Synthesis method of 3,3'-diindolylmethane
By synthesizing 3,3'-diindolemethane with 4-dimethylaminopyridine and phase transfer catalyst under the condition of water as a solvent, the problems of high solvent costs and harsh reaction conditions in the prior art are solved, and the synthesis effect of high yield and high purity is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202211432034.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-11-16
- Publication Date
- 2025-08-15
- Estimated Expiration
- 2042-11-16
AI Technical Summary
In the prior art, when 3,3' diindole methane is prepared using indole and aldehydes as raw materials, the solvent cost is high, the reaction conditions are harsh and the yield is low, making it difficult to be suitable for industrial production.
3,3'-diindolemethane was synthesized under the condition of water as solvent using 4-dimethylaminopyridine and phase transfer catalyst, avoiding the use of organic solvents and ultrasonic waves, and improving product yield and purity by optimizing reaction conditions.
It realizes the efficient synthesis of 3,3'-diindole methane under mild conditions, reduces production costs, improves product yield and purity, and is suitable for industrial applications.
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Figure CN115784964B_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 3,3'-diindolylmethane. Background Art
[0002] 3,3′-diindolylmethane is a white or off-white crystalline powder that is widely found in natural plants of the Cruciferae family. It has important biological and pharmacological activities and is widely used in the fields of medicine and health products. It can be used in clinical medicine to treat various cancers and tumors.
[0003] The synthesis of 3,3'-diindolylmethane includes methods using indole and aldehydes as the main raw materials, indole-3-methanol as the main raw materials, and indole and N-hydroxymethyl acrylamide as the main raw materials. Among them, the preparation of 3,3'-diindolylmethane using indole and aldehydes as raw materials has been reported more frequently.
[0004] The existing technology for preparing 3,3′-diindolylmethane using indole and aldehydes as raw materials has the following main problems: (1) a large amount of ethanol is often used in the solvent, resulting in high production costs; (2) nitrogen and other protective gases are required during the synthesis process, which is not suitable for industrial production; (3) the synthesis method using water as the solvent often relies on ultrasonic radiation and other reaction conditions, which are harsh and have a very low yield (only 45%).
[0005] In view of this, the present invention is proposed. Summary of the Invention
[0006] The purpose of the present invention is to provide a method for synthesizing 3,3'-diindolylmethane, aiming to achieve the synthesis of 3,3'-diindolylmethane using water as a solvent without harsh conditions, and to maintain a high product yield and purity.
[0007] The present invention is achieved in that:
[0008] The present invention provides a method for synthesizing 3,3'-diindolylmethane, comprising the steps of mixing indole, formaldehyde and water for reaction in the presence of a catalyst, cooling and crystallizing the mixture after the reaction is completed;
[0009] The catalyst includes 4-dimethylaminopyridine and a phase transfer catalyst.
[0010] The present invention has the following beneficial effects: The target product, 3,3'-diindolylmethane, is synthesized from indole and formaldehyde as raw materials in the presence of a phase transfer catalyst and 4-dimethylaminopyridine, using water as the reaction solvent. The reaction route provided by the present invention boasts a fast reaction rate, avoids the use of organic solvents, and does not require harsh reaction conditions such as ultrasound, making it an environmentally friendly organic synthesis technology. The resulting product has a relatively high yield and purity, facilitating industrialization. BRIEF DESCRIPTION OF THE DRAWINGS
[0011] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.
[0012] Figure 1 A flow chart of a synthesis method provided in an embodiment of the present invention;
[0013] Figure 2 This is a test result diagram of the product prepared in Example 1. DETAILED DESCRIPTION
[0014] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be purchased commercially.
[0015] Please refer to Figure 1 An embodiment of the present invention provides a method for synthesizing 3,3'-diindolylmethane, comprising mixing indole, formaldehyde, and water for reaction in the presence of a catalyst, and cooling and crystallizing the mixture after the reaction is completed; wherein the catalyst comprises 4-dimethylaminopyridine (DMAP) and a phase transfer catalyst.
[0016] The inventors creatively utilized 4-dimethylaminopyridine and a phase transfer catalyst for the synthesis of 3,3'-diindolylmethane. This allows the reaction to be completed using only water as a solvent, eliminating the need for extensive ethanol solvents and reducing reaction costs. The reaction also eliminates the need for harsh reaction conditions such as ultrasound, facilitating industrial application. More importantly, the present invention further improves product yield and purity through catalyst optimization.
