Preparation method of 5,6-dihydroxyindoline

Abstract

This invention belongs to the field of eumelanin biopolymers, and particularly relates to a method for preparing 5,6-dihydroxyindoline, comprising the following steps: dissolving 3,4-dibenzyloxybenzaldehyde in a reaction solvent, adding a brominating reagent, and reacting to obtain 3,4-dibenzyloxy-6-bromobenzaldehyde; mixing the obtained 3,4-dibenzyloxy-6-bromobenzaldehyde with ammonium formate and nitromethane, and stirring and heating, followed by a condensation reaction to obtain 3,4-dibenzyloxy-6-bromo-β-nitrostyrene; and subjecting the obtained 3,4-dibenzyloxy-6-bromo-β-nitrostyrene to hydrogenation reduction, cyclization, and debenzylation reactions in the presence of a catalyst, cuprous halide, and alkali, using water as the reaction solvent, to obtain the target product. The synthesis method of this invention has the advantages of readily available raw materials, good reaction selectivity, good yield, mild reaction conditions, easy product separation, and environmental friendliness, making it suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of eumelanin biopolymers, and more specifically relates to a method for preparing 5,6-dihydroxyindoline. Background Technology

[0002] Indole plays a vital role in biochemistry, and from a biological perspective, the most important aspect of indole oxidative synthesis may lie in its evolutionary value in melanin. The biosynthetic pathway of eumelanin involves the enzymatic oxidation of tyrosine or related homologs such as 3,4-dihydroxyalanine (DOPA), followed by intramolecular cyclization to generate indoline; indoline, in further oxidation and tautomerism involving five-membered ring aromatization, yields 5,6-dihydroxyindole. This highly efficient indole derivative oxidation pathway, commonly known as the Raper-Mason pathway (Advances in Heterocyclic Chemistry, 2005, 89, 1-63), has significant theoretical implications for biological evolution.

[0003] Natural melanin is an endogenous substance that is widely present in living organisms. The blackness of human hair and the blackness of human hair are all due to the biochemical catalysis of tyrosinase in melanocytes, which converts amino acids containing phenolic hydroxyl groups into small molecules of melanin precursors (or precursors), which are then polymerized into melanin polymers, making human hair, human skin, and animal skin appear black.

[0004] 5,6-Dihydroxyindole is a key component of eumelanin biopolymers and holds promise for designing and developing multifunctional molecular systems for novel functional aromatic scaffolds, biomimetic polymers, and nanomaterials with customized optical and electronic properties. Over the past few decades, research on the photophysics, synthesis, π-electronic manipulation, and reactive behavior of 5,6-dihydroxyindole has transcended the traditional boundaries of biology and medicine, involving physicists, organic chemists, and materials scientists.

[0005] 5,6-Dihydroxyindoline and its related derivatives are small molecules that serve as melanin precursors (or precursors), exhibiting good stability and ease of storage.

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

[0007] Based on the biological mechanisms of melanin formation, companies such as Kao Corporation of Japan and L'Oréal of France began researching the development of hair dyes using melanin precursor molecules in the 1990s. European patent (EP0530229B1) was the first to report 5,6-dihydroxyindoline and its derivatives as dyeing materials. The advantage of hair dyes prepared from this material is that by applying natural melanin to the hair, oxygen in the air is used as the sole oxidant for dyeing, producing a color similar to natural pigments.

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

[0009]

[0010] World Patent (WO: 93-05017) describes a method for preparing 5,6-dihydroxyindoline from 5,6-dimethoxyindoline as a starting material via hydrobromic acid demethylation. This method uses a large amount of hydrobromic acid (10 times the normal concentration), and the bromomethane produced during the reaction is a highly toxic substance to humans, which is difficult to recover and poses a safety hazard.

[0011]

[0012] A Chinese patent (CN: 117247345A) describes a process for preparing 5,6-dihydroxyindoline from 3,4-dihydroxybenzaldehyde as a starting material through steps including condensation with nitromethane, reduction of nitrobenzene, amino protection, iodination, cyclization, and deprotection. This method involves lengthy reaction steps and uses expensive iodine as the halogenation reagent for the aromatic ring, making it difficult to control the cost of large-scale preparation.

[0013]

[0014] Furthermore, the patent (CN: 107540596A) describes a process for preparing 5,6-dihydroxyindoline from 3,4-dimethoxyphenethylamine as a starting material, through amino protection, halogenation (iodo or bromination), and cyclization under the action of copper oxalate salt, finally completing demethylation in hydrobromic acid. The large amount of bromomethane generated during the hydrobromic acid demethylation process is a significant factor limiting the large-scale production of this process.

