A synthetic method for 6-substituted 5,6-dihydropyridinebisindole compounds

Abstract

A method for synthesizing 6-substituted 5,6-dihydropyridinebisindole compounds includes the following steps: 1) mixing a bisindole derivative with DMF, stirring at a certain temperature to dissolve the bisindole derivative, and then adding an organic amine; 2) dissolving a catalyst CuCl2·2H2O in DMF, adding the CuCl2·2H2O DMF solution to the mixed solution from step 1), and reacting; 3) repeatedly extracting with ethyl acetate and ultrapure water, collecting the organic layer, removing water and ethyl acetate, eluting the collected solution, removing the solvent, and obtaining the product. This method efficiently synthesizes 6-substituted 5,6-dihydropyridinebisindole compounds through a one-step reaction of a bisindole derivative with an organic amine, providing a synthetic basis for the study of the biological functions of these compounds.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more particularly to a method for synthesizing 6-substituted 5,6-dihydropyridinebisindole compounds. Background Technology

[0002] Bisindolomethane compounds, derived from cruciferous vegetables, have attracted considerable attention due to their wide range of pharmacological effects. Currently, only compound 1 (α-carboline) and compound 2 (5,7-dihydropyridobisindol) have been reported in the literature; the structural formulas of compounds 1 and 2 are shown below:

[0003]

[0004] Due to limitations in synthetic methods, no compounds with 6-position substitution have been reported to date. Summary of the Invention

[0005] The purpose of this invention is to address the aforementioned problems in the prior art and provide a method for synthesizing 6-substituted 5,6-dihydropyridobisindole compounds. This method involves a one-step reaction of a bisindole derivative with an organic amine to efficiently synthesize 6-substituted 5,6-dihydropyridobisindole compounds, providing a synthetic basis for the study of the biological functions of these compounds. This invention was supported by the Xiamen Youth Innovation Fund Project (3502Z20206033).

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A method for synthesizing a 6-substituted 5,6-dihydropyridobisindole compound, comprising the following steps:

[0008] 1) Mix the bisindole derivative and DMF, stir at a certain temperature to dissolve the bisindole derivative, and then add an organic amine;

[0009] 2) Dissolve the catalyst CuCl2·2H2O in DMF, add the CuCl2·2H2O DMF solution to the mixed solution in step 1), and carry out the reaction;

[0010] 3) The product was obtained by multiple extractions with ethyl acetate and ultrapure water, collecting the organic layer, removing water and ethyl acetate, eluting and collecting the solution, and removing the solvent.

[0011] In step 1), the specified temperature is 60–100°C.

[0012] In step 1), the molar ratio of the bisindole derivative to the organic amine is 1:3 to 1:7.

[0013] In step 1), the organic amine includes aliphatic amines containing various substituents, such as n-propylamine and isobutylamine, or aromatic amines containing various substituents, such as aniline and pyridineamine.

[0014] In step 2), the reaction temperature is 60–100℃ and the reaction time is 1–3 hours.

[0015] In step 2), the molar ratio of CuCl2·2H2O to the bisindole derivative is 0.3 to 1.2.

[0016] In step 3), the pH of the ultrapure water is 9-11, the water removal is performed using anhydrous sodium sulfate, and the elution is performed using the MeOH-CH2Cl2 system.

[0017] The synthetic route for the 6-substituted 5,6-dihydropyridobisindole compound is as follows:

[0018]

[0019] Wherein, R1 is an aliphatic chain containing various substituents of C1 to C8, or an aromatic group containing various substituents of C1 to C18; R2 is an aromatic group containing various substituents of C1 to C18.

[0020] Compared with the prior art, the beneficial effects achieved by the technical solution of this invention are:

[0021] Existing technologies can only synthesize compounds 1 and 2. This invention, based on bisindolemethane compounds and organic amines, innovatively optimizes a new and simple method for synthesizing 6-substituted 5,6-dihydropyridinebisindole compounds with a yield of 93%, providing a synthetic basis for the functional development of such compounds. Detailed Implementation

[0022] To make the technical problems, technical solutions and beneficial effects of the present invention clearer and more understandable, the present invention will be further described in detail below with reference to the embodiments.

