Process for the preparation of 5,6-dihydroxyindole

Abstract

The application provides a preparation method of a compound 5,6-dihydroxyindole, which comprises the following steps: taking phenolic hydroxyl-protected 4-methyl-5-nitro-o-benzoquinone as raw material, reacting with N,N-dimethylformamide dimethyl acetal and a secondary amine to obtain compound IV, then performing a reduction ring closure reaction to obtain compound V, and removing a phenolic hydroxyl protection group to obtain 5,6-dihydroxyindole. The method is a brand-new process route, the raw material is cheap and easy to obtain, the reaction yield is high, the side reaction is less, and the method is suitable for industrial production. In addition, the method has the advantages of less operation steps, short reaction flow, simple reaction post-treatment, and high product purity.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a method for preparing 5,6-dihydroxyindole. Background Art

[0002] Melanin is a pigment formed in living organisms that has antioxidant, free radical scavenging, and UV absorption properties. Because it is naturally occurring, melanin is highly safe and can be used in cosmetics, food, sunscreens, sunglasses, and as an antioxidant in foods and plastics.

[0003] The color of human hair is determined by the melanin content. With aging, melanin production gradually decreases, causing hair to gray. Melanin is produced by melanocytes through the catalytic oxidation of tyrosine to dopachrome via tyrosinase. Dopachrome then decarboxylates to form 5,6-dihydroxyindole, or tautomerase to form 5,6-dihydroxyindole-2-carboxylic acid. These are then polymerized to form eumelanin, giving hair its black color.

[0004] Aniline compounds are commonly used as effective blackening ingredients in hair dyes. These compounds have adverse effects on humans, including carcinogenicity, teratogenicity, and allergies, posing a significant health hazard. 5,6-Dihydroxyindole was first discovered in a plant in nature and is non-toxic to humans. As a key intermediate in the formation of melanin, 5,6-dihydroxyindole forms melanin in hair, darkening it. In daily chemical products such as hair dyes and colorants, 5,6-dihydroxyindoline and its salts have a strong dyeing effect on keratin fibers. Because they are less irritating to human skin and much less toxic than traditional hair dyes like aniline and phenol, they are ideal alternatives to aniline compounds in hair dyes and are a promising active ingredient in a new generation of green and safe hair dyes.

[0005] 5,6-Dihydroxyindole can also serve as an intermediate in the synthesis of some amino acids, alkaloids, and tryptamines. Due to its diverse applications, several major companies worldwide began developing 5,6-dihydroxyindole in the 1990s and filed patents. In recent years, research on its synthesis has increased significantly. However, due to its high oxidative sensitivity, the synthesis of 5,6-dihydroxyindole is extremely challenging. Currently reported methods for its synthesis remain at the research stage, hindering its application to large-scale industrial production.

[0006] According to existing literature reports, there are several methods for synthesizing 5,6-dihydroxyindole:

[0007] One method uses benzaldehyde compounds containing two adjacent or protected hydroxyl groups on the benzene ring, such as piperonal, vanillin, and dihydroxybenzaldehyde, as starting materials. Nitration, removal of the protecting group, and reduction are performed to produce 5,6-dihydroxyindole. As is well known, nitration reactions are highly hazardous and require strict management. The reaction requires the use of highly hazardous nitromethane. Furthermore, using piperonal as a starting material eliminates the need for introducing a hydroxyl protecting group. However, piperonal is classified as a Class I precursor chemical and is subject to regulatory control. Furthermore, the electron-withdrawing effect of the aldehyde group results in a slow nitration reaction, making purification of the intermediate difficult. This makes practical operations challenging and unsuitable for large-scale production.

[0008]

[0009] The second method uses 3,4-dimethoxyphenylacetonitrile as the starting material and proceeds through demethylation, hydroxyl protection, nitration, and reductive cyclization. The demethylation process is difficult; in addition, this method requires the use of highly irritating benzyl chloride to protect the phenolic hydroxyl group. The nitration reaction is a strictly controlled process with a long reaction time and complex intermediate purification, making it unsuitable for large-scale production.

[0010]

[0011] The third type uses dopamine intermediates and their derivatives as starting materials. Through a cyclization reaction, the ethylamino or alanine group on the side chain is directly cyclized with the adjacent position of the benzene ring or with a substituent at the ortho position to obtain the target compound, 5,6-dihydroxyindole. This method has high raw material costs, uses strong acids, is difficult to treat wastewater, produces many oxidation byproducts, has low yields, is costly, and is difficult to manufacture on a large scale.

[0012]

[0013] Therefore, those skilled in the art still expect new methods for preparing 5,6-dihydroxyindole, especially methods for preparing 5,6-dihydroxyindole under mild reaction conditions that are suitable for large-scale production. Summary of the Invention

[0014] The present invention addresses the shortcomings and deficiencies of existing 5,6-dihydroxyindole synthesis technology and provides a method for preparing 5,6-dihydroxyindole. The method has mild reaction conditions and can easily achieve large-scale production.