[0015] Summary of the Invention

[0016] The purpose of this invention is to provide a method for preparing 5,6-dihydroxyindoline with readily available raw materials, easily controllable conditions, good selectivity, high yield, and simple operation.

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

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

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

[0020] (2) The 3,4-dibenzyloxy-6-bromobenzaldehyde obtained in step (1) was mixed with ammonium formate and nitromethane and then stirred and heated. After the condensation reaction was completed, it was recrystallized and dried to obtain 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

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

[0022] Further, in step (1), the brominating agent is bromine, tetrabutylammonium tribromide, phenyltrimethylammonium tribromide, pyridine tribromide, or 1-methyl-3-butylimidazole 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 or formic acid.

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

[0026] Furthermore, in step (3), the catalyst is a palladium catalyst supported on activated carbon.

[0027] Furthermore, the palladium loading in the palladium catalyst is 5-30%; the amount of catalyst used is 0.5-30% of the weight of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

[0028] Further, 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.

[0029] Further, in step (3), the alkali is an alkali metal or alkaline earth metal hydroxide or carbonate.

[0030] Further, the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, or cesium carbonate.

[0031] Furthermore, in step (3), the reaction pressure is 5 to 80 atmospheres; the reaction temperature is 30 to 150°C.

[0032] The method for synthesizing 5,6-dihydroxyindoline according to the present invention comprises the following steps: 1) using 3,4-dibenzyloxybenzaldehyde as a raw material, selective bromination is used to obtain the 6-brominated product -- 3,4-dibenzyloxy-6-bromobenzaldehyde; 2) β-nitrostyrene is obtained by condensation with nitromethane; 3) 5,6-dihydroxyindoline is synthesized by hydrogenation reduction under the action of palladium on carbon, cuprous halide and base.

[0033] The reaction principle is as follows:

[0034]

[0035] First, by selectively brominating 3,4-dibenzyloxybenzaldehyde, the brominated product was synthesized as 3,4-dibenzyloxy-6-bromobenzaldehyde with the following structure.

[0036]

[0037] The brominating reagent is bromine, tetrabutylammonium tribromide, phenyltrimethylammonium tribromide, pyridine tribromide, 1-methyl-3-butylimidazole tribromide, etc., preferably phenyltrimethylammonium tribromide or 1-methyl-3-butylimidazole tribromide; the reaction solvent is methanol, ethanol, chloroform, dichloromethane, dichloroethane, dimethylformamide, dimethylacetamide, etc., preferably ethanol or dichloroethane; the reaction temperature is -20 to 40°C, preferably -10 to 30°C.

[0038] Secondly, β-nitroethylene is obtained by condensation reaction of the brominated product with nitromethane.

[0039] The ammonium formate salt is formic acid-ethanolamine, formic acid-diethanolamine, formic acid-triethanolamine, or a formic acid-triethylamine complex, preferably formic acid-ethanolamine or formic acid-diethanolamine. The reaction temperature is 20–120°C, preferably 30–100°C.

[0040] Finally, through the action of palladium on carbon, cuprous halide, and base, the hydrogenation, cyclization, and debenzylation reactions of β-nitrostyrene were completed using water as the reaction solvent.

[0041] The palladium-on-carbon catalyst is a palladium catalyst supported on activated carbon, with a palladium loading of 5-20% and a catalyst dosage of 0.5-30% of the weight of β-nitroethylene, preferably 1-20%.

[0042] The cuprous halide used in this process is cuprous chloride or cuprous bromide, and its amount is 0.5% to 30% of the weight of β-nitroethylene, preferably 1% to 20%.

[0043] The alkali 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 or potassium carbonate.

[0044] The hydrogen gas is introduced at a pressure of 5–80 atmospheres, preferably 10–60 atmospheres, during the reaction. The reaction temperature is 30–150°C, preferably 60–130°C.

[0045] The starting material 3,4-dibenzyloxybenzaldehyde involved in this invention can be prepared by reacting readily available 3,4-dihydroxybenzaldehyde with benzyl chloride under mild reaction conditions, according to the method described in the reference (J.Org.Chem.1997,62,908-915).

[0046] Compared with existing technologies, the present invention has the following advantages:

[0047] (1) The method for synthesizing 5,6-dihydroxyindoline involved in this invention is suitable for the requirements of high purity and high efficiency in the fields of chemical industry and pharmaceutical industry.

[0048] (2) The synthesis process of 5,6-dihydroxyindoline involved in this invention is simple to operate, the raw materials are readily available, the production is safe, and it is conducive to large-scale production. Detailed Implementation

[0049] The present invention will be further described in conjunction with specific embodiments, but the content of the present invention is not limited to these embodiments.

