Preparation method of 5, 6-dihydroxyindole
By using hydroquinone and glyoxylic acid as raw materials, combined with DMF solvent and potassium carbonate hydrochloric acid catalyst, and precisely controlling the reaction conditions, the problems of the existing preparation method being cumbersome and having low yield are solved, and an efficient, economical and environmentally friendly synthesis of 5,6-dihydroxyindole is achieved.
Patent Information
- Application Number
- CN202510620271.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-14
- Publication Date
- 2025-09-19
AI Technical Summary
Existing methods for preparing 5,6-dihydroxyindole are cumbersome, have low yields, and use expensive or toxic reagents, limiting their large-scale production and application.
Hydroquinone and glyoxylic acid are used as starting materials to prepare 5,6-dihydroxyindole through condensation, cyclization and oxidation reactions. DMF is used as solvent, potassium carbonate and hydrochloric acid are used as catalysts, and the reaction temperature and time are precisely controlled to avoid side reactions and selectively and efficiently synthesize the target product.
The efficient, economical and environmentally friendly preparation of 5,6-dihydroxyindole was achieved with a yield of over 70%, which reduced production costs, reduced environmental pollution and complied with the concept of green chemistry.
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Figure BDA0005402299770000051
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing 5,6-dihydroxyindole. Background Art
[0002] 5,6-Dihydroxyindole, a critical organic compound, has extensive applications in medicine, cosmetics, and other fields. It is a core intermediate in the synthesis of a variety of bioactive molecules. For example, in the pharmaceutical field, in the development of drugs for the treatment of neurological diseases, the structural unit of 5,6-dihydroxyindole can bind to specific biological targets to regulate physiological functions. Its unique chemical structure makes it a promising candidate for the construction of complex drug molecules, providing a crucial material foundation for the development of innovative drugs. In the cosmetics industry, 5,6-dihydroxyindole has attracted significant attention for its outstanding antioxidant properties. With the increasing demand for skin health and anti-aging, the use of antioxidant ingredients in skincare products is becoming increasingly widespread. 5,6-Dihydroxyindole effectively scavenges free radicals within skin cells, reducing oxidative stress-induced damage, delaying skin aging, and improving skin radiance and elasticity. Therefore, it is widely used in the formulation of high-end skincare products, becoming a key ingredient in enhancing product efficacy.
[0003] Existing preparation methods have many drawbacks, such as cumbersome reaction steps, low yields, and the use of expensive or toxic reagents, which limit their large-scale production and application. Therefore, developing an efficient, economical, and environmentally friendly method for preparing 5,6-dihydroxyindole is of great practical significance. Summary of the Invention
[0004] (1) Technical problems solved
[0005] In view of the deficiencies of the prior art, the present invention provides a method for synthesizing bis-ethylhexyloxyphenol methoxyphenyl triazine, which solves at least one technical problem raised in the background art.
[0006] (2) Technical solution
[0007] The technical solution adopted in the present invention is:
[0008] A method for preparing 5,6-dihydroxyindole, comprising the following steps:
[0009] Step S1: Condensation reaction: hydroquinone and glyoxylic acid are added to a reaction vessel containing DMF in a certain proportion, and a base catalyst is added under stirring to carry out a condensation reaction to generate an intermediate product;
[0010] Step S2: Cyclization reaction: an acid catalyst is added to the intermediate product obtained in the reaction of step S1. Under acidic conditions, the intermediate product undergoes an intramolecular cyclization reaction to generate a precursor of 5,6-dihydroxyindole.
[0011] Step S3: Oxidation reaction: The precursor of 5,6-dihydroxyindole obtained in step S2 is cooled to room temperature, an oxidant is added, and an oxidation reaction is carried out to produce the target product 5,6-dihydroxyindole.
[0012] Preferably, in step S1, the molar ratio of the hydroquinone to the glyoxylic acid is 1:1.1-1.5.
[0013] Preferably, the condensation reaction in step S1 is controlled at a reaction temperature of 50-60° C. and a reaction time of 3-4 hours.
[0014] Preferably, the reaction temperature of the cyclization reaction in step S2 is 80-90° C., and the reaction time is 5-6 hours.
[0015] Preferably, the temperature of the oxidation reaction in step S3 is controlled at 30-40° C., and the reaction time is 2-3 hours.
[0016] Preferably, the base catalyst is potassium carbonate.
[0017] Preferably, the acid catalyst is hydrochloric acid.
