2-azabicyclo [2.2. 2] octane compound as well as preparation method and application thereof

Abstract

The invention discloses a 2-azabicyclo [2.2. 2] octane compound as well as a preparation method and application of the 2-azabicyclo [2.2. 2] octane compound. The compound has a structural formula shown as a formula I: # imgabs0 #, wherein R1 is selected from C1-12 alkyl groups; and R2 is selected from H, halogen, alkyl of C1-12, halogenated alkyl of C1-12 and alkoxy of C1-12. The 2-azabicyclo [2.2. 2] octane compound provided by the invention has anti-tumor activity.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, in particular to a 2-azabicyclo[2.2.2]octane compound and a preparation method and application thereof. Background Art

[0002] 2-Azabicyclo[2.2.2]octane is an important class of nitrogen-containing heterocycles. Its unique structure gives it broad application prospects in various fields, including pharmaceuticals, demonstrating significant development value and attracting widespread attention. For example, ibogaine has been found to have a detoxifying effect, with preclinical studies demonstrating its ability to reduce cocaine and morphine self-administration and alleviate morphine withdrawal symptoms. Synthetic 2-azabicyclo[2.2.2]octane has also attracted attention as a potential drug, exhibiting potent antimalarial activity.

[0003]

[0004] 2-Azabicyclo[2.2.2]octane is a unique molecular structure with important theoretical and practical applications. This property makes 2-Azabicyclo[2.2.2]octane an important structural basis for many natural products and bioactive molecules.

[0005] Therefore, it is necessary to develop novel and biologically active 2-azabicyclo[2.2.2]octane compounds. Summary of the Invention

[0006] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention provides a 2-azabicyclo[2.2.2]octane compound in a first aspect, which has anti-tumor cell activity.

[0007] The second aspect of the present invention also provides a method for preparing a 2-azabicyclo[2.2.2]octane compound.

[0008] The third aspect of the present invention also provides an application of a 2-azabicyclo[2.2.2]octane compound.

[0009] According to a first aspect of the present invention, there is provided a 2-azabicyclo[2.2.2]octane compound having the structural formula shown in Formula I:

[0010]

[0011] Among them, R 1 Selected from C 1～12 Alkyl; R 2 Selected from H, C 1～12 Alkyl, C 1～12haloalkyl, C 1～12 of alkoxy.

[0012] According to a preferred embodiment of the present invention, R 2 Selected from H, halogen, C 1～6 Alkyl, C 1～6 haloalkyl, C 1～6 of alkoxy.

[0013] According to a preferred embodiment of the present invention, R 2 Selected from H, Cl, Br, C 1～3 of alkoxy.

[0014] According to a preferred embodiment of the present invention, R 1 Selected from C 1～16 of alkyl.

[0015] According to a preferred embodiment of the present invention, R 1 Selected from methyl, ethyl, propyl, n-butyl and tert-butyl.

[0016] According to a preferred embodiment of the present invention, the 2-azabicyclo[2.2.2]octane compound is selected from the following structural formula:

[0017]

[0018] The 2-azabicyclo[2.2.2]octane compound according to the embodiment of the present invention has at least the following beneficial effects:

[0019] The present invention provides a series of 2-azabicyclo[2.2.2]octane compounds with novel structures, which have an inhibitory effect on tumor cells.

[0020] According to a second aspect of the present invention, there is provided a method for preparing a 2-azabicyclo[2.2.2]octane compound, comprising the steps of:

[0021] Compound 1, compound 2, compound 3, a metal catalyst and a base are mixed and reacted to obtain the product;

[0022] The structural formulas of Compound 1, Compound 2 and Compound 3 are as follows:

[0023]

[0024] According to a preferred embodiment of the present invention, the molar ratio of compound 1, compound 2, compound 3 and base is 1: (0.5-10): (0.5-10): (0.1-4).

[0025] According to a preferred embodiment of the present invention, the metal catalyst includes at least one of a copper catalyst, a cobalt catalyst, an iron catalyst, a palladium catalyst, a ruthenium catalyst or an iridium catalyst.

[0026] According to a preferred embodiment of the present invention, the copper catalyst includes at least one of copper acetate, copper trifluoromethanesulfonate, copper sulfate, copper chloride, cuprous chloride, and cuprous iodide.

