A process for the preparation of a 3,3'-biindolylmethane compound

Abstract

The application discloses a preparation method of a 3,3'-bisindolylmethane compound. The method comprises the following steps: carrying out heteroarylation reaction of N-methyl indole compound and indole phosphonium salt in a solvent at 25-100 DEG C under the promotion of water; quenching the reaction; and extracting, washing, drying and concentrating the reaction product to obtain a crude product; and purifying the crude product to obtain the 3,3'-bisindolylmethane compound. The preparation method has the characteristics of mild reaction condition, good functional group tolerance, simple post-treatment, green step, low pollution and high economic benefit.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, and particularly relates to a method for preparing a 3,3'-bisindolylmethane compound. Background Technology

[0002] Indole derivatives are a fundamental structural unit in many natural products, drug molecules, agricultural compounds, and fine chemicals (Chem.Rev.2010,110,4489). The 3,3'-bisindolylmethane (3,3'-BIM) unit is particularly important due to its wide range of applications in various fields. These compounds exhibit a variety of important biological activities in antibacterial (Eur. J. Med. Chem. 2013, 63, 435), anticancer (J. Nutr. 2010, 140, 1) and antioxidant (J. Nutr. 2008, 138, 17) fields. Among them, the 3,3'-bisindolylmethane compounds that have been clearly described are documented in CN104177283A, CN 107235887 A, CN103880728A and in literature (Chin. J. Org. Chem. 2021, 41, 52; Synthesis 2019, 51, 829; Adv. Synth. Catal. 2020, 362, 150). Although many methods for synthesizing symmetrical 3,3'-bisindolemethanes have been reported, there is still considerable potential for developing synthetic methods for asymmetric 3,3'-bisindolemethanes and their derivatives.

[0003] Traditional methods for synthesizing asymmetric 3,3'-bisindolylmethane compounds involve the functionalization of indole derivatives via CO, CN, and CS bonds (Org. Lett. 2017, 19, 6164). Vallée et al. reported the synthesis of 3,3'-bisindolylmethane compounds via the reaction of nitroketones with indole using ClSiCH3 as a promoter (Chin. J. Org. Chem. 2021, 41, 52). In 2006, Csák et al. achieved Rh(I)-catalyzed reactions of allyl indole and C-3 benzyl derivatives via the in-situ conjugation addition of the CC-CN bond with boric acid (Synthesis 2019, 51, 829). In 2020, Marino Petrini's team synthesized a series of 3,3'-bisindolylmethane compounds by coupling Grignard reagents with indole compounds containing sulfonyl groups (Adv. Synth. Catal. 2020, 362, 1509). While the above methods can be used to synthesize asymmetric 3,3'-bisindolylmethane compounds, they still have some limitations, such as the use of expensive metal catalysts, moisture-sensitive reagents, or toxic organic reagents, which makes them less efficient in establishing homologues. Aqueous phase reactions have the advantages of being inexpensive, non-toxic, and pollution-free, meeting the requirements of green chemistry. Researchers often use water as a reaction solvent to achieve the green synthesis of target compounds.

[0004] Therefore, developing an efficient method for synthesizing symmetrical and asymmetric 3,3'-bisindolylmethane compounds via aqueous phase reaction without metal catalysis remains challenging. Summary of the Invention

[0005] To overcome the shortcomings and deficiencies of the prior art, the present invention aims to provide a method for preparing 3,3'-bisindolylmethane compounds.

[0006] This invention is achieved by providing a method for preparing a 3,3'-bisindolylmethane compound, the method comprising the following steps:

[0007] (1) The N-methylindole compound shown in formula (III) and the indole phosphonium salt shown in formula (II) are subjected to a heteroarylation reaction in a solvent at 25-100°C with the aid of water; wherein the solvent is selected from any one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tert-butanol, and water.

[0008]

[0009] (2) Quench the reaction, extract, wash, dry, and concentrate the reaction product to obtain a crude product; purify the crude product to obtain the compound shown in formula (I):

[0010]

[0011] In each formula, R is selected from one of phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, cyano-substituted phenyl, nitro-substituted phenyl, hydroxy-substituted phenyl, thiophene, and naphthyl-substituted phenyl;

[0012] R 1 Selected from one of hydrogen, bromine, or methoxy atoms;

[0013] R 2 It is selected from one of hydrogen, bromine, or methoxy groups.