[0018] Preferably, the molar amount of the base catalyst added is:
[0019] n k =[(1-0.001(T1-300))(1+0.01V1)]n A
[0020] Wherein, T1 is the reaction temperature of the condensation reaction, in K; V1 is the reaction volume of the condensation reaction, in L, n A is the amount of substance of diphenol, in mol.
[0021] Preferably, the molar amount of the acid catalyst added is:
[0022] n H =[(1.5-0.002(T2-320))(1+0.02V2)]n int
[0023] Wherein, T2 is the reaction temperature of the cyclization reaction, in K; V2 is the reaction volume of the cyclization reaction, in L, n int is the amount of substance of the intermediate product, in mol.
[0024] (3) Beneficial effects
[0025] The present invention provides a method for preparing 5,6-dihydroxyindole, which has the following beneficial effects compared with the prior art:
[0026] 1. Hydroquinone and glyoxylic acid were selected as starting materials. Hydroquinone is not only widely available and relatively inexpensive, but its two active hydroxyl groups can react with glyoxylic acid under specific reaction conditions. Compared with traditional starting materials, the reactivity and selectivity of hydroquinone are easier to control. As an organic synthesis intermediate, glyoxylic acid, with its unique carbonyl and carboxyl structures, can undergo condensation reactions with hydroquinone, initiating a series of subsequent reaction pathways to produce the target product. This raw material combination has not been widely used in the preparation of 5,6-dihydroxyindole before, providing new possibilities for the synthetic route.
[0027] 2. The choice of N,N-dimethylformamide (DMF) as a solvent is not solely based on its good solubility. DMF can form specific weak interactions with the raw materials and catalysts in the reaction system, stabilizing the reaction transition state and thus promoting the reaction. This new understanding of the solvent's mechanism of action allows DMF to have better compatibility with acid-base catalysts in the reaction system, facilitating the fine-tuning of reaction conditions. Specific implementation methods
[0028] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.
[0029] In order to better understand the above technical solution, the above technical solution will be described in detail below in combination with specific implementation methods:
[0030] Step S1: Condensation reaction: hydroquinone and glyoxylic acid are added to a reaction vessel filled with DMF in a certain ratio, and an appropriate amount of base catalyst potassium carbonate is slowly added under stirring. The reaction temperature is controlled at 50-60°C and the reaction time is 3-4 hours. This condensation reaction adopts a unique base catalytic system. Potassium carbonate can accurately activate one hydroxyl group of hydroquinone in a DMF solvent environment, causing it to undergo a condensation reaction with the carbonyl group of glyoxylic acid to generate an intermediate product with a specific structure. Compared with traditional condensation reaction conditions, the reaction conditions are mild and highly selective, which effectively reduces the occurrence of side reactions. Specifically, the above-mentioned hydroquinone and glyoxylic acid are in a substance ratio of 1:1.1--1.5.
[0031] Step S2: Cyclization reaction: Add an appropriate amount of acid catalyst hydrochloric acid to the intermediate product obtained in the first step. Adjust the reaction temperature to 80-90°C and continue the reaction for 5-6 hours. Under acidic conditions, the intermediate product undergoes an intramolecular cyclization reaction to form a precursor of 5,6-dihydroxyindole. The embodiment of the present invention achieves an efficient cyclization reaction by precisely controlling the type and concentration of the acid as well as the reaction temperature and time. Unlike conventional cyclization methods, this method utilizes the intramolecular rearrangement and cyclization characteristics of the intermediate product generated by the first step reaction in an acidic environment. The reaction path is novel and the yield and selectivity of the cyclization reaction are improved.
[0032] Step S3: Oxidation reaction: The product obtained in the second step is cooled to room temperature and an appropriate amount of hydrogen peroxide as an oxidant is added. The reaction is carried out for 2-3 hours under mild conditions (temperature controlled at 30-40°C) to oxidize the precursor of 5,6-dihydroxyindole to the target product 5,6-dihydroxyindole. The use of hydrogen peroxide as an oxidant has the advantage of being green and environmentally friendly. At the same time, by optimizing the reaction temperature and time, the embodiment of the present invention found that hydrogen peroxide can selectively oxidize the precursor in a unique manner in the reaction system, avoiding the occurrence of over-oxidation and other side reactions, which has not been reported in the previous oxidation preparation of 5,6-dihydroxyindole.
