Synthesis method for 5,6-dihydroxyindole and intermediate thereof

Abstract

Provided in the present invention are a synthesis method for 5,6-dihydroxyindole and an intermediate thereof. The method comprises: by using a hydrohalide salt or other acid salts (IC241-01) of 5,6-dihydroxyindoline as raw materials, sequentially protecting the heteroatom nitrogen and phenolic hydroxyl, so as to obtain an intermediate compound 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03); then performing an oxidation reaction to obtain an intermediate compound 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04); and in the presence of trace amounts of an antioxidant and a polymerization inhibitor, performing catalytic hydrogenation to remove the protecting group, so as to obtain 5,6-dihydroxyindole (DHI). The method in the present invention involves reactions with mild conditions, can stably realize mass production, uses feasible raw materials, and achieves controllable cost and good process reproducibility. In addition, on the basis of the synthesis strategy of removing the protecting group in the final step, and because of the functions of the trace amounts of the antioxidant and the polymerization inhibitor, the target product 5,6-dihydroxyindole (DHI) has the comprehensive advantages of light color, high purity, convenient storage and subsequent use, etc.

Description

A synthetic method of 5,6-dihydroxyindole and its intermediates Technical Field

[0001] The present invention belongs to the technical field of organic synthesis processes and relates to a synthesis process route and purification preparation method for a high-purity functional chemical 5,6-dihydroxyindole (DHI) used in healthy hair dyes, and specifically relates to a synthesis method for 5,6-dihydroxyindole and an intermediate thereof. Background Art

[0002] Melanin is a natural pigment formed in living organisms and possesses antioxidant, free radical scavenging, and UV absorption properties. 5,6-Dihydroxyindole (DHI) is a key intermediate in melanin, originally discovered in nature. Studies have shown that it has no toxic side effects on humans. Pure 5,6-dihydroxyindole (DHI) is relatively stable in its crystalline state, but rapidly oxidizes into a melanin-like substance in slightly alkaline solutions. Aniline compounds are commonly used as effective blackening ingredients in traditional hair dyes, which have potential carcinogenic, teratogenic, and allergenic properties. Because 5,6-dihydroxyindole (DHI) is less irritating to human skin, it is used in some daily hair dyes to replace aniline compounds, a core ingredient in traditional hair dyes. It is an ideal active ingredient in a new generation of safe and healthy hair dyes. It is also a good antioxidant and serves as an important intermediate in the synthesis of some amino acids, alkaloids, and tryptamines.

[0003] Because 5,6-dihydroxyindole (DHI) has important uses in many fields, internationally renowned daily chemical companies such as L'Oréal in France began researching the production process and applications of 5,6-dihydroxyindole (DHI) in the 1980s and applied for a number of patents. In recent years, there has been an increasing number of studies on 5,6-dihydroxyindole (DHI) both internationally and domestically. Because 5,6-dihydroxyindole (DHI) is easily oxidized or polymerized, the process of synthesizing this product in batches with a purity of more than 95% is very difficult. Most of the synthetic methods reported so far are still in the laboratory research stage and are difficult to apply to large-scale industrial production. According to existing domestic and foreign literature reports, its synthetic methods mainly fall into the following three categories:

[0004] Category 1: Classical indole heterocycle construction method

[0005] Based on reports in U.S. Patents 4,595,765 (1986) (synthesis of indole from nitroolefins), 5,410,067 (1995) (synthesis of indole from o-nitrophenylacetonitrile), and 6,160,127 (2000) (synthesis of indole from nitroolefins), as shown in the two representative routes above, starting with raw materials such as 3,4-dialkoxy-substituted benzaldehyde and benzyl cyanide, a multi-step reaction, particularly a nitration reaction, is followed by a subsequent ring-closure reaction to close the ortho-functional groups to form the indole core structure, directly or indirectly obtaining the target molecule 5,6-dihydroxyindole (DHI). Common problems with these methods include the use of dangerous nitration reactions in the intermediate reactions, lengthy steps, and low overall yields. A particularly prominent problem is that the final step in synthesizing the target molecule 5,6-dihydroxyindole (DHI) is prone to product deterioration, making it difficult to obtain qualified product for subsequent application development.

[0006] Category II: DOPA or dopamine redox method

[0007] 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 Redox, 2007, England), U.S. Patent US2020 / 270208, A1 (DOPA Oxidation, 2020), and Chinese Patent CN 110981782 A (Dopamine Oxidation and Reduction, 2020), as shown in the above roadmap, the target molecule 5,6-dihydroxyindole (DHI) is obtained by oxidation reaction of dopa or dopamine and then reduction reaction. A common problem is that the actual yield of the target molecule 5,6-dihydroxyindole (DHI) is low, the product is dark in color and easily deteriorates, making it difficult to obtain qualified products for subsequent industrialization.

