Preparation method of 5, 6-dihydroxyindoline

Abstract

The invention belongs to the field of eumelanin biopolymers, and particularly relates to a preparation method of 5, 6-dihydroxyindoline, which comprises the following steps: dissolving 3, 4-dibenzyloxybenzaldehyde in a reaction solvent, adding a bromination reagent, and reacting to obtain 3, 4-dibenzyloxy-6-bromobenzaldehyde; mixing the obtained 3, 4-dibenzyloxy-6-bromobenzaldehyde with ammonium formate and nitromethane, stirring and heating, and carrying out a condensation reaction to obtain 3, 4-dibenzyloxy-6-bromo-beta-nitrostyrene; and under the action of a catalyst, cuprous halide and alkali, carrying out hydrogenation reduction, cyclization and debenzylation reaction on the obtained 3, 4-dibenzyloxy-6-bromo-beta-nitrostyrolene by using water as a reaction solvent to obtain a target product. The synthesis method provided by the invention has the characteristics of easily available raw materials, good reaction selectivity, good yield, mild reaction conditions, easy product separation, environmental friendliness and the like, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of eumelanin biopolymers, and more particularly relates to a method for preparing 5,6-dihydroxyindoline. Background Art

[0002] Indole plays an important role in biochemistry. From a biological perspective, perhaps the most important aspect of indole oxidation synthesis lies in the evolutionary value of melanin. The biosynthetic pathway of eumelanin involves the enzymatic oxidation of tyrosine or related homologues such as 3,4-dihydroxyalanine (dopa), followed by intramolecular cyclization to generate indoline; indoline undergoes further oxidation and tautomerization reactions involving the aromatization of the five-membered ring to produce 5,6-dihydroxyindole. This efficient oxidation pathway of indole derivatives, commonly known as the Raper-Mason pathway (Advances in Heterocyclic Chemistry, 2005, 89, 1-63), has strong theoretical guiding significance in biological evolution.

[0003] Natural melanin is an endogenous substance widely present in organisms. Melanin in animals and black human hair are both converted from phenolic hydroxyl group-containing amino acids into melanin precursor (or precursor) small molecules through the biochemical catalytic action of tyrosinase in melanocytes, and then polymerized into melanin polymers, making human hair, human skin color, and animal skin color appear black.

[0004] 5,6-Dihydroxyindole is a key component of eumelanin biopolymers and is expected to become a multifunctional molecular system for designing and developing new functional aromatic scaffolds, biomimetic polymers, and nanomaterials with customized optical and electronic properties. In the past few decades, research on the photophysics, synthesis, π-electron manipulation, and reaction behavior of 5,6-dihydroxyindole has gone beyond the traditional boundaries of biology and medicine, involving physicists, organic chemists, and materials scientists.

[0005] 5,6-Dihydroxyindoline and its related derivatives, as melanin precursor (or precursor) small molecules, have good stability and are easy to preserve.

[0006] In addition, indoline compounds are of great significance in both synthetic chemistry and medicinal chemistry. Such compounds and their derivatives are widely present in nature and are important structural units and components of natural products, pharmaceutical intermediates, biological inhibitors, organic dyes, and even organic optoelectronic materials.

[0007] According to the biological mechanism of melanin formation, companies such as Kao in Japan and L'Oréal in France began to research the development of hair dyes using melanin precursor molecules in the 1990s. European Patent (EP0530229B1) first reported 5,6-dihydroxyindoline and its derivatives as dyeing raw materials. The hair dye prepared from this dyeing raw material has the advantage that when the natural hair dye melanin is applied to the hair and air oxygen is used as the only oxidant for dyeing, a natural-like color is produced.

[0008] As an existing method for preparing 5,6-dihydroxyindoline, in the literature (J.Chem.Soc., 1967, 1423 - 1427), a synthesis method starting from 5,6-dimethoxyindol-2-one was introduced. This process has a relatively long synthesis route, a high reaction temperature (140 °C), many side reactions, and poor selectivity.