[0033] According to the tracking of the above examples, in the condensation reaction stage, the temperature of 50-60°C can not only ensure the reaction rate, but also avoid the occurrence of side reactions by stabilizing the conformation of the reaction intermediates. The cyclization reaction requires a higher temperature (80-90°C) to overcome the energy barrier of intramolecular cyclization and promote the reaction. The oxidation reaction is carried out at a relatively mild temperature of 30-40°C. This is based on a comprehensive consideration of the oxidation activity of hydrogen peroxide and the stability of the target product. By precisely controlling the temperature, the efficient progress of each step of the reaction is achieved. This temperature control strategy is innovative.
[0034] The condensation reaction proceeds under alkaline conditions, and the amount of potassium carbonate added is precisely calculated and experimentally verified to provide the most suitable alkaline environment for the condensation reaction of hydroquinone and glyoxylic acid to achieve optimal results. The cyclization reaction proceeds under acidic conditions, and the concentration and amount of hydrochloric acid added are adjusted according to the specific conditions of the reaction system, such as the amount of intermediates, reaction temperature, and reaction volume, to ensure the smooth progress of the cyclization reaction. This precise control of pH, based on a deep understanding of the reaction mechanism, differs significantly from the simple acid-base adjustment used in traditional preparation methods and offers significant advantages.
[0035] The embodiments of the present invention reduce unnecessary reaction steps and improve synthesis efficiency by rationally designing the reaction route. For example, traditional methods may require multiple protection and deprotection steps. However, through clever raw material selection and control of reaction conditions, these tedious steps are avoided, and the target product can be synthesized directly from simple raw materials.
[0036] Low raw material costs: Using common and inexpensive hydroquinone and glyoxylic acid as starting materials reduces production costs and facilitates large-scale production. This offers significant economic advantages over traditional preparation methods that use expensive raw materials.
[0037] High Yield: By optimizing reaction conditions, including temperature, pH, and reaction time, the present method achieves a high yield of over 70%. This yield, higher than most traditional methods, is primarily due to the innovative reaction steps and controlled conditions, which effectively improve the selectivity and conversion rate of the reaction.
[0038] Environmentally friendly: The reaction avoids the use of expensive or toxic reagents, reducing environmental pollution and aligning with the concept of green chemistry. For example, using hydrogen peroxide as an oxidant, the only byproduct after the reaction is water, which is environmentally friendly and in stark contrast to traditional methods that use toxic and hazardous oxidants.
[0039] Furthermore, in the above condensation reaction, the molar amount of the base catalyst added is:
[0040] n k =[(1-0.001(T1-300))(1+0.01V1)]n A
[0041] Wherein, T1 is the reaction temperature of the condensation reaction, in K; V1 is the reaction volume of the condensation reaction, in L, n A is the amount of substance of diphenol, in mol.
[0042] In the above cyclization reaction, the molar amount of the acid catalyst added is:
[0043] n H =[(1.5-0.002(T2-320))(1+0.02V2)]n int
[0044] Wherein, T2 is the reaction temperature of the cyclization reaction, in K; V2 is the reaction volume of the cyclization reaction, in L, n int is the amount of substance of the intermediate product, in mol.
[0045] The embodiments of the present invention control the addition amount of the alkaline catalyst and the acidic catalyst, and fully combine the amount of the reactant substrate and the reaction conditions.
[0046] If the amount of the reaction substrates hydroquinone and glyoxylic acid is large, then in order to ensure that the reaction proceeds fully, the amount of the base catalyst also needs to be increased accordingly, but it usually does not exceed the amount of the substrate, otherwise it may cause side reactions or cause difficulties in separating subsequent products. When the reaction temperature is high, the kinetic energy of the reactants increases, the reaction rate will accelerate, and the amount of the base catalyst can be appropriately reduced. When the temperature is low, the amount of the base catalyst needs to be increased. Therefore, the selection of adding an appropriate amount of basic catalyst and acidic catalyst has a significant effect on controlling the progress of the reaction, avoiding the occurrence of side reactions or damaging the product.
[0047] Assume that the amount of hydroquinone is n A =0.1 mol, reaction temperature of condensation reaction T1=310K, reaction volume of condensation reaction V1=0.5 L;
[0048] The molar amount of the basic catalyst, preferably potassium carbonate, added is:
[0049] n k =[(1-0.001(310-300))(1+0.01x0.5)]0.1=0.10045mol.