[0023] This invention, through screening of six aspects—catalyst type, reaction solvent, catalyst equivalent, reaction substrate equivalent, reaction temperature, and reaction time—finally determined the optimal synthesis method for series compound 3, which includes the following steps:

[0024] Weigh 1 mmol of the bisindole derivative into a 100 mL round-bottom flask, add 7 mL of DMF as solvent, and stir at 75 °C until the bisindole derivative (compound 4) is completely dissolved. Add 295.55 mg (5 mmol) of compound 5 organic amine (such as n-propylamine) and mix thoroughly. Dissolve 102 mg of catalyst CuCl2·2H2O (0.6 mmol) completely in 0.5 mL of DMF, and add the CuCl2·2H2O DMF solution to the above mixture. React at 75 °C for 100 min. After 100 min, the reaction solution changes from orange-red to yellow-green. TLC (MeOH:CH2Cl2 = 1:12) monitoring of the reaction shows that only a very small amount of starting material remains, and a bright yellow fluorescent spot appears below the starting material spot, indicating that the reaction proceeds relatively completely.

[0025] Subsequently, the reaction solution was repeatedly extracted with ethyl acetate and ultrapure water at pH = 10 to remove the remaining catalyst CuCl2·2H2O. The organic layer was collected, dehydrated with anhydrous sodium sulfate, and then transferred to a round-bottom flask for rotary evaporation to remove ethyl acetate, yielding the crude product. The crude product was then subjected to column chromatography by dry loading, eluted with a MeOH-CH2Cl2 system, and the solution was collected and the solvent was removed to obtain a yellow solid product (such as compound 3a). The solid product was dried and weighed, and the calculated yield of compound 3a was 93%.

[0026] The synthesis route is as follows:

[0027]

[0028] Table 1

[0029]

[0030] Table 1 shows the seven substituted 5,6-dihydropyridinebisindole compounds synthesized by the method of this invention, along with their yield data.

[0031] The properties, yield, and magnetic resonance spectral data of the compound are shown below:

[0032]

[0033] Compound name:

[0034] 6-propyl-12-(4-(trifluoromethyl)phenyl)-5,6-dihydropyrido[2,3-b:6,5-b']diindole. Yellow solid, yield 93%. 1H NMR (600MHz, DMSO-d6) δ = 8.22 (d, J = 7.9Hz, 2H), 7.99 (d, J = 7.7Hz, 2H), 7.80 (d, J = 7.9Hz, 2H), 7.53 (t, J = 7.5Hz, 2H), 7.21(t,J=7.5Hz,2H), 6.88(d,J=7.9Hz,2H), 4.96(t,J=7.7Hz,2H), 2.11(sxt,J=7.7Hz,2H), 1.16(t,J=7.1Hz,3H). 13 C NMR (151MHz, DMSO-d6)δ=144.5,141.8,141.7,139.0,138.2,138.0,131.1,130.8,130.6,130 .4,128.9,127.1,125.2,123.4,122.4,121.6,120.7,120.6,113.1,111.0,51.3,20.7,10.6.

[0035]

[0036] Compound name:

[0037] 6-phenyl-12-(4-(trifluoromethyl)phenyl)-5,6-dihydropyrido[2,3-b:6,5-b']diindole. A deep yellow solid in 30% yield. 1 H NMR (600MHz, DMSO-d6) δ = 8.27 (d, J = 7.9Hz, 2H), 8.08-8.05 (m, J = 1.8, 3.1, 3.9Hz, 2H), 8.03 (d, J = 7.9Hz, 2H), 7. 99(t,J=3.5Hz,3H),7.62(d,J=8.1Hz,2H),7.49(t,J=7.5Hz,2H),7.22(t,J=7.6Hz,2H),6.94(d,J=7.9Hz,2H). 13 C NMR (151MHz, DMSO-d6)δ=145.0,142.3,142.1,138.5,137.7,137.5,133.5,132.0,131.3,130.8,130.5,130.3,1 30.1,128.4,127.2,126.7,126.6,126.5,124.7,122.9,122.1,121.1,120.2,120.0,115.9,114.1,112.8,110.5.

