Process for the preparation of 3,3'-biindolylmethane and derivatives thereof involving carbon dioxide

Abstract

The application provides a preparation method of carbon dioxide participated 3,3'-biindolylmethane and derivatives thereof, which uses carbon dioxide (CO2) and an indole compound shown in formula I as starting materials, sodium borohydride as a reducing agent, and an organic base as a reaction aid, and realizes the reduction synthesis of 3,3'-biindolylmethane and derivatives thereof (formula II) under normal pressure. The method is simple to operate, does not need the participation of a transition metal, a noble metal and other catalysts in the synthesis process, avoids high-pressure reaction and metal residues in drugs, is safe and efficient, meets the development requirements of low carbon and environmental protection, and has important practical value and good application prospect in the medical, health care product, agricultural fertilizer and other industries.

Description

Technical Field

[0001] This invention belongs to the field of organic synthetic drug molecules, specifically relating to a method for preparing 3,3'-diindolemethane and its derivatives from carbon dioxide. Background Technology

[0002] 3,3'-Diindolemethane is widely found in natural plants of the Brassicaceae family and is a potent androgen receptor (AR) antagonist with important biological and pharmacological activities, finding wide application in pharmaceuticals, health products, agriculture, and fertilizers. Numerous experiments have demonstrated that 3,3'-Diindolemethane can alter estrogen metabolism, antagonize estrogen and androgen receptor activity, and is also an effective radiation protectant and alleviator, acting by stimulating ATM-driven DDR-like responses and NF-κB survival signaling. 3,3'-Diindolemethane can inhibit tumor cell invasion, angiogenesis, proliferation, and induce apoptosis by modulating signaling pathways such as AKT, NF-κB, and FOXOChemicalbook3. It can also inhibit estrogen-induced gene expression and induce endoplasmic reticulum stress responses. Furthermore, as a novel plant growth promoter, the functions of 3,3'-Diindolemethane and its derivatives have been applied in eco-friendly systems research.

[0003] Currently, there are relatively few reports on the synthesis of 3,3'-diindolemethane and its derivatives from indole and carbon dioxide. The only retrievable literature is from Matthias Beller's group in 2014, who observed approximately 10% formation of 3,3'-diindolemethane in a reaction using carbon dioxide as the C1 source under tridentate ruthenium catalysis (Angew. Chem. Int. Ed. 2014, 53, 10476-10480). This synthetic method requires very high pressure [CO2 / H2 (20 / 60 bar)] and temperature (140-160 °C), making it difficult to operate. Furthermore, ruthenium catalysts are expensive, and the presence of metal catalysts can lead to metal residues in the synthesized drug, which does not meet the requirements of environmentally friendly development. In 2021, Tadashi Ema's group reported the synthesis of 3,3'-diindolemethane and its derivatives from carbon dioxide and indole using a pentanuclear organometallic zinc compound as a catalyst and six equivalents of phenylsilane as a reducing agent (Chem. Commun., 2021, 57, 8083-8086). In 2022, the same group further synthesized 3,3'-diindolemethane and its derivatives from carbon dioxide and indole using triphenylborone as a catalyst and phenylsilane as a reducing agent (Green Chem., 2022, 24, 2385-2390). However, the indole compounds used in the above studies were all N-methyl-substituted indole compounds.

[0004] Therefore, this invention seeks a novel method for the reduction synthesis of 3,3'-diindolemethane and its derivatives from carbon dioxide without using transition / noble metal catalysts, without employing high-pressure reaction conditions, and without requiring indole compounds that protect N atoms as reaction substrates. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing 3,3'-diindolemethane and its derivatives by carbon dioxide under normal pressure. This method can achieve the reduction synthesis of 3,3'-diindolemethane and its derivatives by carbon dioxide without the use of transition / noble metal catalysts and high pressure reaction conditions.

[0006] This invention provides a method for preparing carbon dioxide-mediated 3,3'-diindolemethane and its derivatives, comprising the following steps: adding sodium borohydride and an indole compound of Formula I to a reaction flask, purging with vacuum to replace carbon dioxide 1-3 times, adding an organic base as a reaction promoter, and acetonitrile as a reaction solvent, heating to 70-110 degrees Celsius, stirring for 10-25 hours, quenching the reaction with water after the reaction is completed, extracting with ethyl acetate, combining the organic phases, drying with anhydrous magnesium sulfate, concentrating, and separating by column chromatography to obtain 3,3'-diindolemethane and its derivatives of Formula II. The substituent R in Formulas I and II can be any one of hydrogen, alkyl, or halogen groups, and the position of the substituent R can be any position at the 2, 4, 5, 6, and 7 positions of the indole ring.