[0009]

[0010] In World Patent (WO: 93 - 05017), a method for preparing 5,6-dihydroxyindoline by demethylation with hydrobromic acid starting from 5,6-dimethoxyindoline was introduced. This method is carried out using a large amount of hydrobromic acid (10 times), and methyl bromide produced during the reaction is a highly toxic substance to the human body, which is difficult to recover and poses a safety hazard.

[0011]

[0012] In Chinese Patent (CN: 117247345A), a process for preparing 5,6-dihydroxyindoline starting from 3,4-dihydroxybenzaldehyde through steps such as condensation with nitromethane, reduction of nitroethylene, amino protection, iodination, cyclization, and deprotection was introduced. This scheme has a long reaction step and uses expensive iodine as a halogenating reagent for the aromatic ring, making it difficult to control the large-scale production cost.

[0013]

[0014] In addition, in Patent (CN: 107540596A), a process for preparing 5,6-dihydroxyindoline starting from 3,4-dimethoxyphenethylamine through steps such as amino protection, halogenation (iodination or bromination), and cyclization reaction under the action of copper oxalate salt, and finally demethylation in hydrobromic acid was introduced. The large amount of methyl bromide produced during the demethylation process using hydrobromic acid is an important factor restricting the large-scale production of this process.

[0015] Summary of the Invention

[0016] The object of the present invention is to provide a method for preparing 5,6-dihydroxyindoline, which has easily available reaction raw materials, easily controllable conditions, good selectivity, high yield and simple operation process.

[0017] To solve the above technical problems, the present invention is implemented as follows:

[0018] A method for preparing 5,6-dihydroxyindoline, comprising the following steps:

[0019] (1) Dissolve 3,4-dibenzyloxybenzaldehyde in a reaction solvent, add a brominating reagent, after the bromination reaction is completed, concentrate under reduced pressure to remove the reaction solvent, and obtain 3,4-dibenzyloxy-6-bromobenzaldehyde after recrystallization and drying.

[0020] (2) Mix the 3,4-dibenzyloxy-6-bromobenzaldehyde obtained in step (1) with ammonium formate salt and nitromethane, stir and heat, after the condensation reaction is completed, obtain 3,4-dibenzyloxy-6-bromo-β-nitrostyrene after recrystallization and drying.

[0021] (3) Under the action of a catalyst, cuprous halide and a base, use water as the reaction solvent to carry out hydrogenation reduction, cyclization and debenzylation reaction on the 3,4-dibenzyloxy-6-bromo-β-nitrostyrene obtained in step (2), and the target product 5,6-dihydroxyindoline is obtained.

[0022] Further, in step (1), the bromination reagent is bromine, tetrabutylammonium tribromide, phenyltrimethylammonium tribromide, pyridinium tribromide or 1-methyl-3-butylimidazolium tribromide.

[0023] Further, in step (1), the reaction solvent is methanol, ethanol, chloroform, dichloromethane, dichloroethane, dimethylformamide or dimethylacetamide; the reaction temperature is -20 to 60 °C.

[0024] Further, in step (2), the ammonium formate salt is formic acid-ethanolamine, formic acid

[0025] -diethanolamine, formic acid-triethanolamine or formic acid-triethylamine; the reaction temperature is 20 to 120 °C.

[0027] Further, in step (3), the catalyst is a palladium catalyst supported on activated carbon.

[0028] Further, the palladium loading amount in the palladium catalyst is 5 to 30%; the amount of the catalyst used is 0.5 to 30% of the weight of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

[0029] Further, in step (3), the cuprous halide is cuprous chloride or cuprous bromide, and its dosage is 0.5-30% of the weight of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

[0031] Further, in step (3), the base is a hydroxide or carbonate of an alkali metal or an alkaline earth metal.

[0032] Further, the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate.

[0033] Further, in step (3), the reaction pressure is 5-80 atmospheres; the reaction temperature is 30-150 °C.