[0014] Preferably, the indolephosphonium salt is selected from ((3,4-dimethoxyphenyl)(1-methyl-1H-indole-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indole-3-yl)(3,4,5-trimethoxyphenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indole-3-yl)(phenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-bromophenyl)(1-methyl) (1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-iodophenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((2-bromophenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(4-(trifluoromethyl)phenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4- ((1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(4-nitrophenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((2-hydroxyphenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(naphth-1-yl)methyl)triphenylphosphonium trifluoromethanesulfonate The salt, ((1-methyl-1H-indol-3-yl)(thiophen-2-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((5-bromo-1-methyl-1H-indol-3-yl)(3,4,5-trimethoxyphenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, and ((4-methoxy-1-methyl-1H-indol-3-yl)(3,4,5-trimethoxyphenyl)methyl)triphenylphosphonium trifluoromethanesulfonate.

[0015] Preferably, the N-methylindole compound is selected from any one of 5-bromo-1-methyl-1H-indole, 4-methoxy-1-methylindole, and N-methylindole.

[0016] Preferably, the molar ratio of the indole phosphonium salt to the N-methylindole compound is 1–1.5:1–1.8.

[0017] Preferably, the molar ratio of the indole phosphonium salt to the N-methylindole compound is 1.5:1.

[0018] This invention overcomes the shortcomings of existing technologies and provides a method for preparing 3,3'-bisindolylmethane compounds. The 3,3'-bisindolylmethane compound is prepared under metal-free conditions in a green solvent water via a heteroarylation reaction of an N-methylindole compound and an indole phosphonium salt, with the reaction promoted by water. The chemical structural formula of this 3,3'-bisindolylmethane compound is shown in formula (I) below:

[0019]

[0020] Wherein, R is selected from one of phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, cyano-substituted phenyl, nitro-substituted phenyl, hydroxy-substituted phenyl, thiophene, and naphthyl-substituted phenyl;

[0021] R 1 Selected from one of hydrogen, bromine, or methoxy atoms;

[0022] R 2 It is selected from one of hydrogen, bromine, or methoxy groups.

[0023] The optimal reaction equations for the preparation method of this invention are shown below:

[0024]

[0025] Compared with the shortcomings and deficiencies of the prior art, the present invention has the following beneficial effects: the reaction conditions of the preparation method of the present invention are mild, the functional groups are well tolerant, and the post-processing is simple, the steps are green, the pollution is low, and the economic benefits are high. Attached Figure Description

[0026] Figure 1 The proton spectrum of target product a in Example 1 of this invention;

[0027] Figure 2 The carbon spectrum of target product a in Example 1 of this invention;

[0028] Figure 3 The proton spectrum of target product b in Example 2 of this invention;

[0029] Figure 4 The carbon spectrum of target product b in Example 2 of this invention;

[0030] Figure 5The proton spectrum of target product c in Example 3 of this invention;

[0031] Figure 6 This is the carbon spectrum of the target product c in Example 3 of the present invention.

[0032] Figure 7 The proton spectrum of the target product d in Example 4 of this invention;

[0033] Figure 8 The carbon spectrum of the target product d in Example 4 of this invention;

[0034] Figure 9 The proton spectrum of target product e in Example 5 of this invention;

[0035] Figure 10 The carbon spectrum of target product e in Example 5 of this invention;

[0036] Figure 11 The proton spectrum of the target product f in Example 6 of this invention;

[0037] Figure 12 The carbon spectrum of the target product f in Example 6 of this invention. Detailed Implementation

[0038] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0039] Example 1

[0040] (1) Add ((3,4-dimethoxyphenyl)(1-methyl-1H-indole-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate (311.0 mg, 0.45 mmol, 1.5 equiv.), 5-bromo-1-methyl-1H-indole (63.0 mg, 0.3 mmol, 1 equiv.), tetrabutylammonium hydrogen sulfate (101.9 mg, 0.3 mmol, 1 equiv.), and water (1 mL) to a 10 mL Schlenk tube in sequence, and stir the reaction mixture at 100 °C for 12 h in air.

[0041] (2) After the reaction in step (1) is completed, the mixture is quenched with saturated NH4Cl solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: the stationary phase is 300-400 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1:20. Finally, 89.5 mg of the target product a is obtained.

