A kind of ethenyl indole and mid-cycle compound and its synthesis method

Abstract

A kind of ethenyl indole and medium ring compound and its synthesis method, compound includes axial chiral ethenyl indole and nine-membered ring compound and ethenyl indole and eight-membered ring compound, structural formula is as shown in formula 3 and formula 6 respectively;Synthesis method: with formula 1 compound 3-ethynyl-2-indole methanol and formula 2 compound 2-indole ethanol / formula 5 compound 2-indole methanol as reaction raw material is added to organic solvent, additive is added, under the catalysis of catalyst and under certain temperature condition stirring reaction, TLC is tracked to complete reaction, filter, concentrate, purify and obtain.The ethenyl indole and medium ring compound synthesized in the application, through biological activity test, shows that the two types of derivatives have high sensitivity and strong cytotoxic activity to human prostate cancer cell PC-3.The reaction condition of the application is relatively conventional, the reaction process is mild, simple, low in cost, suitable for industrial large-scale production, and the application range of the method is widened.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis, specifically relating to a vinylindolol cyclic compound and its synthesis method. Background Technology

[0002] Indole derivatives and axially chiral aryl-ring compounds are widely found in antitumor drug molecules and natural products, and have broad application prospects in the life sciences. Combining indole with an axially chiral aryl-ring skeleton is expected to have good antitumor activity. However, currently, axially chiral vinylindole-9-membered ring compounds and vinylindole-8-membered ring compounds are a class of compounds that have never been studied, and their synthetic methods and cytotoxicity against human prostate tumor cells PC-3 have not been investigated. Summary of the Invention

[0003] One objective of this invention is to provide a vinylindole-1,000 medium-cyclic compound, expanding the range of axially chiral indole-1,000 medium-cyclic compounds. This derivative exhibits good sensitivity and cytotoxic activity against human prostate cancer cells PC-3.

[0004] The second objective of this invention is to provide a method for synthesizing the above-mentioned vinylindolol cyclic compounds. This method is mild, simple, safe and easy to operate, has high enantioselectivity, and has the advantages of low cost and good yield.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is: a vinylindolocyclic cyclic compound, characterized in that it comprises an axially chiral vinylindolocyclic nine-membered ring compound and a vinylindolocyclic eight-membered ring compound, the chemical structural formulas of which are shown in Formula 3 and Formula 6, respectively:

[0006]

[0007] In Formula 3, Ar is selected from one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, and halogen-substituted phenyl; R is selected from one of hydrogen, methoxy, methyl, and halogen; R 1 Selected from one of methoxy, methyl, and halogen;

[0008] In Formula 6, Ar is selected from one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, tert-butyl-substituted phenyl, and halogen-substituted phenyl; R is selected from one of hydrogen, methoxy, methyl, and halogen; R 1 It is selected from one of methoxy, methyl, and halogen.

[0009] The present invention also provides a method for synthesizing the above-mentioned vinylindole-2-indole methanol and compound 2-indoleethanol / compound 5 as reactants in an organic solvent, adding additives, stirring the reaction under the catalysis of a catalyst and at a certain temperature, monitoring the reaction by TLC until complete, and then filtering, concentrating and purifying to obtain the product.

[0010] The structural formula of compound 3-ethynyl-2-indoleethanol of formula 1 is as follows: R is selected from one of hydrogen, methoxy, methyl, and halogen;

[0011] The structural formula of compound 2-indoethanol of formula 2 is as follows: The structural formula of compound 2-indolemethyl is as follows: Among them, R 1 All are selected from one of hydrogen, methoxy, methyl, and halogen;

[0012] When the vinylindolyl ring compound is a nine-membered ring compound of formula 3, the reaction raw materials are 3-ethynyl-2-indole methanol of formula 1 and 2-indoleethanol of formula 2, with a molar ratio of 2:(1-4); the reaction temperature is 0-50℃, the reaction time is 5-24h; the catalyst is chiral phosphoric acid; the molar ratio of 3-ethynyl-2-indole methanol of formula 1 to the catalyst is 1:(0.1-0.35); in formula 1, Ar is selected from phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, and halogen-substituted phenyl.

