Process for the synthesis of 5,6-dihydroxyindole and intermediates thereof

Abstract

The application provides a synthesis method of 5,6-dihydroxyindole and intermediates thereof, which takes 5,6-dihydroxyindoline hydrogen halide or other acid salt (IC241-01) as raw material, protects heteroatom nitrogen and phenolic hydroxyl group in sequence to obtain intermediate compound 1-benzyloxy carbonyl-5,6-dibenzyl oxy indoline (IC241-03), further obtains intermediate compound 1-benzyloxy carbonyl-5,6-dibenzyl oxy indole (IC241-04) through an oxidation reaction, and removes the protection group through catalytic hydrogenation in the presence of trace antioxidants and polymerization inhibitors to obtain 5,6-dihydroxyindole (DHI). The method disclosed by the application is mild in reaction condition, can stably realize large-scale production, is easy in raw material obtaining, controllable in cost and good in process reproducibility; based on the synthesis strategy of removing the protection group at last, and due to the action of trace antioxidants and polymerization inhibitors, the target product 5,6-dihydroxyindole (DHI) has the comprehensive advantages of light color, good purity, easy storage and subsequent use.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and relates to a synthetic process route and purification preparation method of 5,6-dihydroxyindole (DHI), a functional chemical for healthy hair dyes, with high purity. Specifically, it relates to a synthetic method of 5,6-dihydroxyindole and its intermediates. Background Technology

[0002] Melanin is a natural pigment formed in living organisms, possessing functions such as anti-oxidation, free radical scavenging, and ultraviolet absorption. 5,6-Dihydroxyindole (DHI) is one of the key intermediates in melanin production. Originally discovered in natural organisms, studies have shown it to have no toxic side effects on humans. Pure 5,6-dihydroxyindole (DHI) is relatively stable in its crystalline state, but it quickly oxidizes in slightly alkaline solutions to form melanin-like substances. Traditional hair dyes commonly use aniline compounds as the effective blackening agent, which have potential carcinogenic, teratogenic, and allergenic effects on the human body. Because 5,6-dihydroxyindole (DHI) is less irritating to human skin, it has been used in some daily chemical hair dye products to replace the core ingredient of traditional hair dyes, aniline compounds, making it an ideal effective ingredient for a new generation of safe and healthy hair dyes. It is also a good antioxidant and an important intermediate in the synthesis of some amino acids, alkaloids, and tryptamines.

[0003] Due to the numerous important applications of 5,6-dihydroxyindole (DHI), renowned international cosmetics companies such as L'Oréal of France began researching its production processes and applications in the 1980s, and filed several patents. In recent years, research on 5,6-dihydroxyindole (DHI) has increased significantly both internationally and domestically. However, because 5,6-dihydroxyindole (DHI) is highly susceptible to oxidation or polymerization, the process for synthesizing this product in batches with a purity exceeding 95% is extremely difficult. Currently, most reported synthesis methods remain at the laboratory research stage and are difficult to apply to large-scale industrial production. According to existing domestic and international literature, its synthesis methods mainly fall into three categories:

[0004] Category 1: Classical Indole Heterocycle Construction Method

[0005]

[0006]

[0007] Based on US patents such as US 4,595,765 (Synthesis of Indole from Nitroalkenes, 1986), US 5,410,067 (Synthesis of Indole from Ortho-Nitrophenylacetonitrile, 1995), and US 6,160,127 (Synthesis of Indole from Nitroalkenes, 2000), as shown in the two representative routes above, the process starts from 3,4-dialkoxy-substituted benzaldehyde, phenylacetonitrile, etc., and involves multiple reactions, especially nitration, followed by a ring-cloning reaction to construct an indole core structure from the ortho-bifunctional group, directly or indirectly yielding the target molecule 5,6-dihydroxyindole (DHI). A common problem is the use of a dangerous nitration reaction in the intermediate steps, the long process, and the low overall yield. A particularly prominent issue is that the final step of synthesizing the target molecule 5,6-dihydroxyindole (DHI) is prone to product deterioration, making it difficult to obtain a qualified product for subsequent application development.

[0008] Category 2: Dopa or dopamine redox method

[0009]

[0010]

[0011] Based on published papers (Tetrahedron, 1996, vol. 52, #11, p. 3947-3952; Bioorganic and Medicinal Chemistry, 2012, vol. 20, #14, p. 4364-4370), as well as European patent EP 1820491 A1 (DOPA oxidation-reduction, 2007, English), US patent US2020 / 270208, A1 (DOPA oxidation, 2020), and Chinese patent CN 110981782 A (Dopamine oxidation-reduction, 2020), the route described above involves starting with dopamine or dopamine, undergoing oxidation, and then reduction to obtain the target molecule 5,6-dihydroxyindole (DHI). The common problem is that the actual yield of the target molecule 5,6-dihydroxyindole (DHI) is not high, the product is dark in color and easily deteriorates, making it difficult to obtain qualified products for subsequent industrialization.