[0027] According to a preferred embodiment of the present invention, the iron catalyst includes at least one of ferric chloride, ferric bromide and ferric sulfate.

[0028] According to a preferred embodiment of the present invention, the cobalt catalyst includes at least one of cobalt acetate, cobalt chloride, cobalt acetylacetonate, and cobalt carbonate.

[0029] According to a preferred embodiment of the present invention, the palladium catalyst includes at least one of palladium acetate, bis(triphenylphosphine)palladium chloride, and tetrakis(triphenylphosphine)palladium.

[0030] According to a preferred embodiment of the present invention, the ruthenium catalyst includes at least one of triruthenium dodecacarbonyl, ruthenium trichloride, and tris(2,2'-bipyridyl)ruthenium chloride.

[0031] According to a preferred embodiment of the present invention, the iridium catalyst includes at least one of dichloro(pentamethylcyclopentadienyl)iridium(III) dimer and iridium chloride.

[0032] According to a preferred embodiment of the present invention, the base includes at least one of sodium acetate, sodium methoxide, sodium hydroxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, cesium carbonate or aniline.

[0033] According to a preferred embodiment of the present invention, the reaction temperature is 60°C to 150°C.

[0034] According to a preferred embodiment of the present invention, the reaction time is 2 hours to 24 hours.

[0035] According to some embodiments of the present invention, the reaction is carried out under air or nitrogen conditions.

[0036] According to some embodiments of the present invention, the reaction is carried out in a solvent comprising at least one of ethanol, tert-amyl alcohol, isopropanol, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, p-xylene, and water.

[0037] According to some embodiments of the present invention, the volume molar ratio of the solvent to the compound 1 is 5-10 mL:1 mmol.

[0038] According to some embodiments of the present invention, the method further comprises a purification step after the reaction, and the purified eluent is a mixed solution of petroleum ether, dichloromethane and ethyl acetate.

[0039] According to some embodiments of the present invention, the eluent for column chromatography purification is a mixed solution of petroleum ether: dichloromethane: ethyl acetate in a volume ratio of (10-100): (0-20): 1.

[0040] The third aspect of the present invention provides a use of the above-mentioned 2-azabicyclo[2.2.2]octane compound in the preparation of a drug for treating and / or preventing anti-tumor.

[0041] According to some embodiments of the present invention, the tumor includes chronic myeloid leukemia, acute promyelocytic leukemia, cervical cancer and gastric cancer.

[0042] Definitions and General Terms

[0043] "Halogen" includes fluorine, chlorine, bromine and iodine.

[0044] “C 1-6 "alkyl" means an alkyl group having a total carbon number of 1 to 6, including C 1-6 Straight chain alkyl, C 1-6 Branched alkyl and C 3-6 The cycloalkyl group may be, for example, a straight-chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, a branched-chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, or a cycloalkyl group having 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, etc. 1-12 The "alkyl group" has a similar explanation, except that the number of carbon atoms is different.

[0045] “C 1～6 "Haloalkyl" means "C 1-6 The definition of "alkyl" is similar, except that "C 1-6 Any one H atom in the "halogenated alkyl" is replaced by any halogen. 1～12 The haloalkyl" and C 1～6 The definition of haloalkyl is similar to that of alkyl halide, except that the number of carbon atoms is different.

[0046] “C 1-6 "alkoxy" means an alkoxy group having a total carbon number of 1 to 6, including C 1-6 Straight chain alkoxy, C 1-6 Branched alkoxy and C 2-6The cycloalkoxy group may be, for example, a straight chain alkoxy group having 1, 2, 3, 4, 5 or 6 carbon atoms, a branched chain alkoxy group having 1, 2, 3, 4, 5 or 6 carbon atoms, or a cycloalkoxy group having 2, 3, 4, 5 or 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, etc. 1-12 Alkoxy", "C 1-3 The "alkoxy group" has a similar explanation, except that the number of carbon atoms is different.