[0013] When the vinylindolyl ring compound is a vinylindolyl eight-membered ring compound of formula 6, the reaction raw materials are 3-ethynyl-2-indolyl methanol of formula 1 and 2-indolyl methanol of formula 5, with a molar ratio of 3:(2-6); the reaction temperature is -20-50℃; the catalyst is a Brønsted acid or a Lewis acid; the molar ratio of 3-ethynyl-2-indolyl methanol of formula 1 to the catalyst is 1:(0.1-0.2); in the compound of formula 1, Ar is selected from phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, tert-butyl-substituted phenyl, and halogen-substituted phenyl.

[0014] Preferably, the chiral phosphoric acid is selected from one of the following: a binatidine skeleton derivative, an octahydrobinatidine skeleton derivative, and a spirocyclic skeleton derivative;

[0015] The aforementioned binaphthyl skeleton derivative is a compound of formula 4, and its structural formula is as follows: In the formula, G is selected from one of 4-chlorophenyl, 9-anthrayl, 9-phenanthyl, 2,4,6-triisopropylphenyl, 2-naphthyl, 1-naphthyl, triphenylsilyl, 2,4,6-tricyclohexylphenyl, 2,4,6-trimethylphenyl, 2,6-diisopropyl-4-adamantylphenyl, and 3,5-di-tert-butyl-4-methoxyphenyl;

[0016] The octahydrobinaphthyl skeleton derivative is a compound of formula 8, and its structural formula is as follows: In the formula, G is selected from one of 2,4,6-triisopropylphenyl, 2,4,6-tricyclohexylphenyl, and 2,4,6-trimethylphenyl;

[0017] The spirocyclic skeleton derivative is a compound of formula 9, and its structural formula is as follows: In the formula, G is selected from 2,4,6-triisopropylphenyl and 2,4,6-trimethylphenyl;

[0018] The Lewis acid is selected from one of scandium trifluoromethanesulfonate, magnesium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, and copper trifluoromethanesulfonate; the Brønsted acid is selected from one of trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, acetic acid, benzoic acid, diphenylphosphonic acid, diphenyl phosphate, and binatidine phosphate.

[0019] The naphthyl phosphate is a compound of formula 7, and the structural formula of the compound of formula 7 is as follows:

[0020] Preferably, the chiral phosphoric acid is a binaphthyl skeleton derivative, and G is selected from 2,6-diisopropyl-4-adamantylphenyl; the Brønsted acid is binaphthyl phosphoric acid.

[0021] Preferably, the molar ratio between compound 3-ethynyl-2-indoleethanol of formula 1 and compound 2-indoleethanol of formula 2 is 1:2; the molar ratio between compound 3-ethynyl-2-indoleethanol of formula 1 and compound 2-indoleethanol of formula 5 is 1:2.

[0022] Preferably, when the vinylindolono-medium ring compound is a compound of formula 3, the reaction temperature is 30°C and the reaction time is 5 hours; when the vinylindolono-medium ring compound is a compound of formula 6, the reaction temperature is 0°C.

[0023] Preferably, when the vinylindolano ring compound is an axially chiral vinylindolano nine-membered ring compound of Formula 3, the organic solvent is selected from acetonitrile, acetone, ethyl acetate, 1,2-dichloroethane, toluene, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride, and 1,1,2-trichloroethane; the volume ratio of the organic solvent to the molar amount of the compound 3-ethynyl-2-indole methanol of Formula 1 is (5-80) mL: 1 mmol; when the vinylindolano ring compound is a vinylindolano eight-membered ring compound of Formula 6, the organic solvent is selected from acetonitrile, acetone, ethyl acetate, 1,2-dichloroethane, toluene, tetrahydrofuran, dichloromethane, chloroform, and carbon tetrachloride; the volume ratio of the organic solvent to the molar amount of the compound 3-ethynyl-2-indole methanol of Formula 1 is (5-40) mL: 1 mmol.