[0012] Category 3: Direct dehydrogenation of indoline

[0013]

[0014] Based on published papers (Molecules, vol. 23; nb. 8; (2018); Art.No:1943.) and US patents US 5,536,843 (sodium fumarate or ammonium persulfate dehydrogenation, 1996) and US 5,578,735 (cyclohexene dehydrogenation, 1996), as shown in the above-mentioned routes, starting from 5,6-bisprotected hydroxyl groups or naked dihydroxyindoline, the dehydrogenation reaction is directly achieved through hydrogen transfer reagents such as sodium fumarate, ammonium persulfate, or cyclohexene, directly converting the corresponding indoline into the target molecule 5,6-dihydroxyindoline (DHI). Although these synthetic routes are relatively short, the obvious problems are that they require high-temperature reaction conditions, the dehydrogenation reaction is difficult to control, side reactions are significant, the actual yield of the target molecule 5,6-dihydroxyindoline (DHI) is not high, the product is dark in color and easily deteriorates, and it is still difficult to obtain a qualified product that meets industrial applications.

[0015] Therefore, researchers in this field are still conducting various exploratory research and development work, hoping to find new processes and methods to produce high-purity and stable 5,6-dihydroxyindole (DHI) products that meet the needs of multiple fields. In particular, they are looking forward to process routes and preparation methods that have mild reaction conditions, are suitable for large-scale production, have controllable costs, and are easy to store and use. Summary of the Invention

[0016] In view of the shortcomings and deficiencies of the existing synthetic routes and processes for 5,6-dihydroxyindole (DHI), the first objective of this invention is to provide a synthetic method for 5,6-dihydroxyindole (DHI) that has mild reaction conditions, can stably achieve large-scale production, has readily available raw materials, controllable costs, and good process reproducibility.

[0017] The second objective of this invention is to provide a method for preventing the deterioration of 5,6-dihydroxyindole (DHI) products: by adding antioxidants and polymerization inhibitors, the 5,6-dihydroxyindole (DHI) products are made to have a light color, good purity, and are easy to store and use.

[0018] A third objective of this invention is to provide an intermediate compound of formula (IC241-03) for the synthesis of 5,6-dihydroxyindole (DHI) and a method thereof for its preparation.

[0019] A fourth object of the present invention is to provide an intermediate compound of formula (IC241-04) for the synthesis of 5,6-dihydroxyindole (DHI) and a method thereof for its preparation.

[0020] To achieve the above-mentioned objectives, the technical solution adopted by this invention is as follows:

[0021] A method for synthesizing 5,6-dihydroxyindole, starting from readily available 5,6-dihydroxyindoleline hydrohalide or other acid salts, and through the preparation of key intermediates 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-03) and 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04), ultimately achieves the synthesis of 5,6-dihydroxyindole (DHI), comprising the following four steps:

[0022] (1) The starting reactant 5,6-dihydroxyindoline hydrohalate or other acid salt (IC241-01) is reacted with a benzyloxycarbonyl reagent under suitable solvent, suitable base and suitable temperature conditions to prepare intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02).

[0023] (2) The intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) obtained in step (1) is reacted with benzyl halide reagent under suitable solvent, suitable base and suitable temperature conditions to obtain intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03).

[0024] (3) The intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) obtained in step (2) is oxidized by reacting with a suitable oxidant in a suitable solvent and at a suitable temperature to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-04).

[0025] (4) The intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04) obtained in step (3) is dissolved in a suitable solvent, and appropriate amounts of antioxidants and polymerization inhibitors are added. A suitable metal catalyst is also added, and the protecting group is removed under suitable hydrogen pressure and temperature conditions to obtain the target product molecule 5,6-dihydroxyindole (DHI).

[0026] Further, in step (1), the solvent used in the reaction is selected from ether, ester, haloalkanes, acetonitrile, DMSO, DMF, water or a combination thereof; the base used in the reaction is selected from organic bases such as triethylamine, DIEA, etc., and inorganic bases such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc.; the reaction temperature is from 0 to 50°C; the benzyloxycarbonyl reagent used in the reaction includes benzyl chloroformate or benzyl succinimide carbonate.

[0027] Further, in step (1), more preferably, ethyl acetate with a volume ratio of 5-10 is used as the solvent, benzyl chloroformate and 5,6-dihydroxyindoline hydrohalide (IC241-01) are added in equimolar amounts, calcium carbonate is used as the base (1.2 molar equivalents), the reaction is carried out at room temperature, the reaction progress is monitored by TLC, and the reaction is usually completed in 5-24 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02).