[0015] To this end, the first aspect of the present invention provides a method for preparing 5,6-dihydroxyindole, comprising the following steps:

[0016] (1) reacting a compound of formula I with a compound of formula II and compound III in a reaction solvent to obtain compound IV:

[0017]

[0018] wherein R1 and R2 are each independently selected from any one of an alkyl group (e.g., a C1-C4 alkyl group), a benzyl group, a p-methoxybenzyl group, or a phenyl group, or R1 and R2 together form -CH2-; R3 and R4 are each independently selected from any one of an alkyl group (e.g., a C1-C4 alkyl group, such as a methyl group), a benzyl group, or R3 and R4 together with the nitrogen atom to which they are attached form a 5- to 7-membered, for example, a 5- to 6-membered, cyclic amine (e.g., compound III is tetrahydropyrrole or piperidine);

[0019] (2) Reduction ring-closure reaction of the compound of formula IV and the hydrazine compound in a reaction solvent to generate a compound of formula V:

[0020]

[0021] (3) In the presence of a catalyst and a hydrogen atmosphere, the compound of formula V is reduced and the protecting group is removed in a reaction solvent to obtain the compound of formula VI, i.e., 5,6-dihydroxyindole:

[0022]

[0023] According to the method of the first aspect of the present invention, in step (1), the reaction solvent is selected from alkanes, halogenated hydrocarbons, ethers, DMF, DMSO, tetrahydrofuran or a combination thereof.

[0024] According to the method of the first aspect of the present invention, in step (1), the reaction temperature is 70-150° C., for example, 80-120° C.; and / or the reaction time is 2-10 hours, for example, 3-6 hours.

[0025] According to the method of the first aspect of the present invention, in step (1), the reaction of the compound of formula I with the compound of formula II and compound III is carried out as follows: a reaction solvent is added to a reaction vessel, followed by the addition of compound I, the compound of formula II and compound III, and the reaction is carried out at 70-150° C., for example, 80-120° C., for 3-6 hours until the reaction is complete. In one embodiment, the weight ratio of the compound of formula I to the compound of formula II and compound III in step (1) is 100:50-150 (for example, 80-120, for example, 100):40-80 (for example, 50-70, for example, 60).

[0026] According to the method of the first aspect of the present invention, after the reaction of step (1) is completed, the compound IV obtained is treated by the following operation: the reaction solution is cooled to 40-70°C, for example, to 50-60°C, concentrated under reduced pressure, a solvent such as anhydrous ethanol is added to the residue, the temperature is cooled to 0-10°C, crystallized, filtered, optionally rinsed with a solvent such as methanol, and dried to obtain a solid substance as the compound of formula IV.

[0027] According to the method of the first aspect of the present invention, after the reaction in step (1) is completed, the compound IV obtained is treated as follows: the reaction solution is cooled to 50-60°C, and the low-boiling point substance is concentrated under reduced pressure (water bath at 45°C, concentration for 1 hour), anhydrous ethanol is added to the residue, stirred for crystallization, cooled to 0-10°C, and kept warm for crystallization for 1 hour. After the crystallization is completed, the mixture is filtered under reduced pressure, the filter cake is rinsed with methanol, the solid is collected, and dried in a 45°C forced drying oven for 4-8 hours. The collected dried solid is the compound of formula IV.

[0028] According to the method of the first aspect of the present invention, in step (2), the reaction solvent is selected from alkanes such as methanol, halogenated hydrocarbons, ethers, DMF, DMSO, tetrahydrofuran or a combination thereof, and the preferred reaction solvents are tetrahydrofuran and methanol.

[0029] According to the method of the first aspect of the present invention, in step (2), the catalyst is a palladium or nickel catalyst, such as palladium carbon or Raney Ni.

[0030] According to the method of the first aspect of the present invention, in step (2), the hydrazine compound is hydrazine hydrate, such as 70-90% hydrazine hydrate, such as 80% hydrazine hydrate.

[0031] According to the method of the first aspect of the present invention, in step (2), the hydrazine compound is added dropwise to the reaction solution at a temperature below 60°C or below 55°C.

[0032] According to the method of the first aspect of the present invention, in step (2), after the dropwise addition of the hydrazine compound is completed, the reaction is carried out at 40-60° C., for example, 50-55° C., for 1-5 hours, for example, 2-3 hours, until the reaction is complete.

[0033] According to the method of the first aspect of the present invention, in step (2), the reduction ring-closure reaction of the compound of formula IV with the hydrazine compound is carried out as follows: tetrahydrofuran and methanol are added to a reaction flask, the compound of formula IV is added, and then a catalyst is added. The reaction solution is heated to 40°C under mechanical stirring, and the temperature is controlled not to exceed 55°C. 80% hydrazine hydrate is added dropwise. After the addition is complete, the mixture is heated to 50-55°C and kept warm for 2-3 hours until the reaction is complete. In one embodiment, the weight ratio of the compound of formula IV to 80% hydrazine hydrate is 95:45-65 (e.g., 50-60, e.g., 57). In one embodiment, the weight ratio of the compound of formula IV to Raney Ni is 95:10-20 (e.g., 12-16, e.g., 14-15). In one embodiment, the weight ratio of the compound of formula IV to 10% palladium on carbon (wet basis) is 95:2-10 (e.g., 3-8, e.g., 5).

[0034] According to the method of the first aspect of the present invention, after the reaction of step (2) is completed, the compound V obtained is treated by the following operation: the reaction solution is cooled to 15-25°C, the catalyst is filtered out, the filtrate is concentrated to dryness under reduced pressure, methanol is added to the residual solid, the temperature is lowered to 0-10°C, the temperature is kept for crystallization, and the filter is filtered, the filter cake is rinsed with n-heptane, the solid is collected by filtration, and the solid is dried at 40-45°C with air to obtain a dry solid.

[0035] According to the method of the first aspect of the present invention, in step (3), the reaction solvent is an ester such as ethyl acetate.

[0036] According to the method of the first aspect of the present invention, in step (3), the catalyst is a palladium or nickel catalyst, for example, the catalyst is palladium carbon.