[0047] Other features and advantages of the present invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments with reference to the following drawings, in which:

[0049] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 1;

[0050] Figure 2 is the carbon NMR spectrum of the compound of Example 1;

[0051] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 2;

[0052] Figure 4 is the carbon NMR spectrum of the compound of Example 2;

[0053] Figure 5 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 3;

[0054] Figure 6 is the carbon NMR spectrum of the compound of Example 3;

[0055] Figure 7 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 4;

[0056] Figure 8 is the carbon NMR spectrum of the compound of Example 4;

[0057] Figure 9 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 5;

[0058] Figure 10 is the carbon NMR spectrum of the compound of Example 5;

[0059] Figure 11 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 6;

[0060] Figure 12is the carbon NMR spectrum of the compound of Example 6;

[0061] Figure 13 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 7;

[0062] Figure 14 is the carbon NMR spectrum of the compound of Example 7;

[0063] Figure 15 is the hydrogen nuclear magnetic resonance spectrum of the compound of Example 8;

[0064] Figure 16 is the carbon NMR spectrum of the compound of Example 8. DETAILED DESCRIPTION

[0065] The following are specific embodiments of the present invention, and the technical solutions of the present invention are further described in conjunction with the embodiments, but the present invention is not limited to these embodiments.

[0066] Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0067] Example 1

[0068] Example 1 provides a 2-azabicyclo[2.2.2]octane compound having the following structural formula and preparation method:

[0069]

[0070] 41.6 mg of 3-bromoisoquinoline (0.2 mmol), 67.6 mg of benzyl bromide (0.4 mmol), 66.6 mg of N-methylmaleimide (0.6 mmol), cuprous iodide (10 mol%), 97.7 mg of cesium carbonate (0.3 mmol), and 1 mL of acetonitrile were mixed uniformly and stirred at 100° C. under nitrogen for 5 hours to obtain a crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 52%, and the compound was a yellow solid.

[0071] The H NMR spectrum of the obtained compound is as follows Figure 1 , C NMR spectra such as Figure 2 The structural characterization data are as follows:

[0072] H NMR spectrum data: 1H NMR (500MHz, CDCl3) δ7.33–7.29(m,4H),7.27(dd,J=7.4,1.2Hz,1H),7.24–7.12(m,3H),7.01(d,J=7.3Hz,1H),4.89(d,J=4.3Hz,1H),4.6 7(d,J=14.9Hz,1H), 4.54(d,J=14.9Hz,1H), 4.40(d,J=3.5Hz,1H), 3.52(dd,J=8.4,3.5Hz,1H), 3.37(dd,J=8.4,4.3Hz,1H), 2.44(s,3H).

[0073] C NMR spectrum data: 13 C NMR (126MHz, CDCl3) δ174.99,174.52,170.94,135.83,135.37,133.77,128.92,128.8 6,128.21,128.11,127.87,125.85,123.27,57.77,49.01,48.45,47.48,42.37,24.39.

[0074] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 21 H 19 N2O3[M+H] + Theoretical calculated value: 347.1390; test data: 347.1387.

[0075] Example 2

[0076] Example 2 provides a 2-azabicyclo[2.2.2]octane compound having the following structural formula and preparation method:

[0077]

[0078] 41.6 mg of 3-bromoisoquinoline (0.2 mmol), 67.6 mg of benzyl bromide (0.4 mmol), 75.0 mg of N-ethylmaleimide (0.6 mmol), cuprous chloride (10 mol%), 49.2 mg of anhydrous sodium acetate (0.6 mmol), and 1 mL of acetonitrile were mixed uniformly, and stirred at 100° C. under nitrogen for 5 hours to obtain a crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 63%, and the compound was a yellow solid.

[0079] The H NMR spectrum of the obtained compound is as follows Figure 3 , C NMR spectra such as Figure 4 The structural characterization data are as follows:

[0080] H NMR spectrum data: 1 H NMR (500MHz, CDCl3) δ7.33–7.30(m,4H),7.29(d,J=2.5Hz,1H),7.22–7.15(m,3H),7.02(d,J=7.3Hz,1H),4.90(d,J=4.3Hz,1H),4.67(d,J=14.8Hz,1 H),4.54(d,J=14.8Hz,1H),4.41(d,J=3.6Hz,1H),3.49(dd,J=8.4,3.5Hz, 1H), 3.34 (dd, J=8.3, 4.3Hz, 1H), 3.14–2.99 (m, 2H), 0.33 (t, J=7.2Hz, 3H).

[0081] C NMR spectrum data: 13 C NMR (126MHz, CDCl3) δ174.83,174.30,171.01,135.84,135.61,133.94,128.91,128.75,1 28.21,128.10,127.78,125.99,123.39,57.84,49.09,48.45,47.25,42.10,33.35,11.85.