[0028] Further, in step (1), the reaction that converts formula (IC241-01) into formula (IC241-02) is carried out as follows: a solvent is added to the reaction vessel, followed by the main raw material compound (IC241-01), an appropriate amount of base is added, and under an ice-water bath, the mixture is stirred and the benzyloxycarbonyl reagent is added dropwise. The mixture is gradually raised to room temperature and reacted for 5-24 hours. The reaction is monitored by TLC until it is complete.

[0029] Furthermore, in step (1), after the reaction is completed, the obtained compound formula (IC241-02) is treated as follows: filtered, the pH of the filtrate is adjusted to about 5 with dilute hydrochloric acid, extracted with ethyl acetate, and the organic solvent phases are combined and used directly in the next reaction.

[0030] Furthermore, in step (2), preferably, the solvent used in the reaction is selected from ethers, esters, haloalkanes, acetonitrile, acetone, DMSO, DMF, water, or combinations thereof;

[0031] The base used in the reaction is selected from organic bases such as triethylamine and DIEA, and inorganic bases such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide.

[0032] The reaction temperature ranges from 0 to 100°C;

[0033] The benzyl halide reagent used in the reaction includes benzyl chloride or benzyl bromide, etc.

[0034] The molar ratio of the benzyl halide reagent used in the reaction to the reactant 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) is (2-3):1;

[0035] Furthermore, in step (2), ethyl acetate with a volume ratio of 5-8 is used as the solvent, and benzyl chloride and 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) are added in a molar ratio of 2.2:1. Potassium carbonate is used as the base (2.5 molar equivalents). The reaction is carried out at 50°C, and the reaction progress is monitored by TLC. The reaction is usually completed in 8-24 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03).

[0036] Further, in step (2), the reaction that converts formula (IC241-02) into formula (IC241-03) is carried out as follows: add the solution of the compound (IC241-02) obtained in step (1) to the reaction vessel, add an appropriate amount of alkali, stir at room temperature, add benzyl halide reagent dropwise, gradually raise the temperature to 50°C and react for 8-24 hours, and monitor the reaction by TLC until the reaction is complete.

[0037] Further, in step (2), after the reaction is completed, the obtained compound formula (IC241-03) is treated as follows: After the reaction is completed, the pH value is adjusted to about 5-6 with dilute hydrochloric acid, the ethyl acetate is used for separation and extraction, the organic solvent phases are combined and concentrated to obtain a viscous liquid mainly containing the compound formula (IC241-03). Except for taking a small amount for column chromatography purification for NMR characterization, the rest does not need to be purified and proceeds directly to the next step.

[0038] Furthermore, in step (3), the solvent used in the reaction is selected from ethers, esters, haloalkanes, acetonitrile, water, or combinations thereof;

[0039] The reaction temperature ranges from 0 to 50°C;

[0040] The oxidizing agents used in the reaction include DDQ, manganese dioxide, etc.

[0041] The molar ratio of the oxidant used in the reaction to the reactant 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) is (1-10):1;

[0042] Furthermore, in step (3), dichloromethane with a volume ratio of 5-10 is used as a solvent, and manganese dioxide and 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) are added in a 5:1 molar ratio. The reaction is carried out at room temperature, and the reaction progress is monitored by TLC. The reaction is usually completed in 12-36 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-04).

[0043] Further, in step (3), the reaction that converts formula (IC241-03) into formula (IC241-04) is carried out as follows: the crude product of formula (IC241-03) obtained in step (2) is dissolved in a suitable amount of solvent as a viscous liquid, the solvent is transferred to a reaction vessel, a suitable amount of oxidant is added, the reaction is stirred at room temperature for 8-24 hours, and TLC is monitored until the reaction is complete.

[0044] Further, in step (3), after the reaction is completed, the compound formula (IC241-04) is treated as follows: after the reaction is completed, the solution is filtered, an appropriate amount of water is added to the solution for liquid extraction, the organic solvent phases are combined, dried with a desiccant, concentrated, and purified by a short silica gel column to obtain the compound formula (IC241-04), which is a white powder solid, ready to proceed to the next step of the reaction.

[0045] Furthermore, in step (4), the solvent used in the reaction is selected from alcohols, ethers, esters, haloalkanes, acetonitrs, water, or combinations thereof;

[0046] The reaction temperature ranges from 0 to 50°C;

[0047] The antioxidants and polymerization inhibitors used in the reaction include sodium ascorbate, vitamin C, tea polyphenols, phenol, 2,6-di-tert-butylphenol, or combinations thereof, at a mass ratio of 0.01-1%.