[0024] Preferably, the additive is One of sodium sulfate and magnesium sulfate, wherein the mass ratio of the additive to the molar amount of the compound 3-ethynyl-2-indole methanol of Formula 1 is 1 g: 1 mmol.

[0025] Preferably, the additive is The organic solvent is 1,2-dichloroethane; when the vinylindolyl cyclic compound is an axially chiral vinylindolyl 9-membered ring compound of Formula 3, the volume ratio of the organic solvent to the molar amount of the compound 3-ethynyl-2-indole methanol of Formula 1 is 10 mL: 1 mmol; when the vinylindolyl cyclic compound is an octylindolyl 8-membered ring compound of Formula 6, the volume ratio of the organic solvent to the molar amount of the compound 3-ethynyl-2-indole methanol of Formula 1 is 40 mL: 1 mmol.

[0026] Preferably, the purification is performed by silica gel column chromatography, and the eluent is a mixture of petroleum ether and ethyl acetate at a volume ratio of 4:1.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] (1) The vinylindole-1,4-cyclic compounds synthesized in this invention, through bioactivity testing, showed that the two derivatives had high sensitivity and strong cytotoxic activity against human prostate cancer cells PC-3, indicating that the vinylindole-1,4-cyclic compounds synthesized in this invention are expected to be applied in the pharmaceutical field.

[0029] (2) By changing one of the raw materials, catalysts, reaction temperature and other conditions, the present invention can synthesize two compounds: axially chiral vinylindolophore nine-membered ring compounds and vinylindolophore eight-membered ring compounds. The reaction conditions are relatively conventional, the reaction process is mild, simple, easy to operate and low in cost, and suitable for large-scale industrial production, thus broadening the scope of application of the method. The present invention uses a variety of substrates as reactants to obtain products with diverse and complex structures, and the yield is good to high with high enantioselectivity. Detailed Implementation

[0030] The present invention will be further described in detail below with reference to the embodiments.

[0031] In the following examples, unless otherwise stated, 3-ethynyl-2-indoleethanol, 2-indoleethanol, 2-indoleethanol, chiral phosphoric acid, the Brønsted acid and Lewis acid used, and other reagents are all commercially available or obtained as reported in known literature; the experimental methods described are generally performed under conventional conditions or conditions recommended by the manufacturer.

[0032] Example 1

[0033] The synthetic route for the axially chiral vinylindole-9-membered ring compound of formula 3aa is as follows:

[0034]

[0035] 0.1 mmol of 3-ethynyl-2-indole methanol (formula 1a) and 2-indoleethanol (formula 2a) were added to an organic solvent (the molar ratio of the organic solvent volume to the molar amount of 3-ethynyl-2-indole methanol (formula 1) to 1 mmol) as reactants (the molar ratio between compound 3-ethynyl-2-indole methanol of formula 1 and compound 2-indoleethanol of formula 2 was 2:(1-4)). The reaction was carried out under the action of chiral phosphoric acid (formula 4, 8 or 9) (10-30 mol% of 3-ethynyl-2-indole methanol) at 0-50 °C for 5-24 h with stirring. The reaction was monitored by TLC until the end of the reaction. After filtration and concentration, the mixture was purified and separated by silica gel column chromatography (the eluent was a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 4:1) to obtain the axially chiral vinylindole anodic nine-membered ring compound 3aa. The yield and enantioselectivity are shown in Table 1.

[0036] Table 1. Effects of different types of chiral phosphoric acid, solvent, temperature, equivalence ratio, additives, solvent volume, catalytic amount of chiral phosphoric acid, and reaction time on the enantioselectivity and yield of the reaction.

[0037]

[0038]

[0039] Note: In Table 1, ee represents the enantiomer excess ratio, and the amount of additive added is 0.1g.

