Synthesis method and application of cyclobutane chroman skeleton molecular compound

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a synthetic method and application of a cyclobutane and chroman skeleton molecular compound, which is a method for synthesizing a cyclobutane and chroman skeleton molecular compound through a triplet-triplet energy transfer mechanism by using a blue light excitation photocatalyst under a mild condition. The invention discloses a method for constructing a cyclobutane and chroman skeleton molecular compound by efficiently, highly regionally and stereoselectively catalyzing intramolecular [2 + 2] cycloaddition of a 2H-chromene compound, and further explores the application potential of the cyclobutane and chroman skeleton molecular compound in research and development of anti-glioma drugs. The obtained compound can specifically and effectively kill glioma stem cells, and a new lead compound and thought are provided for research and development of anti-glioma drugs.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and more specifically, to a method for synthesizing and applying a cyclobutane-chromium skeleton molecule. Background Technology

[0002] Cyclobutane benzochromate skeletons, as highly ring-strained four-membered ring structures, are widely found in various natural products and drug molecules with important biological activities (such as antibacterial and antitumor activity). Therefore, developing an efficient method for constructing cyclobutane benzochromate skeleton compounds is of great significance for the preparation and structural modification of such bioactive molecules.

[0003] Currently, there are five main methods for constructing a fully colored cyclobutane skeleton: 1. Thermal / alkali-catalyzed intramolecular dipole [2+2] cycloaddition reaction to construct a cyclobutane anolyte skeleton under high temperature conditions of 160℃-175℃; 2. The synthesis of cannabinic acid, a compound containing a cyclobutane-containing benzo[2+2] photocycloaddition of styrene molecules, was achieved by visible light catalytic [2+2] photocycloaddition. 3. At room temperature, using an FeCl3 catalytic system, a cyclobutane anolyte framework was constructed after a 12-hour reaction time. 4. Cyclobutane diachromic skeleton is prepared by oxa[3+3] cyclization and diastereoselective cationic[2+2] cyclization via Brønsted acid or Lewis acid catalysis; 5. The radical oxidative cyclization of 5-hydroxybenzochromene catalyzed by indium trifluoromethanesulfonate and 2,3-dichloro-5,6-dicyanobenzoquinone constructs a cyclobutane-containing benzochrome skeleton, but the substrate applicability is relatively narrow.

[0004] Although the synthetic methods for constructing the cyclobutane diachromic skeleton are constantly improving, the above-mentioned techniques still have some shortcomings, such as: excessively high reaction temperature, use of highly toxic solvents, high cost of catalysts, long reaction time, low yield, complex process and poor substrate universality.

[0005] Gliomas are the most common primary malignant tumors of the central nervous system, with glioblastoma having the highest incidence and malignancy. Glioblastoma stem cells are considered the root cause of glioma recurrence. Standard treatments for gliomas typically include surgical resection, radiotherapy, and chemotherapy. However, due to the rapid proliferation, spread, and drug resistance of gliomas, the prognosis for most patients is poor, thus necessitating the development of new therapeutic drugs. Summary of the Invention

[0006] This invention provides a method for the efficient synthesis and application of cyclobutane chromium skeleton molecules, which enables the rapid and efficient preparation of cyclobutane chromium skeleton molecules under visible light conditions using relatively readily available photocatalysts, and explores their application in glioma treatment research.

[0007] Specifically, the present invention is implemented through the following scheme: A highly efficient synthetic method for constructing cyclobutane benzoxane skeleton compounds, using 2 H Using chromene compounds as raw materials, a photocatalyst and a solvent are added, and the mixture reacts under light to obtain cyclobutane and chromene skeleton molecular compounds.

[0008] The 2 H The structural formulas of chromene compounds are as follows: ; Among them, R 1 It is a hydrogen atom, an electron-withdrawing substituent or an electron-donating substituent at C5-C8; R 2 It is C2 methyl or phenyl; R 3 It is a hydrogen atom or a C12 alkyl group; R 4 X is a hydrogen atom or a C4 phenyl group; X is O or N; Y is C or N.

[0009] The structural formula of the cyclobutane anodic skeletal compound is as follows: ; Among them, R 1 It is a hydrogen atom, an electron-withdrawing substituent or an electron-donating substituent at C5-C8; R 2 It is C2 methyl or phenyl; R 3 It is a hydrogen atom or a C12 alkyl group; R 4 X is a hydrogen atom or a C4 phenyl group; X is O or N; Y is C or N.

[0010] The 2 H The molar ratio of chromene compounds to photocatalysts is 1:0.01.

[0011] The photocatalyst can be a common organometallic catalyst or an organodye catalyst, including one of the following: iridium pyridine catalysts, ruthenium bipyridine catalysts, and organodye catalysts. Specifically, it can be bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridine]iridium di(hexafluorophosphate) ([Ir{dFCF3ppy}2(bpy)]PF6), bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) ([Ir(dF(CF3)ppy)2(dtbbpy)]PF6), or tri(2-phenylpyridine)iridium (...f One of the following: ac-Ir(ppy)3), Eosiny, Ru(bpy)3Cl2, and Methylene Blue.

[0012] The solvent is one of acetonitrile (MeCN), chloroform (CHCl3), dichloromethane (CH2Cl2), tetrahydrofuran (THF), acetone (Acetone), methanol (MeOH), dimethyl sulfoxide (DMSO), etc.

[0013] The light-induced reaction was carried out at a light wavelength range of 365nm~565nm, at 25℃, for 0.5~2 hours.

[0014] The raw material 2 H The concentration of chromene compounds is 0.01M~0.05M.

[0015] The raw materials of this invention are readily available, the substrates are widely applicable, it is suitable for the rapid synthesis of nitrogen-containing heterocyclic molecules, and it is expected to be used for the synthesis of complex molecules and gram-scale preparation.

[0016] The reaction equation of this invention is as follows, and finally 2 is obtained. H -The product of intramolecular [2+2] cycloaddition of chromene is a cyclobutane-chromene skeleton compound:

[0017] Among them, R 1 Selected from hydrogen atoms, C5-C8 electron-withdrawing or electron-donating substituents; R 2 Selected from C2 methyl or phenyl; R 3 Selected from hydrogen atoms or C12 alkyl groups; R 4 Selected from hydrogen atom or C4 phenyl; X selected from O or N; Y selected from C or N.

[0018] The synthesis method of this invention has a wide substrate range, is simple to operate, and operates under mild conditions, enabling gram-scale preparation and meeting the research and development needs of organic, chemical, and pharmaceutical fields.

[0019] The structural formula of the cyclobutane anodic skeletal compound prepared by this invention is as follows: .

[0020] The present invention also provides the application of the cyclobutane-chromium skeleton molecular compound synthesized by the above-described synthetic method in the preparation of a drug for inhibiting the growth of glioma cells, the drug further comprising pharmaceutically acceptable excipients, the excipients comprising diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorbent carriers or lubricants.

[0021] The glioma cells include human glioblastoma cells and glioma stem cells. The human glioblastoma cells are U251, the glioma stem cells are GSC-3, and the normal cell line used is HEK293T.