[0048] The metal catalysts used in the reaction include palladium on carbon, palladium hydroxide on carbon, etc.

[0049] The hydrogen gas used in the reaction is at a pressure ranging from 1 to 5 atmospheres.

[0050] Ethanol (5-10 times by volume) was used as the solvent. Vitamin C (0.1% by mass) and 2,6-di-tert-butylphenol (0.05% by mass) were added as antioxidants and polymerization inhibitors. A wet palladium-carbon catalyst (50% by mass) containing 50% water was added. The air in the reaction system was removed, and hydrogen gas at 1 atmosphere was introduced. The reaction was carried out at room temperature, and the reaction progress was monitored by TLC. The reaction was usually completed in 12-36 hours to obtain the target product 5,6-dihydroxyindole (DHI).

[0051] Further, in step (4), the reaction that converts formula (IC241-04) into the target product 5,6-dihydroxyindole (DHI) is carried out as follows: a solvent is added to the reaction vessel, followed by the compound (IC241-04) obtained in step (3), an appropriate amount of antioxidant and polymerization inhibitor is added, an appropriate amount of metal catalyst is added, the system is evacuated, hydrogen is introduced, and the reaction is carried out at room temperature for 12-36 hours, and TLC is monitored until the reaction is complete.

[0052] Further, in step (4), after the reaction is completed, the target product 5,6-dihydroxyindole (DHI) is treated as follows: after the reaction is completed, the solution is filtered under a nitrogen atmosphere, concentrated to about one-third to one-quarter of its volume, and an appropriate amount of unsuitable solvents such as methyl tert-butyl ether is added. The solution is then recrystallized to obtain the target product 5,6-dihydroxyindole (DHI), which is a light yellow to off-white powder solid.

[0053] The present invention also provides a key intermediate 1 in the method for synthesizing the aforementioned 5,6-dihydroxyindole, wherein the key intermediate is 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03), with the following structural formula:

[0054] .

[0055] The present invention also provides a key intermediate 2 in the method for synthesizing the aforementioned 5,6-dihydroxyindole, wherein the key intermediate is 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04), with the following structural formula:

[0056] .

[0057] The beneficial effects of this invention are:

[0058] (1) The method for preparing 5,6-dihydroxyindole described in this invention has mild reaction conditions, can stably achieve large-scale production, and the raw materials are readily available, the cost is controllable, and the process has good reproducibility.

[0059] (2) The method described in this invention is based on a synthesis strategy of removing the protecting group at the end, and by adding antioxidants and polymerization inhibitors, the target product 5,6-dihydroxyindole (DHI) has comprehensive advantages such as light color, good purity, easy storage and subsequent use. Attached Figure Description

[0060] Figure 1 This is a process route diagram of a method for synthesizing 5,6-dihydroxyindole according to a specific embodiment of the present invention.

[0061] Figure 2 The image shows the 1H-NMR spectrum of the key intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03).

[0062] Figure 3 The image shows the 1H-NMR spectrum of the key intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04).

[0063] Figure 4 This is the 1H-NMR nuclear magnetic spectrum of the target product 5,6-dihydroxyindole (DHI);

[0064] Figure 5 This is a sample appearance image of the final product, 5,6-dihydroxyindole (DHI).

[0065] Figure 6 This is a sample appearance image of the raw material 5,6-dihydroxyindoline hydrobromide (IC241-01). Detailed Implementation

[0066] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments.

[0067] The examples given below are for illustrative purposes only and are not intended to limit the scope of the invention in any way. Those skilled in the art can make conventional modifications and improvements to the following embodiments without departing from the spirit and scope of the invention.

[0068] like Figure 1 As shown, a method for synthesizing 5,6-dihydroxyindole is described. This method starts from readily available 5,6-dihydroxyindoleline hydrohalide (which may also include salts of other acids), and through the preparation of key intermediates 1-benzyloxycarbonyl-5,6-dibenzyloxyindoleline (IC241-03) and 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04), the synthesis of 5,6-dihydroxyindole (DHI) is finally achieved. The method includes the following four steps:

[0069] (1) Based on various methods reported in published papers and patents, the starting reactant 5,6-dihydroxyindoline hydrohalate (IC241-01) was prepared or purchased from the market, and reacted with benzyloxycarbonyl reagent under suitable solvent, suitable base and suitable temperature conditions to prepare intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02).

[0070] (2) The intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) obtained in step (1) is reacted with benzyl halide reagent under suitable solvent, suitable base and suitable temperature conditions to obtain intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03).

[0071] (3) The intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) obtained in step (2) is oxidized by reacting with a suitable oxidant in a suitable solvent and at a suitable temperature to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-04).