[0037] According to the method of the first aspect of the present invention, in step (3), the following operation is used to reduce and remove the protecting group: ethyl acetate is added to a reaction vessel, and then the compound of formula V and the catalyst palladium carbon are added, and the reaction solution is heated to 30-40° C. under a hydrogen atmosphere, and the temperature is kept and stirred until the reaction is complete. In one embodiment, the weight ratio of the compound of formula V to 10% palladium carbon (wet basis) is 20:1-5 (e.g., 1.5-3, e.g., 2). In one embodiment, the hydrogenation reduction reaction is carried out for 3-10 hours, e.g., 4-8 hours, e.g., 6 hours.

[0038] According to the method of the first aspect of the present invention, after the reaction of step (3) is completed, the compound VI obtained is treated by the following operation: after the reaction is completed, the palladium carbon is removed by filtration, the filtrate is concentrated to dryness under reduced pressure, isopropyl ether is added to the residue, and the mixture is heated to 55-65°C to dissolve the material, activated carbon is added, and the mixture is kept warm for decolorization; hot filtration is performed, the filtrate is concentrated to dryness under reduced pressure, dichloromethane is added to the residue, and the mixture is heated to reflux for pulping; stirring and dispersing, cooling to 0-10°C, stirring for crystallization, suction filtering, rinsing the filter cake with dichloromethane, collecting the solid, and drying under reduced pressure to obtain 5,6-dihydroxyindole (7.2g).

[0039] The amount of the reaction solvent used in various operations of the present invention, the amount of the solvent used in the post-treatment and the operation thereof are all within the routine skills of those skilled in the art.

[0040] According to the method of the first aspect of the present invention, in the 5,6-dihydroxyindole prepared therefrom, the residual content of formula (I), formula (IV) and formula (V) is each less than 0.5%, for example, less than 0.25%, for example, less than 0.1%; and / or the residual content of formula (I), formula (IV) and formula (V) is each greater than 0.001%.

[0041] According to the method of the first aspect of the present invention, in the 5,6-dihydroxyindole prepared therefrom, the residual content of formula (II) and formula (III) is respectively less than 0.1%, for example, less than 0.05%; and / or the residual content of formula (II) and formula (III) is respectively greater than 0.0001%.

[0042] Furthermore, the second aspect of the present invention provides a 5,6-dihydroxyindole, which contains less than 0.5%, such as less than 0.25%, such as less than 0.1%, of the compound of formula (I), formula (IV) and / or formula (V).

[0043] The 5,6-dihydroxyindole according to the second aspect of the present invention contains less than 0.1%, for example, less than 0.05%, of the compound of formula (II) and / or formula (III).

[0044] According to the second aspect of the present invention, the residual content of 5,6-dihydroxyindole of formula (I), formula (IV) and formula (V) is less than 0.5%, for example, less than 0.25%, for example, less than 0.1%; and / or the residual content of formula (I), formula (IV) and formula (V) is greater than 0.001%.

[0045] According to the second aspect of the present invention, the residual content of 5,6-dihydroxyindole of formula (II) and formula (III) is less than 0.1%, for example, less than 0.05%; and / or the residual content of formula (II) and formula (III) is greater than 0.0001%.

[0046] The 5,6-dihydroxyindole according to the second aspect of the present invention is prepared using the method described in the first aspect of the present invention.

[0047] The method for preparing 5,6-dihydroxyindole of the present invention has many advantages such as mild reaction conditions and is suitable for large-scale production. DETAILED DESCRIPTION

[0048] The following examples are merely for the purpose of illustrating the present invention and are not intended or construed as limiting 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.

[0049] Example 1: Preparation of 5,6-dihydroxyindole

[0050] 1) Compound IV was prepared using benzyl-protected 4-methyl-5-nitrocatechol as a raw material, and the reaction formula is:

[0051]

[0052] Add 350.0 g of DMF to a 2 L reactor, start stirring, and add 100.0 g of Compound I, followed by 100.0 g of DMF-DMA (N,N-dimethylformamide dimethyl acetal) and 60.0 g of tetrahydropyrrole. Heat to 110-120°C and react for 3 hours. TLC monitoring indicates the reaction is complete.

[0053] After the reaction is complete, the temperature is lowered to 50-60°C, and the low-boiling point material is concentrated under reduced pressure (water bath at 45°C for 1 hour). 1200.0 g of anhydrous ethanol is added to the residue, stirred to crystallize, and the temperature is lowered to 0-10°C, incubated for 1 hour. After crystallization, the mixture is filtered under reduced pressure, the filter cake is rinsed with 200 g of methanol, and the solid is collected and dried in a 45°C forced air drying oven for 4-8 hours. The dried solid (reddish-purple crystalline solid) is weighed to yield 100.2 g. Molar yield: 81.3%.

[0054] The analytical data are as follows: mp 100-101 ° C, 1H-NMR (400 MHz, CDCl3): δ (ppm) = 6.818 (d, 1H, J = 8.01 Hz, Ar-H), 6.742 (d, 1H, J = 2.0 Hz, Ar-H), 6.729 (d, 2H, J = 8.0 Hz, Ar-H), 5.436 (brs, 1H, NH), 3.876 (s, 3H, OCH3), 3.869 ( s, 3H, OCH3), 3.499 (dd, J = 12.8 Hz, 6.8 Hz, 2H, NCH2), 2.74 (t, J = 6.0 Hz, 2H, ArCH2), 1.947 (s, 3H, COCH3). HPLC: purity measured at 214 nm was 97.63%, and purity measured at 254 nm was 100%; LCMS: Found 224.2 ([M+H]+); C12H17NO3, MW calcd. 223.27.