[0022] Compared with the prior art, the beneficial effects of the present invention are: The synthesis method of this invention uses 2 H Using chromene compounds as raw materials, intramolecular [2+2] cycloaddition is achieved in a one-step reaction under photocatalytic conditions. The operation is simple and the conditions are mild. It does not require a strictly anhydrous or high-temperature and high-pressure environment, and the reaction efficiency is high. It can usually be completed within 2 hours.

[0023] The target cycloaddition product of this invention exhibits high yield and selectivity, and the method is applicable to various 2-hydroxyl groups with different substituents. H -The chromene substrates all showed good applicability. Detailed Implementation

[0024] To make the technical problems, technical solutions and beneficial effects of the present invention clearer, the technical solutions of the present invention will be further described in detail below with reference to specific embodiments in the embodiments of the present invention. However, the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field, which can be purchased directly or synthesized by known literature methods.

[0025] Example 1 A method for synthesizing a cyclobutane-based compound with a chromogenic skeleton is provided, and the reaction equation is as follows: , The specific steps are as follows: (1) Under N2 protection, o-bromophenol (3.0 mmol, 1.0 equiv.), linalool (6.0 mmol, 2.0 equiv.), potassium carbonate (9.0 mmol, 3.0 equiv.), and palladium acetate (1 mol%) were added sequentially to a dry reaction tube with a stir bar. The mixture was stirred under reflux at 100°C for 10 hours using toluene as solvent. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, water was added to quench the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Finally, the mixture was purified by rapid column chromatography (petroleum ether / ethyl acetate = 200 / 1) to obtain 2 in 25% yield. H -chromene compounds, namely the compounds shown in formula A1; (2) Under N2 protection, add sequentially to a dry reaction tube equipped with a stir bar. fac-Ir(ppy)3 (1 mol%), compound A1 (0.2 mmol, 1.0 equiv.), were reacted with MeCN (4.0 mL) as solvent under blue light (460 nm-465 nm) for 2 hours. After the reaction, the mixture was concentrated under reduced pressure and then purified by rapid column chromatography (petroleum ether / dichloromethane = 10 / 1) to give product B1 (41.1 mg, 90% yield). dr >20:1); The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 7.11(t, J =9.0Hz,1H),6.89–6.84(m,3H),3.05(d, J =9.6Hz,1H),2.65–2.62(m,1H),2.43(t, J =6.0Hz,1H),1.97–1.92(m,1H),1.72–1.68(m,1H),1.64–1.57(m,2H),1.37(s,3H),1.36(s,3H),0.70(s,3H). 13 CNMR (151MHz, CDCl3) d 153.6,129.7,127.2,124.7,120.4,118.3,83.8,46.6,40.1,39.5,39.2,38.2,35.0,27.1,25.6,19.4.

[0026] Example 1-1 The setup was the same as in Example 1, except that a different type of photocatalyst was used. The results are shown in Table 1 below: Table 1

[0027] Combining Example 1 and Table 1, it can be seen that under the same conditions, fac -Ir(ppy)3 yields the best results, reaching up to 90%.

[0028] Examples 1-2 The setup is the same as in Example 1, except that a different solvent is used. The results are shown in Table 2 below: Table 2

[0029] Combining Example 1 and Table 2, it can be seen that under the same conditions, using MeCN as a solvent is preferable.

[0030] Examples 1-3 The setup is the same as in Example 1, except that the reaction conditions are different, as shown in Table 3: Table 3

[0031] Combining Example 1 and Table 3, it can be seen that under the same conditions, no product is generated without a photocatalyst or without light; when the reactant concentration changes from 0.05M in Example 1 to 0.01M in Table 3, the yield decreases.

[0032] Example 2 A method for synthesizing a cyclobutane-based chromogenic skeleton compound, wherein 2-bromo-3-methylphenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane-based chromogenic skeleton compound (41.6 mg, 86% yield). dr >20:1), its structural formula is shown in B2:

[0033] The NMR data of the product are as follows: 1 HNMR (500MHz, CDCl3) d 7.02(t, J =7.8Hz, 1H), 6.74(dd, J =12.7, 7.7 Hz, 2H), 3.18 (d, J =9.6Hz,1H),2.60–2.56(m,1H),2.47–2.43(m,1H),2.18(s,3H),2.03–1.98(m,1 H),1.78–1.73(m,1H),1.66–1.60(m,2H),1.42(s,3H),1.33(s,3H),0.67(s,3H). 13 CNMR (151MHz, CDCl3) d 153.7,137.2,126.6,123.8,122.4,116.0,82.9,46.6,39.8,39.6,39.4,38.3,34.1,26.5,25.4,20.0,18.6.HRMS(ESI)CalcdforC 17 H 22 O(M+H) + 243.1749, found243.1748.

[0034] Example 3 A method for synthesizing a cyclobutane-based chromogenic skeleton compound, wherein 2-bromo-4-methylphenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane-based chromogenic skeleton compound (32.1 mg, 66% yield). dr >20:1), its structural formula is shown in B3:

[0035] The NMR data of the product are as follows: 1 HNMR (500MHz, CDCl3) d 6.90(d, J =8.2Hz, 1H), 6.75(d, J =8.2Hz, 1H), 6.69(s, 1H), 3.01(d, J =9.6Hz,1H),2.63–2.59(m,1H),2.40(t, J =7.9Hz,1H),2.26(s,3H),1.95(dd, J =10.2Hz,1H),1.72–1.67(m,1H),1.62–1.55(m,2H),1.35(s,6H),0.71(s,3H). 13 CNMR (151MHz, CDCl3) d 151.2,129.9,129.3,127.7,124.3,117.8,83.5,46.5,40.1,39.4,39.0,38.0,34.8,26.8,25.4,20.7,19.4.HRMS(ESI)CalcdforC 17 H 22 O(M+H) + 243.1749, found243.1746.

[0036] Example 4 A method for synthesizing a cyclobutane-based chromogenic skeleton compound, wherein 2-bromo-5-methylphenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane-based chromogenic skeleton compound (34.4 mg, 71% yield). dr >20:1), its structural formula is shown in B4:

[0037] The NMR data of the product are as follows: 1 HNMR (500MHz, CDCl3) d 6.77(d, J =8.1Hz, 1H), 6.68(d,J =5.5Hz,2H),3.01(d, J =9.6Hz, 1H), 2.60(t, J =9.0Hz,1H),2.41(t, J =8.9Hz,1H),2.28(s,3H),1.96–1.91(m,1H),1.71–1.67(m,1H),1.63–1.57(m,2H),1.36(s,3H),1.34(s,3H),0.70(s,3H). 13 CNMR (126MHz, CDCl3) d 153.4,137.0,129.4,121.5,121.3,118.7,83.7,46.6,39.8,39.4,39.0,38.1,34.9,27.1,25.6,21.2,19.4.HRMS(ESI)CalcdforC 17 H 22 O(M+H) + 243.1749, found243.1752.