[0082] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 22 H 21 N2O3[M+H] + Theoretical calculated value: 361.1546; test data: 361.1541.

[0083] Example 3

[0084] Example 3 provides a 2-azabicyclo[2.2.2]octane compound having the following structural formula and preparation method:

[0085]

[0086] 41.6 mg of 3-bromoisoquinoline (0.2 mmol), 67.6 mg of benzyl bromide (0.4 mmol), 83.4 mg of N-propylmaleimide (0.6 mmol), ferrous chloride (10 mol%), 4.0 mg of sodium methoxide (0.075 mmol), and 1 mL of acetonitrile were mixed uniformly, and stirred at 100° C. under nitrogen for 5 hours to obtain a crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 50%, and the compound was a black oil.

[0087] The H NMR spectrum of the obtained compound is as follows Figure 5 , C NMR spectra such as Figure 6 The structural characterization data are as follows:

[0088] H NMR spectrum data: 1 H NMR(500MHz, CDCl3)δ7.32–7.29(m,4H),7.27(dd,J=7.4,1.2Hz,1H),7.21–7.15(m, 3H),7.01(dd,J=7.3,1.1Hz,1H),4.89(d,J=4.3Hz,1H),4.66(d,J=14.8Hz,1H),4.53 (d, J=14.9Hz, 1H), 4.41 (d, J=3.5Hz, 1H), 3.49 (dd, J=8.5, 3.6Hz, 1H), 3.35 (dd, J=8. 5,4.3Hz,1H),2.97(td,J=7.3,3.3Hz,2H),0.80–0.66(m,2H),0.48(t,J=7.5Hz,3H).

[0089] C NMR spectrum data: 13 C NMR (126MHz, CDCl3) δ175.01,174.50,171.07,135.85,135.63,133.95,128.91,128.81,128. 20,128.10,127.83,125.98,123.39,57.80,49.04,48.44,47.29,42.12,40.22,20.25,10.94.

[0090] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 23 H 23 N2O3[M+H] + Theoretical calculated value: 375.1703; test data: 375.1706.

[0091] Example 4

[0092] Example 4 provides a 2-azabicyclo[2.2.2]octane compound having the following structural formula and preparation method:

[0093]

[0094] 41.6 mg of 3-bromoisoquinoline (0.2 mmol), 67.6 mg of benzyl bromide (0.4 mmol), 91.8 mg of N-tert-butylmaleimide (0.6 mmol), palladium acetate (2 mol%), 6.0 mg of sodium hydroxide (0.15 mmol), and 1 mL of acetonitrile were mixed uniformly, and stirred at 100° C. under nitrogen for 5 hours to obtain a crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 48%, and the compound was a yellow oil.

[0095] The H NMR spectrum of the obtained compound is as follows Figure 7 , C NMR spectra such as Figure 8 The structural characterization data are as follows:

[0096] H NMR spectrum data: 1 H NMR (500MHz, CDCl3) δ7.34–7.27(m,5H),7.21(td,J=7.3,1.6Hz,1H),7.18–7.15(m,2H),7.03(dd,J=7.3,1.1Hz,1H),4.84(d,J=4.4Hz,1H), 4.67(d,J=14.8Hz,1H), 4.51(d,J=14.9Hz,1H), 4.36(d,J=3.6Hz,1H), 3.34(dd,J=8.8,3.6Hz,1H), 3.20(dd,J=8.8,4.4Hz,1H), 1.05(s,9H).

[0097] C NMR spectrum data: 13 C NMR (126MHz, CDCl3) δ176.16,175.66,171.19,135.95,135.85,134.22,128.87,128.60,1 28.20,128.04,127.64,126.03,123.47,58.50,58.20,49.41,48.40,46.86,41.66,27.60.

[0098] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 24 H 25 N2O3[M+H] + Theoretical calculated value: 389.1859; test data: 389.1852.