[0038]

[0039] Compound name:

[0040] 6-phenethyl-12-(4-(trifluoromethyl)phenyl)-5,6-dihydropyrido[2,3-b:6,5-b']diindole. Yellow solid, yield 93%. 1 H NMR (600MHz, DMSO-d6) δ=8.23(d,J=7.9Hz,2H),7.99(d,J=7.9Hz,2H),7.78(d,J=8.1Hz,2H),7.53(t,J=7.6Hz,2H),7.47(d,J=7.5Hz,2H) ,7.34(t,J=7.5Hz,2H),7.24(t,J=7.4Hz,1H),7.21(t,J=7.6Hz,2H),6.88(d,J=8.1Hz,2H),5.29(t,J=8.3Hz,2H),3.41(t,J=8.1Hz,2H). 13 C NMR (151MHz, DMSO-d6)δ=144.3,141.3,141.2,138.6,137.8,137.6,136.1,130.7,130.5,130.3,130.1,129.0, 128.5,128.1,126.8,126.6,124.8,123.0,122.1,121.2,120.3,120.2,116.2,114.3,112.7,110.7,49.9,32.0.

[0041]

[0042] Compound name:

[0043] 6-(furan-2-ylmethyl)-12-(4-(trifluoromethyl)phenyl)-5,6-dihydropyrido[2,3-b:6,5-b']diindole. Yellow solid, yield 56%. 1H NMR (600MHz, DMSO-d6) δ = 8.21 (d, J = 8.3Hz, 2H), 8.02 (d, J = 7.9Hz, 2H), 7.83 (d, J = 8.1Hz, 2H), 7.74 (s, 1H), 7.55 (t, J =7.7Hz,2H),7.22(t,J=7.6Hz,2H),7.01(d,J=2.9Hz,1H),6.87(d,J=7.9Hz,2H),6.51(q,J=1.8Hz,1H),6.31(s,2H). 13 CNMR(151MHz,DMSO-d6)δ=145.5,145.2,144.7,141.4,138.6,137.8,137.6,130.9,130.7,130.5,130.3,128.7,127.1, 127.0,126.8,124.9,124.7,123.1,122.4,121.3,120.4,117.9,116.0,114.1,112.9,112.2,111.7,111.0,110.9,46.0.

[0044]

[0045] Compound name:

[0046] 2-(12-(4-(trifluoromethyl)phenyl)pyrido[2,3-b:6,5-b']diindol-6(5H)-yl)ethan-1-ol. Brownish-yellow solid, yield 44%. 1 H NMR (600MHz, DMSO-d6) δ = 8.19 (d, J = 7.3Hz, 2H), 7.96 (d, J = 7.2Hz, 2H), 7.72 (d, J = 7.5Hz, 2H), 7.42 (t,J=7.0Hz,2H),7.10(t,J=6.8Hz,2H),6.84(d,J=7.5Hz,2H),5.16(br.s.,2H),4.16(br.s.,2H). 13 C NMR (151MHz, DMSO-d6)δ=143.7,143.0,139.6,139.6,130.5,130.3,130.1,129.9,128.9, 127.0,126.8,126.0,125.1,123.3,121.5,121.2,120.0,113.4,113.4,110.0,58.3,51.6.