[0034] The synthesis method of 5,6-dihydroxyindoline according to the present invention has the following technical solution: 1) Using 3,4-dibenzyloxybenzaldehyde as a raw material, a 6-bromo product - 3,4-dibenzyloxy-6-bromobenzaldehyde is obtained through a selective bromination reaction; 2) Condensing with nitromethane to obtain β-nitrostyrene; 3) Under the action of palladium carbon, cuprous halide and a base, the synthesis of 5,6-dihydroxyindoline is completed through hydrogenation reduction.

[0035] The reaction principle is as follows:

[0036]

[0037] First, through the selective bromination of 3,4-dibenzyloxybenzaldehyde, a brominated product 3,4-dibenzyloxy-6-bromobenzaldehyde with the following structure is synthesized.

[0038]

[0039] Among them, the bromination reagent is bromine, tetrabutylammonium tribromide, phenyltrimethylammonium tribromide, pyridinium tribromide, 1-methyl-3-butylimidazolium tribromide, etc., preferably phenyltrimethylammonium tribromide, 1-methyl-3-butylimidazolium tribromide; the reaction solvent is methanol, ethanol, chloroform, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, etc., preferably ethanol, dichloroethane, and the reaction temperature is -20-40 °C, preferably -10-30 °C.

[0040] Secondly, β-nitroethylene is obtained through the condensation reaction of the brominated product with nitromethane.

[0041] Among them, the formic acid ammonium salt is formic acid-ethanolamine, formic acid-diethanolamine, formic acid-triethanolamine or formic acid-triethylamine complex, preferably formic acid-ethanolamine or formic acid-diethanolamine. The reaction temperature is 20-120 °C, preferably 30-100 °C.

[0042] Finally, through the action of palladium on carbon, cuprous halide and base, the hydrogenation reduction, cyclization and debenzylation reaction of β-nitrostyrene are completed using water as the reaction solvent.

[0043] Among them, the palladium on carbon catalyst is a palladium catalyst supported on activated carbon, the palladium loading is 5-20%, the catalyst dosage is 0.5-30% of the weight of β-nitroethylene, preferably 1-20%. Its dosage is 0.5-30% of the weight of β-nitroethylene, preferably 1-20%.

[0044] The cuprous halide used in this process is cuprous chloride or cuprous bromide, and its dosage is 0.5-30% of the weight of β-nitroethylene, preferably 1-20%.

[0045] The base used in this process is a hydroxide or carbonate of an alkali metal or alkaline earth metal, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably sodium carbonate and potassium carbonate.

[0046] The hydrogen pressure introduced during this reaction process is 5-80 atmospheres, preferably 10-60 atmospheres. The reaction temperature of this reaction process is 30-150 °C, and the preferred reaction temperature is 60-130 °C.

[0047] The starting material 3,4-dibenzyloxybenzaldehyde involved in the present invention can be prepared from the readily available raw material 3,4-dihydroxybenzaldehyde and benzyl chloride under mild reaction conditions with reference to the literature method (J. Org. Chem. 1997, 62, 908-915).

[0048] The present invention has the following advantages compared with the prior art:

[0049] (1) The synthesis method of 5,6-dihydroxyindoline involved in the present invention can meet the requirements of high purity and high efficiency in the fields of chemical industry, medicine, etc.

[0050] (2) The synthesis process of 5,6-dihydroxyindoline involved in the present invention is easy to operate, the raw materials are readily available, and the production is safe, which is conducive to large-scale production. Specific Embodiments

[0051] The present invention will be further described in conjunction with specific embodiments, but the content of the present invention is not limited by these embodiments.

[0052] Example 1

[0053] (1) Bromination reaction: Synthesis of 3,4-dibenzyloxy-6-bromobenzaldehyde

[0054] In a 250 mL three-necked flask, 3,4-dibenzyloxybenzaldehyde (31.8 g, 0.1 mol) was dissolved in 150 mL of 1,2-dichloroethane under mechanical stirring. Phenyltrimethylammonium tribromide (37.6 g, 0.1 mol) was added portionwise at room temperature over 30 minutes. The reaction mixture was maintained at 40 °C for 5 h (TLC was used to determine the end point of the reaction). After the reaction, the solvent was removed by concentration under reduced pressure. The residue was recrystallized from isopropanol and dried under vacuum to obtain 37 g of the product with a yield of 93%. The structure of the product was confirmed by NMR analysis to be 3,4-dibenzyloxy-6-bromobenzaldehyde.