[0007]

[0008] The molar ratio of the feed ingredients is: compound shown in Formula I: sodium borohydride = 1:2-3.

[0009] Furthermore, the alkyl group can be methyl, ethyl, butyl, etc.; the halogen group is -F, -Cl, -Br, -I; the organic base can be trimethylamine, triethylamine, etc., preferably triethylamine. The reaction temperature is preferably 80-100 degrees Celsius, and the stirring time is preferably 12-24 hours.

[0010] The advantages of this invention compared to the prior art are as follows:

[0011] This invention utilizes carbon dioxide and indole compounds as starting materials, sodium borohydride as a reducing agent, and an organic base as a reaction promoter to achieve the reduction synthesis of 3,3'-diindolemethane and its derivatives under normal pressure. This preparation method eliminates the need for high-temperature and high-pressure operations and transition / noble metal catalysts, thus avoiding metal residues in the product. Furthermore, the nitrogen atoms in the indole compounds do not require special protection and can directly participate in the reaction, reducing reaction steps. It offers advantages such as mild conditions, low cost, and easy product purification. Attached Figure Description

[0012] Figure 1 Example 1 prepared 3,3'-di(5-methylindole)methane 1 H NMR image

[0013] Figure 2 Example 1 prepared 3,3'-di(5-methylindole)methane 13 C NMR spectrum Detailed Implementation

[0014] The following are specific embodiments provided merely for the purpose of illustrating the present invention in detail. These embodiments are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the experimental methods used in the embodiments are conventional methods.

[0015] Example 1

[0016] In a dry 25 mL reaction flask, 0.5 mmol of 5-methylindole and 1.5 mmol of NaBH4 were added sequentially. The mixture was evacuated three times using a vacuum pump to purge carbon dioxide. Triethylamine (1.5 mmol) was added as a reaction promoter, and acetonitrile (1 mL) was added as the reaction solvent. The mixture was stirred at 100 °C for 24 hours. After the reaction was complete, the reaction was quenched with water, and the mixture was extracted three times with 15 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography to obtain the target compound (3,3'-di(5-methylindole)methane). Yield: 83%. 1 H NMR (600MHz, Chloroform-d) δ7.68(s,2H),7.40(s,2H),7.20(d,J=8.4Hz,2H),7.00(d,J=7.9Hz,2H),6.81(s,2H),4.16(s,2H),2.42(s,6H). 13 C NMR (151MHz, Chloroform-d) δ134.94,128.48,127.95,123.60,122.56,118.98,115.32,110.84,21.63,21.29.

[0017]

[0018] Example 2

[0019] In a dry 25 mL reaction flask, indole (0.5 mmol) and NaBH4 (1.25 mmol) were added sequentially. The mixture was evacuated three times using a vacuum pump to replace carbon dioxide. Triethylamine (2.0 mmol) was added as a reaction promoter, and acetonitrile (1 mL) was added as the reaction solvent. The mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction was quenched with water, and the mixture was extracted three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography to obtain the target compound (3,3'-diindolemethane). Yield: 85%. 1 H NMR(600MHz,Chloroform-d)δ7.87(s,2H),7.62(d,J=7.9Hz,2H),7.35(d,J=8.1 Hz,2H),7.18(t,J=7.6Hz,2H),7.09(t,J=7.1Hz,2H),6.93(s,2H),4.24(s,2H). 13 C NMR (151MHz, Chloroform-d) δ136.44,127.55,122.17,121.88,119.21,119.16,115.69,111.02,21.20.

[0020]

[0021] Example 3

[0022] In a dry 25 mL reaction flask, 0.5 mmol of 4-methylindole and 2.0 mmol of NaBH4 were added sequentially. The mixture was evacuated three times using a vacuum pump to purge carbon dioxide. Triethylamine (2.0 mmol) was added as a reaction promoter, and acetonitrile (1 mL) was added as the reaction solvent. The mixture was stirred at 100 °C for 24 hours. After the reaction was complete, the reaction was quenched with water, and the mixture was extracted three times with 15 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography to obtain the target compound (3,3'-di(4-methylindole)methane). Yield: 80%. 1 H NMR (600MHz, Chloroform-d) δ7.78(s,2H),7.20(d,J=8.1Hz,2H),7.11(t,J=7.7Hz,2H),6.88(d,J=7.5Hz,2H),6.69(s,2H),4.53(s,2H),2.70(s,6H). 13 C NMR (151MHz, Chloroform-d) δ137.11,131.46,126.01,123.10,122.12,120.80,117.60,109.13,25.89,20.20.

