A method for preparing a cyclobutene derivative

Abstract

The present invention discloses a method for preparing cyclobutene derivatives. Under the action of a cheap and easily available metal ion catalyst, a conjugated acetyl acid ester reacts with an indole compound in the presence of the catalyst to form a cyclobutene derivative at the 3-position of the indole compound. The cyclobutene derivative can be easily prepared into a cyclobutane derivative through various reduction methods. The present invention proposes reaction raw material substrates different from the prior art, broadening the selection range of the types of quaternary ring compounds prepared by cross-coupling.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound process applications, and more specifically, relates to a quaternary ring derivative, especially a preparation method of cyclobutene derivatives. Background Art

[0002] Quaternary ring compounds, such as cyclobutane and cyclobutene derivatives, are basic structural skeletons widely present in various drug molecules. Most of these derivatives have good drug properties and other biological activities. At the same time, due to the relatively large strain energy of quaternary ring compounds (for example, the strain energy of cyclobutane is 26.3 kcal / mol), it is relatively easy to break the C-C bond under the catalysis of transition metals and undergo ring-opening reactions to synthesize other compounds [Chemical Reviews. 2015, 115, 9410]. Therefore, the synthesis of quaternary ring compounds has attracted more and more attention from researchers.

[0003] The synthesis of quaternary ring derivatives has always been a hot topic in the field of small-ring organic chemistry. In this field, the preparation of quaternary ring compounds with high regioselectivity and high stereoselectivity has always faced great challenges. Currently, the relatively common synthesis methods include: [2+2] cycloaddition reaction, ring expansion reaction, and ring contraction reaction. Among them, the [2+2] cycloaddition reaction is more common. The cycloaddition reaction is a classic organic reaction. Under heating conditions, the [4+2] cycloaddition reaction of alkenes can occur. In contrast, the [2+2] cycloaddition reaction requires light, acid, or transition metal action to proceed. Among them, the [2+2] cycloaddition reaction under light is the most direct and effective method for people to obtain quaternary ring compounds [Chemical Reviews 2016, 116, 7330]. At the same time, cyclobutene derivatives can be easily prepared into cyclobutane derivatives through various reduction methods.

[0004] However, the current synthesis methods all have deficiencies: the raw materials are not widely present in nature, need to be prepared in advance, and the cost is expensive; the reaction steps are lengthy, and the operation steps are complex; the atom utilization rate is low, the product yield is low, and some reagents are harmful to the human body. Therefore, there is an urgent need to develop a more concise method. Summary of the Invention

[0005] In view of the above defects or improvement requirements of the prior art, the present invention provides a preparation method of quaternary ring derivatives, especially a preparation method of cyclobutene derivatives. Cyclobutene derivatives can be easily prepared into cyclobutane derivatives through various reduction methods. The purpose of the present invention is to provide a new preparation technology of quaternary ring derivatives and solve the problems existing in the prior art such as high raw material cost, complex preparation steps, and great harm of reagents.

[0006] The present invention discovers that conjugated acetoacetates react with indole derivatives in the presence of a catalyst to form cyclobutene derivatives, and the chemical reaction formula is as follows:

[0007]

[0008] Among them, R1 is an aromatic hydrocarbon or an aliphatic hydrocarbon;

[0009] R2 is hydrogen, a hydroxyl group, a halogen, a C1-C10 aliphatic hydrocarbon, a C6-C13 aromatic hydrocarbon, a C1-C10 aliphatic hydrocarbon oxy group, or a C6-C13 aromatic hydrocarbon oxy group, and its substitution position can be any position of the 4, 5, 6, or 7 positions of the indole ring;

[0010] R3 is hydrogen, a C1-C10 aliphatic hydrocarbon, a C1-C10 aliphatic hydrocarbon oxy group, a C6-C13 aromatic hydrocarbon, or a C6-C13 aromatic hydrocarbon oxy group.

[0011] Furthermore, in the conjugated acetoacetate, R1 is a C1-C5 aliphatic hydrocarbon, and R2 is a hydroxyl group substituted at the 5 position or a C6-C13 aromatic hydrocarbon oxy group;

[0012] The catalyst is an organometallic catalyst, including indium trichloride, iron chloride, and tin chloride.

[0013] Even further, the conjugated acetoacetate is methyl acetoacetate, ethyl acetoacetate, or butyl acetoacetate;

[0014] The catalyst is indium trichloride.