[0099] Example 5

[0100] Example 5 provides a 2-azabicyclo[2.2.2]octane compound having the following structural formula and preparation method:

[0101]

[0102] 41.6 mg of 3-bromoisoquinoline (0.2 mmol), 81.5 mg of p-chlorobenzyl bromide (0.4 mmol), 75.0 mg of N-ethylmaleimide (0.6 mmol), triruthenium dodecacarbonyl (5 mol%), 14.4 mg of sodium tert-butoxide (0.15 mmol), and 1 mL of acetonitrile were mixed uniformly, and the mixture was stirred at 100° C. under nitrogen for 5 hours to obtain a crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 33%, and the compound was obtained as a white solid.

[0103] The H NMR spectrum of the obtained compound is as follows Figure 9 , C NMR spectra such as Figure 10 The structural characterization data are as follows:

[0104] H NMR spectrum data: 1 H NMR (400MHz, CDCl3) δ7.34–7.26(m,4H),7.25–7.17(m,1H),7.10(d,J=8.2Hz,2H),7.03(d,J=7.3Hz,1H),4.87(d,J=4.2Hz,1H),4.64–4.51 (m,2H),4.41(d,J=3.5Hz,1H),3.48(dd,J=8.4,3.5Hz,1H),3.37(dd,J=8.4,4.2Hz,1H),3.08(qd,J=7.0,2.4Hz,2H),0.34(t,J=7.2Hz,3H).

[0105] C NMR spectrum data: 13 C NMR (101MHz, CDCl3) δ174.69,174.17,171.02,135.47,134.43,134.01,133.83,129.51,129. 08,128.87,127.90,126.06,123.35,57.99,49.00,47.82,47.24,42.03,33.40,29.71,11.85.

[0106] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 22 H 20 ClN2O3[M+H] + Theoretical calculated value: 395.1156; test data: 395.1154.

[0107] Example 6

[0108] Example 6 provides a 2-azabicyclo[2.2.2]octane compound having the following structural formula and preparation method:

[0109]

[0110] 41.6 mg of 3-bromoisoquinoline (0.2 mmol), 99.1 mg of p-bromobenzyl bromide (0.4 mmol), 75.0 mg of N-ethylmaleimide (0.6 mmol), iridium trichloride (1 mol%), 60.1 mg of potassium carbonate (0.45 mmol), and 1 mL of acetonitrile were mixed uniformly, and stirred at 100° C. under nitrogen for 5 hours to obtain a crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 60%, and the compound was a yellow solid.

[0111] The H NMR spectrum of the obtained compound is as follows Figure 11 , C NMR spectra such as Figure 12 The structural characterization data are as follows:

[0112] H NMR spectrum data: 1 H NMR (500MHz, CDCl3) δ7.47–7.41(m,2H),7.35–7.30(m,2H),7.22(td,J=7.3,1.5Hz,1H),7.07–7.01(m,3H),4.87(d,J=4.2Hz,1H),4.65–4.4 7(m,2H),4.41(d,J=3.6Hz,1H),3.48(dd,J=8.4,3.5Hz,1H),3.38(dd,J=8.4,4.2Hz,1H),3.08(qd,J=7.2,4.0Hz,2H),0.34(t,J=7.2Hz,3H).

[0113] C NMR spectrum data: 13 C NMR (126MHz, CDCl3) δ174.69,174.16,171.02,135.45,134.96,133.83,132.04,129.82,1 28.88,127.92,126.07,123.37,122.10,58.01,48.99,47.88,47.24,42.03,33.40,11.86.

[0114] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 22 H 20 BrN2O3[M+H] + Theoretical calculated value: 439.0651; test data: 439.0647.

[0115] Example 7

[0116] Example 7 provides a 2-azabicyclo[2.2.2]octane compound having the following structural formula and preparation method:

[0117]

[0118] 41.6 mg of 3-bromoisoquinoline (0.2 mmol), 99.1 mg of 3-methoxybenzyl bromide (0.4 mmol), 75.0 mg of N-ethylmaleimide (0.6 mmol), palladium chloride (5 mol%), 45.0 mg of potassium bicarbonate (0.45 mmol), and 1 mL of acetonitrile were mixed uniformly and stirred at 100° C. under nitrogen for 5 hours to obtain a crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 43%, and the compound was a red solid.