[0008] The third type: direct hydrogenation and dehydration of indoline

[0009] Based on published papers (Molecules, vol. 23; nb. 8; (2018); Art. No: 1943), as well as U.S. Patents US 5,536,843 (dehydrogenation with sodium fumarate or ammonium persulfate, 1996) and US 5,578,735 (dehydrogenation with cyclohexene, 1996), as shown in the above-mentioned roadmap, starting from 5,6-diprotected hydroxyl or naked dihydroxyindoline, directly through hydrogen transfer reagents such as sodium fumarate, ammonium persulfate, or cyclohexene, a dehydrogenation reaction is achieved to directly convert the corresponding indoline into the target molecule 5,6-dihydroxyindole (DHI). Although these process synthetic pathways are relatively short, the obvious problems are that they require high temperature reaction conditions, the dehydrogenation reaction is difficult to control, side reactions are obvious, the actual yield of the target molecule 5,6-dihydroxyindole (DHI) is low, the product is dark in color and easily deteriorates, and it is still difficult to obtain qualified products that meet industrial applications.

[0010] Therefore, scientific and technological personnel in this field are still carrying out various exploratory research and development work, hoping to have new process methods to produce high-purity and stable-quality 5,6-dihydroxyindole (DHI) products that meet the needs of multiple fields, especially to have process routes and preparation methods with mild reaction conditions, suitable for large-scale production, controllable costs, and convenient storage and use of products. Summary of the Invention

[0011] In view of the shortcomings and deficiencies of the existing synthetic routes and process technologies for 5,6-dihydroxyindole (DHI), the first object of the present invention is to provide a method for synthesizing 5,6-dihydroxyindole (DHI). The method has mild reaction conditions, can stably achieve large-scale production, has readily available raw materials, is cost-controllable, and has good process reproducibility.

[0012] The second object of the present invention is to provide a method for preventing the deterioration of 5,6-dihydroxyindole (DHI) products: by adding antioxidants and inhibitors, the 5,6-dihydroxyindole (DHI) products are made light in color, high in purity, and easy to store and use.

[0013] The third object of the present invention is to provide an intermediate compound of formula (IC241-03) for synthesizing 5,6-dihydroxyindole (DHI) and a preparation method thereof.

[0014] The fourth object of the present invention is to provide an intermediate compound of formula (IC241-04) for synthesizing 5,6-dihydroxyindole (DHI) and a preparation method thereof.

[0015] In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is as follows:

[0016] A method for synthesizing 5,6-dihydroxyindole is disclosed. The method starts with readily available 5,6-dihydroxyindoleline hydrohalide or other acid salts, prepares key intermediates 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) and 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04), and ultimately achieves the synthesis of 5,6-dihydroxyindole (DHI). The method comprises the following four steps:

[0017] (1) The starting reactant 5,6-dihydroxyindoline hydrohalide or other acid salt (IC241-01) is reacted with a benzyloxycarbonyl reagent in a suitable solvent, a suitable base, and a suitable temperature to prepare the intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02);

[0018] (2) The intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) obtained in step (1) is reacted with a benzyl halide reagent in a suitable solvent, a suitable base and a suitable temperature to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03);

[0019] (3) The intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) obtained in step (2) is oxidized with a suitable oxidant in a suitable solvent and at a suitable temperature to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04);

[0020] (4) The intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04) obtained in step (3) is dissolved in a suitable solvent, and an appropriate amount of additives such as an antioxidant and an inhibitor is added, and an appropriate metal catalyst is added. Under appropriate hydrogen pressure and temperature conditions, the protecting group is removed to obtain the target product molecule 5,6-dihydroxyindole (DHI).

[0021] Furthermore, in step (1), the solvent used in the reaction is selected from ether, ester, halogenated hydrocarbon, acetonitrile, DMSO, DMF, water or a combination thereof; the base used in the reaction is selected from an organic base such as triethylamine, DIEA, etc., and an inorganic base 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.

[0022] Furthermore, in step (1), more preferably, ethyl acetate is used as the solvent in a volume ratio of 5-10 times, 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), and the reaction is carried out at room temperature. 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).

[0023] Furthermore, in step (1), the reaction of converting the compound of formula (IC241-01) to the compound of formula (IC241-02) is carried out as follows: a solvent is added to a reaction vessel, followed by the addition of the main raw material compound of formula (IC241-01) and an appropriate amount of base. The mixture is stirred under an ice-water bath, and a benzyloxycarbonyl reagent is added dropwise. The reaction is gradually heated to room temperature and the reaction is carried out for 5-24 hours, monitored by TLC until the reaction is complete.