[0015] The raw materials and reactions used in the present invention are common in the field of organic chemistry, and there are literature reports: under the same raw materials and reaction conditions, reaction products completely different from those of the present invention are obtained. For example, in the literature [J Enzyme Inhib Med Chem, 2009, 24(5): 1148-1153], the authors intended to prepare pyranoindole (2) by the von Pechmann reaction of 1-methyl-5-hydroxyindole (1) with ethyl acetoacetate (EAA), but unexpectedly obtained MIBE (3) or product (4) depending on the amount of ethyl acetoacetate used.

[0016]

[0017] The present invention uses the same raw materials and reaction conditions, originally intending to obtain compound 3, but it is found that the results are inconsistent with the literature in the structural confirmation of the product. After multiple reaction verifications, the present invention determined the structure of the reaction product by two-dimensional nuclear magnetic resonance and discovered a new synthesis method for cyclobutene compounds from it. Cyclobutene derivatives can be easily prepared into cyclobutane derivatives by various reduction methods.

[0018] Compared with the prior art, the present invention has the following effects:

[0019] (1) The present invention provides a preparation method for preparing a quaternary ring compound by cross-coupling reaction of acetoacetate derivatives under the action of a cheap and easily available metal ion catalyst. The metal ion catalyst, such as trivalent indium catalyst, is cheap and easily available and has no harm to the environment. The reaction operation is very simple, the reaction conditions are mild, and the yield is medium.

[0020] (2) The preparation method for the quaternary ring compound proposed by the present invention provides reaction raw material substrates different from the prior art, broadening the selection range of the types of quaternary ring compounds prepared by cross-coupling.

[0021] (3) The reported methods for synthesizing quaternary ring compounds generally have complex and rare raw materials, and harsh and difficult-to-operate conditions, which greatly limit industrial applications. The quaternary ring compounds synthesized by the present invention widely exist in the basic structural skeletons of various drug molecules, and most of these derivatives have good drug properties and other biological activities. The reaction route innovatively designed by the present invention provides a simple preparation method for synthesizing such compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 1H-NMR of Compound 5 1 1H-NMR);

[0023] Figure 2 13C-NMR of Compound 5 13 13C-NMR);

[0024] Figure 3 DEPT-135 of Compound 5;

[0025] Figure 4 HSQC of Compound 5;

[0026] Figure 5 H-H COSY of Compound 5;

[0027] Figure 6 NOE of Compound 5;

[0028] Figure 7 HMBC of Compound 5;

[0029] Figure 8 HRMS of Compound 5;

[0030] Figure 91H-NMR of compound 6

[0031] Figure 10 Partial enlarged view of 1H-NMR of compound 6

[0032] Figure 11 13C-NMR of compound 6

[0033] Figure 12 MS of compound 6 Detailed implementation mode

[0034] The examples and preparation examples provided below further clarify and illustrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparation examples does not limit the scope of the present invention in any way. The raw materials of the present invention can be obtained commercially or prepared by methods known in the art.

[0035] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR measurement was performed using an ACF-400 BRUK nuclear magnetic resonance instrument, and the measurement solvent was deuterated chloroform (CDC13) or deuterated dimethyl sulfoxide (DMSO-d6), with TMS as the internal standard. Column chromatography was performed using silica gel with 200 - 300 mesh.

[0036] Example 1: Preparation of compound 5

[0037]

[0038] Under nitrogen, indium(III) chloride (10 mol%) was added to a mixture of an indole derivative and ethyl acetoacetate (in excess, also used as a solvent). The reaction mixture was heated at 120 °C for 2 hours and then cooled to room temperature. Ice water was added, and the reaction mixture was extracted with ethyl acetate (EtOAc). The organic layer was collected, washed with brine, dried over MgSO4 and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (a mixture of hexane - EtOAc = 6:1 as the eluent) to obtain the desired product, compound 5: yield 25%, white crystals, mp 178 - 180 °C. 1 H-NMR (d6-DMSO) δ: 8.93 (s, 1H, Ar); 7.33 (d, 1H, Ar, J 7,6= 8.8 Hz); 6.90 (d, 1H, Ar); 6.81 (dd, 1H, Ar); 6.05 (s, 1H, C=CH); 4.13 - 4.12 (q, 2H, CH2); 3.94 - 3.90 (m, 2H, CH2); 3.78 (s, 3H, NCH3); 3.75 (d, 1H, C=CH2); 3.27 (d, 1H, C=CH2); 2.75 - 2.63 (dd, 2H, CH2); 1.44 (s, 3H, C-CH3); 1.26 - 1.23 (t, 3H, CH3); 0.97 - 0.95 (t, 3H, CH3). 13 C-NMR (d6-DMSO) δ: 170.8, 166.7, 151.9, 151.0, 140.0, 139.0, 137.5, 121.8, 115.0, 111.3, 104.1, 103.5, 59.5, 59.1, 51.1, 44.9, 40.0, 30.8, 27.1, 14.4, 13.8. HRMS (ESI): calc for C 21 H 25 NO5[M + H] + 372.1824, found 372.1801.