[0055] 2) Compound V is prepared using compound IV as a raw material, and the reaction formula is:

[0056]

[0057] To a 2L three-necked flask, add tetrahydrofuran (522.5g); methanol (427.5g); compound IV (95.0g); and Raney Ni (14.3g). With mechanical stirring, raise the temperature to 40°C. While maintaining the temperature below 55°C, add 80% hydrazine hydrate (57g) dropwise over approximately 2 hours. After the addition is complete, heat to 50-55°C and maintain the reaction for 2-3 hours. Monitor the reaction by TLC until complete.

[0058] After the reaction is complete, cool to 15-25°C; filter to remove the catalyst; collect the filtrate; and concentrate to dryness under reduced pressure. Add anhydrous methanol (95 g) to the residue (solid); stir thoroughly, cool to 0-10°C, and incubate for approximately 1 hour to allow crystallization. Filter and rinse the filter cake with n-heptane (285.0 g) three times. After filtration, collect the solid and air-dry at 40-45°C for 4-8 hours. The dried solid (gray crystalline solid) weighs 53.4 g. Molar yield: 73.5%.

[0059] 3) Compound V is used as a raw material to prepare 5,6-dihydroxyindole VI, and the reaction formula is:

[0060]

[0061] Add ethyl acetate (180 g) to a 500 mL single-necked bottle; add compound V (20 g) and 10% palladium on carbon (2 g, wet basis). Under a hydrogen atmosphere, raise the temperature to 30-40°C; maintain the temperature and stir the reaction until the starting material and the intermediate completely disappear, approximately 6 hours.

[0062] After the reaction is complete, filter to remove the palladium on carbon, collect the filtrate, and concentrate under reduced pressure to dryness. Add isopropyl ether (100 g) to the residue, heat to 55-65°C to dissolve the material as much as possible, add activated carbon (2.0 g), and decolorize by keeping warm for about 10-15 minutes; filter hot and collect the filtrate; concentrate under reduced pressure to dryness; add dichloromethane (200 g) to the residue, heat to reflux and beat for 2 hours; stir to disperse, cool to 0-10°C, and stir to crystallize for about 1 hour. Filter with suction, rinse the filter cake with dichloromethane, collect the solid, and dry under reduced pressure at 45°C. 5,6-dihydroxyindole (7.2 g) is obtained. Molar yield: 79.5%.

[0063] Example 2: Preparation of 5,6-dihydroxyindole

[0064] 1) Compound IV was prepared using benzyl-protected 4-methyl-5-nitrocatechol as a raw material, and the reaction formula is:

[0065]

[0066] Add 350.0 g of DMSO to a 2 L reactor, start stirring, add 100.0 g of compound I, then add 100.0 g of DMF-DMA and 60.0 g of tetrahydropyrrole. After the addition is complete, heat to 110-120° C. and react for 3 hours.

[0067] After the reaction is complete, cool to 50-60°C, and concentrate the low-boiling point substance under reduced pressure (water bath at 45°C, concentrate for 1 hour). Add 1200.0g of anhydrous ethanol to the residue, stir and crystallize, cool to 0-10°C, and keep warm for 1 hour. After crystallization is complete, filter under reduced pressure, rinse the filter cake with 200g of methanol, collect the solid, and dry it in a 45°C forced air drying oven for 4-8 hours. The dried solid (reddish-purple crystalline solid) is collected and weighed to obtain 97.2g. Molar yield: 78.9%

[0068] 2) Compound V is prepared using compound IV as a raw material, and the reaction formula is:

[0069]

[0070] To a 2L three-necked flask, add tetrahydrofuran (522.5g); methanol (427.5g); compound IV (95.0g); and 10% palladium on carbon (5.0g, wet basis). With mechanical stirring, raise the temperature to 40°C. While maintaining the temperature below 55°C, add 80% hydrazine hydrate (57g) dropwise over approximately 2 hours. After the addition is complete, heat to 50-55°C and maintain the reaction for 2-3 hours.

[0071] After the reaction is complete, cool to 15-25°C; filter to remove the catalyst; collect the filtrate; and concentrate to dryness under reduced pressure. Add anhydrous methanol (95 g) to the residue (solid); stir thoroughly, cool to 0-10°C, and incubate for approximately 1 hour to allow crystallization. Filter and rinse the filter cake with n-heptane (285.0 g) three times. After filtration, collect the solid and air-dry at 40-45°C for 4-8 hours. The dried solid (gray crystalline solid) weighs 51.4 g. Molar yield: 70.7%.

[0072] 3) Compound V is used as a raw material to prepare 5,6-dihydroxyindole VI, and the reaction formula is:

[0073]

[0074] Add ethyl acetate (180 g) to a 500 mL single-necked bottle; add compound V (20 g) and 10% palladium on carbon (2 g, wet basis). Under a hydrogen atmosphere, raise the temperature to 30-40°C; maintain the temperature and stir the reaction until the starting material and the intermediate completely disappear, approximately 6 hours.