[0072] (4) The intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04) obtained in step (3) is dissolved in a suitable solvent, and appropriate amounts of antioxidants and polymerization inhibitors are added. A suitable metal catalyst is also added, and the protecting group is removed under suitable hydrogen pressure and temperature conditions to obtain the target product molecule 5,6-dihydroxyindole (DHI).

[0073]

[0074] In this embodiment, in step (1), preferably: the solvent used in the reaction is selected from ether, ester, haloalkanes, acetonitrile, DMSO, DMF, water or a combination thereof; the base used in the reaction is selected from organic bases such as triethylamine, DIEA, etc., and inorganic bases such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc.; the reaction temperature is from 0 to 50°C; the benzyloxycarbonyl reagent used in the reaction includes benzyl chloroformate or benzyl succinimide carbonate, etc.

[0075] In step (1), more preferably, ethyl acetate at a volume ratio of 5-10 is used as the solvent, benzyl chloroformate and 5,6-dihydroxyindoline hydrohalide (IC241-01) are added in equimolar amounts, and calcium carbonate is used as the base (1.2 molar equivalents). The reaction is carried out at room temperature, and the reaction progress is monitored by TLC. The reaction is usually completed in 5-24 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02).

[0076] According to the method of the present invention, in step (1), the reaction of converting formula (IC241-01) into formula (IC241-02) is carried out as follows: a solvent is added to the reaction vessel, followed by the addition of the main raw material compound (IC241-01), an appropriate amount of base is added, and under an ice-water bath, the mixture is stirred and a benzyloxycarbonyl reagent is added dropwise. The mixture is gradually raised to room temperature and reacted for 5-24 hours, and monitored by TLC until the reaction is complete.

[0077] In step (1), after the reaction is completed, the obtained compound formula (IC241-02) is treated as follows: filtered, the pH of the filtrate is adjusted to about 5 with dilute hydrochloric acid, extracted with ethyl acetate, and the organic solvent phases are combined and used directly in the next reaction.

[0078]

[0079] In this embodiment, in step (2), preferably, the solvent used in the reaction is selected from ether, ester, haloalkanes, acetonitrile, acetone, DMSO, DMF, water or a combination thereof;

[0080] In step (2), preferably, the base used in the reaction is selected from organic bases such as triethylamine, DIEA, etc., and inorganic bases such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc.

[0081] In step (2), preferably, the reaction temperature is from 0 to 100°C;

[0082] In step (2), preferably, the benzyl halide reagent used in the reaction includes benzyl chloride or benzyl bromide, etc.

[0083] In step (2), preferably, the molar ratio of the benzyl halide reagent used in the reaction to the reactant 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) is (2-3):1;

[0084] In step (2), more preferably, ethyl acetate with a volume ratio of 5-8 is used as the solvent, and benzyl chloride and 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) are added in a molar ratio of 2.2:1, with potassium carbonate as the base (2.5 molar equivalents). The reaction is carried out at 50°C, and the reaction progress is monitored by TLC. The reaction is usually completed in 8-24 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03).

[0085] According to the method of the present invention, in step (2), the reaction of converting formula (IC241-02) into formula (IC241-03) is carried out as follows: the compound solution of formula (IC241-02) obtained in step (1) is added to the reaction vessel, an appropriate amount of base is added, the mixture is stirred at room temperature, benzyl halide reagent is added dropwise, the temperature is gradually raised to 50°C and the reaction is carried out for 8-24 hours, and TLC is monitored until the reaction is completed.

[0086] In step (2), after the reaction is completed, the obtained compound formula (IC241-03) is treated as follows: After the reaction is completed, the pH value is adjusted to about 5-6 with dilute hydrochloric acid, the ethyl acetate is used for separation and extraction, the organic solvent phases are combined and concentrated to obtain a viscous liquid mainly containing the compound formula (IC241-03). Except for a small amount of column chromatography purification for NMR characterization, the rest does not need to be purified and proceeds directly to the next step.

[0087]

[0088] In this embodiment, in step (3), preferably, the solvent used in the reaction is selected from ether, ester, haloalkanes, acetonitrile, water or a combination thereof;

[0089] In step (3), preferably, the reaction temperature is from 0 to 50°C;

[0090] In step (3), preferably, the oxidant used in the reaction includes DDQ, manganese dioxide, etc.

[0091] In step (3), preferably, the molar ratio of the oxidant used in the reaction to the reactant 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) is (1-10):1;

[0092] In step (3), more preferably, dichloromethane with a volume ratio of 5-10 is used as a solvent, and manganese dioxide and 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) are added in a 5:1 molar ratio. The reaction is carried out at room temperature, and the reaction progress is monitored by TLC. The reaction is usually completed in 12-36 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-04).