[0119] The H NMR spectrum of the obtained compound is as follows Figure 13 , C NMR spectra such as Figure 14 The structural characterization data are as follows:

[0120] H NMR spectrum data: 1 H NMR(500MHz, CDCl3)δ7.32(dd,J=7.4,1.3Hz,1H),7.30–7.27(m,1H),7.25–7.18(m,2H),7.0 3(d,J=7.3Hz,1H),6.83(dd,J=8.2,2.6Hz,1H),6.77(d,J=7.6Hz,1H),6.60(t,J=2.1Hz,1H), 4.89(d,J=4.2Hz,1H),4.65–4.52(m,2H),4.41(d,J=3.5Hz,1H),3.67(s,3H),3.49(dd,J=8.4 ,3.6Hz,1H),3.39(dd,J=8.3,4.3Hz,1H),3.07(qd,J=6.9,4.1Hz,2H),0.33(t,J=7.2Hz,3H).

[0121] C NMR spectrum data: 13 C NMR (126MHz, CDCl3) δ174.82,174.29,170.99,159.95,137.32,135.73,133.94,129.93,128.74,127. 77,125.99,123.44,120.41,113.89,113.22,57.82,55.13,49.07,48.35,47.23,42.10,33.35,11.85.

[0122] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 23 H 23 N2O4[M+H] + Theoretical calculated value: 391.1652; test data: 391.1642.

[0123] Example 8

[0124] Example 8 provides a 2-azabicyclo[2.2.2]octane compound having the following structural formula and preparation method:

[0125]

[0126] 41.6 mg of 3-bromoisoquinoline (0.2 mmol), 99.1 mg of 3-methoxybenzyl bromide (0.4 mmol), 91.8 mg of N-tert-butylmaleimide (0.6 mmol), copper acetate (10 mol%), 293.2 mg of cesium carbonate (0.9 mmol), and 1 mL of acetonitrile were mixed uniformly and stirred at 100° C. under nitrogen for 5 hours to obtain a crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 92%, and the compound was a black solid.

[0127] The H NMR spectrum of the obtained compound is as follows Figure 15 , C NMR spectra such as Figure 16 The structural characterization data are as follows:

[0128] H NMR spectrum data: 1 H NMR(500MHz, CDCl3)δ7.35–7.28(m,2H),7.22(dd,J=8.5,7.0Hz,2H),7.04(d, J=7.3Hz,1H),6.86–6.80(m,1H),6.77(dt,J=7.5,1.3Hz,1H),6.60(t,J=2.0H z,1H),4.84(d,J=4.3Hz,1H),4.65–4.51(m,2H),4.37(d,J=3.6Hz,1H),3.67( s,3H),3.35(dd,J=8.8,3.6Hz,1H),3.25(dd,J=8.8,4.3Hz,1H),1.06(s,9H).

[0129] C NMR spectrum data: 13C NMR (126MHz, CDCl3) δ176.17,175.67,171.21,159.93,137.40,135.95,134.21,129.89,128.60,1 27.64,126.04,123.53,120.42,113.89,113.17,58.53,58.20,55.13,49.40,48.33,46.85,27.60.

[0130] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 25 H 27 N2O4[M+H] + Theoretical calculated value: 419.1965; test data: 419.1959.

[0131] Activity test

[0132] The products obtained in Examples 1-8 of the present invention were tested for their anti-tumor cell activity.

[0133] (1) Test method: Each compound was prepared into 100 μg·mL -1 The methanol solution, positive control drugs 5-fluorouracil (5-FU) and docetaxel (docetaxel) were prepared into 100 μg mL -1 The inhibitory effects of each compound on K562 cells, HL-60 cells and HeLa cells were tested by MTT assay, with methanol and DMSO solvents as blank controls.

[0134] (2) Preparation of cell culture medium: Pour one bag of RPMI-1640 medium powder (Net wt 10.4 g) into a clean beaker, dissolve it with 900 mL of ultrapure water, and add 100 mg mL -1 1 mL of streptomycin, 0.5 mL of penicillin, and 2 g of NaHCO₃ were added. After magnetic stirring, the mixture was sterilized by filtration through a 0.22 μm filter using an autoclaved Zeiss filter in a laminar flow hood. The filtrate was directly stored in a heat-sterilized glass bottle (450 mL / bottle). Before use, frozen serum was inactivated at 56°C for 30 minutes. The serum was then added to the prepared RPMI-1640 medium (50 mL of serum per 450 mL of medium). After gentle shaking, the bottle was capped, sealed with aluminum foil, and stored in a refrigerator at 4°C. To prepare the MTT solution, 50 mg of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) powder was dissolved in 10 mL of PBS, filtered through a 0.22 μm filter, and stored in a refrigerator at 4°C.