[0075] After the reaction is complete, filter to remove the palladium on carbon, collect the filtrate, and concentrate under reduced pressure to dryness. Add isopropyl ether (100 g) to the residue, heat to 55-65°C to dissolve the material as much as possible, add activated carbon (2.0 g), and decolorize at this temperature for about 10-15 minutes. Filter hot and collect the filtrate; concentrate under reduced pressure to dryness; add dichloromethane (200 g) to the residue, heat to reflux and slurry for 2 hours; stir to disperse, cool to 0-10°C, and stir to crystallize for about 1 hour. Filter with suction, rinse the filter cake with dichloromethane, collect the solid, and dry under reduced pressure at 45°C. 5,6-dihydroxyindole (7.4 g) is obtained. Molar yield: 81.7%.

[0076] Example 3: Preparation of 5,6-dihydroxyindole

[0077] 1) Compound IV was prepared using p-methoxybenzyl-protected 4-methyl-5-nitrocatechol as a raw material, and the reaction formula is:

[0078]

[0079] Add 350.0 g of DMF to a 2 L reactor, start stirring, add 100.0 g of compound I, then add 100.0 g of DMF-DMA and 60.0 g of tetrahydropyrrole. After the addition is complete, heat to 110-120° C. and react for 3 hours.

[0080] After the reaction is complete, the temperature is lowered to 50-60°C, and the low-boiling point material is concentrated under reduced pressure (water bath at 45°C for 1 hour). 1200.0 g of anhydrous ethanol is added to the residue, stirred to crystallize, and the temperature is lowered to 0-10°C, where it is kept to crystallize for 1 hour. After crystallization, the mixture is filtered under reduced pressure, and the filter cake is rinsed with 200 g of methanol. The solid is collected and dried in a 45°C air drying oven for 4-8 hours. The dried solid is collected and weighed to yield 109.2 g. Molar yield: 78.0%.

[0081] 2) Compound V is prepared using compound IV as a raw material, and the reaction formula is:

[0082]

[0083] To a 2L three-necked flask, add tetrahydrofuran (522.5g); methanol (427.5g); compound IV (100.0g); and Raney Ni (15.0g). With mechanical stirring, raise the temperature to 40°C; control the temperature not to exceed 55°C, and add 80% hydrazine hydrate (57g) dropwise over approximately 2 hours. After the addition is complete, heat to 50-55°C and maintain the reaction for 2-3 hours.

[0084] After the reaction is complete, cool to 15-25°C; filter to remove the catalyst; collect the filtrate; and concentrate to dryness under reduced pressure. Add 100 g of anhydrous methanol to the residue (solid); stir thoroughly, cool to 0-10°C, and allow to crystallize for approximately 1 hour. Filter and rinse the filter cake with n-heptane (285.0 g) three times. After filtration, collect the solid and air-dry at 40-45°C for 4-8 hours. The dried solid (gray crystalline solid) weighs 55.6 g. Molar yield: 69.8%.

[0085] 3) Compound V is used as a raw material to prepare 5,6-dihydroxyindole VI, and the reaction formula is:

[0086]

[0087] Add ethyl acetate (180 g) to a 500 mL single-necked bottle; add compound V (25 g) and 10% palladium on carbon (2 g, wet basis). Under a hydrogen atmosphere, raise the temperature to 30-40°C; maintain the temperature and stir the reaction until the starting material and the intermediate completely disappear, approximately 6 hours.

[0088] After the reaction is complete, filter to remove the palladium on carbon, collect the filtrate, and concentrate under reduced pressure to dryness. Add isopropyl ether (100 g) to the residue, heat to 55-65°C to dissolve the material as much as possible, add activated carbon (2.0 g), and decolorize at this temperature for about 10-15 minutes. Filter hot and collect the filtrate; concentrate under reduced pressure to dryness; add dichloromethane (200 g) to the residue, heat to reflux and slurry for 2 hours; stir to disperse, cool to 0-10°C, and stir to crystallize for about 1 hour. Filter with suction, rinse the filter cake with dichloromethane, collect the solid, and dry under reduced pressure at 45°C. 5,6-dihydroxyindole (7.1 g) is obtained. Molar yield: 74.0%.

[0089] Example 4: Preparation of 5,6-dihydroxyindole

[0090] 1) Compound IV was prepared using benzyl-protected 4-methyl-5-nitrocatechol as a raw material, and the reaction formula is:

[0091]

[0092] 350.0 g of tetrahydrofuran was added to a 2 L reactor, stirring was started, and 100.0 g of compound I was added, followed by 100.0 g of DMF-DMA and 65.0 g of piperidine. After the addition was complete, heating was started to 85° C. and the reaction was continued for 6 hours.

[0093] After the reaction is complete, the temperature is lowered to 50-60°C, and the low-boiling point material is concentrated under reduced pressure (water bath at 45°C for 1 hour). 1200.0 g of anhydrous ethanol is added to the residue, stirred to allow crystallization, and the temperature is lowered to 0-10°C, where it is kept to allow crystallization for 1 hour. After crystallization is complete, the mixture is filtered under reduced pressure, and the filter cake is rinsed with 200 g of methanol. The solid is collected and dried in a 45°C forced air drying oven for 4-8 hours. The dried solid is collected and weighed to yield 95.2 g. Molar yield: 77.3%.

[0094] 2) Compound V is prepared using compound IV as a raw material, and the reaction formula is:

[0095]

[0096] To a 2L three-necked flask, add tetrahydrofuran (522.5g); methanol (427.5g); compound IV (95.0g); and Raney Ni (15.0g). With mechanical stirring, raise the temperature to 40°C. While maintaining the temperature below 55°C, add 80% hydrazine hydrate (57g) dropwise over approximately 2 hours. After the addition is complete, heat to 50-55°C and maintain the reaction for 2-3 hours.