[0024] Furthermore, in step (1), after the reaction is completed, the compound (IC241-02) is treated as follows: filtering, adjusting the pH of the filtrate to about 5 with dilute hydrochloric acid, extracting with ethyl acetate, combining the organic solvent phases, and directly using them in the next reaction.

[0025] Further, in step (2), preferably, the solvent used in the reaction is selected from ether, ester, halogenated hydrocarbon, acetonitrile, acetone, DMSO, DMF, water or a combination thereof;

[0026] The base used in the reaction is selected from an organic base such as triethylamine, DIEA, etc., an inorganic base such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc.;

[0027] The reaction temperature is from 0 to 100°C;

[0028] The benzyl halide reagent used in the reaction includes benzyl chloride or benzyl bromide;

[0029] The molar ratio of the benzyl halide reagent to the reactant 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) used in the reaction is (2-3):1;

[0030] Furthermore, in step (2), ethyl acetate in a volume ratio of 5 to 8 times is used as the solvent, benzyl chloride and 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) are used in a molar ratio of 2.2:1, potassium carbonate is used as the base (2.5 molar equivalents), and the reaction is carried out at 50° C. The reaction progress is monitored by TLC. The reaction is usually completed in 8 to 24 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03).

[0031] Furthermore, in step (2), the reaction of converting the compound of formula (IC241-02) to formula (IC241-03) is carried out as follows: the solution of the compound of formula (IC241-02) obtained in step (1) is added to a reaction vessel, and an appropriate amount of base is added. At room temperature, the mixture is stirred and a 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 the reaction is monitored by TLC until the reaction is completed.

[0032] Furthermore, in step (2), after the reaction is completed, the compound (IC241-03) is treated as follows: after the reaction is completed, the pH is adjusted to about 5-6 with dilute hydrochloric acid, the mixture is separated and extracted with ethyl acetate, the organic solvent phases are combined, and the mixture is concentrated to obtain a viscous liquid mainly containing the compound (IC241-03). Except for a small amount of column chromatography purification for nuclear magnetic resonance characterization, the rest is not purified and directly proceeds to the next step.

[0033] Furthermore, in step (3), the solvent used in the reaction is selected from ether, ester, halogenated hydrocarbon, acetonitrile, water or a combination thereof;

[0034] The reaction temperature is from 0 to 50°C;

[0035] The oxidizing agent used in the reaction includes DDQ, manganese dioxide, etc.;

[0036] The molar ratio of the oxidant used in the reaction to the reactant 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) is (1-10):1;

[0037] Furthermore, in step (3), 5-10 times the volume ratio of dichloromethane is used as the solvent, and manganese dioxide and 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-03) are added in a 5:1 molar ratio. The reaction is carried out at room temperature and the progress of the reaction is monitored by TLC. The reaction is usually completed in 12-36 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04).

[0038] Furthermore, in step (3), the reaction of converting the compound of formula (IC241-03) to formula (IC241-04) is carried out as follows: the crude viscous liquid of the compound of formula (IC241-03) obtained in step (2) is dissolved in an appropriate amount of solvent, transferred to a reaction vessel, an appropriate amount of oxidant is added, and the reaction is stirred at room temperature for 8-24 hours and monitored by TLC until the reaction is completed.

[0039] Furthermore, in step (3), after the reaction is completed, the compound (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 through a short silica gel column to obtain the compound (IC241-04) as a white powder solid, ready for the next step of the reaction.

[0040] Furthermore, in step (4), the solvent used in the reaction is selected from alcohol, ether, ester, halogenated hydrocarbon, acetonitrile, water or a combination thereof;

[0041] The reaction temperature is from 0 to 50°C;

[0042] The antioxidant and polymerization inhibitor used in the reaction include 0.01-1% by mass of sodium ascorbate, vitamin C, tea polyphenols, phenol, 2,6-di-tert-butylphenol, etc. or a combination thereof;

[0043] The metal catalyst used in the reaction includes palladium carbon, palladium hydroxide carbon, etc.

[0044] The hydrogen pressure used in the reaction is from 1 to 5 atmospheres;

[0045] The method comprises the following steps: selecting 5-10 times by volume of ethanol as a solvent, adding 0.1% by weight of vitamin C and 0.05% by weight of 2,6-di-tert-butylphenol as an antioxidant and a polymerization inhibitor, adding 10% by weight of a wet palladium-carbon catalyst containing 50% water, removing air from the reaction system, introducing 1 atmosphere of hydrogen, reacting at room temperature, and monitoring the reaction progress by TLC. The reaction is usually complete in 12-36 hours to obtain the target product 5,6-dihydroxyindole (DHI).