[0055] 1 H NMR(400MHz, CDCl 3 ): 5.12(2H, s), 5.18(2H, s), 7.21(1H, s), 7.28(1H, s)7.33~7.48(10H, m), 9.94(1H, s).

[0056] (2) Condensation reaction: Synthesis of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene

[0057] In a 500 mL three-necked flask, 3,4-dibenzyloxy-6-bromobenzaldehyde (79.4 g, 0.2 mol), formic acid-ethanolamine (140 g), and nitromethane (18.3 g, 0.3 mol) were added. The mixture was heated to 80 °C with stirring and maintained at this temperature for 4 h (TLC was used to determine the end point of the reaction). After the reaction, the temperature was lowered to 20 °C. The reaction mixture was transferred to 200 mL of water, filtered, recrystallized from methanol, and dried under vacuum to obtain 84 g of the product with a yield of 95%. The structure of the product was confirmed by NMR analysis to be 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

[0058] 1 H NMR(400MHz, CDCl 3 ): 5.32(2H, s), 5.41(2H, s), 7.12~7.34(12H, m).

[0059] (3) Reduction-cyclization reaction: Synthesis of 5,6-dihydroxyindoline

[0060] In a 2 L pressure reactor, 3,4-dibenzyloxy-6-bromo-β-nitrostyrene (88 g, 0.2 mol) prepared in the above reaction process, 10% Pd / C (45 g) catalyst, cuprous bromide (2.8 g, 0.02 mol), potassium carbonate (83 g, 0.6 mol), and water (1000 g) were added. The reaction was carried out at 120 °C for 6 hours under a hydrogen pressure of 5 kg. After the reaction was completed and detected, it was cooled. The reaction solution was neutralized with dilute hydrochloric acid to pH = 5, ethyl acetate (500 mL) was added, and it was stirred for 30 minutes. Then it was filtered (to recover the catalyst). The extract was added with activated carbon for decolorization and evaporated to dryness to obtain a crystalline product. By recrystallization with isopropyl ether - n-hexane, 21.7 g of white crystals were obtained, with a yield of 72%. Melting point: 230 - 232 °C.

[0061] 1 H NMR (400 MHz, D 2 O): 3.05 (t, J = 7.2 Hz, 2H), 3.67 (t, J = 7.2 Hz, 2H), 6.84 (1H, s), 6.91 (1H, s).

[0062] The purity of the product was determined by liquid chromatography to be 99.5%.

[0063] Example 2

[0064] (1) Bromination reaction: Synthesis of 3,4-dibenzyloxy-6-bromobenzaldehyde

[0065] In a 250 mL three-necked flask, 3,4-dibenzyloxybenzaldehyde (31.8 g, 0.1 mol) was dissolved in 200 ml of absolute ethanol under mechanical stirring. 1-Methyl-3-butylimidazolium tribromide (45.5 g, 0.12 mol) was added portionwise at room temperature and added completely within 30 minutes. The reaction was carried out at 30 °C for 6 h (TLC (to determine the end point of the reaction by thin-layer chromatography)). After the reaction was completed, the solvent was removed by reduced pressure concentration, recrystallized with isopropanol, and dried in vacuo to obtain 34.5 g of the product, with a yield of 87%. The structure of the product was confirmed by nuclear magnetic resonance analysis to be 3,4-dibenzyloxy-6-bromobenzaldehyde.