[0093] According to the method of the present invention, in step (3), the reaction of converting formula (IC241-03) into formula (IC241-04) is carried out as follows: the crude product of formula (IC241-03) obtained in step (2) is dissolved in a suitable amount of solvent as a viscous liquid, the solution is transferred to a reaction vessel, a suitable amount of oxidant is added, the reaction is stirred at room temperature for 8-24 hours, and TLC is monitored until the reaction is complete.

[0094] In step (3), after the reaction is completed, the compound formula (IC241-04) is treated as follows: After the reaction is completed, the solution is filtered, an appropriate amount of water is added to the solution for liquid extraction, the organic solvent phases are combined, dried with a desiccant, concentrated, and purified by passing through a short silica gel column to obtain the compound formula (IC241-04), which is a white powder solid, ready to proceed to the next step of the reaction.

[0095]

[0096] In this embodiment, in step (4), preferably, the solvent used in the reaction is selected from alcohol, ether, ester, haloalkanes, acetonitrile, water or a combination thereof;

[0097] In step (4), preferably, the reaction temperature is from 0 to 50°C;

[0098] In step (4), preferably, the antioxidants and polymerization inhibitors used in the reaction include sodium ascorbate, vitamin C, tea polyphenols, phenol, 2,6-di-tert-butylphenol, or combinations thereof, at a mass ratio of 0.01-1%.

[0099] In step (4), preferably, the metal catalyst used in the reaction includes palladium on carbon, palladium hydroxide on carbon, etc.

[0100] In step (4), preferably, the hydrogen pressure used in the reaction is from 1 to 5 atmospheres;

[0101] In step (4), more preferably, ethanol with a volume ratio of 5-10 is used as a solvent, vitamin C with a mass ratio of 0.1% and 2,6-di-tert-butylphenol with a mass ratio of 0.05% are added as antioxidants and polymerization inhibitors, wet palladium-carbon catalyst with a mass ratio of 10% and a water content of 50% is added, the air in the reaction system is removed, hydrogen gas at 1 atmosphere is introduced, the reaction is carried out at room temperature, the reaction progress is monitored by TLC, and the reaction is usually completed in 12-36 hours to obtain the target product 5,6-dihydroxyindole (DHI).

[0102] According to the method of the present invention, in step (4), the reaction of converting formula (IC241-04) into the target product 5,6-dihydroxyindole (DHI) is carried out as follows: a solvent is added to the reaction vessel, followed by the addition of the compound of formula (IC241-04) obtained in step (3), an appropriate amount of antioxidant and polymerization inhibitor, an appropriate amount of metal catalyst, the system is evacuated, hydrogen is introduced, the reaction is carried out at room temperature for 12-36 hours, and TLC is monitored until the reaction is completed.

[0103] In step (4), after the reaction is completed, the target product 5,6-dihydroxyindole (DHI) is treated as follows: After the reaction is completed, the solution is filtered under a nitrogen atmosphere, concentrated to about one-third to one-quarter of its volume, and an appropriate amount of undesirable solvents such as methyl tert-butyl ether is added. The solution is then recrystallized to obtain the target product 5,6-dihydroxyindole (DHI), which is a light yellow to off-white powder solid.

[0104] Example 1: Preparation of the key intermediate compound 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03)

[0105]

[0106] 200 mL of ethyl acetate solution containing 28.5 g (FW: 285, 0.10 mol) of compound (IC241-02) was added to a reaction vessel, along with 34.6 g (2.5 molar equivalents, 0.25 mol, FW: 138.2). The mixture was stirred at room temperature, and 27.8 g (2.2 molar equivalents, 0.22 mol, FW: 126.5) of benzyl chloride was added dropwise. The temperature was gradually increased to 50 °C, and the reaction was monitored by TLC for 15 hours until completion. The pH was adjusted to approximately 6 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic solvent phases were combined and concentrated to give 50.2 g of a pale yellow viscous liquid crude product. Column chromatography purification (EA:PE, 1:50, 1:20, 1:10) yielded 45.1 g of 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03), with a molar yield of 97%.

[0107] like Figure 2As shown, the H1NMR data for 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) are analyzed as follows: 1H-NMR (600MHz, d6-DMSO): δ(ppm)=7.545-7.578(m,1H,Ar-H), 7.116-7.478(m,15H,Ar-H), 6.992(s,1H,Ar-H), 4.862-5.446(m,6H,Bn-CH2), 3.927-3.986(brs,2H,-CH2), 2.507(brs,2H,-CH2).