[0097] After the reaction is complete, cool to 15-25°C; filter to remove the catalyst; collect the filtrate; and concentrate to dryness under reduced pressure. Add 100 g of anhydrous methanol to the residue (solid); stir thoroughly, cool to 0-10°C, and allow to crystallize for approximately 1 hour. Filter and rinse the filter cake with n-heptane (285.0 g) three times. After filtration, collect the solid and air-dry at 40-45°C for 4-8 hours. The dried solid (gray crystalline solid) weighs 49.6 g. Molar yield: 70.5%.

[0098] 3) Compound V is used as a raw material to prepare 5,6-dihydroxyindole VI, and the reaction formula is:

[0099]

[0100] Add ethyl acetate (180 g) to a 500 mL single-necked bottle; add compound V (20 g) and 10% palladium on carbon (2 g, wet basis). Under a hydrogen atmosphere, raise the temperature to 30-40°C; maintain the temperature and stir the reaction until the starting material and the intermediate completely disappear, approximately 6 hours.

[0101] After the reaction is complete, filter to remove the palladium on carbon, collect the filtrate, and concentrate under reduced pressure to dryness. Add isopropyl ether (100 g) to the residue, heat to 55-65°C to dissolve the material as much as possible, add activated carbon (2.0 g), and decolorize at this temperature for about 10-15 minutes. Filter hot and collect the filtrate; concentrate under reduced pressure to dryness; add dichloromethane (200 g) to the residue, heat to reflux and slurry for 2 hours; stir to disperse, cool to 0-10°C, and stir to crystallize for about 1 hour. Filter with suction, rinse the filter cake with dichloromethane, collect the solid, and dry under reduced pressure at 45°C. 5,6-dihydroxyindole (7.3 g) is obtained. Molar yield: 80.6%.

[0102] Example 5a: The treatment was carried out according to step 1) of Examples 1 to 4, except that 20 g of dimethyl ether and 5 g of triethylamine were added together with DMF-DMA, and the molar yield of compound IV was within the range of 89 to 92%. For example, the molar yield was 91.3% when referring to Example 1, which was about 10% higher than the yield of this compound in Examples 1 to 4. The melting point, 1H-NMR, HPLC purity, and LCMS values ​​of all compounds IV obtained in this Example 5a were the same or substantially the same as those in Example 1. For example, the MS measured value of compound IV obtained when referring to Example 1 was 223.9. Therefore, in one embodiment of the preparation method of the present invention, dimethyl ether and triethylamine were added together with DMF-DMA in step (1), and the weight ratio of the three was 100:10 to 30 (for example, 20):2 to 10 (for example, 5). Example 5b: The process was carried out in accordance with step 1) of Examples 1 to 4, except that 20 g of dimethyl ether was added along with the DMF-DMA. The molar yield of compound IV was in the range of 79-81%, for example, the molar yield was 79.6% when referring to Example 1. Example 5b: The process was carried out in accordance with step 1) of Examples 1 to 4, except that 5 g of triethylamine was added along with the DMF-DMA. The molar yield of compound IV was in the range of 80-82%, for example, the molar yield was 80.4% when referring to Example 1.

[0103] Test Example 1: Detection of 5,6-dihydroxyindole by HPLC

[0104] Determine by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). Protect from light. Prepare fresh for immediate use.

[0105] Solvent: 1g / L vitamin C solution.

[0106] Test solution: Take about 100 mg of the product, accurately weigh it, place it in a 100 ml volumetric flask, add solvent to dissolve and dilute to the scale, and shake well.

[0107] Control solution: Accurately measure an appropriate amount of the test sample solution, dissolve it in solvent and dilute it to make a solution containing approximately 10 μg of the product per 1 ml.

[0108] Chromatographic conditions: Octadecyl alkane bonded silica gel as the packing (C18, 4.6 mm × 250 mm, 10 μm or equivalent performance column); methanol as mobile phase A, 0.1% trifluoroacetic acid solution as mobile phase B, detection wavelength at 215 nm; flow rate at 1.0 ml / min; column temperature at 30°C, gradient elution according to the table below. Injection volume: 20 μl.

[0109] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 15 85 60 90 10 65 90 10 65.01 15 85 75 15 85

[0110] Determination method: Accurately measure the test solution and control solution, inject them into liquid chromatograph, and record the chromatogram.

[0111] Calculation: Based on the relative retention time and correction factor of each impurity provided in the table below, the impurity content of the chromatographic peak with the same retention time as formula (I), formula (IV), and formula (V) in the chromatogram of the test solution is calculated using the self-control method with correction factor added. It is usually required not to exceed 0.5%.

[0112] Impurity name Relative retention time Correction Factor Formula (IV) 6.03 2.46 Formula (V) 6.16 1.0 Formula (I) 6.72 2.03 Maximum unknown single impurity — 1.0

[0113] It was determined that the content of Formula (I) remaining in the final product 5,6-dihydroxyindole obtained in Examples 1 to 4 was less than 0.1% and greater than 0.001%, for example, the content of Formula (I) in the final product of Example 1 was 0.002%. The content of Formula (IV) remaining in the final product 5,6-dihydroxyindole obtained in Examples 1 to 4 was less than 0.1% and greater than 0.001%, for example, the content of Formula (IV) in the final product of Example 1 was 0.006%. The content of Formula (V) remaining in the final product 5,6-dihydroxyindole obtained in Examples 1 to 4 was less than 0.1% and greater than 0.001%, for example, the content of Formula (V) in the final product of Example 1 was 0.009%. The amount of these impurities can be minimized through multiple purifications. In this sense, the lower limit of the content of the compounds of Formula (I), Formula (IV), and Formula (V) present as impurities in 5,6-dihydroxyindole can be 0.