[0066] (2) Condensation reaction: Synthesis of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene

[0067] In a 500 mL three-necked flask, add 3,4-dibenzyloxy-6-bromobenzaldehyde (79.4 g, 0.2 mol), formic acid - diethanolamine (120 g), and nitromethane (18.3 g, 0.3 mol) respectively. Heat to 90 °C with stirring and keep the reaction for 2 h (TLC (determine the end point of the reaction by thin-layer chromatography)). After the reaction is completed, cool to 20 °C. Transfer the reaction solution into 200 mL of water, filter, recrystallize with methanol, and dry in vacuum to obtain 81 g of the product with a yield of 92%; the product structure is confirmed by nuclear magnetic resonance analysis to be 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

[0068] (3) Reduction-cyclization reaction: Synthesis of 5,6-dihydroxyindoline

[0069] In a 2 L pressure reactor, add 3,4-dibenzyloxy-6-bromo-β-nitrostyrene (88 g, 0.2 mol) prepared in the above reaction process, 10% Pd / C (50 g) catalyst, copper chloride (3 g, 0.03 mol), potassium carbonate (83 g, 0.6 mol), and water (1000 g). React at 110 °C under 8 kg hydrogen pressure for 7 h. After detecting the completion of the reaction, cool, neutralize the reaction solution with dilute hydrochloric acid to pH = 5, add ethyl acetate (500 mL), stir for 30 minutes, filter (recover the catalyst), add activated carbon to the extract for decolorization, evaporate to dryness to obtain a crystalline product. Recrystallize with isopropyl ether - n-hexane to obtain 20.2 g of white crystals with a yield of 67%; melting point: 230 - 232 °C.

[0070] The purity of the product is determined by liquid chromatography to be 99.6%.

[0071] Example 3

[0072] (1) Bromination reaction: Synthesis of 3,4-dibenzyloxy-6-bromobenzaldehyde

[0073] In a 250 mL three-necked flask, dissolve 3,4-dibenzyloxybenzaldehyde (31.8 g, 0.1 mol) in 200 ml of dichloroethane under mechanical stirring. Add phenyltrimethylammonium tribromide (45.1 g, 0.12 mol) portionwise at room temperature and finish adding in 30 minutes. Keep the reaction at 45 °C for 4 h (TLC (determine the end point of the reaction by thin-layer chromatography)). After the reaction is completed, concentrate under reduced pressure to remove the solvent, recrystallize with isopropanol, and dry in vacuum to obtain 35.7 g of the product with a yield of 90%; the product structure is confirmed by nuclear magnetic resonance analysis to be 3,4-dibenzyloxy-6-bromobenzaldehyde.

[0074] (2) Condensation reaction: Synthesis of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene

[0075] In a 500 mL three-necked flask, add 3,4-dibenzyloxy-6-bromobenzaldehyde (79.4 g, 0.2 mol), formic acid-diethanolamine (120 g), and nitromethane (36.6 g, 0.4 mol) respectively. Heat to 70 °C with stirring and keep the reaction for 3 h (TLC (determine the reaction end point by thin layer chromatography)). After the reaction is completed, cool to 20 °C. Transfer the reaction solution into 200 mL of water, filter, recrystallize with methanol, and dry under vacuum to obtain 79 g of the product with a yield of 90%; the product structure is confirmed to be 3,4-dibenzyloxy-6-bromo-β-nitrostyrene by nuclear magnetic resonance analysis.

[0076] (3) Reduction-cyclization reaction: Synthesis of 5,6-dihydroxyindoline

[0077] In a 2 L pressure reactor, add 3,4-dibenzyloxy-6-bromo-β-nitrostyrene (88 g, 0.2 mol) prepared in the above reaction process, 20% Pd / C (15 g) catalyst, copper chloride (3 g, 0.03 mol), sodium carbonate (85 g, 0.8 mol), and water (1000 g). React at 90 °C under 5 kg hydrogen pressure for 4 h. After detecting the completion of the reaction, cool, neutralize the reaction solution with dilute hydrochloric acid to pH = 5, add ethyl acetate (500 mL), stir for 30 minutes, filter (recover the catalyst), decolorize the extract with activated carbon, evaporate to dryness to obtain a crystalline product. Recrystallize with isopropyl ether-n-hexane to obtain 22.3 g of white crystals with a yield of 74%; melting point: 230 - 232 °C.

[0078] The purity of the product is determined by liquid chromatography to be 99.6%.

