068] 1H NMR(400MHz,Chloroform-d)δ8.54(td,J=5.0,1.8Hz,1H),7.63–7.56(m,1H),7.51–7.48(m,0.4H) ,7.36(d,J=7.5Hz,0.6H),7.32–7.21(m,5H),7.20–7.16(m,1H),7.15–7.08(m,2H),7.04(t,J=7.5 Hz,1H),6.67(t,J=8.5Hz,1H),4.88(d,J=3.4Hz,2H),3.08–2.89(m,0.6H),2.84–2.72(m,2.4H),2 .70–2.62(m,1H),2.50–2.42(m,1H),2.40–2.33(m,1H),2.16–2.07(m,2H),2.03(q,J=7.7Hz,1H).

[0069] 13 C NMR(100MHz,Chloroform-d)δ181.5,179.5,161.9(2C),149.3(2C),142.2(2C),136.4(2C),136.2(2C),135.1,133.5,128.8(2C),127.9,127.6( 2C),127.4,122.9(2C),122.8,122.7(2C),122.2,121.1(2C),108.8,10 8.6,45.0(2C),43.9,43.7,37.9,37.4(2C),36.6,35.8(2C),30.2,29.2.

[0070] HRMS(ESI)m / z calcd for C 25 H 25 N2O1[M+H] + 369.1961, found 369.1953.

[0071] The structure of the target compound is inferred from the above characterization data as follows:

[0072]

[0073] The compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC 50 It is 40.83μM.

[0074] Example 4

[0075] To a 25 mL Shrek tube, weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol) and acetonitrile (3 ml) were added in sequence. Under nitrogen conditions, the mixture was placed under 3 W blue light and fully reacted for 16 hours. After the reaction was completed, it was extracted with ethyl acetate (15 mL × 3), and 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 / 1-2 / 1) to obtain a yellow liquid with a yield of 57%.

[0076] The reaction equation is as follows:

[0077]

[0078] The structural characterization data are shown below:

[0079] 1 H NMR(400MHz,Chloroform-d)δ8.52(t,J=4.8Hz,1H),7.74–7.52(m,4.6H),7.48(d,J= 7.3Hz,0.4H),7.39–7.28(m,7H),7.23–7.13(m,2H),7.11–7.02(m,2H),6.81–6.68(m ,1H),4.15(q,J=5.9Hz,2H),3.75(q,J=6.8Hz,2H),3.26–3.07(m,2H),2.97–2.86(m, 2H),2.82–2.72(m,2H),2.64–2.54(m,1H),2.42–2.23(m,2.4H),2.12–1.93(m,5.6H).

[0080] 13C NMR(100MHz,Chloroform-d)δ181.4,179.3,172.0,161.9–161.7(3C),149.3(2C),145.5,1 42.3,142.2,136.4(2C),135.2(2C),133.6,132.5,129.0,128.7,128.6,128.5,128.1,128. 0,127.7,126.6,123.1,123.0,122.8,122.6(2C),122.3,121.1(2C),107.8,107.6,62.2(2 C),44.9(2C),37.8,37.4,37.3,37.0,36.8,36.5,35.8,31.1,30.2,29.8,29.1,26.7,23.6.

[0081] HRMS(ESI)m / z calcd for C 39 H 36 N3O4[MH] - 610.2711, found 610.2715.

[0082] The structure of the target compound is inferred from the above characterization data as follows:

[0083]

[0084] The compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC 50 It is 42.34μM.

[0085] Example 5

[0086] To a 25 mL Shrek tube, weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol) and acetonitrile (3 ml) were added in sequence. Under nitrogen conditions, the mixture was placed under 3 W blue light and fully reacted for 16 hours. After the reaction was completed, it was extracted with ethyl acetate (15 mL × 3), and 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 / 1-2 / 1) to obtain a yellow liquid with a yield of 87%.

[0087] The reaction equation is as follows:

[0088]

[0089] The structural characterization data are shown below:

[0090] 1 H NMR(400MHz,Chloroform-d)δ8.51(t,J=5.4Hz,1H),8.06(d,J=8.0Hz,2H),7.83(d,J=7.9Hz,2H),7.58(t,J=7.4Hz,1H) ,7.48(d,J=7.3Hz,0.4H),7.34(d,J=7.0Hz,0.6H),7.24–7.18(m,1H),7.15(d,J=7.6Hz,1H),7.08(q,J=7.5Hz,2H),6.86 –6.66(m,1H),4.38(q,J=5.4Hz,2H),3.87(q,J=6.1Hz,2H),3.19–3.03(m,3H),2.94–2.83(m,0.8H),2.78–2.66(m,2.2H ),2.60–2.50(m,1H),2.39–2.22(m,2H),2.19–2.11(m,2H),2.08–1.91(m,4H),1.61–1.42(m,4H),0.86(t,J=7.3Hz,6H).