[0046] Furthermore, in step (4), the reaction of converting the compound of formula (IC241-04) into the target product 5,6-dihydroxyindole (DHI) is carried out as follows: a solvent is added to a reaction vessel, followed by the addition of the compound of formula (IC241-04) obtained in step (3), an appropriate amount of an antioxidant and an inhibitor, an appropriate amount of a metal catalyst, the system is evacuated, hydrogen is introduced, and the reaction is carried out at room temperature for 12-36 hours, and the reaction is monitored by TLC until the reaction is completed.

[0047] Furthermore, in step (4), after the reaction is completed, the target product 5,6-dihydroxyindole (DHI) is treated by the following operation: after the reaction is completed, the solution is filtered under a nitrogen atmosphere, and the volume is concentrated to about one-third to one-quarter. An appropriate amount of a poor solvent such as methyl tert-butyl ether is added, and the target product 5,6-dihydroxyindole (DHI) is recrystallized to obtain a beige to off-white powder solid.

[0048] The present invention also provides a key intermediate 1 in the method for synthesizing the 5,6-dihydroxyindole. The key intermediate is 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03), and the structural formula is as follows:

[0049] The present invention also provides a key intermediate 2 in the method for synthesizing the 5,6-dihydroxyindole. The key intermediate is 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04), and the structural formula is as follows:

[0050] The beneficial effects of the present invention are:

[0051] (1) The method for preparing 5,6-dihydroxyindole according to the present invention has mild reaction conditions, can stably achieve large-scale production, has readily available raw materials, is cost-controllable, and has good process reproducibility.

[0052] (2) The method described in the present invention is based on a synthetic strategy of removing the protecting group at the end, and by adding an antioxidant and an inhibitor, the target product 5,6-dihydroxyindole (DHI) has the comprehensive advantages of light color, good purity, easy storage and subsequent use. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] FIG1 is a process route diagram of a method for synthesizing 5,6-dihydroxyindole according to a specific embodiment of the present invention;

[0054] Figure 2 is the H1-NMR spectrum of the key intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03);

[0055] Figure 3 is the H1-NMR spectrum of the key intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04);

[0056] FIG4 is an H1-NMR spectrum of the target product 5,6-dihydroxyindole (DHI);

[0057] FIG5 is a sample appearance diagram of the final product 5,6-dihydroxyindole (DHI);

[0058] FIG6 is a sample appearance picture of the raw material 5,6-dihydroxyindoline hydrobromide (IC241-01). DETAILED DESCRIPTION

[0059] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0060] The following examples are merely for the purpose of illustrating the present invention and are not intended to limit the present invention in any way. Those skilled in the art may make routine changes and modifications to the following examples without exceeding the spirit and scope of the present invention.

[0061] As shown in Figure 1, a method for synthesizing 5,6-dihydroxyindole is described. This method starts with readily available 5,6-dihydroxyindole hydrohalide (which may also include salts of other acids) and prepares the key intermediates 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) and 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04), ultimately achieving the synthesis of 5,6-dihydroxyindole (DHI). The method comprises the following four steps:

[0062] (1) The starting reactant 5,6-dihydroxyindoline hydrohalide (IC241-01) is prepared based on various methods reported in published papers and patents or purchased from the market, and reacted with a benzyloxycarbonyl reagent under suitable solvent, suitable base, and suitable temperature conditions to prepare the intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02);

[0063] (2) The intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) obtained in step (1) is reacted with a benzyl halide reagent in a suitable solvent, a suitable base and a suitable temperature to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03);

[0064] (3) The intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) obtained in step (2) is oxidized with a suitable oxidant in a suitable solvent and at a suitable temperature to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04);

[0065] (4) The intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04) obtained in step (3) is dissolved in a suitable solvent, and an appropriate amount of additives such as an antioxidant and an inhibitor is added, and an appropriate metal catalyst is added. Under appropriate hydrogen pressure and temperature conditions, the protecting group is removed to obtain the target product molecule 5,6-dihydroxyindole (DHI).

[0066] In this embodiment, in step (1), preferably: the solvent used in the reaction is selected from ether, ester, halogenated hydrocarbon, acetonitrile, DMSO, DMF, water or a combination thereof; the base used in the reaction is selected from an organic base such as triethylamine, DIEA, etc., and an inorganic base 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.

[0067] In step (1), more preferably, ethyl acetate is used as the solvent in a volume ratio of 5 to 10 times, 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), and the reaction is carried out at room temperature. The reaction progress is monitored by TLC. The reaction is usually completed in 5 to 24 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02).

[0068] According to the method of the present invention, in step (1), the reaction of converting the compound of formula (IC241-01) to the compound of formula (IC241-02) is carried out as follows: a solvent is added to a reaction vessel, followed by the addition of the main raw material compound of formula (IC241-01) and an appropriate amount of base. The mixture is stirred under an ice-water bath, and a benzyloxycarbonyl reagent is added dropwise. The mixture is gradually heated to room temperature for reaction for 5-24 hours, and the reaction is monitored by TLC until completion.