[0135] (3) Anti-tumor activity test: K562 cells, HL-60 cells, and HeLa cells in the logarithmic growth phase were taken respectively, centrifuged at 4°C and 3000rpm for 3 minutes, the supernatant was aspirated, and fresh RPMI-1640 medium was added to dilute the cell suspension to 1×105 cells / ml. 200 μL per well was inoculated into a 96-well plate, and cultured in a cell culture incubator at 37°C and 5% CO2 for 1 hour. 2 μL of sample solution was added to each well. Three parallel wells were set for each sample, and two groups of three blank wells were set up for control. After adding the sample, the cells were cultured under the same conditions for 24 hours. After 24 hours, the cells were observed under an optical microscope for morphological changes to preliminarily judge whether the sample had cytotoxic activity. If necessary, photos were taken. 5 mg·mL was added to each well. -1 20 μL of MTT solution was added to each well and cultured in the incubator for another 4 h. The 96-well plate was centrifuged (4°C, 2000 rpm, 20 min) to remove the supernatant. 150 μL of DMSO was added to each well and shaken thoroughly to completely dissolve the purple precipitate. The optical density (OD) value was measured at 570 nm on a microplate reader. The average value of each sample was calculated and the value was calculated as IR% = (OD 空白 -OD 样品 ) / OD 空白 × 100% formula to calculate the inhibition rate (IR%).

[0136] The proliferation inhibitory activities of compounds 1 to 8 against three types of tumor cells were tested using the MTT assay. The results are shown in Table 1.

[0137] Table 1 MTT assay results of the proliferation inhibition activity of compounds 1 to 8 on three types of tumor cells

[0138]

[0139]

[0140] As shown in Table 1, the novel 2-azabicyclo[2.2.2]octane compound provided by the present invention exhibits significant inhibitory effects on K562, HL-60, and HeLa cells, demonstrating its potential application as an anti-tumor drug. The compound provided by the present invention exhibits stronger inhibitory effects on the proliferation of these three tumor cell types than the existing drugs 5-fluorouracil and docetaxel.

[0141] The above is a detailed description of the embodiments of the present invention, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the relevant technical field without departing from the scope of the present invention.

Claims

1. A 2-azabicyclo[2.2.2]octane compound, characterized in that It has the structural formula shown in Formula I: Among them, R 1 Selected from C 1～12 Alkyl; R 2 Selected from H, halogen, C 1～12 Alkyl, C 1～12 haloalkyl, C 1～12 of alkoxy.

2. The 2-azabicyclo[2.2.2]octane compound according to claim 1, characterized in that R 2 Selected from H, C 1～6 Alkyl, C 1～6 haloalkyl, C 1～6 of alkoxy.

3. The 2-azabicyclo[2.2.2]octane compound according to claim 1 or 2, characterized in that The 2-azabicyclo[2.2.2]octane compound is selected from the following structural formula:

4. A method for preparing the 2-azabicyclo[2.2.2]octane compound according to any one of claims 1 to 3, characterized in that: The steps include: Compound 1, compound 2, compound 3, a metal catalyst and a base are mixed and reacted to obtain the product; The structural formulas of Compound 1, Compound 2 and Compound 3 are as follows:

5. The preparation method according to claim 4, characterized in that The molar ratio of the compound 1, the compound 2, the compound 3 and the base is 1: (0.5-10): (0.5-10): (0.1-4).

6. The preparation method according to claim 4, characterized in that The metal catalyst includes at least one of a copper catalyst, a cobalt catalyst, an iron catalyst, a palladium catalyst, a ruthenium catalyst or an iridium catalyst.

7. The preparation method according to claim 4, characterized in that The base includes at least one of sodium acetate, sodium methoxide, sodium hydroxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, cesium carbonate or aniline.

8. The preparation method according to claim 4, characterized in that The reaction temperature is 60°C to 150°C.

9. Use of the 2-azabicyclo[2.2.2]octane compound according to any one of claims 1 to 3 in the preparation of a drug for treating and / or preventing antitumor.

10. The use according to claim 9, characterized in that Such tumors include chronic myeloid leukemia, acute promyelocytic leukemia, cervical cancer, and gastric cancer.

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