[0040] From the data in Table 1, the optimal reaction conditions can be determined as follows: chiral phosphoric acid is formula 4j, the amount of chiral phosphoric acid is 30 mol% of 3-ethynyl-2-indole methanol, the solvent is 1,2-dichloroethane, the volume of the organic solvent is 1.0 mL, the reaction temperature is 30℃, the equivalence ratio is formula 1a: formula 2a = 1:2, the reaction time is 5 hours, and the additive is...

[0041] The steps for obtaining product formula 3aa under optimal reaction conditions in Example 1 are as follows:

[0042] 0.1 mmol of 3-ethynyl-2-indole methanol (formula 1a) and 0.2 mmol of 2-indole ethanol (formula 2a) were added to the organic solvent 1,2-dichloroethane (1.0 mL) as reactants. The mixture was stirred at 30 °C for 5 h in the presence of 0.03 mmol of chiral phosphoric acid (formula 4j). The reaction was monitored by TLC until completion. After filtration and concentration, the mixture was purified by silica gel column chromatography (eluting solution of petroleum ether and ethyl acetate in a volume ratio of 4:1) to obtain the axially chiral vinylindole anodic nine-membered ring compound (formula 3aa).

[0043] The structural characterization data of product formula 3aa obtained under the optimal reaction conditions in Example 1 are as follows:

[0044] 55%yield(28.7mg)as a yellow solid.mp149.9–150.7℃; [α] D 20 =-158.7(c=0.31,acetone); 1 H NMR(400MHz, Acetone-d6)δ(ppm):9.96(s,1H),9.74(s,1H),7.95–7.86(m,1H), 7.74(d,J=7.6Hz,2H),7.56(d,J=7.8Hz,1H),7.40–7.26(m,5H),7.26–7.21(m,3H ),7.21–7.15(m,2H),7.08–6.98(m,3H),6.98–6.93(m,1H),5.94(s,1H),3.87–3. 75(m,1H),3.39–3.28(m,1H),3.17–3.05(m,1H),2.75–2.65(m,1H),0.64(s,9H); 13C NMR(100MHz,Acetone-d6)δ(ppm):146.2,141.1,140.8,135.6,135.4,134.8,134.0 ,130.9,129.9,129.3,128.9,128.1,127.8,127.6,127.1,126.7,126.5,123.9,121 .1,120.2,119.7,119.3,118.8,118.7,117.6,115.2,113.8,110.9,110.3,84.3,64 .8,34.2,29.4,27.6;IR(KBr):3658,3407,2947,2813,1628,1593,1381,1351,741cm -1 HRMS (ESI) for: C 37 H 34 N2O[MH] - calcd: 521.2598, found 521.2627; The enantiomeric excess (ee) value: 94%, determined by HPLC (Daicel Chiralpak ID, hexane / isopropanol=80 / 20, flowrate 1.0mL / min, T=30℃, 254nm): t R =3.763(minor),t R =4.213 (major).

[0045] Example 2-27

[0046] The synthesis methods of Examples 2-27 are the same as those of Example 1, except that compounds 3-ethynyl-2-indoleethanol of Formula 1 and 2-indoleethanol of Formula 2 with different structures are used as raw materials.

[0047] The reactive synthesis route is shown below.

[0048]

[0049] The products, enantioselectivity, and yields are shown in Table 2 below:

[0050] Table 2. Reactants, products, enantioselectivity, and yields of Examples 1-27

[0051]

[0052] [a] The catalytic amount is 35 mol%.

[0053] Except for the catalyst dosage of 35 mol% in Examples 3 and 5, the other parameters and reaction parameters in other examples are the optimal reaction conditions used in Example 1.

[0054] As shown in Table 2, the method of the present invention can not only achieve the synthesis of axially chiral vinylindole-9-membered ring compounds in one step, obtain high enantioselectivity and good yield, high atom economy, environmental friendliness and wide applicability, but also has readily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-processing and diversified product structure, thus having great implementation value and potential social and economic benefits.