[0079] Example 4

[0080] (1) Bromination reaction: Synthesis of 3,4-dibenzyloxy-6-bromobenzaldehyde

[0081] In a 250 mL three-necked flask, dissolve 3,4-dibenzyloxybenzaldehyde (31.8 g, 0.1 mol) in 200 ml of anhydrous ethanol under mechanical stirring. Slowly add bromine (16 g, 0.1 mol) dropwise at -5 °C and finish adding in 50 minutes. Keep the reaction at 30 °C for 8 h (TLC (determine the reaction end point by thin layer chromatography)). After the reaction is completed, concentrate under reduced pressure to remove the solvent, recrystallize with isopropanol, and dry under vacuum to obtain 32.5 g of the product with a yield of 82%; the product structure is confirmed to be 3,4-dibenzyloxy-6-bromobenzaldehyde by nuclear magnetic resonance analysis.

[0082] (2) Condensation reaction: Synthesis of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene

[0083] In a 500 mL three-necked flask, add 3,4-dibenzyloxy-6-bromobenzaldehyde (79.4 g, 0.2 mol), formic acid-triethanolamine (120 g), and nitromethane (24.4 g, 0.4 mol) respectively. Heat to 70 °C with stirring and keep the reaction for 5 h (TLC (determine the reaction end point by thin layer chromatography)). After the reaction is completed, cool to 20 °C. Transfer the reaction solution to 200 mL of water, filter, recrystallize with methanol, and dry in vacuo to obtain 71 g of the product with a yield of 90%; the product structure is confirmed by nuclear magnetic resonance analysis to be 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

[0084] (3) Reduction-cyclization reaction: Synthesis of 5,6-dihydroxyindoline

[0085] In a 2 L pressure reactor, add 3,4-dibenzyloxy-6-bromo-β-nitrostyrene (88 g, 0.2 mol) prepared in the above reaction process, 20% Pd / C (10 g) catalyst, copper chloride (1.5 g, 0.03 mol), sodium carbonate (64 g, 0.6 mol), and water (1000 g). React at 110 °C for 5 h under a hydrogen pressure of 10 kg. After detecting the completion of the reaction, cool, neutralize the reaction solution with dilute hydrochloric acid to pH = 5, add ethyl acetate (500 mL), stir for 30 minutes, filter (recover the catalyst), decolorize the extract with activated carbon, evaporate to dryness to obtain a crystalline product. Recrystallize with isopropyl ether-n-hexane to obtain 20.5 g of white crystals with a yield of 68%; melting point: 230-232 °C.

[0086] The purity of the product determined by liquid chromatography is 99.7%.

[0087] Example 5

[0088] (1) Bromination reaction: Synthesis of 3,4-dibenzyloxy-6-bromobenzaldehyde

[0089] In a 1500 mL three-necked flask, dissolve 3,4-dibenzyloxybenzaldehyde (159 g, 0.5 mol) in 650 ml of dichloroethane under mechanical stirring. Add phenyltrimethylammonium tribromide (206.8 g, 0.55 mol) portionwise at room temperature and finish adding in 40 minutes. Keep the reaction at 45 °C for 5 h (TLC (determine the reaction end point by thin layer chromatography)). After the reaction is completed, concentrate under reduced pressure to remove the solvent, recrystallize with isopropanol, and dry in vacuo to obtain 178.6 g of the product with a yield of 92%; the product structure is confirmed by nuclear magnetic resonance analysis to be 3,4-dibenzyloxy-6-bromobenzaldehyde.

[0090] (2) Condensation reaction: Synthesis of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene

[0091] In a 1000 mL three-necked flask, add 3,4-dibenzyloxy-6-bromobenzaldehyde (198.5 g, 0.5 mol), formic acid - diethanolamine (300 g), and nitromethane (50.2 g, 0.75 mol) respectively. Heat to 80 °C with stirring and keep the reaction for 4 h (TLC (thin-layer chromatography is used to determine the end point of the reaction)). After the reaction is completed, cool to 20 °C. Transfer the reaction solution to 800 mL of water, filter, recrystallize with methanol, and dry under vacuum to obtain 200 g of the product with a yield of 91%. The structure of the product is confirmed by nuclear magnetic resonance analysis to be 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