[0042] The target product a was characterized as follows: Figure 1 , 2 As shown, the result is: a red solid; the characterization data are:

[0043] 1 H NMR (400MHz, CDCl3): δ=7.53 (d, J=1.9Hz, 1H), 7.36 (dt, J=7.9, 1.0Hz, 1H), 7.31 (dt, J=8. 2,1.0Hz,1H),7.28(dd,J=8.6,1.9Hz,1H),7.21(ddd,J=8.2,7.0,1.1Hz,1H),7.16(d,J=8 .7Hz,1H),7.01(ddd,J=8.0,7.0,1.0Hz,1H),6.90(d,J=1.8Hz,1H),6.83-6.76(m,2H),6. 51(d,J=14.9Hz,2H),5.76(s,1H),3.87(s,3H),3.79(s,3H),3.70(s,3H),3.66(s,3H)ppm.

[0044] 13 C NMR (100MHz, CDCl3): δ=148.7,147.3,137.4,136.6,136.0,129.3,129.0,128.1,127.3,124.3,122.3,121.5,1 20.4,119.9,118.7,118.05,118.04,112.12,112.05,110.9,110.6,109.1,55.82,55.78,39.5,32.8,32.7ppm.

[0045] HRMS(m / z):calcd for C 27 H 26 BrN2O2[M+H] + 489.1172, found: 489.1172.

[0046] Characterization data revealed that the obtained reaction product was 5-bromo-3-((3,4-dimethoxyphenyl)(1-methyl-1H-indole-3-yl)methyl)-1-methyl-1H-indole (purity > 98%), and the structural formula of this compound is:

[0047]

[0048] The product yield was calculated to be 61%.

[0049] Example 2

[0050] (1) Add ((1-methyl-1H-indol-3-yl)(naphth-1-yl)methyl)triphenylphosphonium trifluoromethanesulfonate (306.5 mg, 0.45 mmol, 1.5 equiv.), 5-bromo-1-methyl-1H-indol (63.0 mg, 0.3 mmol, 1 equiv.), tetrabutylammonium hydrogen sulfate (101.9 mg, 0.3 mmol, 1 equiv.), and water (1 mL) to a 10 mL Schlenk tube in sequence, and stir the reaction mixture at 100 °C for 12 h in air.

[0051] (2) After the reaction in step (1) is completed, the mixture is quenched with saturated NH4Cl solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: the stationary phase is 300-400 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1:25. Finally, 84.8 mg of the target product b is obtained.

[0052] The target product b was characterized as follows: Figure 3 , 4 As shown, the result is: a red solid; the characterization data are:

[0053] 1H NMR (400MHz, CDCl3): δ = 8.13 (d, J = 8.4Hz, 1H), 7.90 (d, J = 8.6Hz, 1H), 7.76 (d, J = 8.1Hz, 1H) ,7.54(d,J=1.9Hz,1H),7.50-7.45(m,1H),7.43-7.39(m,1H),7.39-7.36(m,1H),7.35(s,1H ),7.33(s,1H),7.32-7.30(m,1H),7.25-7.23(m,1H),7.23-7.21(m,1H),7.17(d,J=8.7Hz,1 H),7.04-6.97(m,1H),6.60(s,1H),6.45(s,1H),6.42(s,1H),3.66(s,3H),3.62(s,3H)ppm.

[0054] 13 C NMR (100MHz, CD2Cl2): δ=139.4,137.4,136.1,133.9,131.7,130.0,129.0,128.8,128.6,127.2,127.0,126.9,125.9 ,125.4,125.3,124.3,124.2,122.1,121.5,119.8,118.7,117.48,117.46,112.2,110.7,109.1,35.4,32.9,32.7ppm.

[0055] HRMS(m / z):calcd for C 29 H 24 BrN2[M+H] + 479.1117, found: 479.1114.

[0056] Characterization data revealed that the obtained reaction product was 5-bromo-1-methyl-3-((1-methyl-1H-indol-3-yl)(naphth-1-yl)methyl)-1H-indol (purity > 98%), and the structural formula of this compound is:

[0057]

[0058] The product yield was calculated to be 59%.