[0055] The axially chiral vinylindolyl-9-membered ring compounds of this invention were tested using the MTT assay to assess the cytotoxic activity against human prostate cancer cells PC-3, specifically compounds synthesized in Examples 3, 5-6, 8-9, 11, 14, 22, and 26. The activity assay procedure was as follows: Human prostate cancer cells PC-3 were seeded at a density of 4000 cells / 100 μL of culture medium in 96-well plates. After 48 hours of cell adhesion, the test compound of formula 3 was added to the culture medium at final concentrations of 15.625, 31.25, 62.5, 125, and 250 μg / mL (only compound formula 3ah was added to the culture medium at final concentrations of 7.81, 15.625, 31.25, 62.5, and 125 μg / mL). Cells were cultured for another 24 hours. Cells without the addition of compound 3 served as the control group, while cells with only the addition of culture medium served as the blank group. After compound stimulation, 20 μL MTT was added to each well, and the mixture was incubated for another 4 hours. The supernatant was removed, and 150 μL of dimethyl sulfoxide was added to each well. The mixture was then incubated at 37°C for 15 minutes, followed by shaking of the plate for 2 minutes. The optical density (OD) value was read at 490 nm. Finally, the IC50 of the compound of formula 3 was calculated using GraphPad software. 50 The values ​​are shown in Tables 3 and 4. The experimental results indicate that these compounds have high cytotoxic activity against human prostate cancer cells PC-3.

[0056] Table 3 shows the cytotoxic activity of the compound of formula 3 in this invention against human prostate cancer cells PC-3.

[0057]

[0058] Note: IC in Table 3 50 The half-maximal inhibitory concentration (MCI) is the concentration of the inhibitory component of a drug.

[0059] Table 4. Cytotoxic activity of compound formula 3ah in this invention against human prostate cancer cells PC-3.

[0060]

[0061] Note: IC in Table 4 50 The half-maximal inhibitory concentration (MCI) is the concentration of the inhibitory component of a drug.

[0062] Example 28

[0063] The synthetic route for the vinylindolophine eight-membered ring compound of formula 6aa is as follows:

[0064]

[0065] 0.1 mmol of 3-ethynyl-2-indole methanol (formula 1a) and 2-indole methanol (formula 5a) were added to an organic solvent (the molar ratio of the organic solvent to the molar amount of 3-ethynyl-2-indole methanol was (5-40) mL: 1 mmol) as reactants (the molar ratio between compound 3-ethynyl-2-indole methanol of formula 1 and compound 2-indole methanol of formula 5 was 3: (2-6)). The reaction was carried out under the action of Brønsted acid or Lewis acid (10-20 mol% of 3-ethynyl-2-indole methanol) at -20-50 °C for 5 h with stirring. The reaction was monitored by TLC until the end. After filtration and concentration, the mixture was purified and separated by silica gel column chromatography (the eluent was a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 4:1) to obtain the vinylindole octagonal ring compound formula 6aa. The yield is shown in Table 5.

[0066] Table 5. Effects of different catalyst types, solvents, temperatures, equivalence ratios, additives, solvent volumes, and catalytic amounts on reaction yield.

[0067]

[0068]

[0069] Note: The amount of additives added in Table 1 is 0.1g.

[0070] The optimal reaction conditions, derived from the data in Table 5, are as follows: the catalyst is compound naphthalenephosphonic acid (Formula 7), the catalyst dosage is 20 mol% of 3-ethynyl-2-indole methanol, the solvent is 1,2-dichloroethane, the volume of the organic solvent is 4.0 mL, the reaction temperature is 0 °C, the equivalence ratio is Formula 1a:Formula 5a = 1:2, and the additive is...