[0023]

[0024] Example 4

[0025] In a dry 25 mL reaction flask, 0.5 mmol of 7-methylindole and 2.0 mmol of NaBH4 were added sequentially. The mixture was evacuated three times using a vacuum pump to purge carbon dioxide. Triethylamine (2.0 mmol) was added as a reaction promoter, and 1.5 mL of acetonitrile was added as the reaction solvent. The mixture was stirred at 100 °C for 24 hours. After the reaction was complete, the reaction was quenched with water, and the mixture was extracted three times with 15 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography to obtain the target compound (3,3'-di(7-methylindole)methane). Yield: 72%. 1 H NMR (600MHz, Chloroform-d) δ7.83(s,2H),7.48(d,J=7.6Hz,2H),7.01(dt,J=12.1,7.0Hz,4H),6.95(s,2H),4.24(s,2H),2.49(s,6H). 13 CNMR(151MHz,Chloroform-d)δ136.05,127.16,122.44,122.00,120.25,119.43,117.01,116.28,21.53,16.72.

[0026]

[0027] Example 5

[0028] In a dry 25 mL reaction flask, 0.5 mmol of 5-chloroindole and 1.0 mmol of NaBH4 were added sequentially. The mixture was evacuated three times using a vacuum pump to replace the carbon dioxide. Triethylamine (1.0 mmol) was added as a reaction promoter, and acetonitrile (1 mL) was added as the reaction solvent. The mixture was stirred at 80 °C for 24 hours. After the reaction was complete, the reaction was quenched with water, and the mixture was extracted three times with 15 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography to obtain the target compound (3,3'-di(5-chloroindole)methane). Yield: 70%. 1 H NMR (600MHz, Chloroform-d) δ7.96(s,2H),7.53(s,2H),7.26(d,J=8.6Hz,2H),7.14(dd,J=8.6,2.0Hz,2H),6.95(s,2H),4.14(s,2H). 13C NMR (151MHz, Chloroform-d) δ134.89,128.59,125.07,123.71,122.37,118.71,115.02,112.23,21.19.

[0029]

[0030] Example 6

[0031] In a dry 25 mL reaction flask, 0.5 mmol of 5-bromoindole and 1.25 mmol of NaBH4 were added sequentially. The mixture was evacuated three times using a vacuum pump to purge carbon dioxide. Triethylamine (1.5 mmol) was added as a reaction promoter, and acetonitrile (1 mL) was added as the reaction solvent. The mixture was stirred at 80 °C for 24 hours. After the reaction was complete, the reaction was quenched with water, and the mixture was extracted three times with 15 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the crude product was purified by column chromatography to obtain the target compound (3,3'-di(5-bromoindole)methane). Yield: 75%. 1 H NMR (600MHz, Chloroform-d) δ7.97(s,2H),7.70(s,2H),7.28 -7.21(m,4H),6.94(s,2H),4.13(s,2H). 13 C NMR (151MHz, Chloroform-d) δ135.14,129.23,124.93,123.49,121.80,114.95,112.66,112.62,21.18.

[0032]

Claims

1. A method for preparing 3,3'-diindolemethane and its derivatives involving carbon dioxide, characterized in that, The process includes the following steps: Sodium borohydride and the indole compound shown in Formula I are added to a reaction flask; the mixture is evacuated to purge carbon dioxide 1-3 times; an organic base is added as a reaction aid; acetonitrile is used as the reaction solvent; the temperature is raised to 70-110 degrees Celsius; and the mixture is stirred for 10-25 hours. After the reaction is complete, water is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, concentrated, and separated by column chromatography to obtain 3,3'-diindolemethane and its derivatives shown in Formula II. The structural formulas of Formulas I and II are as follows: In Formula I and Formula II, the substituent R can be any one of hydrogen, alkyl, or halogen groups, and the substituent R can be located at any position of the indole ring at the 2, 4, 5, 6, and 7 positions.

2. The method for preparing carbon dioxide-involved 3,3'-diindolemethane and its derivatives as described in claim 1, characterized in that, The alkyl group is methyl, ethyl, or butyl.

3. The method for preparing 3,3'-diindolemethane and its derivatives involving carbon dioxide as described in claim 1, characterized in that, The halogen groups are -F, -Cl, -Br, and -I.

4. The method for preparing carbon dioxide-involved 3,3'-diindolemethane and its derivatives as described in claim 1, characterized in that, The organic base is trimethylamine or triethylamine.

5. The method for preparing carbon dioxide-involved 3,3'-diindolemethane and its derivatives as described in claim 1, characterized in that, The amount of reactants added in the reaction step, based on the molar ratio, is: indole compound shown in Formula I: sodium borohydride = 1:2-3.

6. The method for preparing carbon dioxide-involved 3,3'-diindolemethane and its derivatives as described in claim 1, characterized in that, The reaction temperature is 80-100 degrees Celsius, and the stirring time is 12-24 hours.

Images