[0017] In a preferred embodiment of the present invention, the phase transfer catalyst is tetrabutylammonium bromide (TBAB), and the specific principle is as follows:
[0018]
[0019] Using tetrabutylammonium bromide as the phase transfer catalyst maintains high product yield and purity, paving the way for industrial application of the process. Replacing the phase transfer catalyst with tetraethylammonium bromide significantly reduces product yield and purity.
[0020] Furthermore, the reaction temperature is 50-80°C, preferably 50-70°C. The reaction time is 6.5-10.5h; preferably 7.5-10.5h. If the reaction temperature is too low, the raw materials cannot dissolve. The reaction temperature needs to be above 50°C, and the reaction efficiency increases accordingly with the increase in reaction temperature. If the reaction temperature is too high, energy consumption increases significantly, but the reaction rate does not improve significantly. The inventors found that the reaction temperature is preferably 50-70°C and the reaction time is preferably 7.5-10.5h.
[0021] Specifically, the reaction temperature can be 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, or 80°C; preferably 50°C, 55°C, 60°C, 65°C, or 70°C, or any value between two adjacent values. The reaction time is determined according to the reaction temperature to ensure a complete reaction. The lower the reaction temperature, the longer the reaction time.
[0022] In a preferred embodiment of the present invention, the temperature is lowered by 20-25°C after the reaction is completed, and crystallization is carried out for 0.5-1.5 hours to allow the product to be fully precipitated. Specifically, the temperature can be lowered by 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, or any value between two adjacent values. Crystallization is an approximate time. After the crystals are completely precipitated, filtration can be carried out. The approximate crystallization time is 1 hour.
[0023] In some embodiments, the process further includes filtering and rinsing after cooling and crystallizing, then filtering again and drying the filter cake. The product is separated by filtration, and then rinsed to remove unreacted raw materials remaining on the crystal surface, and then filtered again and dried to obtain a product of higher purity. Specifically, rinsing can be performed with ethanol or other organic reagents, which are not listed here.
[0024] In order to further increase the yield of the reaction, the inventors further optimized the dosage of each raw material:
[0025] The molar ratio of formaldehyde to indole is 1:1.8-2.3, preferably 1:2-2.2. The ratio of formaldehyde to indole has a certain impact on the yield of the product. It is best to control the ratio of formaldehyde to indole to 1:2-2.2. Too large or too small is not conducive to improving the yield.
[0026] The amount of water used is 2-5 times the mass of indole, preferably 3-4 times. The amount of water used is to ensure that formaldehyde and indole can be fully dissolved, and the amount of water used is preferably 3-4 times the amount of indole used.
[0027] Furthermore, the mass ratio of tetrabutylammonium bromide to formaldehyde is 1.5-5:100, preferably 2.5-4:100. The yield of the product increases with increasing amount of tetrabutylammonium bromide, but the yield tends to stabilize at 2.5-4:100, and is preferably controlled at 2.5-4:100.
[0028] Furthermore, the mass ratio of 4-dimethylaminopyridine to formaldehyde is 1-5:100; preferably 2-4:100. The mass ratio of 4-dimethylaminopyridine to formaldehyde is preferably controlled at 2-4:100. If the dosage is too low, the yield is not ideal, and increasing the dosage does not significantly improve the yield.
[0029] The features and performance of the present invention are further described in detail below with reference to the embodiments.
[0030] Example 1
[0031] This embodiment provides a method for synthesizing 3,3'-diindolylmethane, comprising: adding 468g of indole and 60g of formaldehyde to 1500mL of water, heating to 60°C with stirring to dissolve the raw materials, adding 1.8g of tetrabutylammonium bromide, and then adding 1.8g of 4-dimethylaminopyridine, reacting for 7h, controlling the liquid phase, cooling by 20°C after the reaction, gradually precipitating the product during the cooling process, crystallizing for 1h, filtering, rinsing the filter cake once with ethanol, draining, and drying the filter cake to obtain 427g of the product 3,3'-diindolylmethane with a purity of 99.5% and a yield of 86.8%.
[0032] In this embodiment, the molar ratio of formaldehyde to indole is 1:2, the mass ratio of formaldehyde to 4-dimethylaminopyridine is 100:3.0, and the mass ratio of formaldehyde to tetrabutylammonium bromide is 100:3.0.