[0069] In step (1), after the reaction is completed, the compound (IC241-02) is treated as follows: filtering, adjusting the pH of the filtrate to about 5 with dilute hydrochloric acid, extracting with ethyl acetate, combining the organic solvent phases, and directly using them in the next reaction.

[0070] In this embodiment, in step (2), preferably, the solvent used in the reaction is selected from ether, ester, halogenated hydrocarbon, acetonitrile, acetone, DMSO, DMF, water or a combination thereof;

[0071] In step (2), preferably, the base used in the reaction is selected from an organic base such as triethylamine, DIEA, etc., an inorganic base such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc.;

[0072] In step (2), preferably, the reaction temperature is from 0 to 100°C;

[0073] In step (2), preferably, the benzyl halide reagent used in the reaction includes benzyl chloride or benzyl bromide;

[0074] 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;

[0075] In step (2), more preferably, ethyl acetate is used as the solvent in a volume ratio of 5 to 8 times, 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), and the reaction is carried out at 50° C. The reaction progress is monitored by TLC. The reaction is usually completed in 8 to 24 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03).

[0076] According to the method of the present invention, in step (2), the reaction of converting the compound of formula (IC241-02) to formula (IC241-03) is carried out as follows: the solution of the compound of formula (IC241-02) obtained in step (1) is added to a reaction vessel, and an appropriate amount of base is added. At room temperature, the mixture is stirred and a 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 the reaction is monitored by TLC until the reaction is completed.

[0077] In step (2), after the reaction is completed, the compound (IC241-03) is treated as follows: after the reaction is completed, the pH is adjusted to about 5-6 with dilute hydrochloric acid, the phases are separated and extracted with ethyl acetate, the organic solvent phases are combined and concentrated to obtain a viscous liquid mainly containing the compound (IC241-03). Except for a small amount of column chromatography purification for nuclear magnetic resonance characterization, the rest is not purified and directly proceeds to the next step.

[0078] In this embodiment, in step (3), preferably, the solvent used in the reaction is selected from ether, ester, halogenated hydrocarbon, acetonitrile, water or a combination thereof;

[0079] In step (3), preferably, the reaction temperature is from 0 to 50°C;

[0080] In step (3), preferably, the oxidant used in the reaction includes DDQ, manganese dioxide, etc.;

[0081] 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;

[0082] In step (3), more preferably, 5-10 times the volume ratio of dichloromethane is used as the solvent, manganese dioxide and 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-03) are used as the raw materials 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 usually completed in 12-36 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04).

[0083] According to the method of the present invention, in step (3), the reaction of converting the compound of formula (IC241-03) to the compound of formula (IC241-04) is carried out as follows: the crude viscous liquid of the compound of formula (IC241-03) obtained in step (2) is dissolved in an appropriate amount of solvent, the solution is transferred to a reaction vessel, an appropriate amount of oxidant is added, and the reaction is stirred at room temperature for 8-24 hours, and monitored by TLC until the reaction is completed.

[0084] In step (3), after the reaction is completed, the compound (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 on a short silica gel column to obtain the compound (IC241-04) as a white powder solid, ready for the next step of the reaction.

[0085] In this embodiment, in step (4), preferably, the solvent used in the reaction is selected from alcohol, ether, ester, halogenated hydrocarbon, acetonitrile, water or a combination thereof;

[0086] In step (4), preferably, the reaction temperature is from 0 to 50°C;

[0087] In step (4), preferably, the antioxidant and polymerization inhibitor used in the reaction include 0.01-1% by mass of sodium ascorbate, vitamin C, tea polyphenols, phenol, 2,6-di-tert-butylphenol, etc. or a combination thereof;

[0088] In step (4), preferably, the metal catalyst used in the reaction includes palladium carbon, palladium hydroxide carbon, etc.;

[0089] In step (4), preferably, the hydrogen pressure used in the reaction is from 1 to 5 atmospheres;

[0090] In step (4), more preferably, 5-10 times the volume ratio of ethanol is selected 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 a wet palladium-carbon catalyst containing 50% water is added, the air in the reaction system is evacuated, 1 atmosphere of hydrogen is introduced, 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 target product 5,6-dihydroxyindole (DHI).

[0091] According to the method of the present invention, in step (4), the reaction of converting the compound of formula (IC241-04) into the target product 5,6-dihydroxyindole (DHI) is carried out as follows: a solvent is added to a reaction vessel, followed by the addition of the compound of formula (IC241-04) obtained in step (3), an appropriate amount of an antioxidant and an inhibitor, an appropriate amount of a metal catalyst, the system is evacuated, hydrogen is introduced, the reaction is carried out at room temperature for 12-36 hours, and TLC monitoring is performed until the reaction is completed.