[0038] Example 5 A method for synthesizing a cyclobutane-based chromogenic skeleton compound, wherein 6-bromo-2-methylphenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane-based chromogenic skeleton compound (37.2 mg, 77% yield). dr >20:1), its structural formula is shown in B5:

[0039] The NMR data of the product are as follows: 1 HNMR (500MHz, CDCl3) d 6.98(d, J =6.0Hz,1H),6.78–6.72(m,2H),3.05(d, J =9.6Hz, 1H), 2.60(t, J =7.5Hz, 1H), 2.41(t, J =7.9Hz,1H),2.21(s,3H),1.95–1.91(m,1H),1.73–1.68(m,1H),1.64–1.54(m,2H),1.37(s,3H),1.35(s,3H),0.69(s,3H). 13 CNMR (126MHz, CDCl3) d151.8,128.2,127.3,127.1,124.3,119.6,83.7,46.6,40.4,39.7,39.2,38.4,34.9,26.9,25.6,19.5,16.1.HRMS(ESI)CalcdforC 17 H 22 O(M+H) + 243.1749, found243.1747.

[0040] Example 6 A method for synthesizing a cyclobutane chromium skeleton compound, wherein 2-bromo-4-methoxyphenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane chromium skeleton compound (39.3 mg, 76% yield). dr >20:1), its structural formula is shown in B6:

[0041] The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 6.78(d, J =8.8Hz, 1H), 6.68(dd, J =8.5, 3.4 Hz, 1H), 6.43 (d, J =3.1Hz, 1H), 3.75(s, 3H), 3.02(d, J =9.6Hz, 1H), 2.61(t, J =9.0Hz,1H),2.40(t, J =7.9Hz,1H),1.97–1.92(m,1H),1.70–1.68(m,1H),1.63–1.60(m,1H),1.54–1.52(m,1H),1.35(s,3H),1.35(s,3H),0.72(s,3H). 13 CNMR (151MHz, CDCl3) d 153.4,147.5,125.6,118.7,114.6,112.7,83.7,55.7,46.5,40.7,39.4,39.3,38.0,34.9,26.9,25.5,19.5.HRMS(ESI)CalcdforC 17 H 22 O2(M+H) + 259.1698, found259.1693.

[0042] Example 7 A method for synthesizing a cyclobutane chromium skeleton compound, wherein 2-bromo-5-methoxyphenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane chromium skeleton compound (38.4 mg, 74% yield). dr >20:1), its structural formula is shown in B7:

[0043] The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 6.78(d, J =8.3Hz, 1H), 6.46(dd, J =8.3, 2.6 Hz, 1H), 6.43 (d, J =2.6Hz, 1H), 3.76(s, 3H), 2.99(d, J =9.6Hz, 1H), 2.63(t, J =9.0Hz,1H),2.39(t, J =8.0Hz,1H),1.96–1.92(m,1H),1.70–1.66(m,1H),1.63–1.60(m,1H),1.57–1.56(m,1H),1.37(s,3H),1.33(s,3H),0.69(s,3H). 13 CNMR (151MHz, CDCl3) d 159.1,154.4,130.1,116.6,107.5,103.0,83.9,55.3,46.6,39.5,39.3,39.0,38.2,34.9,27.1,25.6,19.4.HRMS(ESI)CalcdforC 17 H 22 O2(M+H) + 259.1698, found259.1694.

[0044] Example 8 A method for synthesizing a cyclobutane benzoxane skeleton compound, wherein 6-bromo-2-methoxyphenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane benzoxane skeleton compound (33.9 mg, 66% yield). dr >20:1), its structural formula is shown in B8:

[0045] The NMR data of the product are as follows: 1HNMR (600MHz, CDCl3) d 6.80(t, J =7.8Hz, 1H), 6.72(d, J =9.8Hz, 1H), 6.52(d, J =7.6Hz, 1H), 3.85(s, 3H), 3.05(d, J =9.6Hz, 1H), 2.65(t, J =8.9Hz,1H),2.41(t, J =7.2Hz,1H),2.00–1.97(m,1H),1.73–1.69(m,1H),1.64–1.61(m,2H),1.43(s,3H),1.35(s,3H),0.71(s,3H). 13 CNMR (151MHz, CDCl3) d 149.8,143.0,125.7,121.8,119.7,109.6,84.0,56.2,46.6,40.3,39.6,39.3,38.1,34.9,27.0,25.6,19.4.HRMS(ESI)CalcdforC 17 H 22 O2(M+Na) + 281.1527, found 281.1518.

[0046] Example 9 A method for synthesizing a cyclobutane chromium skeleton compound, wherein 2-bromo-3-fluorophenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane chromium skeleton compound (36.0 mg, 73% yield). dr >20:1), its structural formula is shown in B9:

[0047] The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 7.07(q, J =8.0Hz, 1H), 6.66(d, J =8.3Hz, 1H), 6.59(t, J =9.1Hz, 1H), 3.17(d, J =8.3Hz, 1H), 2.62(t, J =6.0Hz,1H),2.44(t, J=9.0Hz,1H),1.97–1.91(m,1H),1.71–1.68(m,1H),1.64–1.59(m,2H),1.40(s,3H),1.38(s,3H),0.77(d, J =1.7Hz, 3H). 13 CNMR (151MHz, CDCl3) d 161.5(d, J =243.4Hz),154.7,127.4,113.8,112.7,107.0,84.0,46.4,39.2,37.9,37.6,35.6,33.8,27.6,25.7,18.2. 19 FNMR (471MHz, CDCl3) d -114.3.HRMS(ESI)CalcdforC 16 H 19 FO(M+H) + 247.1498, found247.1491.

[0048] Example 10 A method for synthesizing a cyclobutane chromium skeleton compound, wherein 2-bromo-4-fluorophenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane chromium skeleton compound (36.5 mg, 74% yield). dr >20:1), its structural formula is shown in B10:

[0049] The NMR data of the product are as follows: 1 HNMR (500MHz, CDCl3) d 6.80–6.77 (m, 2H), 6.59 (d, J =8.9Hz, 1H), 3.02(d, J =9.5Hz, 1H), 2.63(t, J =7.5Hz, 1H), 2.43(t, J =7.5Hz,1H),1.94–1.89(m,1H),1.68–1.56(m,3H),1.35(d, J =2.3Hz, 6H), 0.71(s, 3H). 13 CNMR (151MHz, CDCl3) d 156.9(d, J=238.0Hz),149.5,126.1,119.1,115.4,113.9,84.1,46.6,40.5,39.3,39.2,38.0,34.8,26.8,25.5,19.4. 19 FNMR (471MHz, CDCl3) d -123.8.HRMS(ESI)CalcdforC 16 H 19 FO(M+Na) + 269.1318, found 269.1317.

[0050] Example 11 A method for synthesizing a cyclobutane chromium skeleton compound, wherein 2-bromo-5-fluorophenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane chromium skeleton compound (39.5 mg, 80% yield). dr >20:1), its structural formula is shown in B11:

[0051] The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 6.82–6.79(m,1H),6.60–6.56(m,2H),3.01(d, J =9.6Hz, 1H), 2.64(t, J =9.0Hz,1H),2.41(t, J =8.1Hz,1H),1.93–1.88(m,1H),1.69–1.58(m,3H),1.36(s,3H),1.34(s,3H),0.68(s,3H). 13 CNMR (151MHz, CDCl3) d 161.9(d, J =242.7Hz),154.5,130.1,120.2,107.5,105.4,84.1,46.5,39.5,39.1,38.9,38.2,34.7,26.8,25.4,19.2. 19 FNMR (471MHz, CDCl3) d -115.5.HRMS(ESI)CalcdforC 16 H 19 FO(M+Na) + 269.1318, found269.1321.