[0050] Example 1

[0051] (1) Bromination reaction: Synthesis of 3,4-dibenzyloxy-6-bromobenzaldehyde

[0052] 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. Phenyletrimethylammonium tribromide (37.6 g, 0.1 mol) was added in portions over 30 minutes at room temperature. The reaction was maintained at 40 °C for 5 h (TLC, with the reaction endpoint determined by thin-layer chromatography). After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the product was recrystallized from isopropanol and dried under vacuum to obtain 37 g of product, with a yield of 93%. Nuclear magnetic resonance analysis confirmed that the product structure was 3,4-dibenzyloxy-6-bromobenzaldehyde.

[0053] 1 H NMR (400MHz, CDCl3): 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).

[0054] (2) Condensation reaction: Synthesis of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene

[0055] 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 to a 500 mL three-necked flask. The mixture was heated to 80 °C with stirring and maintained at this temperature for 4 h (TLC was used to determine the reaction endpoint). After the reaction was completed, the temperature was lowered to 20 °C. The reaction solution was transferred to 200 mL of water, filtered, recrystallized from methanol, and dried under vacuum to obtain 84 g of product, with a yield of 95%. Nuclear magnetic resonance analysis confirmed that the product structure was 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

[0056] 1 H NMR (400MHz, CDCl3): 5.32 (2H, s), 5.41 (2H, s), 7.12~7.34 (12H, m).

[0057] (3) Reduction-cyclization reaction: Synthesis of 5,6-dihydroxyindoline

[0058] In a 2-liter pressure reactor, 88 g (0.2 mol) of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene prepared in the above reaction process, 45 g (10% Pd / C) catalyst, 2.8 g (0.02 mol) of cuprous bromide, 83 g (0.6 mol) of potassium carbonate, and 1000 g of water were added. The reaction was carried out at 120 °C for 6 hours under 5 kg hydrogen pressure. After the reaction was completed, the mixture was cooled, and the reaction solution was neutralized to pH 5 with dilute hydrochloric acid. Ethyl acetate (500 mL) was added, and the mixture was stirred for 30 minutes. The mixture was filtered (catalyst recovery), and the extract was decolorized with activated carbon and evaporated to dryness to obtain a crystalline product. Recrystallization from isopropyl ether and n-hexane yielded 21.7 g of white crystals, with a yield of 72%. Melting point: 230-232 °C.

[0059] 1 H NMR (400MHz, D2O): 3.05 (t, J = 7.2 Hz, 2H), 3.67 (t, J = 7.2 Hz, 2H), 6.84 (1H, s), 6.91 (1H, s).

[0060] The purity of the product was determined to be 99.5% by liquid chromatography.

[0061] Example 2

[0062] (1) Bromination reaction: Synthesis of 3,4-dibenzyloxy-6-bromobenzaldehyde

[0063] In a 250 mL three-necked flask, 3,4-dibenzyloxybenzaldehyde (31.8 g, 0.1 mol) was dissolved in 200 mL of anhydrous ethanol under mechanical stirring. 1-methyl-3-butylimidazolium tribromide (45.5 g, 0.12 mol) was added in portions over 30 minutes at room temperature. The reaction was maintained at 30 °C for 6 h (TLC was used to determine the reaction endpoint). After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the product was recrystallized from isopropanol and dried under vacuum to obtain 34.5 g of product, with a yield of 87%. Nuclear magnetic resonance analysis confirmed that the product structure was 3,4-dibenzyloxy-6-bromobenzaldehyde.

[0064] (2) Condensation reaction: Synthesis of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene

[0065] 3,4-Dibenzyloxy-6-bromobenzaldehyde (79.4 g, 0.2 mol), formic acid-diethanolamine (120 g), and nitromethane (18.3 g, 0.3 mol) were added to a 500 mL three-necked flask. The mixture was heated to 90 °C with stirring and maintained at this temperature for 2 h (TLC was used to determine the reaction endpoint). After the reaction was completed, the temperature was lowered to 20 °C. The reaction solution was transferred to 200 mL of water, filtered, recrystallized from methanol, and dried under vacuum to obtain 81 g of product, with a yield of 92%. Nuclear magnetic resonance analysis confirmed that the product structure was 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

[0066] (3) Reduction-cyclization reaction: Synthesis of 5,6-dihydroxyindoline

[0067] In a 2-liter pressure reactor, 88 g (0.2 mol) of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene prepared in the above reaction process, 50 g of 10% Pd / C catalyst, 3 g (0.03 mol) of cuprous chloride, 83 g (0.6 mol) of potassium carbonate, and 1000 g of water were added. The reaction was carried out at 110 °C for 7 hours under 8 kg hydrogen pressure. After the reaction was completed, the mixture was cooled, and the reaction solution was neutralized to pH 5 with dilute hydrochloric acid. Ethyl acetate (500 mL) was added, and the mixture was stirred for 30 minutes. The mixture was filtered (to recover the catalyst), and the extract was decolorized with activated carbon and evaporated to dryness to obtain a crystalline product. Recrystallization from isopropyl ether to n-hexane yielded 20.2 g of white crystals, with a yield of 67%. Melting point: 230-232 °C.