[0071] The steps for obtaining product formula 6aa under optimal reaction conditions in Example 28 are as follows:

[0072] 0.1 mmol of 3-ethynyl-2-indole methanol (formula 1a) and 0.2 mmol of 2-indole methanol (formula 5a) were added to an organic solvent (4.0 mL) as reactants. The mixture was stirred at 0 °C for 5 h in the presence of 0.02 mmol of compound 7 (binaphthyl phosphate). The reaction was monitored by TLC until completion. After filtration and concentration, the mixture was purified by silica gel column chromatography (eluting solution of petroleum ether and ethyl acetate in a volume ratio of 4:1) to obtain vinylindole octagonal ring compound 6aa.

[0073] The structural characterization data of product formula 6aa obtained under the optimal reaction conditions in Example 28 are as follows:

[0074] 86%yield(87.4mg)as a yellow solid.mp178.0–180.0℃; 1 H NMR (400MHz, CDCl3) δ (ppm): 8.12 (s, 1H), 7.95 (d, J = 7.8Hz, 1H), 7.65–7.55 (m, 4H), 7.55–7.52 (m, 2H), 7.47–7.41 (m, 3H), 7.33–7.27 (m, 3H),7.23–7.16(m,3H),7.16–7.11(m,2H),7.08–7.03(m,1H),6.09(s,1H),4.96(d,J=15.2Hz,1H),4.56(d,J=15.6Hz,1H),0.58(s,9H); 13 C NMR(100MHz,CDCl3)δ(ppm):144.6,143.5,142.5,135.5,134.6,133.9,1 32.5,129.9,129.5,128.7,128.5,127.9,127.6,126.8,126.6,122.2,121 .5,120.5,120.4,119.8,119.1,117.9,114.7,110.6,110.4,85.0,61.5,3 4.4,29.5;IR(KBr):3411,3057,2949,2861,1599,1449,1324,1070,744cm -1 HRMS (ESI) for: C 36 H 32 N2O[MH] - calcd:507.2442,found507.2457.

[0075] Examples 29-46

[0076] The synthesis methods of Examples 29-46 are the same as those used in Example 28 under the same optimal reaction conditions, except that compounds 3-ethynyl-2-indoleethanol of Formula 1 and 2-indoleethanol of Formula 5 with different structures are used as raw materials.

[0077] The reactive synthesis route is shown below.

[0078]

[0079] The products and yields are shown in Table 6 below:

[0080] Table 6. Reactants, products, and yields of Examples 28-46

[0081]

[0082]

[0083] As shown in Table 6, the method of the present invention can not only achieve the synthesis of vinylindole octagonal ring compounds in one step, obtain high yield, have high atom economy, be environmentally friendly, and have a wide range of applications, but also has readily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-processing, and diversified product structures. Therefore, it has great implementation value and potential social and economic benefits.

[0084] The cytotoxic activity of the vinylindolyl octagonal ring compounds synthesized in Examples 28, 30-32, 37, and 42-45 against human prostate cancer cells PC-3 was tested using the MTT assay. The activity test procedure was as follows: Human prostate cancer cells PC-3 were seeded in 96-well plates at a density of 4000 cells / 100 μL of culture medium. After 48 hours of cell adhesion, the test compound of formula 6 was added to the culture medium at final concentrations of 1.953, 3.906, 7.812, 15.625, and 31.25 μg / mL, respectively. The cells were cultured for another 24 hours. Cells without the addition of the formula 6 compound served as the control group, and cells with only the culture medium served as the blank group. After compound stimulation, 20 μL MTT was added to each well, and the mixture was incubated for another 4 hours. The supernatant was removed, and 150 μL of dimethyl sulfoxide was added to each well. The mixture was then incubated at 37°C for 15 minutes, followed by shaking the plate for 2 minutes. The optical density (OD) value was read at 490 nm. Finally, the IC50 of the compound of formula 6 was calculated using GraphPad software. 50 The results are shown in Table 7. The experimental results indicate that these compounds have high cytotoxic activity against human prostate cancer cells PC-3.

[0085] Table 7 shows the cytotoxic activity of the compound of formula 6 in this invention against human prostate cancer cells PC-3.