[0052] Example 12 A method for synthesizing a cyclobutane chromium skeleton compound, wherein 6-bromo-2-fluorophenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane chromium skeleton compound (39.9 mg, 81% yield). dr >20:1), its structural formula is shown in B12:

[0053] The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 6.89(t, J =10.2Hz,1H),6.77–6.75(m,1H),6.66(d, J =7.7Hz, 1H), 3.07(d, J =9.5Hz, 1H), 2.68(t, J =9.0Hz,1H),2.44(t, J =7.8Hz,1H),1.98–1.96(m,1H),1.74–1.71(m,1H),1.67–1.62(m,2H),1.42(s,3H),1.36(s,3H),0.70(s,3H). 13 CNMR (151MHz, CDCl3) d 152.9(d, J =244.5Hz),141.6,127.3,124.4,119.5,113.6,84.4,46.5,39.9,39.4,39.3,38.2,34.7,26.6,25.4,19.3. 19 FNMR (471MHz, CDCl3) d -136.9.HRMS(ESI)CalcdforC 16 H 19 FO(M+Na) + 269.1318, found269.1309.

[0054] Example 13 A method for synthesizing a cyclobutane chromium skeleton compound, wherein 2-bromo-4-(trifluoromethyl)phenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane chromium skeleton compound (48.6 mg, 82% yield). dr >20:1), its structural formula is shown in B13:

[0055] The NMR data of the product are as follows: 1 HNMR (500MHz, CDCl3) d 7.34(d, J =8.5Hz, 1H), 7.12(s, 1H), 6.91(d, J =8.5Hz, 1H), 3.07(d, J =9.5Hz, 1H), 2.69(t, J =6.7Hz, 1H), 2.46(t, J =6.7Hz,1H),1.92–1.86(m,1H),1.70–1.60(m,3H),1.38(d, J =3.1Hz, 6H), 0.70(s, 3H). 13 CNMR (151MHz, CDCl3) d 156.4, 126.6, 124.9, 124.3 (d, J =283.8Hz), 124.3(d, J =31.7Hz),118.5,84.5,46.5,39.8,39.1,38.3,34.7,29.7,26.8,25.4,19.2. 19 FNMR (471MHz, CDCl3) d -61.4.HRMS(ESI)CalcdforC 17 H 19 F3O(M+H) + 297.1466, found297.1474.

[0056] Example 14 A method for synthesizing a cyclobutane chromium skeleton compound, wherein 2-bromo-4-chlorophenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane chromium skeleton compound (43.4 mg, 83% yield). dr >20:1), its structural formula is shown in B14:

[0057] The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 7.04(dd, J =8.6, 2.7 Hz, 1H), 6.86 (d, J =2.6Hz, 1H), 6.78(d, J =8.6Hz, 1H), 3.01(d,J =9.6Hz, 1H), 2.63(t, J =9.0Hz,1H),2.43(t, J =9.0Hz,1H),1.93–1.88(m,1H),1.72–1.68(m,1H),1.63–1.57(m,2H),1.35(s,3H),1.35(s,3H),0.71(s,3H). 13 CNMR (151MHz, CDCl3) d 152.3,129.1,127.2,126.5,125.1,119.6,84.2,46.6,40.2,39.3,39.3,38.2,34.8,26.9,25.5,19.4.HRMS(ESI)CalcdforC 16 H 19 ClO(M+Na)+285.1022,found285.1017.

[0058] Example 15 A method for synthesizing a cyclobutane chromium skeleton compound, wherein 6-bromo-4-chloro-2-fluorophenol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane chromium skeleton compound (50.0 mg, 89% yield). dr >20:1), its structural formula is shown in B15:

[0059] The NMR data of the product are as follows: 1 HNMR (500MHz, CDCl3) d 6.93(dd, J =10.3, 2.6 Hz, 1H), 6.66 (t, J =1.4Hz, 1H), 3.03(d, J =9.5Hz, 1H), 2.67(t, J =6.7Hz, 1H), 2.44(t, J =7.9,2.7Hz,1H),1.96–1.92(m,1H),1.74–1.70(m,1H),1.67–1.62(m,2H),1.40(s,3H),1.35(s,3H),0.71(s,3H). 13 CNMR (126MHz, CDCl3) d 152.7(d, J=248.5Hz),140.6,128.7,124.3,124.1,114.6,84.9,46.6,40.1,39.6,39.4,38.4,34.7,26.5,25.5,19.4. 19 FNMR (471MHz, CDCl3) d -133.8.HRMS(ESI)CalcdforC 16 H 18 ClFO(M+H)+281.1108,found281.1109.

[0060] Example 16 A method for synthesizing a cyclobutane-based chromogenic skeleton compound, wherein 3-bromonaphthol is used instead of o-bromophenol in step (1) of Example 1, and the remaining operations are the same, to obtain a cyclobutane-based chromogenic skeleton compound (42.1 mg, 76% yield). dr >20:1), its structural formula is shown in B16:

[0061] The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 7.72(t, J =9.0Hz,2H),7.38(s,1H),7.36–7.35(m,1H),7.32–7.28(m,2H),3.28(d, J =9.6Hz, 1H), 2.73(t, J =9.0Hz,1H),2.50(t, J =8.2,2.9Hz,1H),2.02–1.99(m,1H),1.77–1.75(m,1H),1.72–1.68(m,1H),1.64–1.61(m,1H),1.42(s,3H),1.39(s,3H),0.70(s,3H). 13 CNMR (151MHz, CDCl3) d 152.4,133.5,129.1,127.9,127.2,126.7,126.4,125.3,123.5,113.3,84.3 ,46.5,40.7,39.8,39.7,39.0,34.8,26.3,25.3,19.5.HRMS(ESI)CalcdforC 20 H 22 O(M+H)+279.1749,found279.1747.