[0114] Test Example 2: Detection of 5,6-dihydroxyindole by gas chromatography

[0115] Determined by gas chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0521).

[0116] Test solution: Take 300 mg of this product, accurately weigh it, place it in a 20 ml headspace bottle, accurately add 3 ml of dimethyl sulfoxide, seal it, and shake it well.

[0117] Reference solution: Take 10 mg of formula (II) and 10 mg of formula (III), accurately weigh them, place them in a 200 ml volumetric flask containing 5 ml of dimethyl sulfoxide, add dimethyl sulfoxide to dilute to the scale, and shake well; accurately measure 3 ml and place it in a 20 ml headspace bottle, seal it, and shake well.

[0118] Chromatographic conditions: a capillary column with 5% phenyl-methylpolysiloxane (HP-5, 30 m × 0.320 mm × 0.25 μm or similar polarity) as the stationary phase; the starting temperature was 60°C, maintained for 2 minutes, then raised to 250°C at a rate of 20°C per minute and maintained for 5 minutes; the injection port temperature was 200°C; the detector temperature was 250°C; the carrier gas was N2; the flow rate was 1.0 ml / min; the detector was FID; the split ratio was 50:1; and the injection volume was 0.2 μl.

[0119] System suitability requirements: Take the reference solution for headspace injection, and the separation between the peaks of each component should meet the requirements.

[0120] Determination method: Take the test solution and the reference solution, inject them into the headspace respectively, and record the chromatograms.

[0121] Limit: Calculate the residual content of formula (II) and formula (III) in the test sample by peak area according to the external standard method, which is usually required not to exceed 0.05%.

[0122] It was determined that the residual content of Formula (II) in the final product 5,6-dihydroxyindole obtained in Examples 1 to 4 was less than 0.05% and greater than 0.0001%. For example, the content of Formula (II) in the final product of Example 1 was 0.0002%. The residual content of Formula (III) in the final product 5,6-dihydroxyindole obtained in Examples 1 to 4 was less than 0.05% and greater than 0.0001%. For example, the content of Formula (III) in the final product of Example 1 was 0.0004%. The amount of these impurities can be minimized through multiple purifications. In this sense, the lower limit of the content of the compounds of Formula (II) and Formula (III) present as impurities in 5,6-dihydroxyindole can be 0.

[0123] In some typical examples of the method for preparing 5,6-dihydroxyindole according to the present invention, 4-methyl-5-nitrocatechol protected with a phenolic hydroxyl group is reacted with N,N-dimethylformamide dimethyl acetal and a secondary amine to obtain compound IV. Compound V is then obtained through a reductive ring-closure reaction, and the phenolic hydroxyl protecting group is removed to obtain 5,6-dihydroxyindole. The method of the present invention represents a novel process route, utilizing inexpensive and readily available raw materials, achieving a high reaction yield, and minimizing side reactions, making it suitable for industrial production. Furthermore, the method comprises a minimal number of steps, a short reaction flow, simple post-reaction treatment, and a high-purity product. The 5,6-dihydroxyindole prepared according to the present invention has numerous uses, including as a hair dye component.

Claims

1. A method for preparing 5,6-dihydroxyindole, comprising the following steps: (1) Add a reaction solvent to a reaction vessel, then add compound I, compound II (i.e., N,N-dimethylformamide dimethyl acetal), dimethyl ether, triethylamine, and compound III, and react at 85-120° C. for 3-6 hours until the reaction is complete to obtain compound IV: ， wherein R1 and R2 are both benzyl or p-methoxybenzyl; R3 and R4, together with the nitrogen atom to which they are attached, form tetrahydropyrrole or piperidine; the weight ratio of the compound of formula I to the compound of formula II and compound III is 100:50-150:40-80; the weight ratio of the compound of formula II, dimethyl ether, and triethylamine is 100:20:5; and the reaction solvent is selected from DMF, DMSO, and tetrahydrofuran; (2) Add tetrahydrofuran and methanol to the reaction flask, add the compound of formula IV, then add the catalyst palladium carbon or Raney Ni, and heat the reaction solution to 40°C under mechanical stirring, controlling the temperature not to exceed 55°C. Add 80% hydrazine hydrate dropwise. After the addition is complete, heat to 50-55°C and keep the temperature for 2-3 hours until the reaction is complete to generate the compound of formula V: ， The weight ratio of the compound of formula IV to 80% hydrazine hydrate is 95:57, the weight ratio of the compound of formula IV to Raney Ni is 95:14-15, and the weight ratio of the compound of formula IV to 10% wet-basis palladium on carbon is 95:5; (3) In the presence of a catalyst and a hydrogen atmosphere, the compound of formula V is reduced in a reaction solvent to remove the protecting group, Ethyl acetate was added to the reaction vessel, followed by the compound of formula V and a 10% wet palladium-carbon catalyst in a weight ratio of 20:1-5. The reaction solution was heated to 30-40°C under a hydrogen atmosphere and stirred for 3-10 hours until the reaction was complete to obtain the compound of formula VI, i.e., 5,6-dihydroxyindole: 。 2. The method according to claim 1, wherein after the reaction in step (1) is completed, the compound IV obtained is treated by the following operation: the reaction solution is cooled to 40-70° C., concentrated under reduced pressure, anhydrous ethanol is added to the residue, the temperature is cooled to 0-10° C., crystallized, filtered, rinsed with methanol solvent, and dried to obtain a solid substance as the compound of formula IV.