[0091] 13 C NMR(100MHz,Chloroform-d)δ181.5,179.4,165.2,161.8(2C),149.3(2C),144.3,14 2.2(2C),136.5(2C),135.2,133.7,133.4,130.3,128.0,127.8,127.1,123.2,123.0, 122.8–122.7(3C),122.4,121.2(2C),107.8,107.6,63.1,50.1,44.9,37.8,37.4,37. 2,37.1,36.9,36.5,35.8,34.0,30.2,29.4,29.1,27.3,26.8,25.7,25.0,22.1,11.3.

[0092] HRMS(ESI)m / z calcd for C 34 H 42 N3O5S1[M+H] + 604.2840, found 604.2825.

[0093] The structure of the target compound is inferred from the above characterization data as follows:

[0094]

[0095] The compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC 50 It is 40.32μM.

[0096] Example 6

[0097] To a 25 mL Shrek tube, weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol) and acetonitrile (3 ml) were added in sequence. Under nitrogen conditions, the mixture was placed under 3 W blue light and fully reacted for 16 hours. After the reaction was completed, it was extracted with ethyl acetate (15 mL × 3), and 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 / 1-2 / 1) to obtain a yellow liquid with a yield of 87%.

[0098] The reaction equation is as follows:

[0099]

[0100] The structural characterization data are shown below:

[0101] 1 H NMR (400MHz, DMSO-d6) δ8.61–8.35(m,2H),7.54(d,J=7.2Hz,0.55H),7.48(d,J=7.2Hz,0.45H),7.31–7.20(m,3H),7.11–7.02(m,1H),6.99– 6.86(m,1H),3.09(s,3H),2.79–2.62(m,1H),2.61–2.52(m,2H),2.45– 2.33(m,1H),2.27–2.13(m,2H),2.09–2.00(m,1H),1.91–1.78(m,2H).

[0102] 13 C NMR(101MHz,DMSO-d6)δ180.0,178.1,150.8(2C),149.4(2C),142.9,142.8,134.2,132.7,127.9,127.7,123.9 (2C),122.8,122.3,122.2,121.9,108.1,107.8,44.1(2C),36.8(3C),36.6,31.8,31.7,29.1,28.3,26.0,25.8.

[0103] HRMS(ESI)m / z calcd for C 19 H 21 N2O1[M+H] + 293.1648, found 293.1641.

[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 H1975 human lung adenocarcinoma cells, IC 50 It is 35.29μM.

[0107] Example 7

[0108] To a 25 mL Shrek tube, weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol) and acetonitrile (3 ml) were added in sequence. Under nitrogen conditions, the mixture was placed under 3 W blue light and fully reacted for 16 hours. After the reaction, it was extracted with ethyl acetate (15 mL × 3), and the ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. It was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-2 / 1) to obtain a yellow liquid with a yield of 94%.

[0109] The reaction equation is as follows:

[0110]

[0111] The structural characterization data are shown below:

[0112] 1 H NMR (400MHz, DMSO-d6) δ8.32(d,J=5.0Hz,1H),7.55(d,J=7.2Hz,0.45H),7.46(d,J=7.2Hz,0.55H),7.25(q,J=6.9Hz,1H),7.12–7.03(m,2H),7.00( d,J=4.6Hz,1H),6.97–6.86(m,1H),3.09(s,3H),2.83–2.57(m,3H),2.44– 2.35(m,1H),2.30–2.10(m,5H),2.08–1.98(m,1H),1.91(q,J=7.5Hz,2H).

[0113] 13 C NMR(100MHz,DMSO-d6)δ180.1,178.2,161.1,148.7,148.6,146.8,146.7,142.9,142.7,134.3,132.8,127.9,127.7,123.3(2C),12 3.2,122.7,122.4,122.3,122.0,121.9,108.1,107.8,44.1(2C),36.9,36.7,36.4,36.2,34.8,34.7,29.3,28.4,26.0,25.8,20.4.

[0114] HRMS(ESI)m / z calcd for C 20 H 23 N2O[M+H] + 307.1805, found 307.1799.