[0086]

[0087]

[0088] Note: IC in Table 7 50 The half-maximal inhibitory concentration (MCI) is the concentration of the inhibitory component of a drug.

Claims

1. A vinyl indolizine intermediate compound, characterized in that, The compound is selected from axially chiral ethenyl indole nona ring compound and ethenyl indole octa ring compound, and the chemical structural formula is shown in formula 3 and formula 6 respectively. ； In formula 3, Ar is selected from one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl; R is selected from one of hydrogen, methoxy, methyl, halogen; R 1 is selected from one of methoxy, methyl, halogen. In Formula 6, Ar is selected from one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, t-butyl-substituted phenyl, halogen-substituted phenyl; R is selected from one of hydrogen, methoxy, methyl, halogen; R 1 is selected from one of methoxy, methyl, halogen.

2. A method of synthesizing the indolocyclophane compound of claim 1, wherein, The specific steps are as follows: the compound 3-ethynyl-2-indolylmethanol of formula 1 and the compound 2-indolyl ethanol of formula 2 or the compound 2-indolyl methanol of formula 5 are used as raw materials, added into an organic solvent, an additive is added, stirred under the catalysis of a catalyst and under a certain temperature condition, the reaction is tracked to completion by TLC, and then filtered, concentrated and purified to obtain the compound. The structural formula of the compound 3-ethynyl-2-indolylmethanol of the formula 1 is wherein R is selected from one of hydrogen, methoxy, methyl, halogen. The structural formula of the compound 2-indole ethanol of the formula 2 is The structural formula of the compound 2-indole methanol of the formula 5 is wherein, R 1 are all selected from one of methoxy, methyl and halogen. When the ethenyl indole medium ring compound is the compound 3 of axially chiral ethenyl indole nona ring compound, the compound 3-ethynyl-2-indolylmethanol of formula 1 and the compound 2-indolyl ethanol of formula 2 are used as raw materials, the molar ratio between the two is 2: (1-4), the reaction temperature is 0-50 ℃, the reaction time is 5-24 h, the catalyst is chiral phosphoric acid, the molar ratio between the compound 3-ethynyl-2-indolylmethanol of formula 1 and the catalyst is 1: (0.1-0.35), and in the compound of formula 1, Ar is selected from one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl and halogen-substituted phenyl. When the ethenyl indole medium ring compound is the compound 6 of ethenyl indole octa ring compound, the compound 3-ethynyl-2-indolylmethanol of formula 1 and the compound 2-indolyl methanol of formula 5 are used as raw materials, the molar ratio between the two is 3: (2-6), the reaction temperature is-20-50 ℃, the catalyst is Bronsted acid or Lewis acid, the molar ratio between the compound 3-ethynyl-2-indolylmethanol of formula 1 and the catalyst is 1: (0.1-0.2), and in the compound of formula 1, Ar is selected from one of phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, tert-butyl-substituted phenyl and halogen-substituted phenyl.

3. The method of claim 2, wherein the method is a method of synthesizing a vinylindolizine compound. The chiral phosphoric acid is selected from one of binaphthyl skeleton derivative, octahydrobinaphthyl skeleton derivative and spiro skeleton derivative. The binaphthyl skeleton derivative is a compound of formula 4, whose structural formula is wherein G is selected from one of 4-chlorophenyl, 9-anthryl, 9-phenanthryl, 2,4,6-triisopropylphenyl, 2-naphthyl, 1-naphthyl, triphenylsilyl, 2,4,6-tricyclohexylphenyl, 2,4,6-trimethylphenyl, 2,6-diisopropyl-4-adamantylphenyl, 3,5-di-tert-butyl-4-methoxyphenyl. The octahydrobinaphthyl skeleton derivative is a compound of formula 8, whose structural formula is wherein G is selected from one of 2,4,6-triisopropylphenyl, 2,4,6-tricyclohexylphenyl, 2,4,6-trimethylphenyl; The spiro skeleton derivative is a compound of formula 9, whose structural formula is wherein G is selected from one of 2,4,6-triisopropylphenyl, 2,4,6-trimethylphenyl; The Lewis acid is selected from one of scandium triflate, magnesium triflate, zinc triflate and copper triflate, and the Bronsted acid is selected from one of trifluoroacetic acid, triflic acid, p-toluenesulfonic acid, acetic acid, benzoic acid, diphenylphosphoric acid, diphenyl phosphate and binaphthyl phosphoric acid. The binaphthyl phosphonic acid is of the formula 7 The compound is of the formula 7 The compound is of the formula .