3. The method according to claim 1, wherein after the reaction in step (1) is completed, the compound IV obtained is treated by the following operation: the reaction solution is cooled to 50-60° C., the low-boiling point substance is concentrated under reduced pressure, anhydrous ethanol is added to the residue, stirred for crystallization, cooled to 0-10° C., and kept warm for crystallization for 1 hour. After the crystallization is completed, the mixture is filtered under reduced pressure, the filter cake is rinsed with methanol, the solid is collected, and the dried solid is dried in a 45° C. air drying oven for 4-8 hours. The dried solid is collected as the compound of formula IV.

4. The method according to claim 1, after the reaction in step (2) is completed, the compound V obtained is treated by the following operation: the reaction solution is cooled to 15-25 ° C, the catalyst is filtered out, the filtrate is concentrated to dryness under reduced pressure, methanol is added to the residual solid, the temperature is lowered to 0-10 ° C, the crystallization is carried out by insulation, and the filter cake is washed with n-heptane, the solid is collected by suction filtration, and dried at 40-45 ° C with air to obtain a dry solid.

5. The method according to claim 1, wherein after the reaction in step (3) is completed, the obtained compound VI is treated by the following operation: after the reaction is completed, the palladium carbon is removed by filtration, the filtrate is concentrated to dryness under reduced pressure, isopropyl ether is added to the residue, the mixture is heated to 55-65° C. to dissolve the material, activated carbon is added, and the mixture is kept warm for decolorization; hot filtration is performed, the filtrate is concentrated to dryness under reduced pressure, dichloromethane is added to the residue, the mixture is heated to reflux and pulped; stirring and dispersing, cooling to 0-10° C., stirring and crystallizing, suction filtering, rinsing the filter cake with dichloromethane, collecting the solid, and drying under reduced pressure to obtain 5,6-dihydroxyindole.

6. The method according to claim 1, wherein the residual content of formula (I), formula (IV) and formula (V) in the 5,6-dihydroxyindole prepared therefrom is less than 0.1% respectively.

7. The method according to claim 1, wherein the residual contents of the compounds of formula (II) and formula (III) in the 5,6-dihydroxyindole prepared are each less than 0.05%.

8. The method according to claim 1, comprising the steps of: 1) Compound IV was prepared using p-methoxybenzyl-protected 4-methyl-5-nitrocatechol as a raw material, and the reaction formula is: ， 350.0 g of DMF was added to a 2 L reactor, stirring was started, 100.0 g of compound I was added, and then 100.0 g of DMF-DMA, 20 g of dimethyl ether, 5 g of triethylamine and 60.0 g of tetrahydropyrrole were added. After the addition was completed, the mixture was heated to 110-120° C. and reacted for 3 hours. After the reaction was completed, the temperature was lowered to 50-60° C., and the low-boiling point substance was concentrated under reduced pressure. The mixture was concentrated in a water bath at 45° C. for 1 hour. 1200.0 g of anhydrous ethanol was added to the residue, stirred for crystallization, cooled to 0-10° C., and kept warm for crystallization for 1 hour. After crystallization was completed, the mixture was filtered under reduced pressure, the filter cake was rinsed with 200 g of methanol, the solid was collected, and dried in a 45° C. forced air drying oven for 4-8 hours. The dried solid was collected as compound IV. 2) Compound V is prepared using compound IV as a raw material, and the reaction formula is: ， To a 2 L three-necked flask, add 522.5 g of tetrahydrofuran, 427.5 g of methanol, 100.0 g of compound IV, and 15.0 g of Raney Ni. With mechanical stirring, raise the temperature to 40°C. While controlling the temperature not to exceed 55°C, add 57 g of 80% hydrazine hydrate dropwise over 2 h. After the addition is complete, heat to 50-55°C and keep warm for 2-3 h. After the reaction is completed, cool to 15-25°C; filter to remove the catalyst; collecting the filtrate; The mixture was concentrated to dryness under reduced pressure, and 100 g of anhydrous methanol was added to the solid residue; after stirring evenly, the temperature was lowered to 0-10°C; the temperature was kept to crystallize for about 1 hour; the mixture was filtered, and the filter cake was rinsed with 285.0 g of n-heptane three times. After filtration, the solid was collected and dried with air at 40-45°C for 4-8 hours. The dried solid was compound V. 3) Compound V is used as a raw material to prepare 5,6-dihydroxyindole VI, and the reaction formula is: ， Add 180 g of ethyl acetate to a 500 mL single-necked bottle; add 25 g of compound V and 2 g of 10% wet palladium carbon; under a hydrogen atmosphere, raise the temperature to 30-40°C; maintain the temperature and stir the reaction until the raw material and the intermediate completely disappear, which should be 6 hours; After the reaction is completed, filter to remove palladium carbon and collect the filtrate; concentrate to dryness under reduced pressure; add 100 g of isopropyl ether to the residue, heat to 55-65 ° C to dissolve the material as much as possible, add 2.0 g of activated carbon, keep warm and decolorize for 10-15 minutes; filter hot and collect the filtrate; Concentrate to dryness under reduced pressure; Add 200 g of dichloromethane to the residue, heat to reflux and beat for 2 hours; stir and disperse, cool to 0-10°C and stir to crystallize for 1 hour; filter, rinse the filter cake with dichloromethane, collect the solid, and dry it under reduced pressure at 45°C to obtain 5,6-dihydroxyindole.

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