[0115] The structure of the target compound is inferred from the above characterization data as follows:

[0116]

[0117] The compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC 50 It is 32.82μM.

[0118] Example 8

[0119] To a 25 mL Shrek tube, weighed N-iodoarylbicyclobutylamide compound (0.3 mmol), vinylpyridine compound (0.6 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (0.003 mmol), triethylamine (3 mmol) and acetonitrile (3 ml) were added in sequence. Under nitrogen conditions, the mixture was placed under 3 W blue light and fully reacted for 16 hours. After the reaction was completed, it was extracted with ethyl acetate (15 mL × 3), and 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 / 1-2 / 1) to obtain a yellow liquid with a yield of 82%.

[0120] The reaction equation is as follows:

[0121]

[0122] The structural characterization data are shown below:

[0123] 1H NMR (400MHz, DMSO-d6) δ8.31(d,J=4.2Hz,1H),7.56(d,J=7.3Hz,0.4H),7.51–7.43(m,1.6H),7.25(q,J=7.3Hz,1H),7.14–7.02(m,2H ),6.98–6.85(m,1H),3.09(s,3H),2.87–2.56(m,3H),2.45–2.36(m,1H),2.31–2.12(m,5H),2.06–1.98(m,1H),1.91(q,J=7.5Hz,2H).

[0124] 13 C NMR(100MHz,DMSO-d6)δ180.1,178.2,159.5,146.3(2C),142.8(2C),137.3(2C),134.3,132.8,130.6(2C),127.9,127.6,122 .7,122.3,122.2,121.9,121.2(2C),108.0,107.8,44.1,37.0,36.7,35.1,34.8,32.0(2C),29.4,28.6,25.9(2C),18.2(2C).

[0125] HRMS(ESI)m / z calcd for C 20 H 23 N2O[M+H]+307.1805,found 307.1799.

[0126] The structure of the target compound is inferred from the above characterization data as follows:

[0127]

[0128] The compound has an inhibitory effect on H1975 human lung adenocarcinoma cells, IC 50 It is 35.47μM.

[0129] 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 principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A spirobutane indole derivative, characterized in that: It has the structure shown in formula I: In Formula I, R 1 is hydrogen, alkoxy or alkyl, R 2 is an alkyl group or a benzyl group, R 3 is hydrogen or methyl.

2. A method for preparing the spirobutane indole derivative according to claim 1, characterized in that: Dissolving an N-iodoaryl bicyclobutylamide compound and a vinyl pyridine compound in an organic solvent, adding a catalyst and an additive, and reacting under blue light catalysis to obtain the spirobutane indole one derivative; The structural formula of the N-iodoaryl bicyclobutylamide compound is: The structural formula of the vinyl pyridine compound is Among them, in the N-iodoaryl bicyclobutylamide compound and the vinyl pyridine compound, R 1 、R 2 、R 3 R in claim 1 1 、R 2 、R 3 same.

3. The preparation method according to claim 2, characterized in that The catalyst is (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, tris(2-phenylpyridine)iridium, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate), 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile or tris(2,2'-bipyridine)ruthenium di(hexafluorophosphate); The additive is triethylamine, 8-diazabicycloundec-7-ene or diisopropylamine; The organic solvent is acetonitrile, N,N-dimethylformamide, dichloroethane, toluene or N,N-dimethylacetamide.

4. The preparation method according to claim 2, characterized in that The molar ratio of the N-iodinated aryl bicyclobutylamide compound to the vinyl pyridine compound is 1:2; the molar ratio of the N-iodinated aryl bicyclobutylamide compound to the catalyst is 1:0.01-0.2; the molar ratio of the N-iodinated aryl bicyclobutylamide compound to the additive is 1:10-15; the amount ratio of the N-iodinated aryl bicyclobutylamide compound to the organic solvent is 0.1mmol:1mL-3mL.

5. The preparation method according to claim 2, characterized in that The power of the blue light is 3 to 10W, and the reaction time is 12 to 24 hours.

6. The preparation method according to claim 2, characterized in that After the reaction is completed, the method further includes the steps of separating and purifying the obtained product.

7. Use of the spirobutane indole derivative according to claim 1 in the preparation of a drug for treating H1975 human lung adenocarcinoma.

8. A drug for treating H1975 human lung adenocarcinoma, characterized in that: The raw materials include the spirobutane indole derivative according to claim 1 and pharmaceutically acceptable excipients.

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