Preparation method of 3, 3 '-bisindolyl methane compound

Abstract

The invention discloses a preparation method of a 3, 3 '-bisindolyl methane compound. The method comprises the following steps: carrying out heteroarylation reaction on an N-methylindole compound and an 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; the crude product is purified, and the 3, 3 '-bisindolyl methane compound is obtained.The preparation method is mild in reaction condition and good in functional group tolerance and has the advantages of being simple in aftertreatment, green in step, low in pollution, high in economic benefit and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound synthesis, and in particular relates to a method for preparing a 3,3'-bisindolylmethane compound. Background Art

[0002] Indole derivatives are a basic building block 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 application in many fields. These compounds exhibit a variety of important biological activities in the fields of antibacterial (Eur.J.Med.Chem.2013,63,435), anticancer (J.Nutr.2010,140,1) and antioxidant (J.Nutr.2008,138,17). Among them, the clearly recorded 3,3'-bisindolylmethane compounds are recorded in CN104177283A, CN 107235887 A, CN103880728A and literature (Chin.J.Org.Chem.2021,41,52; Synthesis 2019,51,829; Adv.Synth.Catal.2020,362,150) and so on. Although many methods for synthesizing symmetrical 3,3'-bisindolylmethane have been reported, there is still considerable potential for developing synthetic methods for asymmetrical 3,3'-bisindolylmethane and its derivatives.

[0003] The traditional method for asymmetric 3,3'-bisindolylmethane compounds is achieved through the functionalization reaction of CO, CN and CS bonds of indole derivatives (Org.Lett.2017,19,6164). Vallée et al. reported the synthesis of 3,3'-bisindolylmethane compounds by the reaction of nitrone and indole using ClSiCH3 as a promoter (Chin.J.Org.Chem.2021,41,52). In 2006, Csák et al. achieved the reaction of Rh(I)-catalyzed allyl indole and C-3 benzyl derivatives by the reaction of the in situ conjugate addition product of 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 reactions with indole compounds containing sulfonyl groups using Grignard reagents (Adv. Synth. Catal. 2020, 362, 1509). Although the above method can be used to synthesize asymmetric 3,3'-bisindolylmethane compounds, there are still 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 cheap, non-toxic and pollution-free, which meets the requirements of green chemistry. Researchers often use water as a reaction solvent to achieve green synthesis of target compounds.

[0004] Therefore, it remains challenging to develop an efficient method for the synthesis of symmetrical and asymmetrical 3,3'-bisindolylmethane compounds via aqueous phase reactions without metal catalysis. Summary of the invention

[0005] In order to overcome the shortcomings and deficiencies of the prior art, the object of the present invention is to provide a method for preparing a 3,3'-bisindolylmethane compound.

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

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

[0008]

[0009] (2) quenching the reaction, extracting, washing, drying and concentrating the reaction product to obtain a crude product; purifying the crude product to obtain a compound represented by 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, thienyl, and naphthyl substituted phenyl;

[0012] R 1 One selected from hydrogen, bromine atom, and methoxy group;

[0013] R 2 One selected from hydrogen, bromine atom and methoxy group.

[0014] Preferably, the indole phosphonium salt is selected from ((3,4-dimethoxyphenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(3,4,5-trimethoxyphenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(phenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-bromophenyl)(1-methyl ((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-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, ((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)(naphthalen-1-yl)methyl)triphenylphosphonium trifluoromethanesulfonate any one of trifluoromethanesulfonate, ((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-methyl indole compound is 1-1.5:1-1.8.

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

[0018] The present invention overcomes the deficiencies of the prior art and provides a method for preparing a 3,3'-bisindolylmethane compound. The preparation of the 3,3'-bisindolylmethane compound of the present invention is achieved by heteroarylization reaction of N-methylindole compounds and indole phosphonium salts in green solvent water under metal-free conditions under the promotion of water. The chemical structure of the 3,3'-bisindolylmethane compound is shown in the following formula (I):

[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, thienyl, and naphthyl substituted phenyl;

[0021] R 1 One selected from hydrogen, bromine atom, and methoxy group;

[0022] R 2 One selected from hydrogen, bromine atom and methoxy group.