[0092] 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, and the solution is concentrated to about one-third to one-quarter of the volume. An appropriate amount of a poor solvent such as methyl tert-butyl ether is added, and the target product 5,6-dihydroxyindole (DHI) is recrystallized to obtain a beige to off-white powder solid.

[0093] Example 1: Preparation of the key intermediate compound 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03)

[0094] A solution of 28.5 g (FW: 285, 0.10 mol) of compound (IC241-02) in 200 ml of ethyl acetate was added to a reaction vessel. Add 34.6 g (2.5 mol equivalents, 0.25 mol, FW: 138.2) of potassium carbonate. Stirring was continued at room temperature, and 27.8 g (2.2 mol equivalents, 0.22 mol, FW: 126.5) of benzyl chloride was added dropwise. The temperature was gradually raised to 50°C. After 15 hours, the reaction was complete, as monitored by TLC. The pH was adjusted to approximately 6 with dilute hydrochloric acid. Extraction was performed with ethyl acetate, and the organic solvent phases were combined and concentrated to yield 50.2 g of a crude, pale yellow, viscous liquid. Purification by column chromatography (EA:PE, 1:50, 1:20, 1:10) afforded 45.1 g of 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) in a molar yield of 97%.

[0095] As shown in Figure 2, the H1NMR data of 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) are analyzed as follows: 1H-NMR (600 MHz, 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).

[0096] Example 2: Preparation of the key intermediate compound 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04)

[0097] 37.2 g (FW: 465, 0.08 mol) of 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) was dissolved in 250 ml of dichloromethane. 34.8 g (5.0 eq, FW: 87, 0.08 mol) of manganese dioxide was added and allowed to react at room temperature. TLC monitored the reaction progress and it was complete after 24 hours. The mixture was filtered, and 100 ml of water was added. Extraction was performed twice. The organic solvent phases were combined, dried over a desiccant, concentrated, and purified on a short silica gel column to obtain 35.2 g of 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04) as a white powdery solid in a 95% yield.

[0098] As shown in Figure 3, the H1NMR data of 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04) are analyzed as follows: 1H-NMR (600 MHz, CDCl 3): 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).

[0099] Example 3: Preparation of target product 5,6-dihydroxyindole (DHI)

[0100] 32.4 g (FW: 463, 0.07 mol) of 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04) was dissolved in 200 ml of ethanol. 0.1% (by weight) ascorbic acid (32 mg) and 0.05% (by weight) 2,6-di-tert-butylphenol (16 mg) were added as antioxidants and polymerization inhibitors. 10% (by weight) of a 50% aqueous palladium-on-carbon catalyst (3.24 g) was added. The air in the reaction system was evacuated and hydrogen was introduced at 1 atm. The reaction was allowed to proceed at room temperature. TLC monitored the reaction progress and the reaction was complete within 24 hours. The reaction was filtered under a nitrogen atmosphere, and the solution was concentrated to approximately 60 ml. 100 ml of methyl tert-butyl ether was added. The solution was allowed to clear by gentle heating, then cooled to 0°C. The solution gradually crystallized to yield an off-white solid powder. Filtration under nitrogen atmosphere gave 9.6 g of off-white powder, which was characterized by H1NMR to be the target product 5,6-dihydroxyindole (DHI) with a yield of 91%.

[0101] As shown in Figure 4 , the H₁NMR data for 5,6-dihydroxyindole (DHI) are as follows: H₁NMR (400 MHz, d₁-DMSO): δ (ppm) = 10.429 (s, 1H, NH₂), 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 analysis at 214 nm revealed a purity of 98.2%.

[0102] As shown in FIG5 , FIG5 is a sample appearance diagram of the final product, i.e., the target product 5,6-dihydroxyindole (DHI).

[0103] As shown in FIG6 , FIG6 is a sample appearance diagram of the raw material 5,6-dihydroxyindoline hydrobromide (IC241-01).

[0104] While the above describes specific embodiments of the present invention, those skilled in the art should understand that the present invention is not limited to the foregoing embodiments. The foregoing embodiments and description merely illustrate the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. Such changes and modifications are intended to fall within the scope of the present invention. The scope of protection claimed in the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing 5,6-dihydroxyindole, characterized in that, The method starts from readily available 5,6-dihydroxyindoline hydrohalide or other acid salts, and finally realizes the synthesis of 5,6-dihydroxyindole (DHI) by preparing key intermediates 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) and 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04), including the following four steps: (1) The starting reactant 5,6-dihydroxyindoline hydrohalide or other acid salts (IC241-01) reacts with a benzyloxycarbonyl reagent under appropriate solvent, appropriate base, and appropriate temperature conditions to prepare the intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02); (2) The intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) obtained in step (1) reacts with a benzyl halide reagent under appropriate solvent, appropriate base, and appropriate temperature conditions to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03); (3) The intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) obtained in step (2) reacts with an appropriate oxidant in an appropriate solvent under appropriate temperature conditions and is oxidized to obtain the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04); (4) The intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindole (IC241-04) obtained in step (3) is dissolved in an appropriate solvent, an appropriate amount of antioxidant and inhibitor additives are added, and an appropriate metal catalyst is added. Under appropriate hydrogen pressure and temperature conditions, the protecting group is removed to obtain the target product molecule 5,6-dihydroxyindole (DHI).