[0047]

[0048] Compound name: 6-isobutyl-12-(naphthalen-1-yl)-5,6-dihydropyrido[2,3-b:6,5-b']diindole. Yellow solid, yield 80%. 1 H NMR (600MHz, DMSO-d6) δ = 8.38 (d, J = 8.3Hz, 1H), 8.22 (d, J = 8.3Hz, 1H), 7.90 (t, J =8.1Hz,1H),7.85(d,J=6.6Hz,1H),7.78(d,J=8.1Hz,2H),7.60(t,J=7.5Hz,1H), 7.42(t,J=7.7Hz,3H),7.30(t,J=7.5Hz,1H),6.96(t,J=7.6Hz,2H),6.42(d,J=8. 1Hz, 2H), 5.03 (d, J = 7.9Hz, 2H), 2.72 (quin, J = 7.0Hz, 1H), 1.15 (d, J = 6.6Hz, 6H). 13 CNMR(151MHz,DMSO-d6)δ=144.7,142.1,141.9,138.0,137.8,133.5,132.1,130.3,129.6,128.9,127.5,127.1,126.7,12 6.4,125.8,124.7,122.0,120.7,120.7,120.5,118.1,116.2,114.3,112.8,112.8,112.4,112.0,112.0,56.1,27.0,19.1.

[0049]

[0050] Compound name:

[0051] 6-(pyridin-2-yl)-12-(4-(trifluoromethyl)phenyl)-5,6-dihydropyrido[2,3-b:6,5-b']diindole. Deep yellow solid, yield 37%. 1H NMR(600MHz,DMSO-d6)δ=9.03(d,J=4.6Hz,1H),8.51(td,J=1.5,6.2Hz,1H),8.30-8.24(m,J=2.7,7.8Hz,3H),8.07(d,J=7.3Hz,2H),8.06-8.03(m,J=5.1Hz,1H),7.65(d,J=8.1Hz,2H),7.50(t,J=7.6Hz,2H),7.22(t,J=7.6Hz,2H),6.92(d,J=8.1Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ=151.7,146.8,146.2,142.1,141.4,138.7,138.0,131.0,130.6,130.4,128.7,127.9,127.0,126.8,125.0,123.2,123.1,122.5,121.4,120.4,120.4,118.0,116.1,114.2,113.1,112.3,111.0.

Claims

1. A method for synthesizing a 6-substituted 5,6-dihydropyridinebisindole compound, characterized in that... Includes the following steps: 1) Mix the bisindole derivative and DMF, stir at a certain temperature to dissolve the bisindole derivative, and then add an organic amine; 2) Dissolve the catalyst CuCl2·2H2O in DMF, add the CuCl2·2H2O DMF solution to the mixed solution in step 1), and carry out the reaction; 3) The organic layer was extracted multiple times with ethyl acetate and ultrapure water. The water and ethyl acetate were removed, the solution was eluted and collected, and the solvent was removed to obtain the product. The synthesis route is as follows: When R1 is R2 is 4-CF3-Ph, and the product is... When R1 is -Ph and R2 is 4-CF3-Ph, the product is When R1 is R2 is 4-CF3-Ph, and the product is... When R1 is R2 is 4-CF3-Ph, and the product is... When R1 is R2 is 4-CF3-Ph, and the product is... When R1 is R2 is The product is When R1 is R2 is 4-CF3-Ph, and the product is...

2. The method for synthesizing a 6-substituted 5,6-dihydropyridobisindole compound as described in claim 1, characterized in that: In step 1), the specified temperature is 60–100°C.

3. The method for synthesizing a 6-substituted 5,6-dihydropyridobisindole compound as described in claim 1, characterized in that: In step 1), the molar ratio of the bisindole derivative to the organic amine is 1:3 to 1:

7.

4. The method for synthesizing a 6-substituted 5,6-dihydropyridobisindole compound as described in claim 1, characterized in that: In step 2), the reaction temperature is 60–100℃ and the reaction time is 1–3 hours.

5. The method for synthesizing a 6-substituted 5,6-dihydropyridobisindole compound as described in claim 1, characterized in that: In step 2), the molar ratio of CuCl2·2H2O to the bisindole derivative is 0.3 to 1.

2.

6. The method for synthesizing a 6-substituted 5,6-dihydropyridobisindole compound as described in claim 1, characterized in that: In step 3), the pH of the ultrapure water is 9-11, the water removal is performed using anhydrous sodium sulfate, and the elution is performed using the MeOH-CH2Cl2 system.

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