[0050] Assume that the amount of substance of the condensation product is n int =0.08 mol, wherein the reaction temperature of the cyclization reaction T2 =330K; the reaction volume of the cyclization reaction V2 =0.5 L;
[0051] The molar amount of the acidic catalyst, preferably hydrochloric acid, added is:
[0052]
[0053] The following is a detailed description with reference to specific embodiments:
[0054] Example 1:
[0055] In a 250 mL three-necked flask equipped with a stirrer, thermometer, and reflux condenser, add 10 g (0.09 mol) of hydroquinone, 12 g (0.11 mol) of glyoxylic acid, and 100 mL of DMF. After stirring, slowly add 15 g (0.11 mol) of potassium carbonate. Keep the reaction temperature at 50°C and allow to react for 3 hours.
[0056] 10 mL of concentrated hydrochloric acid was added dropwise to the reaction mixture, and the temperature was raised to 80° C., and the reaction was continued for 5 hours.
[0057] The reaction solution was cooled to room temperature, and 10 mL of 30% hydrogen peroxide solution was slowly added, followed by reaction at 30° C. for 2 hours.
[0058] After the reaction, the reaction mixture was poured into ice water and extracted three times with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to obtain 8.5 g of 5,6-dihydroxyindole, with a yield of 72%.
[0059] Example 2:
[0060] In the same reaction apparatus, add 12 g (0.11 mol) of hydroquinone, 14 g (0.13 mol) of glyoxylic acid, and 120 mL of DMF. After stirring, add 18 g (0.13 mol) of potassium carbonate. Keep the reaction temperature at 55°C and allow the reaction to proceed for 3.5 hours.
[0061] 12 mL of concentrated hydrochloric acid was added, the temperature was raised to 85° C., and the reaction was carried out for 5.5 hours.
[0062] After cooling to room temperature, 12 mL of 30% hydrogen peroxide solution was added and the mixture was reacted at 35°C for 2.5 hours.
[0063] The subsequent treatment was the same as in Example 1 to obtain 9.2 g of 5,6-dihydroxyindole with a yield of 75%.
[0064] Example 3:
[0065] 15 g (0.14 mol) of hydroquinone, 18 g (0.17 mol) of glyoxylic acid, and 150 mL of DMF were added to a reaction apparatus. 20 g (0.14 mol) of potassium carbonate was added, and the reaction temperature was controlled at 60° C. for 4 hours.
[0066] Add 15 mL of concentrated hydrochloric acid, raise the temperature to 90°C, and react for 6 hours.
[0067] After cooling to room temperature, 15 mL of 30% hydrogen peroxide solution was added and the mixture was reacted at 40°C for 3 hours.
[0068] The subsequent treatment was the same as in Example 1 to obtain 10.5 g of 5,6-dihydroxyindole with a yield of 73%.
[0069] Comparative Example 1:
[0070] In a 250 mL three-necked flask equipped with a stirrer, thermometer, and reflux condenser, add 10 g (0.09 mol) of hydroquinone, 12 g (0.11 mol) of glyoxylic acid, and 100 mL of DMF. After stirring, slowly add 15 g (0.11 mol) of potassium carbonate. Keep the reaction temperature at 40°C and allow to react for 3 hours.
[0071] 10 mL of concentrated hydrochloric acid was added dropwise to the reaction mixture, and the temperature was raised to 70° C., and the reaction was continued for 5 hours.
[0072] The reaction solution was cooled to room temperature, and 10 mL of 30% hydrogen peroxide solution was slowly added, and the mixture was reacted at 20° C. for 2 hours.
[0073] After the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate three times (50 mL each time). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to yield 5.5 g of 5,6-dihydroxyindole.
[0074] Comparative Example 2
[0075] In a 250 mL three-necked flask equipped with a stirrer, thermometer, and reflux condenser, add 10 g (0.09 mol) of hydroquinone, 12 g (0.11 mol) of glyoxylic acid, and 100 mL of DMF. After stirring, slowly add 10 g (0.07 mol) of potassium carbonate. Keep the reaction temperature at 50°C and allow to react for 3 hours.
[0076] 8 mL of concentrated hydrochloric acid was added dropwise to the reaction mixture, and the temperature was raised to 80° C., and the reaction was continued for 5 hours.
[0077] The reaction solution was cooled to room temperature, and 10 mL of 30% hydrogen peroxide solution was slowly added, followed by reaction at 30° C. for 2 hours.
[0078] After the reaction, the reaction mixture was poured into ice water and extracted three times with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 3:1) to yield 6.2 g of 5,6-dihydroxyindole.