[0062] Example 17 A method for synthesizing a cyclobutane-based compound with a chromogenic skeleton is provided, and the reaction equation is as follows: , The specific synthesis method is as follows: (1) First step reaction: Under air conditions, the dry reaction tube with a stirrer was cooled to 0°C, and the compound of formula A1 (20.0 mmol, 1.0 equiv.) prepared according to the method of Example 1 was added to it. After dissolving it in dichloromethane, m-chloroperoxybenzoic acid diluted with dichloromethane was slowly added. m -CPBA (28.0 mmol, 1.4 equiv.) was stirred at room temperature for 30 minutes, and the reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and the organic phase was extracted with ethyl acetate. After drying with anhydrous magnesium sulfate, the reaction solution was concentrated under reduced pressure, and then separated and purified by rapid column chromatography using petroleum ether / ethyl acetate (15 / 1) as eluent to obtain the epoxy compound in 80% yield. Step 2: The obtained epoxy compound (16.0 mmol, 1.0 equiv.) was added to a reaction tube with a stir bar. After being dissolved and diluted with tetrahydrofuran, sodium periodate was dissolved in an equal volume of water and added to the tetrahydrofuran mixture. A few drops of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for two hours. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and the organic phase was extracted with ethyl acetate. After drying with anhydrous magnesium sulfate, the reaction solution was concentrated under reduced pressure. Then, the mixture was separated and purified by rapid column chromatography using petroleum ether / ethyl acetate (20 / 1) as the eluent to obtain compound A2 in 50% yield. Step 3: Under N2 protection at 0°C, methyltriphenylphosphine bromide (1.5 mmol, 1.5 equiv.) was added to a reaction tube with a stir bar, dissolved and diluted with ultra-dry tetrahydrofuran, and then n-butyllithium (1.5 mmol, 1.5 equiv.) was slowly added dropwise. The mixture was stirred at 0°C for 30 minutes, and then compound A2 diluted with ultra-dry tetrahydrofuran (1.0 mmol, 1.0 equiv.) was added. The mixture was stirred at 0°C for 2 hours. The reaction was monitored by thin-layer chromatography until the substrate was completely reacted. After the reaction was completed, the reaction was quenched with saturated ammonium chloride aqueous solution. The organic phase was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the reaction solution was concentrated under reduced pressure. Using petroleum ether / ethyl acetate (60 / 1) as the eluent, the mixture was separated and purified by rapid column chromatography to obtain compound A3 in 60% yield. (2) Under N2 protection, add sequentially to a dry reaction tube equipped with a stir bar. fac-Ir(ppy)3 (1 mol%), compound A3 (0.2 mmol, 1.0 equiv.), were reacted with MeCN (4.0 mL) as solvent. The resulting mixture was reacted under blue light (460 nm-465 nm) for 2 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by rapid column chromatography (petroleum ether / dichloromethane = 10 / 1) to give product B17 (35.6 mg, 89% yield). dr >20:1); The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 7.09(t, J =6.7Hz, 1H), 6.99(d, J =8.6Hz, 1H), 6.88(t, J =9.0Hz,2H),3.45–3.43(m,1H),2.85–2.80(m,2H),2.60–2.56(m,1H),2.21–2.18(m,1H),1.77–1.72(m,1H),1.65(dd, J =12.7,6.9Hz,1H),1.59–1.57(m,1H),1.49(dd, J =12.9,7.1Hz,1H),1.38(s,3H). 13 CNMR (151MHz, CDCl3) d 152.7,127.8,127.7,127.1,120.8,118.1,83.6,35.4,34.4,34.3,31.0,27.0,26.7.HRMS(ESI)CalcdforC 14 H 16 O(M+H) + 201.1279, found201.1275.

[0063] Example 18 A method for synthesizing a cyclobutane chromium skeleton compound, wherein allyltriphenylphosphine bromide is used instead of methyltriphenylphosphine bromide in step (1) of Example 17, and the remaining operations are the same, to obtain a cyclobutane chromium skeleton compound (21.2 mg, 47% yield). dr =10:1), and its structural formula is shown in B18:

[0064] The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 7.11(t,J =7.7Hz, 1H), 7.00(d, J =7.8Hz,1H),6.88–6.85(m,2H),6.13–6.10(m,1H),5.08–5.01(m,2H),3.22(t, J =9.3, 6.8 Hz, 1H), 2.63 (q, J =6.5Hz,1H),2.53(t, J =12.0Hz, 1H), 2.45(q, J =6.0Hz,1H),2.17–2.12(m,1H),1.78–1.75(m,1H),1.71–1.67(m,1H),1.57(dd, J =13.1,7.1Hz,1H),1.39(s,3H). 13 CNMR (151MHz, CDCl3) d 152.5,141.9,127.5,127.3,126.5,120.9,118.2,112.7,83.4,51.7,41.1,39.8,36.2,33.6,30.2,27.1.HRMS(ESI)CalcdforC 16 H 18 O(M+H)+227.1436,found227.1435.

[0065] Example 19 A method for synthesizing a cyclobutane chromium skeleton compound, wherein cinnamyltriphenylphosphine bromide is used instead of methyltriphenylphosphine bromide in the third step of (1) of Example 17, and the remaining operations are the same, to obtain a cyclobutane chromium skeleton compound (32.5 mg, 54% yield). dr =3:1), and its structural formula is shown in B19:

[0066] The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 7.20–7.18(m,2H),7.15(t, J =7.3Hz,1H),7.13–7.10(m,3H),6.98(d, J =9.5Hz, 1H), 6.87(d, J =8.2Hz, 1H), 6.83(t, J =7.4Hz, 1H), 6.44(d, J =11.6Hz, 1H), 6.03(t,J =9.0Hz,1H),3.29(t, J =9.0Hz,1H),2.94–2.92(m,1H),2.62–2.61(m,2H),2.13–2.10(m,1H),1.83–1.79(m,1H),1.69–1.65(m,2H),1.37(s,3H). 13 CNMR (151MHz, CDCl3) d 152.8,136.7,133.8,128.5,128.0,127.7,127.4,126.6,126.1,120.9,118.3,83.6,46.7,42.6,40.8,37.0,35.9,30.1,26.6.HRMS(ESI)CalcdforC 22 H 22 O(M+H)+303.1749,found303.1745.

[0067] Example 20 A method for synthesizing a cyclobutane chromium skeleton compound, wherein benzyltriphenylphosphine bromide is used instead of methyltriphenylphosphine bromide in the third step of (1) of Example 17, and the remaining operations are the same, to obtain a cyclobutane chromium skeleton compound (50.0 mg, 90% yield). dr >20:1), its structural formula is shown in B20:

[0068] The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 7.41–7.35(m,4H),7.28–7.25(m,1H),7.16(t, J =6.0Hz, 1H), 6.98(d, J =5.9Hz, 1H), 6.93(d, J =8.2Hz, 1H), 6.87(t, J =7.4Hz, 1H), 3.47(dd, J =9.4, 7.0 Hz, 1H), 3.03(t, J =6.4Hz, 1H), 2.93(q, J =6.7Hz, 1H), 2.69(t, J =9.0Hz,1H),2.32–2.26(m,1H),1.88–1.85(m,1H),1.78–1.76(m,1H),1.72(dd, J=8.4, 4.9 Hz, 1H), 1.45 (s, 3H). 13 CNMR (151MHz, CDCl3) d 152.6,145.5,128.6,127.6,127.5,126.8,126.7,126.2,121.0,118.4,83.6,53.6,43.3,40.2,36.6,36.2,30.7,27.0.HRMS(ESI)CalcdforC 20 H 20 O(M+Na) + 299.1412, found299.1416.