[0092] (3) Reduction-cyclization reaction: Synthesis of 5,6-dihydroxyindoline

[0093] In a 5 L pressure reactor, add 3,4-dibenzyloxy-6-bromo-β-nitrostyrene (220 g, 0.5 mol) prepared in the above reaction process, 10% Pd / C (50 g) catalyst, copper chloride (6 g, 0.06 mol), sodium carbonate (220.8 g, 1.6 mol), and water (25000 g). React at 100 °C under a hydrogen pressure of 10 kg for 7 h. After detecting that the reaction is completed, cool. Neutralize the reaction solution with dilute hydrochloric acid to pH = 5, add ethyl acetate (3 x 500 mL), stir for 30 minutes, filter (recover the catalyst), add activated carbon to the extract for decolorization, evaporate to dryness to obtain a crystalline product. Recrystallize with isopropyl ether - n-hexane to obtain 52.8 g of white crystals with a yield of 70%. Melting point: 230 - 232 °C.

[0094] The purity of the product is determined by liquid chromatography to be 99.5%.

Claims

1. A method for preparing 5,6-dihydroxyindoline, characterized in that: The steps include: (1) dissolving 3,4-dibenzyloxybenzaldehyde in a reaction solvent, adding a bromination reagent, and after the bromination reaction is completed, concentrating under reduced pressure to remove the reaction solvent, and then recrystallizing and drying to obtain 3,4-dibenzyloxy-6-bromobenzaldehyde; (2) mixing the 3,4-dibenzyloxy-6-bromobenzaldehyde obtained in step (1) with ammonium formate and nitromethane, stirring and heating, and after the condensation reaction is completed, recrystallizing and drying to obtain 3,4-dibenzyloxy-6-bromo-β-nitrostyrene; (3) In the presence of a catalyst, cuprous halide and a base, the 3,4-dibenzyloxy-6-bromo-β-nitrostyrene obtained in step (2) is subjected to hydrogenation reduction, cyclization and debenzylation reaction in water as a reaction solvent to obtain the target product 5,6-dihydroxyindoline.

2. The method for preparing 5,6-dihydroxyindoline according to claim 1, characterized in that: In step (1), the bromination reagent is bromine, tetrabutylammonium tribromide, phenyltrimethylammonium tribromide, pyridinium tribromide or 1-methyl-3-butylimidazole tribromide.

3. The method for preparing 5,6-dihydroxyindoline according to claim 2, characterized in that: In step (1), the reaction solvent is methanol, ethanol, chloroform, dichloromethane, dichloroethane, dimethylformamide or dimethylacetamide; and the reaction temperature is -20 to 60°C.

4. The method for preparing 5,6-dihydroxyindoline according to claim 3, characterized in that: In step (2), the ammonium formate salt is formic acid-ethanolamine, formic acid-diethanolamine, formic acid-triethanolamine or formic acid-triethylamine; and the reaction temperature is 20 to 120°C.

5. The method for preparing 5,6-dihydroxyindoline according to claim 4, characterized in that: In step (3), the catalyst is an activated carbon-supported palladium catalyst.

6. The method for preparing 5,6-dihydroxyindoline according to claim 5, characterized in that: The palladium loading in the palladium catalyst is 5 to 30%; the catalyst dosage is 0.5 to 30% of the weight of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

7. The method for preparing 5,6-dihydroxyindoline according to claim 6, characterized in that: In step (3), the cuprous halide is cuprous chloride or cuprous bromide, and its amount is 0.5 to 30% of the weight of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

8. The method for preparing 5,6-dihydroxyindoline according to claim 7, characterized in that: In step (3), the base is a hydroxide or carbonate of an alkali metal or an alkaline earth metal.

9. The method for preparing 5,6-dihydroxyindoline according to claim 8, characterized in that: The base is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate.

10. The method for preparing 5,6-dihydroxyindoline according to any one of claims 1 to 9, characterized in that: In step (3), the reaction pressure is 5 to 80 atmospheres; the reaction temperature is 30 to 150°C.

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