4. The method for synthesizing a vinylindolocyclic compound according to claim 3, characterized in that, The chiral phosphoric acid is binaphthyl skeleton derivative, and G is selected from 2, 6-diisopropyl-4-adamantyl phenyl.

5. A method for synthesizing a vinylindolocyclic compound according to claim 2 or 3, characterized in that, The molar ratio between the compound 3-ethynyl-2-indolylmethanol of formula 1 and the compound 2-indolyl ethanol of formula 2 is 1:2, and the molar ratio between the compound 3-ethynyl-2-indolylmethanol of formula 1 and the compound 2-indolyl methanol of formula 5 is 1:

2.

6. The method of claim 2 or 3, wherein the method is a method of synthesizing a vinylindolizine compound. When the ethenyl indole medium ring compound is the compound 3 of axially chiral ethenyl indole nona ring compound, the reaction temperature is 30 ℃, and the reaction time is 5 h; when the ethenyl indole medium ring compound is the compound 6 of ethenyl indole octa ring compound, the reaction temperature is 0 ℃.

7. The synthesis method of the ethenyl indole medium ring compound according to claim 2. When the ethenylindole and medium ring compound is the compound of formula 3, the axially chiral ethenylindole and nona-ring compound, the organic solvent is selected from one of acetonitrile, acetone, ethyl acetate, 1,2-dichloroethane, toluene, tetrahydrofuran, dichloromethane, trichloromethane, carbon tetrachloride, 1,1,2-trichloroethane; the ratio of the volume of the organic solvent to the molar amount of the compound of formula 1, 3-ethynyl-2-indanemethanol, is (5-80) mL:1 mmol; When the ethenylindole and medium ring compound is the compound of formula 6, the ethenylindole and octa-ring compound, the organic solvent is selected from one of acetonitrile, acetone, ethyl acetate, 1,2-dichloroethane, toluene, tetrahydrofuran, dichloromethane, trichloromethane, carbon tetrachloride; the ratio of the volume of the organic solvent to the molar amount of the compound of formula 1, 3-ethynyl-2-indanemethanol, is (5-40) mL:1 mmol.

8. The method of claim 2, wherein the method is a method of synthesizing a vinylindolizine compound. The additive is one of 3 Å MS, 4 Å MS, 5 Å MS, sodium sulfate, magnesium sulfate, and the ratio of the mass of the additive to the molar amount of the compound of formula 1, 3-ethynyl-2-indanemethanol, is 1 g:1 mmol.

9. The method of claim 7 or 8, wherein the method is a method of synthesizing a vinylindolizine medium ring compound. The additive is 3 Å MS; the organic solvent is 1,2-dichloroethane; When the ethenylindole and medium ring compound is the compound of formula 3, the axially chiral ethenylindole and nona-ring compound, the ratio of the volume of the organic solvent to the molar amount of the compound of formula 1, 3-ethynyl-2-indanemethanol, is 10 mL:1 mmol; When the ethenylindole and medium ring compound is the compound of formula 6, the ethenylindole and octa-ring compound, the ratio of the volume of the organic solvent to the molar amount of the compound of formula 1, 3-ethynyl-2-indanemethanol, is 40 mL:1 mmol.

10. A method for synthesizing a vinylindolocyclic compound according to claim 2 or 3, characterized in that, The purification is silica gel column chromatography, and the eluent is a mixture of petroleum ether / ethyl acetate in a volume ratio of 4:1.

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