[0059] Example 3

[0060] (1) Add (1-methyl-1H-indol-3-yl)(thiophen-2-yl)methyl)triphenylphosphonium trifluoromethanesulfonate (286.7 mg, 0.45 mmol, 1.5 equiv.), N-methylindol (39.4 mg, 0.3 mmol, 1 equiv.), tetrabutylammonium hydrogen sulfate (101.9 mg, 0.3 mmol, 1 equiv.), and water (1 mL) to a 10 mL Schlenk tube in sequence, and stir the reaction mixture at 100 °C for 12 h in air.

[0061] (2) After the reaction in step (1) is completed, the mixture is quenched with saturated NH4Cl solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1:20. Finally, 96.1 mg of the target product c is obtained.

[0062] The target product c was characterized as follows: Figure 5 and 6 As shown, the result is: yellow oily; characterization data are:

[0063] 1 H NMR (400MHz, CDCl3): δ=7.47 (dt, J=8.0, 1.0Hz, 2H), 7.31 (dt, J=8.3, 1.0Hz, 2H), 7.22 (ddd, J=8.1, 6.9, 1.2Hz, 2H), 7.15 (dd, J=5. 0,1.4Hz,1H),7.03(ddd,J=8.0,6.9,1.1Hz,2H),6.94-6.89(m,2H),6.72(d,J=1.0Hz,2H),6.16(q,J=1.0Hz,1H),3.71(s,6H)ppm.

[0064] 13 C NMR (100MHz, CDCl3): δ=149.2,137.3,127.8,127.2,126.4,125.0,123.5,121.5,119.8,118.8,118.2,109.1,35.1,32.7ppm.

[0065] HRMS(m / z):calcd for C 23 H 21 N2S[M+H] + 357.1420, found: 357.1421.

[0066] Characterization data revealed that the obtained reaction product was 3,3'-(thiophene-2-ylmethylene)bis(1-methyl-1H-indole) (purity > 98%), and the structural formula of this compound is:

[0067]

[0068] The product yield was calculated to be 90%.

[0069] Example 4

[0070] (1) Add ((1-methyl-1H-indol-3-yl)(phenyl)methyl)triphenylphosphine trifluoromethanesulfonate (284.2 mg, 0.45 mmol, 1.5 equiv.), N-methylindol (39.4 mg, 0.3 mmol, 1 equiv.), tetrabutylammonium hydrogen sulfate (101.9 mg, 0.3 mmol, 1 equiv.), and water (1 mL) to a 10 mL Schlenk tube in sequence, and stir the reaction mixture at 100 °C for 12 h in air.

[0071] (2) After the reaction in step (1) is completed, the mixture is quenched with saturated NH4Cl solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: the stationary phase is 300-400 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1:12. Finally, 88.6 mg of the target product d is obtained.

[0072] The target product d was characterized as follows: Figure 7 and 8 As shown, the result is: yellow oily; characterization data are:

[0073] 1 H NMR (400MHz, CDCl3): δ = 7.40 (dt, J = 8.0, 1.0Hz, 2H), 7.38-7.34 (m, 2H), 7.32-7.27 (m, 4H), 7.25-7 .19(m,3H),7.01(ddd,J=8.0,7.0,1.1Hz,2H),6.54(d,J=1.1Hz,2H),5.90(s,1H),3.69(s,6H)ppm.

[0074] 13C NMR (100MHz, CDCl3): δ=144.4,137.3,128.7,128.24,128.17,127.4,126.0,121.4,120.0,118.6,118.2,109.0,40.0,32.7ppm.

[0075] HRMS(m / z):calcd for C 25 H 23 N2[M+H] + 351.1856, found: 351.1859.

[0076] Characterization data revealed that the obtained reaction product was 3,3'-(benzylmethyl)bis(1-methyl-1H-indole) (purity > 98%), and the structural formula of this compound is:

[0077]

[0078] The product yield was calculated to be 84%.

[0079] Example 5

[0080] (1) Add ((2-bromophenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphine trifluoromethanesulfonate (319.7 mg, 0.45 mmol, 1.5 equiv.), N-methylindol (39.4 mg, 0.3 mmol, 1 equiv.), tetrabutylammonium hydrogen sulfate (101.9 mg, 0.3 mmol, 1 equiv.), and water (1 mL) to a 10 mL Schlenk tube in sequence, and stir the reaction mixture at 100 °C for 12 h in air.

[0081] (2) After the reaction in step (1) is completed, the mixture is quenched with saturated NH4Cl solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: the stationary phase is 300-400 mesh silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1:15. Finally, 69.6 mg of the target product e is obtained.