[0033] Examples 2-5
[0034] This embodiment provides a method for synthesizing 3,3'-diindolylmethane, which differs from Example 1 only in that the molar ratio of formaldehyde to indole is changed.
[0035] In Examples 2-5, the molar ratios of formaldehyde and indole were controlled to be 1:1.8, 1:2.1, 1:2.2, and 1:2.3, respectively.
[0036] Examples 6-11
[0037] This embodiment provides a method for synthesizing 3,3'-diindolylmethane, which is different from Example 1 only in that the amount of tetrabutylammonium bromide is changed.
[0038] In Examples 6-11, the mass ratios of formaldehyde to tetrabutylammonium bromide are controlled to be 100:1.5, 100:2.0, 100:2.5, 100:3.5, 100:4.0, and 100:5.0, respectively.
[0039] Examples 12-15
[0040] This embodiment provides a method for synthesizing 3,3'-diindolylmethane, which is different from Example 1 only in that the amount of 4-dimethylaminopyridine is changed.
[0041] In Examples 12-15, the mass ratios of formaldehyde to 4-dimethylaminopyridine were controlled to be 100:1.0, 100:2.0, 100:4.0, and 100:5.0, respectively.
[0042] Examples 16-19
[0043] This embodiment provides a method for synthesizing 3,3'-diindolylmethane, which differs from Example 1 only in that the reaction temperature and the reaction end time are changed.
[0044] Example 16 The reaction temperature was 50°C and the reaction completion time was 10.5h;
[0045] In Example 17, the reaction temperature was 70° C. and the reaction completion time was 7.5 h.
[0046] In Example 18, the reaction temperature was 80° C. and the reaction completion time was 6.5 h.
[0047] In Example 19, the reaction temperature was 90° C. and the reaction completion time was 6.5 h.
[0048] Comparative Example 1
[0049] This comparative example provides a method for synthesizing 3,3'-diindolylmethane, which differs from Example 1 only in that tetraethylammonium bromide (TEAB) is used instead of tetrabutylammonium bromide.
[0050] Comparative Example 2
[0051] This comparative example provides a method for synthesizing 3,3'-diindolylmethane, which differs from Example 1 only in that tetrabutylammonium bromide is replaced by tetrabutylammonium chloride (TBACl).
[0052] Comparative Example 3
[0053] This comparative example provides a method for synthesizing 3,3'-diindolylmethane, which is different from Example 1 only in that tetrabutylammonium bromide is replaced by tetrabutylammonium iodide (TBAI).
[0054] Comparative Example 4
[0055] This comparative example provides a method for synthesizing 3,3'-diindolylmethane, which is different from Example 1 only in that 4-dimethylaminopyridine is replaced by 1-hydroxybenzotriazole (HOBT).
[0056] Comparative Example 5
[0057] This comparative example provides a method for synthesizing 3,3'-diindolylmethane, which is different from Example 1 only in that 4-dimethylaminopyridine is replaced by 4-pyrrolidinylpyridine (4-PPY).
[0058] Test Example 1
[0059] The liquid chromatogram of the product obtained in Test Example 1 is shown in FIG. Figure 2 .Depend on Figure 2 It can be seen that the product prepared in the embodiment of the present invention has a very high purity.
[0060] Test Example 2
[0061] The yield and purity of each example were tested using conventional methods. The data of Examples 1-5 are shown in Table 1:
[0062] Table 1 Effect of formaldehyde to indole molar ratio
[0063] Example Formaldehyde and indole molar ratio Yield % purity% Example 1 1∶2 86.8 99.5 Example 2 1∶1.8 77.2 98.7 Example 3 1∶2.1 87.6 99.4 Example 4 1∶2.2 88.5 99.7 Example 5 1∶2.3 87.8 99.6
[0064] As can be seen from Table 1, when the molar ratio of formaldehyde to indole is lower than 1:2, the raw material reaction is incomplete, and when it is higher than 1:2, the yield can reach more than 85%. In order to avoid the waste of raw materials, it is more appropriate to set the ratio to 1:2-2.2.