[0069] Example 21 A method for synthesizing a cyclobutane-based compound with a chromogenic skeleton is provided, and the reaction equation is as follows:

[0070] The specific synthesis method is as follows: (1) Under N2 protection, compound A2 (1.0 mmol, 1.0 equiv.) and methyl (triphenylphosphine) acetate (2.0 mmol, 2.0 equiv.) were added to a dry reaction tube with a stir bar. Toluene was used as solvent and the mixture was refluxed at 100 °C for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by rapid column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound A4 in 70% yield. (2) Under N2 protection, add sequentially to a dry reaction tube equipped with a stir bar. f ac-Ir(ppy)3 (1 mol%), compound A4 (0.2 mmol, 1.0 equiv.), were reacted with MeCN (4.0 mL) as solvent. The resulting mixture was reacted under blue light (460 nm-465 nm) for 2 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by rapid column chromatography (petroleum ether / ethyl acetate = 15 / 1) to give product B21 (39.4 mg, 76% yield). dr >20:1); The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 7.15–7.10(m,2H),6.92–6.84(m,2H),3.77(s,3H),3.70(t, J =9.0Hz,1H),3.02(q, J =6.6Hz, 1H), 2.67(t, J =6.0Hz,1H),2.58(t, J=9.0Hz,1H),2.11–2.09(m,1H),1.83–1.80(m,1H),1.74–1.70(m,1H),1.66–1.62(m,1H),1.39(s,3H). 13 CNMR (151MHz, CDCl3) d 175.3,152.6,128.0,127.9,125.2,121.1,118.3,83.2,52.0,50.3,40.5,38.8,35.9,30.7,30.3,26.9.HRMS(ESI)CladforC 16 H 18 O3 (Manna) + 281.1154, found281.1151.

[0071] Example 22 A method for synthesizing a cyclobutane-based compound with a chromogenic skeleton is provided, and the reaction equation is as follows:

[0072]

[0073] The specific synthesis method is as follows: (1) First step reaction: Under N2 protection and ice bath conditions, a dichloromethane solution of 4-pentenoic acid (5.0 mmol, 1.0 equiv.) was added to a dry reaction tube with a stir bar, followed by 0.7 mL of triethylamine. Then, isobutyl chloroformate (5.5 mmol, 1.1 equiv.) was added dropwise over 30 minutes. After stirring for 10 minutes, dimethylhydroxylamine hydrochloride (5.3 mmol, 1.0 equiv.) and 0.7 mL of triethylamine were slowly added. Bubbles were immediately observed. The reaction was allowed to proceed overnight at room temperature. After the reaction was completed, the mixture was quenched with saturated sodium bicarbonate aqueous solution. The organic phase was washed with brine and water in sequence, and then extracted with dichloromethane. The combined organic phase was dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by rapid column chromatography with petroleum ether / ethyl acetate (V / V=3 / 1) as the eluent. The target N-methoxy-N-methylpent-4-eneamide product was obtained in 90% yield. Step 2: Under N2 protection, the obtained N-methoxy-N-methylpent-4-enamide (4.5 mmol, 1.0 equiv.) was added to a dry reaction tube with a stir bar. Anhydrous tetrahydrofuran was used as the solvent, and then phenyl magnesium bromide (5.0 mL, 1.0 M, 1.1 equiv.) was slowly added dropwise. The mixture was stirred until it became clear, and then stirred for another 2 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride aqueous solution. The organic phase was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by rapid column chromatography using petroleum ether / ethyl acetate (6 / 1) as the eluent. The corresponding 1-phenyl-4-penten-1-one was obtained in 81% yield. Step 3: Under N2 protection, the obtained 1-phenyl-4-penten-1-one (3.6 mmol, 1.0 equiv.) was added to a dry reaction tube with a stir bar, using anhydrous tetrahydrofuran as solvent. Then, vinyl magnesium bromide (8.0 mL, 1.0 M, 2.0 equiv.) was slowly added dropwise. The mixture was stirred until it became clear, and then stirred for another 2 hours. After the reaction was completed, the mixture was quenched with saturated ammonium chloride aqueous solution. The organic phase was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by rapid column chromatography using a petroleum ether / ethyl acetate (10 / 1) solvent system to give 3-phenyl-1,6-heptadien-3-ol in 93% yield. Fourth step reaction: Under N2 protection, the above-obtained 3-phenyl-1,6-heptadien-3-ol (3.3 mmol, 2.0 equiv.), 2-bromophenol (1.7 mmol, 1.0 equiv.), potassium carbonate (5.0 mmol, 3.0 equiv.), and palladium acetate (1 mol%) were added sequentially to a dry reaction tube with a stir bar. Toluene was used as solvent, and the mixture was stirred at 100°C under reflux for 10 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by rapid column chromatography using a petroleum ether / ethyl acetate (200 / 1) solvent system to give compound A5 in 21% yield. (2) Under N2 protection, add sequentially to a dry reaction tube equipped with a stir bar. f ac-Ir(ppy)3 (1 mol%), compound A5 (0.2 mmol, 1.0 equiv.), were reacted with MeCN (4.0 mL) as solvent. The resulting mixture was reacted under blue light (460 nm-465 nm) for 2 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by rapid column chromatography (petroleum ether / dichloromethane = 10 / 1) to give product B22 (38.3 mg, 73% yield). dr >20:1); The NMR data of the product are as follows: 1HNMR (600MHz, CDCl3) d 7.46(d, J =7.3Hz,2H),7.34(t, J =7.8Hz,2H),7.26(t, J =9.0Hz,1H),7.12(t, J =7.6Hz, 1H), 7.04(d, J =7.4Hz, 1H), 6.97(d, J =8.1Hz, 1H), 6.90(t, J =7.4Hz, 1H), 3.62(q, J =9.0Hz,1H),3.28(t, J =8.9Hz,1H),3.00–2.93(m,2H),2.60–2.54(m,1H),1.98–1.92(m,2H),1.70–1.68(m,1H),1.65–1.61(m,1H). 13 CNMR (151MHz, CDCl3) d 152.9,145.3,128.7,128.1,127.5,127.2,127.0,125.6,121.2,118.7,87.1,44.4,38.3,35.6,34.9,31.5,27.3.HRMS(ESI)CalcdforC 19 H 18 O(M+H) + 263.1436, found263.1436.

[0074] Example 23 A method for synthesizing a cyclobutane-based compound with a chromogenic skeleton is provided, and the reaction equation is as follows:

[0075] The specific synthesis method is as follows: (1) First step reaction: Under N2 protection, palladium dichloride (5 mol%) and cuprous iodide (10 mol%) were added sequentially to a dry reaction tube with a stir bar. A mixed solution of tetrahydrofuran and triethylamine (V / V=3 / 1) was used as the solvent. 3,7-dimethyloct-6-en-1-yn-3-ol (5.0 mmol, 1.0 equiv.) and o-iodophenol (6.0 mmol, 1.2 equiv.) were diluted with the solvent and added. The mixture was stirred at room temperature and the reaction was monitored by thin-layer chromatography until the substrate reaction was complete. The reaction was quenched with saturated ammonium chloride aqueous solution and the organic phase was extracted with ethyl acetate. After drying with anhydrous magnesium sulfate, the reaction solution was concentrated under reduced pressure and then purified by rapid column chromatography using petroleum ether / ethyl acetate (3 / 1) as the eluent. The coupling product 2-(3-hydroxy-3,7-dimethyloct-6-en-1-yn-1-yl)phenol was obtained in 60% yield. Step 2: Under N2 protection, 2-(3-hydroxy-3,7-dimethyloct-6-en-1-yn-1-yl)phenol (4.5 mmol, 1.0 equiv.) obtained in Step 1 was added to a dry reaction tube equipped with a magnetic stir bar. Dichloromethane was used as the solvent, and hydroiodic acid (6.8 mmol, 1.5 equiv.) diluted with dichloromethane was slowly added. The mixture was stirred at room temperature, and the reaction was monitored by thin-layer chromatography until the substrate reaction was complete. The reaction was quenched with a saturated sodium bicarbonate aqueous solution, and the organic phase was extracted with dichloromethane. After drying with anhydrous magnesium sulfate, the reaction solution was concentrated under reduced pressure. Then, the product was separated by rapid column chromatography using petroleum ether / ethyl acetate (100 / 1) as the eluent, and the iodinated product was obtained in 54% yield. Step 3: Under N2 protection, the iodinated product obtained in step 2 (0.4 mmol, 1.0 equiv.), palladium dichloride (1 mol%), potassium carbonate (0.8 mmol, 2.0 equiv.), and phenylboronic acid (0.6 mmol, 1.5 equiv.) dissolved in a mixed solution of acetonitrile and water (V / V=3 / 1) were added sequentially to a dry reaction tube equipped with a stir bar. The mixture was stirred and refluxed at 85 °C, and the reaction was monitored by thin-layer chromatography until the substrate reaction was complete. The reaction was quenched with a saturated sodium bicarbonate aqueous solution, and the organic phase was extracted with ethyl acetate. After drying with anhydrous magnesium sulfate, the reaction solution was concentrated under reduced pressure, and then separated by rapid column chromatography using petroleum ether / ethyl acetate (100 / 1) as the eluent to obtain compound A6 in 80% yield. (2) Under N2 protection, add sequentially to a dry reaction tube equipped with a stir bar. fac-Ir(ppy)3 (1 mol%), compound A6 (0.2 mmol, 1.0 equiv.), were reacted with MeCN (4.0 mL) as solvent under blue light (460 nm-465 nm) for 2 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by rapid column chromatography (petroleum ether / dichloromethane = 15 / 1) to give product B23 (46.3 mg, 76% yield). dr >20:1); The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 7.31(d, J =7.2Hz,2H),7.23(t, J =7.8Hz,2H),7.18(d, J =6.2Hz, 1H), 7.11(t, J =12.0Hz, 1H), 6.97(t, J =6.8Hz,1H),6.83–6.74(m,2H),3.32(d, J =8.6Hz,1H),2.32–2.30(m,1H),2.16–2.10(m,1H),1.71–1.66(m,3H),1.65(s,3H),1.25(s,3H),1.16(s,3H). 13 CNMR (151MHz, CDCl3) d 152.4,147.7,129.1,128.7,126.8,126.1,125.5,124.2,119.4,117.5,84.0 ,48.8,48.5,46.0,41.6,39.4,30.7,27.0,25.5,22.7.HRMS(ESI)CalcdforC 22 H 24 O(M+H) + 305.1905, found 305.1906.

[0076] Example 24 A method for synthesizing a cyclobutane-based compound with a chromogenic skeleton is provided, and the reaction equation is as follows:

[0077] The specific synthesis method is as follows: (1) Under N2 protection, compound A2 (1.0 mmol, 1.0 equiv.) was added to a dry reaction tube with a stir bar, using dichloromethane as solvent, followed by sodium acetate (4.0 mmol, 4.0 equiv.) and benzyloxyamine hydrochloride (2.0 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was quenched with saturated sodium bicarbonate aqueous solution. The organic phase was extracted with dichloromethane and purified by rapid column chromatography using a petroleum ether / ethyl acetate (10 / 1) mixed solvent as eluent to obtain compound A7 in 58% yield. (2) Under N2 protection, add sequentially to a dry reaction tube equipped with a stir bar. f ac-Ir(ppy)3 (1 mol%), compound A7 (0.2 mmol, 1.0 equiv.), were reacted with MeCN (4.0 mL) as solvent. The resulting mixture was reacted under blue light (460 nm-465 nm) for 0.5 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by rapid column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give product B24 (45.3 mg, 74% yield). dr >20:1); The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 7.39–7.27(m,5H),7.22(t, J =9.0Hz, 1H), 7.13(d, J =5.5Hz,1H),6.94–6.85(m,2H),4.76(d, J =11.3Hz, 1H), 4.65(dd, J =12.0,12.0Hz,2H),4.10(dd, J =7.2,4.4Hz,1H),2.67(dd, J =9.8,7.1Hz,1H),2.23–2.20(m,1H),1.67(dd, J =12.6, 6.6 Hz, 1H), 1.54 (dd, J =13.4,7.0Hz,1H),1.50–1.44(m,1H),1.39(s,3H). 13 CNMR (151MHz, CDCl3) d152.9,138.2,129.2,128.7,128.4,128.2,127.8,122.2,120.7,118.0,81.8,76.5,72.7,61.2,36.5,35.7,30.8,27.5.HRMS(ESI)CalcdforC 20 H 21 NO2(M+H) + 308.1651, found 308.1654.

[0078] Example 25 A method for synthesizing a cyclobutane-based compound with a chromogenic skeleton is provided, and the reaction equation is as follows:

[0079] The specific synthesis method is as follows: (1) First step reaction: Under N2 protection, compound 3,7-dimethyloct-6-en-1-yn-3-ol (7.0 mmol, 1.0 equiv.) was added to a dry reaction tube with a stir bar. Acetyl chloride (9.1 mmol, 1.3 equiv.) was slowly added with dichloromethane as solvent and stirred continuously. Then, pyridine was slowly added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was quenched with saturated ammonium chloride aqueous solution. The organic phase was extracted with dichloromethane, the organic layers were combined, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by rapid column chromatography with petroleum ether / ethyl acetate (10 / 1) as eluent. The esterified product was obtained in 89% yield. Second step reaction: Under N2 protection, the esterification product obtained in the first step (5.7 mmol, 1.0 equiv.) and 4-methoxyaniline (11.4 mmol, 2.0 equiv.) were added sequentially to a tetrahydrofuran solution containing CuCl (10 mol%). The mixture was stirred at 50 °C for 2 hours. After the reaction was completed, it was quenched sequentially with triethylamine (2.0 equiv.) and water, then extracted with dichloromethane, concentrated under reduced pressure, and purified by rapid column chromatography with petroleum ether / ethyl acetate (10 / 1) as eluent to obtain the target product N-(3,7-dimethyloct-6-en-1-yn-3-yl)-4-methoxyaniline in 40% yield. Third step reaction: Under N2 protection, Au(JohnPhos)Cl (10 mol%) and AgSbF6 (11 mol%) were added to a dry reaction tube with a stir bar. Ultra-dry dichloromethane was used as solvent, and then N-(3,7-dimethyloct-6-en-1-yn-3-yl)-4-methoxyaniline (2.0 mmol, 1.0 equiv.) obtained in the second step was added. The reaction mixture was stirred at room temperature for 40 hours. After the reaction was completed, it was quenched with triethylamine and extracted with dichloromethane. The organic layer was dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by rapid column chromatography with petroleum ether / ethyl acetate (30 / 1) to obtain product A8 in 62% yield. (2) Under N2 protection, add sequentially to a dry reaction tube equipped with a stir bar. fac -Ir(ppy)3 (1 mol%), compound A8 (0.2 mmol, 1.0 equiv.), were reacted with MeCN (4.0 mL) as solvent. The resulting mixture was reacted under blue light (460 nm-465 nm) for 2 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by rapid column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give product B25 (21.9 mg, 43% yield). dr >20:1); The NMR data of the product are as follows: 1 HNMR (600MHz, CDCl3) d 6.60(dd, J =8.6, 2.9 Hz, 1H), 6.49 (d, J =8.5Hz, 1H), 6.40(d, J =3.0Hz, 1H), 3.73(s, 3H), 3.04(d, J =9.7Hz, 1H), 2.58(dd, J =9.8, 7.4 Hz, 1H), 2.35 (t, J =7.6Hz,1H),1.86–1.83(m,1H),1.72–1.63(m,2H),1.36–1.35(m,1H),1.34(s,3H),1.21(s,3H),0.76(s,3H). 13 CNMR (151MHz, CDCl3) d 151.9,138.1,125.2,116.2,115.1,112.2,59.5,55.7,46.7,41.9,41.2,38.7,38.6,35.2,28.4,26.7,19.5.