[0023] The optimal reaction equation of the preparation method of the present invention is as follows:

[0024]

[0025] Compared with the shortcomings and deficiencies of the prior art, the present invention has the following beneficial effects: the preparation method of the present invention has mild reaction conditions, good functional group tolerance, simple post-treatment, green steps, low pollution, high economic benefits, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the hydrogen spectrum of the target product a in Example 1 of the present invention;

[0027] Figure 2 is the carbon spectrum of the target product a of Example 1 of the present invention;

[0028] Figure 3 is the hydrogen spectrum of the target product b of Example 2 of the present invention;

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

[0030] Figure 5is the hydrogen spectrum of the target product c of Example 3 of the present invention;

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

[0032] Figure 7 is the hydrogen spectrum of the target product d of Example 4 of the present invention;

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

[0034] Fig. 9 is the hydrogen spectrum of the target product e of Example 5 of the present invention;

[0035] Fig.10 The carbon spectrum of the target product e of Example 5 of the present invention;

[0036] Fig.11 is the hydrogen spectrum of the target product f of Example 6 of the present invention;

[0037] Fig.12 This is the carbon spectrum of the target product f of Example 6 of the present invention. DETAILED DESCRIPTION

[0038] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0039] Example 1

[0040] (1) To a 10 mL Schlenk tube were added ((3,4-dimethoxyphenyl)(1-methyl-1H-indol-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) in sequence, and the reaction mixture was stirred at 100° C. for 12 h in air.

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

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

[0043] 1 H NMR (400MHz, CDCl3): δ = 7.53 (d, J = 1.9 Hz, 1H), 7.36 (dt, J = 7.9, 1.0 Hz, 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] According to the characterization data, the obtained reaction product is 5-bromo-3-((3,4-dimethoxyphenyl)(1-methyl-1H-indol-3-yl)methyl)-1-methyl-1H-indole (purity>98%), and the structural formula of the compound is:

[0047]

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

[0049] Example 2

[0050] (1) To a 10 mL Schlenk tube were added ((1-methyl-1H-indol-3-yl)(naphthalen-1-yl)methyl)triphenylphosphonium trifluoromethanesulfonate (306.5 mg, 0.45 mmol, 1.5 equiv.), 5-bromo-1-methyl-1H-indole (63.0 mg, 0.3 mmol, 1 equiv.), tetrabutylammonium hydrogensulfate (101.9 mg, 0.3 mmol, 1 equiv.), and water (1 mL) in sequence, and the reaction mixture was stirred at 100° C. for 12 h in air.

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

[0052] The above target product b is characterized, such as Figure 3 , 4 As shown, the result is: 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] According to the characterization data, the obtained reaction product is 5-bromo-1-methyl-3-((1-methyl-1H-indol-3-yl)(naphthalen-1-yl)methyl)-1H-indole (purity>98%), and the structural formula of the compound is:

[0057]

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

[0059] Example 3

[0060] (1) To a 10 mL Schlenk tube were added (1-methyl-1H-indol-3-yl)(thiophen-2-yl)methyl)triphenylphosphonium trifluoromethanesulfonate (286.7 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) in sequence, and the reaction mixture was stirred at 100° C. for 12 h in air.

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

[0062] The target product c is characterized as follows: Figure 5 and 6 As shown, the result is: yellow oil; the 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] According to the characterization data, the obtained reaction product is 3,3'-(thiophene-2-ylmethylene)bis(1-methyl-1H-indole) (purity>98%), and the structural formula of the compound is:

[0067]

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

[0069] Example 4

[0070] (1) To a 10 mL Schlenk tube were added ((1-methyl-1H-indol-3-yl)(phenyl)methyl)triphenylphosphine trifluoromethanesulfonate (284.2 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) in sequence, and the reaction mixture was stirred at 100° C. for 12 h in air.

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

[0072] The above target product d is characterized, such as Figure 7 and 8 As shown, the result is: yellow oil; the 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] According to the characterization data, the obtained reaction product is 3,3'-(benzylidene)bis(1-methyl-1H-indole) (purity>98%), and the structural formula of the compound is:

[0077]

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

[0079] Example 5

[0080] (1) To a 10 mL Schlenk tube were added ((2-bromophenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphine trifluoromethanesulfonate (319.7 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) in sequence, and the reaction mixture was stirred at 100° C. for 12 h in air.