[0039] One-dimensional and two-dimensional magnetic nuclear spectra and HRMS are shown in the appendix Figures 1 - 8 。

[0040] Example 2: Preparation of Compound 6

[0041]

[0042] According to the method of Example 1, using 1-methyl-5-benzyloxyindole instead of 1-methyl-5-hydroxyindole, Compound 6 was obtained with a yield of 30%, white crystals, mp 162 - 163 °C. 11H-NMR (d6-DMSO) δ: 7.48 (d, 2H, Ar); 7.39 (t, 2H, Ar); 7.32 (t, 1H, Ar); 7.20 (d, 1H, Ar); 7.11 (d, 1H, Ar); 7.02 (dd, 1H, Ar); 6.05 (t, 1H, C=CH); 5.09 (s, 2H, Ar-CH2); 4.25 - 4.15 (q, 2H, CH2); 4.07 - 3.98 (m, 2H, CH2); 3.91 (dd, 1H, CH); 3.87 (s, 3H, NCH3); 3.46 - 3.41 (dd, 2H, C=CH2); 2.81 - 2.66 (dd, 2H, CH2); 1.55 (s, 3H, C-CH3); 1.35 - 1.31 (t, 3H, CH3); 1.09 - 1.06 (t, 3H, CH3). 13 13C-NMR (d6-DMSO) δ: 171.5, 167.6, 153.2, 152.1, 140.8, 140.1, 138.5, 137.3, 128.6, 128.0, 127.6, 122.2, 115.5, 110.8, 105.1, 103.4, 71.0, 60.2, 60.0, 51.7, 45.7, 40.5, 31.1, 27.3, 14.5, 14.1. MS (EI) m / z (%): 461 (M + , 72.0), 416.3 (10.0), 374.3 (100), 370.25 (24.0), 284.2 (38.0), 91.1 (61.0).

[0043] 1H-NMR and MS spectra are shown in the appendix Figures 9 - 12 .

[0044] Example 3. Proliferation inhibitory activity against tumor cells

[0045] Take tumor cell lines in logarithmic growth phase (HepG2 liver cancer, MCF-7 breast cancer cells, H1299 human lung cancer cells, 786-O human renal clear cell carcinoma cells), inoculate them at 4000 cells / well in 96-well culture medium, and set up a control group (DMSO) and a compound treatment group. The highest concentration of the compound is 50 μg / mL, and it is diluted in a 5-fold gradient, with a total of 5 concentrations, and three replicates for each concentration. After the compound acts on the cells for 72 hours, discard the culture medium, add 100 μL of pre-cooled 10% trichloroacetic acid (TCA) solution to each well to fix the cells, place them in a 4°C refrigerator for 1 hour, wash each well of the culture medium five times with deionized water to remove the TCA solution, air dry, add 50 μL of SRB solution (4 mg / mL) prepared with 1% acetic acid to each well, place it at room temperature for 20 minutes, discard the liquid in each well after that, wash it five times with 1% acetic acid, air dry after washing off the unbound SRB dye, add 100 μL of 10 mM Tris-base (tris(hydroxymethyl)aminomethane) solution with pH = 10.5 to each well to dissolve, shake on a plate for 5 minutes, and measure the absorbance OD value at a wavelength of 515 nm with an enzyme-linked immunosorbent assay (ELISA) reader.

[0046] The IC of the compound measured by the MTT method 50 values are shown in the following table:

[0047] Table. Compound IC 50 (μM) values

[0048]

[0049] It can be seen that the compound synthesized by the method provided by the present invention has good inhibitory activity on the proliferation of tumor cells and shows certain selectivity for different cell lines (HepG2 liver cancer, MCF-7 breast cancer cells, H1299 human lung cancer cells, 786-O human renal clear cell carcinoma cells). Therefore, it can be used in the preparation of drugs for the treatment, prevention and alleviation of cancer.

Claims

1. A method for preparing a cyclobutene derivative, characterized in that, The conjugated acetate of the formula III structure reacts with the indole compound of the formula II structure in the presence of the catalyst indium trichloride to form a cyclobutene derivative of the formula I structure at the 3-position of the indole compound. The chemical reaction formula is as follows: The cyclobutene derivative of the formula I structure is specifically compound 5 or compound 6. Among them, R1, R2, and R3 in the cyclobutene derivative of the formula I structure correspond to the groups in compounds 5 and 6, and R1, R2, and R3 in formulas I, II, and III have the same meaning;

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