2. The synthetic method of 5,6-dihydroxyindole according to claim 1, characterized in that, In step (1), the solvent used in the reaction is selected from ethers, esters, halogenated hydrocarbons, acetonitrile, DMSO, DMF, water or a combined solvent thereof; the base used in the reaction is selected from an organic base such as triethylamine, DIEA, and an inorganic base such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide; the reaction temperature ranges from 0 to 50 °C; the benzyloxycarbonyl reagent used in the reaction includes benzyl chloroformate or benzyl succinimidyl carbonate.

3. The synthesis method of 5,6-dihydroxyindole according to claim 2, characterized in that, In step (1), ethyl acetate with a volume ratio of 5-10 times is selected as the solvent, benzyl chloroformate and 5,6-dihydroxyindoline hydrohalide (IC241-01) are fed in equimolar amounts, calcium carbonate is used as the base (1.2 molar equivalents), and the reaction is carried out at room temperature. The reaction progress is monitored by TLC. Usually, the reaction is complete in 5-24 hours to obtain the intermediate 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02).

4. A method for synthesizing 5,6-dihydroxyindole according to claim 2, characterized in that, In step (1), the reaction of converting 5,6-dihydroxyindoline hydrohalide (IC241-01) to 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) is carried out as follows: Add a solvent to the reaction vessel, then add the main raw material 5,6-dihydroxyindoline hydrohalide (IC241-01) compound, add an appropriate amount of base, under an ice-water bath, stir, dropwise add the benzyloxycarbonyl reagent, gradually raise the temperature to room temperature and react for 5 - 24 hours, monitor by TLC until the reaction 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 obtained compound 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) is treated by the following operations: Filter, adjust the pH value of the filtrate to about 5 with dilute hydrochloric acid, extract with ethyl acetate by liquid separation, combine the organic solvent phases, and directly use it for the next step of the reaction.

6. The synthesis method of 5,6-dihydroxyindole according to claim 1, wherein In step (2), the solvent used in the reaction is selected from ethers, esters, halogenated hydrocarbons, acetonitrile, acetone, DMSO, DMF, water or a combined solvent thereof; The base used in the reaction is selected from an organic base such as triethylamine, DIEA, and an inorganic base such as calcium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide; The reaction temperature ranges from 0 to 100 °C; The benzyl halide reagent used in the reaction includes benzyl chloride or benzyl bromide.

7. A method for synthesizing 5,6-dihydroxyindole according to claim 6, 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 (IC241-02) is (2 - 3):

1.

8. The synthesis method of 5,6-dihydroxyindole according to claim 6, characterized in that, In step (2), ethyl acetate with a volume ratio of 5 - 8 times is selected as the solvent, benzyl chloride and 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) are fed 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, monitor the reaction progress by TLC, usually the reaction is complete in 8 - 24 hours, and the intermediate 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) is obtained.

9. A method for synthesizing 5,6-dihydroxyindole according to any one of claims 6-8, characterized in that, In step (2), the reaction of converting 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) to 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) is carried out as follows: Add the 1-benzyloxycarbonyl-5,6-dihydroxyindoline (IC241-02) compound solution obtained in step (1) to the reaction vessel, add an appropriate amount of base, at room temperature, stir, dropwise add the benzyl halide reagent, gradually raise the temperature to 50 °C and react for 8 - 24 hours, monitor by TLC until the reaction is complete.

10. A method for synthesizing 5,6-dihydroxyindole according to claim 6, characterized in that, In step (2), after the reaction is completed, the obtained compound 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03) is treated by the following operations: After the reaction is completed, adjust the pH value to about 5 - 6 with dilute hydrochloric acid, extract with ethyl acetate by liquid separation, combine the organic solvent phases, concentrate, and obtain a viscous liquid mainly of the compound 1-benzyloxycarbonyl-5,6-dibenzyloxyindoline (IC241-03). Except for taking a small amount for column chromatography purification for NMR characterization, the others do not need purification and directly enter the next step.

11. The synthesis method of 5,6-dihydroxyindole according to claim 1, wherein, In step (3), the solvent used in the reaction is selected from ethers, esters, halogenated hydrocarbons, acetonitrile, water or a combined solvent thereof; The reaction temperature ranges from 0 to 50 °C; The oxidants used in the reaction include DDQ and manganese dioxide; The molar ratio of the oxidant used in the reaction to the reactant 1-carbobenzoxy-5,6-dibenzyloxyindoline (IC241-03) is (1-10):

1.