[0065] Test Example 3
[0066] The yield and purity of each example were tested using conventional methods. The data for Example 1 and Examples 6-11 are shown in Table 2:
[0067] Table 2 Effect of tetrabutylammonium bromide dosage
[0068] Example Formaldehyde and TBAB mass ratio Yield % purity% Example 1 100∶3.0 86.8 99.5 Example 6 100∶1.5 79.8 97.4 Example 7 100∶2.0 83.5 98.8 Example 8 100∶2.5 85.7 99.4 Example 9 100∶3.5 87.1 99.5 Example 10 100∶4.0 86.8 99.7 Example 11 100∶5.0 86.6 99.7
[0069] As can be seen from Table 2, the yield increases with the increase of catalyst, but when it reaches 2.5%-4% (i.e. 100:2.5-4.0), the yield tends to be stable, so the dosage of TBAB is more suitable at 2.5-4%.
[0070] Test Example 4
[0071] The yield and purity of each example were tested using conventional methods. The data for Example 1 and Examples 12-15 are shown in Table 3:
[0072] Table 34-Effect of dimethylaminopyridine dosage
[0073] Example Formaldehyde and DMAP mass ratio Yield % purity% Example 1 100∶3.0 86.8 99.5 Example 12 100∶1.0 74.3 97.8 Example 13 100∶2.0 85.7 98.5 Example 14 100∶4.0 86.5 99.8 Example 15 100∶5.0 86.7 99.7
[0074] As can be seen from Table 3, when the amount of DMAP is above 2%, the yield remains at a high level. When it is greater than 4%, there is no significant change. Therefore, it is appropriate to determine the amount to be 2-4%, that is, to control the mass ratio of formaldehyde to DMAP to 100:2-4.
[0075] Test Example 5
[0076] The yield and purity of each example were tested using conventional methods. The data for Example 1 and Examples 16-19 are shown in Table 4:
[0077] Table 4 Effect of reaction temperature
[0078]
[0079]
[0080] When the reaction temperature is below 40°C, the raw materials do not dissolve well, so the reaction temperature is set above 50°C. As shown in Table 4, the reaction efficiency increases with increasing reaction temperature. When the temperature reaches above 80°C, the reaction rate, although it also varies, tends to be stable. Therefore, a reaction temperature of 50-70°C is more suitable, as it can maintain a relatively fast reaction rate while maintaining a mild reaction temperature that is more conducive to production.
[0081] Test Example 6
[0082] The yield and purity of each example were tested using conventional methods. The data for Example 1 and Comparative Examples 1-6 are shown in Table 5:
[0083] Table 5 Effect of catalyst
[0084]
[0085] From the test data in Table 5, it can be seen that the use of TBAB combined with DMAP as a reaction catalyst is more suitable for the reaction system provided in the embodiment of the present invention, and the yield and purity of the product are relatively ideal.
[0086] In summary, the present invention uses indole and formaldehyde as raw materials, in the presence of a phase transfer catalyst and 4-dimethylaminopyridine, and water as the reaction solvent to synthesize the target product, 3,3'-diindolylmethane. The reaction route provided by the present invention offers a fast reaction rate, avoids the use of organic solvents, and does not require harsh reaction conditions such as ultrasound, making it an environmentally friendly organic synthesis technology. The resulting product has a high yield and purity, facilitating industrialization.
[0087] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.
Claims
1. A method for synthesizing 3,3'-diindolylmethane, characterized in that: In the presence of a catalyst, indole, formaldehyde and water are mixed to react, and after the reaction is completed, the temperature is lowered to crystallize; Wherein, the catalyst comprises 4-dimethylaminopyridine and a phase transfer catalyst; The phase transfer catalyst is tetrabutylammonium bromide; The mass ratio of tetrabutylammonium bromide to formaldehyde is 2.5-4:100, and the mass ratio of 4-dimethylaminopyridine to formaldehyde is 2-4:100; The reaction temperature is 50-70°C and the reaction time is 7.5-10.5h; The molar ratio of formaldehyde to indole is 1:2-2.
2.
2. The synthesis method according to claim 1, wherein The amount of water used is 2-5 times the mass of indole.
3. The synthesis method according to claim 2, characterized in that The amount of water used is 3-4 times the mass of indole.
4. The synthesis method according to claim 1, characterized in that The cooling and crystallization is to cool down the temperature by 20-25°C after the reaction is completed and crystallize for 0.5-1.5h.
5. The synthesis method according to claim 4, characterized in that The method further comprises filtering and rinsing after cooling and crystallization, and then filtering again and drying the filter cake.
6. The synthesis method according to claim 5, characterized in that Rinse with ethanol.