[0080] Table 4 shows a summary of the products and yields of [2+2] cycloaddition for different substituents: Table 4

[0081] As can be seen from the above embodiments, the method of the present invention is effective for 2 substituents containing different electronic effects and steric hindrance. H - Chromene substrates and their nitrogen-containing heterocyclic analogs all exhibit good applicability. The reaction proceeds smoothly and yields the corresponding cyclobutane-chromium skeleton molecules in high yield and with high selectivity, indicating its potential as a general synthetic strategy for this type of skeleton molecule.

[0082] Application Example 1 Activity screening of cyclobutane-chromium skeleton molecules to investigate their inhibitory effects on two glioma cell lines.

[0083] Test sample: pass 1 HNMR (600MHz, CDCl3) and 13 The cyclobutane anolyte skeleton molecule obtained in the example was correctly detected by CNMR (151MHz, CDCl3), and further experiments can be conducted.

[0084] Activity screening: (1) Based on the differences in electronegativity and substitution sites, the representative cyclobutane chromium skeleton molecules B3, B6, B8, B9, B14, B18, B21, and B23 were selected and dissolved in DMSO to prepare a mother liquor with an initial concentration of 10 mg / mL. (2) Set up a control group: 200 μL LDMSO solvent; (3) Three cell lines, U251, GSC-3, and HEK293T (all provided by the Tumor Animal Model Preparation and Application Research Laboratory of West China Hospital, Sichuan University), were respectively divided into 2×10 4 Inoculate the cells per well into a 96-well plate, and add 100 μL of culture medium (DMEM + 10% FBS + 1% antibiotic medium) to each well. (3) After the cells have been inoculated, place them in a cell culture incubator and culture for 24 hours. Once the cells have adhered well, discard the culture medium in the 96-well plate. (4) Dilute the mother liquor (10 mg / mL) of the above cyclobutane-chromium skeleton molecular compound with DMSO to the working solution concentration (10 μg / mL). (5) Add 200 μL of DMSO solution of the tested cyclobutane chromogenic backbone molecule to each well of cells. The experiment was repeated 3 times. The control group was added with 200 μL of DMSO solvent. (6) Place the 96-well plate in a cell culture incubator and continue to culture at 37°C and 5% CO2 for 72 hours. Discard 100 μL of DMSO solution of cyclobutane and color-complete skeleton molecules in each well (discard 100 μL of DMSO solvent in the control group). Add 20 μL of LMTS (CellTiter AQueous Non-Radioactive Cell Proliferation Assay, #G3581), mix well, and continue to incubate in the cell culture incubator for 2 hours. (7) Measure the absorbance at 490 nm using an ELISA reader and calculate the cell viability; The cell viability calculation method is as follows: Cell viability = (OD of drug-treated group - OD of blank culture medium) / (OD of DMSO group - OD of blank culture medium), where OD is the absorbance value.

[0085] Using the above method, the above representative cyclobutane-chromium skeleton molecules were screened for activity. The summary of their activity against the three cell lines GSC-3, U251, and HEK293T is shown in Table 5. Table 5

[0086] As shown in Table 5, the screened cyclobutane-based chromosomes exhibited good selective killing activity against glioma stem cells (GSC-3). When the substituent was on the benzene ring, electron-donating alkyl, alkoxy, or halogen substituents could selectively kill glioma stem cells. Although the activity decreased when the methoxy group was at the C8 position, it still showed good selectivity. When the substituent was on cyclobutane, the activity completely disappeared, indicating that the cyclobutane moiety in the skeleton may be the key pharmacophore. When the substituent was on the oxygen ring, it could still selectively kill glioma stem cells and exert an inhibitory effect.

[0087] The above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. It should be noted that those skilled in the art can make several improvements without departing from the principle of the present invention, and these improvements should also be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing a cyclobutane-based skeletal compound, characterized in that, With 2 H Using chromene compounds as raw materials, a photocatalyst and a solvent are added, and the mixture reacts under light to obtain cyclobutane and chromene skeleton molecules.

2. The method for synthesizing the cyclobutane-based chromogenic skeleton compound according to claim 1, characterized in that, The 2 H The structural formulas of chromene compounds are as follows: ； Among them, R 1 It is a hydrogen atom, an electron-withdrawing substituent or an electron-donating substituent at C5-C8; R 2 It is C2 methyl or phenyl; R 3 It is a hydrogen atom or a C12 alkyl group; R 4 X is a hydrogen atom or a C4 phenyl group; X is O or N; Y is C or N.

3. The method for synthesizing the cyclobutane-based chromogenic skeleton compound according to claim 1, characterized in that, The structural formula of the cyclobutane anodic skeletal compound is as follows: ； Among them, R 1 It is a hydrogen atom, an electron-withdrawing substituent or an electron-donating substituent at C5-C8; R 2 It is C2 methyl or phenyl; R 3 It is a hydrogen atom or a C12 alkyl group; R 4 X is a hydrogen atom or a C4 phenyl group; X is O or N; Y is C or N.

4. The method for synthesizing the cyclobutane-based chromogenic skeletal compound according to claim 1, characterized in that, 2 H The molar ratio of chromene compounds to photocatalysts is 1:0.

01.

5. The method for synthesizing the cyclobutane-based chromogenic skeletal compound according to claim 1, characterized in that, The photocatalysts are [Ir{dFCF3ppy}2(bpy)]PF6 and [Ir(dF(CF3)ppy)2(dtbbpy)]PF6. f One of ac-Ir(ppy)3, Eosiny, Ru(bpy)3Cl2, and Methylene Blue.

6. The method for synthesizing the cyclobutane-based chromogenic skeleton compound according to claim 1, characterized in that, The solvent is one of acetonitrile, chloroform, dichloromethane, tetrahydrofuran, acetone, methanol, and dimethyl sulfoxide.

7. The method for synthesizing the cyclobutane-based chromogenic skeleton compound according to claim 1, characterized in that, The reaction under light irradiation was carried out at 25°C for 0.5 to 2 hours, with an irradiation wavelength range of 365 nm to 565 nm.

8. The method for synthesizing the cyclobutane-based skeletal compound according to claim 1, characterized in that, 2 H The reaction concentration of chromene compounds in solvents is 0.01M~0.05M.

9. The use of the cyclobutane-chromium skeleton compound synthesized by the method of claim 1 in the preparation of drugs that inhibit the growth of glioma cells.

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