[0108] Example 2: Preparation of the key intermediate compound 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04)

[0109]

[0110] 37.2 g (FW: 465, 0.08 mol) of 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) was dissolved in 250 mL of dichloromethane, and 34.8 g (5.0 eq, FW: 87, 0.08 mol) of manganese dioxide was added. The reaction was carried out at room temperature, and the reaction progress was monitored by TLC. The reaction was completed after 24 hours. The solution was filtered, and 100 mL of water was added. The mixture was extracted twice by separation, and the organic solvent phases were combined, dried with a drying agent, concentrated, and purified by passing through a short silica gel column to give 35.2 g of 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-04) as a white powder solid, with a yield of 95%.

[0111] like Figure 3 As shown, the H1NMR data for 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04) are analyzed as follows: 1H-NMR (600MHz, CDCl3): δ(ppm)=7.888(brs,1H,Ar'-H), 7.285-7.521(m,16H,Ar-H), 7.107(s,1H,Ar-H), 6.469-6.475(m,1H,Ar'-H), 5.444(s,2H,Ar-H), 5.166-5.198(m,4H,Ar-H).

[0112] Example 3: Preparation of the target product 5,6-dihydroxyindole (DHI)

[0113]

[0114] 32.4 g (FW: 463, 0.07 mol) of 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04) was dissolved in 200 mL of ethanol. Vitamin C (32 mg) at 0.1% by mass and 2,6-di-tert-butylphenol (16 mg) at 0.05% by mass were added as antioxidants and polymerization inhibitors, respectively. A wet palladium-carbon catalyst (3.24 g) containing 50% water at 10% by mass was added. Air was removed from the reaction system, and hydrogen gas at 1 atmosphere was introduced. The reaction was carried out at room temperature, and the reaction progress was monitored by TLC. The reaction was completed in 24 hours. The solution was filtered under a nitrogen atmosphere and concentrated to approximately 60 mL. 100 mL of methyl tert-butyl ether was added, and the system was gently heated until dissolved. The solution was then cooled to 0 °C, and a white solid powder gradually crystallized out. The product was filtered under a nitrogen atmosphere to obtain 9.6 g of off-white powder, which was characterized by nuclear magnetic resonance (NMR) as the target product 5,6-dihydroxyindole (DHI), with a yield of 91%.

[0115] like Figure 4 As shown, the ¹H NMR data for 5,6-dihydroxyindole (DHI) are analyzed as follows: ¹H-NMR (400 MHz, d6-DMSO): δ (ppm) = 10.429 (s, ¹H, NH), 8.370 (brs, 2H, -OH), 6.995-7.006 (m, ¹H, Ar'-H), 6.827 (s, ¹H, Ar-H), 6.757 (s, ¹H, Ar-H), 6.130-6.133 (m, 3H, Ar'-H); HPLC: purity 98.2% as measured at 214 nm.

[0116] like Figure 5 As shown, Figure 5 This is a sample appearance image of the final product, namely the target product 5,6-dihydroxyindole (DHI).

[0117] like Figure 6 As shown, Figure 6 This is a sample appearance image of the raw material 5,6-dihydroxyindoline hydrobromide (IC241-01).

[0118] The specific embodiments of the present invention have been described above. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection claimed by the appended claims and their equivalents is defined.

Claims

1. A method for synthesizing 5,6-dihydroxyindole, characterized in that, The method starts with readily available 5,6-dihydroxyindoline hydrohalide, and through the preparation of key intermediates 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline and 1-benzyloxycarbonyl-5,6-dibenzyloxyindole, ultimately achieves the synthesis of 5,6-dihydroxyindole, comprising the following four steps: (1) The starting reactant 5,6-dihydroxyindoline hydrohalate was reacted with a benzyloxycarbonyl reagent under suitable solvent, suitable base and suitable temperature conditions to prepare the intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline; (2) The intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline obtained in step (1) is reacted with a benzyl halide reagent under suitable solvent, suitable base and suitable temperature conditions to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline; the structural formula of the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline is as follows: ； (3) The intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline obtained in step (2) is reacted with an oxidant, namely DDQ or manganese dioxide, in a suitable solvent and at a suitable temperature to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline; the structural formula of the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline is as follows: ； (4) The intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole obtained in step (3) is dissolved in the solvent ethanol. 5-10 times the volume ratio of ethanol is used as the solvent. 0.1% by mass of vitamin C and 0.05% by mass of 2,6-di-tert-butylphenol are added as antioxidants and polymerization inhibitors. 10% by mass of wet palladium carbon catalyst containing 50% water is added. The air in the reaction system is removed, and hydrogen gas at 1 atmosphere is introduced. The reaction is carried out at room temperature. The reaction progress is monitored by TLC. The reaction is completed in 12-36 hours, and the protecting group is removed. After the reaction is complete, the target product 5,6-dihydroxyindole is treated as follows: After the reaction is complete, the solution is filtered under a nitrogen atmosphere, concentrated to one-third to one-quarter of its volume, and an appropriate amount of methyl tert-butyl ether (a poor solvent) is added. The solution is then recrystallized to obtain the target product 5,6-dihydroxyindole, which is a pale yellow to off-white powder solid.