[0079] Compared with Example 1, the reaction temperature of Comparative Example 1 in each step is lower than that of Example 1. At the same time, the addition amount of the alkaline catalyst and the acidic catalyst is not adjusted according to the temperature, and is adjusted based on the addition method of the embodiment of the present invention. The lower reaction temperature slows down the reaction rate and incomplete conversion of the raw materials. In the condensation reaction stage, the low temperature leads to a decrease in the reactivity of hydroquinone and glyoxylic acid, and a decrease in the amount of condensation product generated; in the cyclization reaction stage, the temperature does not reach the appropriate range, the cyclization reaction is not fully carried out, and less 5,6-dihydroxyindole precursor is generated; in the oxidation reaction stage, the low temperature reduces the oxidation efficiency of hydrogen peroxide, and the yield of the final product is only 46%, which is much lower than the 72% in Example 1. This shows that the reaction temperature used in Example 1 of the present invention and the addition amount of the alkaline catalyst and the acidic catalyst controlled based on the reaction temperature conditions are crucial to improving reaction efficiency and product yield.
[0080] In Comparative Example 2, the amounts of the base catalyst potassium carbonate and the acid catalyst hydrochloric acid were both less than those in Example 1. In the condensation reaction, the insufficient amount of potassium carbonate failed to provide a sufficient alkaline environment, resulting in incomplete condensation of hydroquinone and glyoxylic acid and reduced intermediate product production. During the cyclization reaction, the insufficient amount of hydrochloric acid failed to effectively promote the cyclization of the intermediate product, resulting in a reduction in the production of 5,6-dihydroxyindole precursors and a final product yield of 52%. In contrast, in Example 1, by precisely controlling the amount of the acid-base catalyst, the smooth progress of each reaction step was ensured, achieving a yield of 72%. This fully demonstrates that the appropriate amount of acid-base catalyst is one of the key factors in achieving high yields in the embodiments of the present invention.
[0081] It should be noted that, in this article, the terms "comprises", "includes" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article or apparatus that includes a series of elements includes not only those elements, but also includes other elements not explicitly listed, or also includes elements that are inherent to such process, method, article or apparatus.
[0082] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.
Claims
1. A method for preparing 5,6-dihydroxyindole, characterized in that: The preparation method comprises the following steps: Step S1: Condensation reaction: hydroquinone and glyoxylic acid are added to a reaction vessel containing DMF in a certain proportion, and a base catalyst is added under stirring to carry out a condensation reaction to generate an intermediate product; Step S2: Cyclization reaction: an acid catalyst is added to the intermediate product obtained in the reaction of step S1. Under acidic conditions, the intermediate product undergoes an intramolecular cyclization reaction to generate a precursor of 5,6-dihydroxyindole. Step S3: Oxidation reaction: The precursor of 5,6-dihydroxyindole obtained in step S2 is cooled to room temperature, an oxidant is added, and an oxidation reaction is carried out to produce the target product 5,6-dihydroxyindole.
2. The method for preparing 5,6-dihydroxyindole according to claim 1, wherein: In step S1, the molar ratio of the hydroquinone to the glyoxylic acid is 1:1.1-1.
5.
3. The method for preparing 5,6-dihydroxyindole according to claim 1, wherein: The condensation reaction in step S1 is controlled at a reaction temperature of 50-60° C. and a reaction time of 3-4 hours.
4. The method for preparing 5,6-dihydroxyindole according to claim 1, wherein: The reaction temperature of the cyclization reaction in step S2 is 80-90° C., and the reaction time is 5-6 hours.
5. The method for preparing 5,6-dihydroxyindole according to claim 3, wherein: The temperature of the oxidation reaction in step S3 is controlled to be 30-40° C., and the reaction time is 2-3 hours.
6. The method for preparing 5,6-dihydroxyindole according to claim 1, wherein: The base catalyst is potassium carbonate.
7. The method for preparing 5,6-dihydroxyindole according to claim 6, characterized in that: The acid catalyst is hydrochloric acid.
8. The method for preparing 5,6-dihydroxyindole according to claim 6, characterized in that: The molar amount of the base catalyst added is: n k =[(1-0.001(T1-300))(1+0.01V1)]n A Wherein, T1 is the reaction temperature of the condensation reaction, in K; V1 is the reaction volume of the condensation reaction, in L, n A is the amount of substance of diphenol, in mol.
9. The method for preparing 5,6-dihydroxyindole according to claim 6, characterized in that: The added molar amount of the acid catalyst is: n H =[(1.5-0.002(T2-320))(1+0.02V2)]n int Wherein, T2 is the reaction temperature of the cyclization reaction, in K; V2 is the reaction volume of the cyclization reaction, in L, n int is the amount of substance of the intermediate product, in mol.