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

[0082] The above target product e is characterized, such as Fig. 9 and 10 As shown, the result is: yellow oil; the 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] According to the characterization data, the obtained reaction product is 3,3'-((2-bromophenyl)methylene)bis(1-methyl-1H-indole) (purity>98%), and the structural formula of the compound is:

[0088]

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

[0090] Example 6

[0091] (1) To a 10 mL Schlenk tube were added (bis(1-methyl-1H-indol-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) in sequence, and the reaction mixture was stirred at 100° C. for 12 h in air.

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

[0093] The above target product f is characterized, such as Fig.11 and 12 As shown, the result is: yellow oil; the 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] According to the characterization data, the obtained reaction product is tri(1-methyl-1H-indol-3-yl)methane (purity>98%), and the structural formula of the compound is:

[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 reaction for 12 hours, as shown in Table 1 below:

[0102] Table 1

[0103]

[0104]

[0105] It can be seen from Table 1 that under the same reaction conditions, the yield gradually increases with increasing reaction temperature, and the highest reaction yield is 51% at 100°C.

[0106] Example 8

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

[0108] Table 2

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

[0110] It can be seen from Table 2 that under the same reaction conditions, the reaction yields are different in different solvents. When water is used as the solvent, the highest reaction yield is 55%.

[0111] Example 9

[0112] Example 9 is basically the same as Example 1, except that in step (1), the molar ratio of the indole phosphonium salt and the N-methyl indole compound is different when the reaction is performed for 12 hours, 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] It can be seen from Table 3 that under the same reaction conditions, the yields are different when the molar ratio of the N-methyl indole compound to the indole phosphonium salt is different. When the molar ratio of the N-methyl indole compound to the indole phosphonium salt is 1.5:1, the yield is the highest, which is 55%.

[0116] Example 10

[0117] Example 10 is basically the same as Example 1, except that in step (1), different additives are used when reacting in water at 100° C. for 12 h, 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] It can be seen from Table 4 that under the same reaction conditions, the reaction yields are different when different additives are used. When tetrabutylammonium hydrogen sulfate is used, the reaction yield is the highest at 61%.

[0121] Embodiment 11

[0122] Example 11 is basically the same as Example 1, except that in step (1), when 5-bromo-1-methyl-1H-indole is used, a different indole phosphonium salt is used. The 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-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate is used, and the indole compound used is different. The target product obtained is specifically 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 in the protection scope of the present invention.

Claims

1. A method for preparing a 3,3'-bisindolylmethane compound, characterized in that: The method comprises the following steps: (1) subjecting the N-methylindole compound represented by formula (III) and the indole phosphonium salt represented by formula (II) to a heteroarylation reaction at 25 to 100° C. in a solvent under the promotion of water; wherein the solvent is selected from any one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tert-butanol, and water; (2) quenching the reaction, extracting, washing, drying and concentrating the reaction product to obtain a crude product; purifying the crude product to obtain a compound represented by 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, thienyl, and naphthyl substituted phenyl; R 1 One selected from hydrogen, bromine atom, and methoxy group; R 2 One selected from hydrogen, bromine atom and methoxy group.

2. The method according to claim 1, characterized in that The indole phosphonium salt is selected from ((3,4-dimethoxyphenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(3,4,5-trimethoxyphenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((1-methyl-1H-indol-3-yl)(phenyl)methyl)triphenylphosphonium trifluoromethanesulfonate, ((4-bromophenyl)(1-methyl-1H ((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-cyanophenyl)(1-methyl-1H-indol-3-yl)methyl)triphenylphosphonium trifluoromethanesulfonate ((phenyl)(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)(naphthalen-1-yl)methyl)triphenylphosphonium trifluoromethanesulfonate any one of ((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.

3. The method according to claim 1, characterized in that The N-methylindole compound is selected from any one of 5-bromo-1-methyl-1H-indole, 4-methoxy-1-methylindole and N-methylindole.

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

8.

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

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