12. A method for synthesizing 5,6-dihydroxyindole according to claim 11, characterized in that, In step (3), dichloromethane with a volume ratio of 5-10 times is selected as the solvent, and manganese dioxide and 1-carbobenzoxy-5,6-dibenzyloxyindoline (IC241-03) are fed in a molar ratio of 5:

1. The reaction is carried out at room temperature, and the reaction progress is monitored by TLC. Usually, the reaction is complete in 12-36 hours to obtain the intermediate 1-carbobenzoxy-5,6-dibenzyloxyindole (IC241-04).

13. A method for synthesizing 5,6-dihydroxyindole according to claim 11, characterized in that, In step (3), the reaction for converting 1-carbobenzoxy-5,6-dibenzyloxyindoline (IC241-03) to 1-carbobenzoxy-5,6-dibenzyloxyindole (IC241-04) is carried out as follows: The crude viscous liquid of the 1-carbobenzoxy-5,6-dibenzyloxyindoline (IC241-03) compound obtained in step (2) is dissolved in an appropriate amount of solvent, and the solvent is transferred to a reaction vessel. An appropriate amount of oxidant is added, and the reaction is stirred at room temperature for 8-24 hours, and the reaction is monitored by TLC until completion.

14. A method for synthesizing 5,6-dihydroxyindole according to any one of claims 11-13, characterized in that, In step (3), after the reaction is completed, the obtained compound of formula (IC241-04) is treated by the following operations: After the reaction is completed, it is filtered, an appropriate amount of water is added to the solution for liquid-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 1-carbobenzoxy-5,6-dibenzyloxyindole (IC241-04), which is a white powder solid and is ready to enter the next reaction.

15. A method for synthesizing 5,6-dihydroxyindole according to claim 1, characterized in that, In step (4), the solvent used in the reaction is selected from alcohols, ethers, esters, halogenated hydrocarbons, acetonitrile, water or a combined solvent thereof; The reaction temperature ranges from 0 to 50 °C; The antioxidants and inhibitors used in the reaction include sodium ascorbate, vitamin C, tea polyphenols, phenol, 2,6-di-tert-butylphenol or a combination thereof with a mass ratio of 0.01-1%; The metal catalysts used in the reaction include palladium on carbon and palladium hydroxide on carbon; The hydrogen pressure used in the reaction ranges from 1 to 5 atmospheres.

16. A method for synthesizing 5,6-dihydroxyindole according to claim 15, characterized in that, In step (4), ethanol with a volume ratio of 5-10 times is selected 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 inhibitors, 10% by mass of wet palladium on carbon catalyst containing 50% water is added, the air in the reaction system is evacuated, hydrogen at 1 atmosphere is introduced, and the reaction is carried out at room temperature. The reaction progress is monitored by TLC. Usually, the reaction is complete in 12-36 hours to obtain the target product 5,6-dihydroxyindole (DHI).

17. A method for synthesizing 5,6-dihydroxyindole according to claim 15, characterized in that, In step (4), the reaction for converting 1-carbobenzoxy-5,6-dibenzyloxyindole (IC241-04) into the target product 5,6-dihydroxyindole (DHI) is carried out as follows: Add a solvent to the reaction vessel, then add the 1-carbobenzoxy-5,6-dibenzyloxyindole (IC241-04) compound obtained in step (3), add an appropriate amount of antioxidant and inhibitor, add an appropriate amount of metal catalyst, evacuate the system, introduce hydrogen, and react at room temperature for 12 - 36 hours, monitoring by TLC until the reaction is complete.

18. A method for synthesizing 5,6-dihydroxyindole according to any one of claims 15-17, characterized in that, In step (4), the following operations are used to process the obtained target product 5,6-dihydroxyindole (DHI) after the reaction: After the reaction is completed, filter under a nitrogen atmosphere, concentrate the solution to about one-third to one-fourth of the original volume, add an appropriate amount of methyl tert-butyl ether as a poor solvent, and recrystallize to obtain the target product 5,6-dihydroxyindole (DHI), which is a light beige to off-white powder solid.

19. An intermediate in a method for synthesizing 5,6-dihydroxyindole as described in any one of claims 1-18, characterized in that, The intermediate is 1-carbobenzoxy-5,6-dibenzyloxyindoline (IC241-03), and its structural formula is as follows:

20. An intermediate in a method for synthesizing 5,6-dihydroxyindole as described in any one of claims 1-18, characterized in that, The intermediate is 1-carbobenzoxy-5,6-dibenzyloxyindole (IC241-04), and its structural formula is as follows:

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