2. The method for synthesizing 5,6-dihydroxyindole according to claim 1, characterized in that, In step (1), the solvent used in the reaction is selected from ether, ester, haloalkanes, acetonitrile, DMSO, DMF, water or a combination thereof; the base used in the reaction is selected from organic bases and inorganic bases; the reaction temperature is from 0 to 50°C; and the benzyloxycarbonyl reagent used in the reaction is selected from benzyl chloroformate or benzyl succinimide carbonate.

3. The method for synthesizing 5,6-dihydroxyindole according to claim 1, characterized in that, In step (1), ethyl acetate with a volume ratio of 5-10 is used as solvent, benzyl chloroformate and 5,6-dihydroxyindoline hydrohalide are added in equimolar amounts, and 1.2 molar equivalents of calcium carbonate are used as base. The reaction is carried out at room temperature, and the reaction progress is monitored by TLC. The reaction is completed in 5-24 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline.

4. The method for synthesizing 5,6-dihydroxyindole according to claim 1, characterized in that, In step (1), the reaction of converting 5,6-dihydroxyindoline hydrohalate to 1-benzyloxycarbonyl-5,6-dihydroxyindoline is carried out as follows: a solvent is added to the reaction vessel, followed by the main raw material 5,6-dihydroxyindoline hydrohalate and an appropriate amount of alkali. The mixture is stirred and benzyloxycarbonyl reagent is added dropwise under an ice-water bath. The mixture is gradually raised to room temperature and reacted for 5-24 hours. The reaction is monitored by TLC until it is complete.

5. A method for synthesizing 5,6-dihydroxyindole according to any one of claims 2-4, characterized in that, In step (1), after the reaction is completed, the compound 1-benzyloxycarbonyl-5,6-dihydroxyindoline is treated as follows: filtered, the pH of the filtrate is adjusted to about 5 with dilute hydrochloric acid, extracted with ethyl acetate, and the organic solvent phases are combined and used directly in the next reaction.

6. The method for synthesizing 5,6-dihydroxyindole according to claim 1, characterized in that, In step (2), the solvent used in the reaction is selected from ether, ester, haloalkanes, acetonitrile, acetone, DMSO, DMF, water or a combination thereof; The base used in the reaction is selected from organic bases and inorganic bases; The reaction temperature ranges from 0 to 100°C; The benzyl halide reagent used in the reaction is selected from benzyl chloride or benzyl bromide.

7. The method for synthesizing 5,6-dihydroxyindole according to claim 1, characterized in that, In step (2), the molar ratio of the benzyl halide reagent used in the reaction to the reactant 1-benzyloxycarbonyl-5,6-dihydroxyindoline is (2-3):

1.

8. The method for synthesizing 5,6-dihydroxyindole according to claim 6, characterized in that, In step (2), ethyl acetate with a volume ratio of 5-8 is used as the solvent, and benzyl chloride and 1-benzyloxycarbonyl-5,6-dihydroxyindoline are added in a molar ratio of 2.2:

1. 2.5 molar equivalents of potassium carbonate are used as the base. The reaction is carried out at 50°C, and the reaction progress is monitored by TLC. The reaction is completed in 8-24 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline.

9. The method for synthesizing 5,6-dihydroxyindole according to claim 6, characterized in that, In step (2), after the reaction is completed, the compound 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline is treated as follows: After the reaction is completed, the pH value is adjusted to 5-6 with dilute hydrochloric acid, the mixture is extracted with ethyl acetate, the organic solvent phases are combined and concentrated to obtain a viscous liquid mainly composed of compound 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline. Except for a small amount of column chromatography purification for NMR characterization, the rest does not need to be purified and proceeds directly to the next step.

10. The method for synthesizing 5,6-dihydroxyindole according to claim 1, characterized in that, In step (3), the solvent used in the reaction is selected from ether, ester, haloalkanes, acetonitrile, water or a combination thereof; The reaction temperature ranges from 0 to 50°C; The molar ratio of the oxidant used in the reaction to the reactant 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline is (1-10):

1.

11. The method for synthesizing 5,6-dihydroxyindole according to claim 1, characterized in that, In step (3), dichloromethane with a volume ratio of 5-10 is used as a solvent, and manganese dioxide and 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline are added in a molar ratio of 5:

1. The reaction is carried out at room temperature, and the reaction progress is monitored by TLC. The reaction is completed in 12-36 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline.

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