[0082] The target product e is characterized as follows: Figure 9 and 10 As shown, the result is: yellow oily; characterization data are:

[0083] 1H NMR (400MHz, CDCl3): δ = 7.62 (dd, J = 7.9, 1.4Hz, 1H), 7.41 (dt, J = 8.0, 1.0Hz, 2H),7.31(dt,J=8.3,1.0Hz,2H),7.28-7.24(m,1H),7.22(ddd,J=8.1,6.9,1. 2Hz,2H),7.16(td,J=7.5,1.4Hz,1H),7.08(td,J=7.6,1.8Hz,1H),7.02(ddd ,J=8.0,7.0,1.1Hz,2H),6.50(d,J=1.1Hz,2H),6.32(s,1H),3.69(s,6H)ppm.

[0084] 13 C NMR (100MHz, CDCl3): δ=143.4,137.4,132.8,130.5,128.4,127.7,127.4,127.2,124.7,121.5,120.0,118.7,117.0,109.1,39.4,32.7ppm.

[0085] HRMS(m / z):calcd for C 25 H 22 BrN2[M+H] + 429.0961, found: 429.0958.

[0086] HRMS(m / z):calcd for C 25 H 23 N2[M+H] + 351.1856, found: 351.1859.

[0087] Characterization data revealed that the obtained reaction product was 3,3'-((2-bromophenyl)methylene)bis(1-methyl-1H-indole) (purity > 98%), and the structural formula of this compound is:

[0088]

[0089] The product yield was calculated to be 54%.

[0090] Example 6

[0091] (1) Add (bis(1-methyl-1H-indole-3-yl)methyl)triphenylphosphine trifluoromethanesulfonate (308.1 mg, 0.45 mmol, 1.5 equiv.), N-methylindole (39.4 mg, 0.3 mmol, 1 equiv.), tetrabutylammonium hydrogen sulfate (101.9 mg, 0.3 mmol, 1 equiv.), and water (1 mL) to a 10 mL Schlenk tube in sequence, and stir the reaction mixture at 100 °C for 12 h in air.

[0092] (2) After the reaction in step (1) is completed, the product is quenched with saturated NH4Cl solution and extracted with ethyl acetate (20 mL × 3). The combined organic phases are washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, and concentrated under vacuum to obtain crude product. The crude product is purified by silica gel column chromatography. The column chromatography separation conditions are: stationary phase is 300-400 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), and the mobile phase change program (A:B) is 1:10. Finally, 105.1 mg of the target product f is obtained.

[0093] The target product f is characterized as follows: Figure 11 and 12 As shown, the result is: yellow oily; characterization data are:

[0094] 1 H NMR (400MHz, CD2Cl2): δ = 7.44 (dt, J = 8.0, 1.0Hz, 3H), 7.27 (dt, J = 8.2, 1.0Hz, 3H), 7.13 (ddd, J = 8.2, 7.0, 1.1Hz, 3H), 6.93 (ddd, J=8.0, 7.0, 1.0Hz, 3H), 6.69 (d, J=0.9Hz, 3H), 6.13-6.10 (m, 1H), 3.66 (s, 9H)ppm.

[0095] 13 C NMR (100MHz, CD2Cl2): δ=137.0,127.2,126.9,120.7,119.2,117.9,117.7,108.6,32.1,30.3ppm.

[0096] HRMS(m / z):calcd for C 28 H 26 N3[M+H] + 404.2121, found: 404.2125.

[0097] Characterization data revealed that the obtained reaction product was tris(1-methyl-1H-indol-3-yl)methane (purity > 98%), and the structural formula of this compound is as follows:

[0098]

[0099] The product yield was calculated to be 87%.

[0100] Example 7

[0101] Example 7 is basically the same as Example 1, except that in step (1), the temperature in the dimethyl sulfoxide solvent is different during the 12-hour reaction, as shown in Table 1 below:

[0102] Table 1

[0103]

[0104]

[0105] As can be seen from Table 1, under the same reaction conditions, increasing the reaction temperature gradually increases the yield, with the highest yield of 51% at 100℃.

[0106] Example 8

[0107] Example 8 is basically the same as Example 1, except that the solvent used in step (1) when reacting at 100°C for 12 hours is different, as shown in Table 2 below:

[0108] Table 2

[0109] solvent Yield (%) DMSO 51 MeCN 0 <![CDATA[H2O]]> 55 DMF 35 <![CDATA[ t BuOH]]> 42

[0110] As can be seen from Table 2, under the same reaction conditions, the reaction yield is different in different solvents, and the highest reaction yield is 55% when water is used as the solvent.

[0111] Example 9

[0112] Example 9 is basically the same as Example 1, except that in step (1), the molar ratio of indole phosphonium salt and N-methylindole compound is different after 12 hours of reaction, as shown in Table 3 below:

[0113] Table 3

[0114] Molar ratio (mmol) Yield (%) 1:1.5 51 1:1.8 48 1.5:1 55

[0115] As can be seen from Table 3, under the same reaction conditions, the yields differ depending on the molar ratio of N-methylindole compounds to indole phosphonium salts. The highest yield, 55%, is achieved when the molar ratio of N-methylindole compounds to indole phosphonium salts is 1.5:1.

[0116] Example 10

[0117] Example 10 is basically the same as Example 1, except that the additives used in step (1) are different when reacting in water at 100°C for 12 hours, as shown in Table 4 below:

[0118] Table 4

[0119] additive Yield (%) TBAHS 61 TBAI 11 TBAB 43 TBAF 36 <![CDATA[NH4OAc]]> 33 <![CDATA[NaHSO4]]> 38

[0120] As can be seen from Table 4, under the same reaction conditions, the reaction yield varies when different additives are used. When tetrabutylammonium hydrogen sulfate is used, the reaction yield is the highest at 61%.

[0121] Example 11

[0122] Example 11 is basically the same as Example 1, except that in step (1), when using 5-bromo-1-methyl-1H-indole, the indole phosphonium salt used is different. The specific target products obtained are shown in Table 5 below:

[0123] Table 5

[0124]

[0125]

[0126] Example 12

[0127] Example 12 is basically the same as Example 1, except that in step (1), ((3,4-dimethoxyphenyl)(1-methyl-1H-indole-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate is used. The indole compound used is different. The specific target products obtained are shown in Table 6 below:

[0128] Table 6

[0129]

[0130] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a 3,3'-bisindolylmethane compound, characterized in that, The method includes the following steps: (1) The N-methylindole compound shown in formula (III) and the indole phosphonium salt shown in formula (II) were subjected to a heteroarylation reaction at 100 °C, 1 equiv. of tetrabutylammonium hydrogen sulfate, and air for 12 h in the presence of water; Formula (II); Formula (Ⅲ); (2) Quench the reaction, extract, wash, dry and concentrate the reaction product to obtain a crude product; purify the crude product to obtain the compound shown in formula (I): Formula (I); In each formula, R is selected from one of phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, cyano-substituted phenyl, nitro-substituted phenyl, hydroxy-substituted phenyl, thiophene, and naphthyl-substituted phenyl; R 1 Selected from one of hydrogen, bromine, or methoxy atoms; R 2 It is selected from one of hydrogen, bromine, or methoxy groups.

2. The preparation method according to claim 1, characterized in that, The indole phosphonium salt is selected from ((1-methyl-1-phosphonium salt)). H -indol-3-yl)(phenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-bromophenyl)(1-methyl-1 H -indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-iodophenyl)(1-methyl-1 H -indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((2-bromophenyl)(1-methyl-1 H -indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1 H -indol-3-yl)(4-(trifluoromethyl)phenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-cyanophenyl)(1-methyl-1 H -indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1 H -indol-3-yl)(4-nitrophenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((2-hydroxyphenyl)(1-methyl-1 H -indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1 H Any one of (indol-3-yl)(thiophen-2-yl)methyl)triphenylphosphonium trifluoromethanesulfonate.

3. The preparation method according to claim 1, characterized in that, The N -Methylindole compounds are selected from 5-bromo-1-methyl-1- H -Indole, 4-Methoxy-1-methylindole, N Any one of methylindole.

4. The preparation method according to claim 1, characterized in that, The indole phosphonium salt and N The molar ratio of methylindole compounds is 1~1.5:1~1.

8.

5. The preparation method according to claim 4, characterized in that, The molar ratio of the indole phosphonium salt to the N-methylindole compound is 1.5:1.

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