[0068] The purity of the product was determined to be 99.6% by liquid chromatography.

[0069] Example 3

[0070] (1) Bromination reaction: Synthesis of 3,4-dibenzyloxy-6-bromobenzaldehyde

[0071] In a 250 mL three-necked flask, 3,4-dibenzyloxybenzaldehyde (31.8 g, 0.1 mol) was dissolved in 200 mL of dichloroethane under mechanical stirring. Phenyletrimethylammonium tribromide (45.1 g, 0.12 mol) was added in portions over 30 minutes at room temperature. The reaction was maintained at 45 °C for 4 h (TLC was used to determine the reaction endpoint). After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the product was recrystallized from isopropanol and dried under vacuum to obtain 35.7 g of product, with a yield of 90%. Nuclear magnetic resonance analysis confirmed that the product structure was 3,4-dibenzyloxy-6-bromobenzaldehyde.

[0072] (2) Condensation reaction: Synthesis of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene

[0073] 3,4-Dibenzyloxy-6-bromobenzaldehyde (79.4 g, 0.2 mol), formic acid-diethanolamine (120 g), and nitromethane (36.6 g, 0.4 mol) were added to a 500 mL three-necked flask. The mixture was heated to 70 °C with stirring and maintained at this temperature for 3 h (TLC was used to determine the reaction endpoint). After the reaction was completed, the temperature was lowered to 20 °C. The reaction solution was transferred to 200 mL of water, filtered, recrystallized from methanol, and dried under vacuum to obtain 79 g of product, with a yield of 90%. Nuclear magnetic resonance analysis confirmed that the product structure was 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

[0074] (3) Reduction-cyclization reaction: Synthesis of 5,6-dihydroxyindoline

[0075] In a 2-liter pressure reactor, 88 g (0.2 mol) of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene prepared in the above reaction process, 15 g (20% Pd / C) catalyst, 3 g (0.03 mol) of cuprous chloride, 85 g (0.8 mol) of sodium carbonate, and 1000 g of water were added. The reaction was carried out at 90 °C for 4 hours under 5 kg hydrogen pressure. After the reaction was completed, the mixture was cooled, and the reaction solution was neutralized to pH 5 with dilute hydrochloric acid. Ethyl acetate (500 mL) was added, and the mixture was stirred for 30 minutes. The mixture was filtered (catalyst recovery), and the extract was decolorized with activated carbon and evaporated to dryness to obtain a crystalline product. Recrystallization from isopropyl ether to n-hexane yielded 22.3 g of white crystals, with a yield of 74%. Melting point: 230-232 °C.

[0076] The purity of the product was determined to be 99.6% by liquid chromatography.

[0077] Example 4

[0078] (1) Bromination reaction: Synthesis of 3,4-dibenzyloxy-6-bromobenzaldehyde

[0079] In a 250 mL three-necked flask, 3,4-dibenzyloxybenzaldehyde (31.8 g, 0.1 mol) was dissolved in 200 mL of anhydrous ethanol under mechanical stirring. Bromine (16 g, 0.1 mol) was slowly added dropwise at -5 °C over 50 minutes. The reaction was maintained at 30 °C for 8 h (TLC was used to determine the reaction endpoint). After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the product was recrystallized from isopropanol and dried under vacuum to obtain 32.5 g of product, with a yield of 82%. Nuclear magnetic resonance analysis confirmed that the product structure was 3,4-dibenzyloxy-6-bromobenzaldehyde.

[0080] (2) Condensation reaction: Synthesis of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene

[0081] 3,4-Dibenzyloxy-6-bromobenzaldehyde (79.4 g, 0.2 mol), formic acid-triethanolamine (120 g), and nitromethane (24.4 g, 0.4 mol) were added to a 500 mL three-necked flask. The mixture was heated to 70 °C with stirring and maintained at this temperature for 5 h (TLC was used to determine the reaction endpoint). After the reaction was completed, the temperature was lowered to 20 °C. The reaction solution was transferred to 200 mL of water, filtered, recrystallized from methanol, and dried under vacuum to obtain 71 g of product, with a yield of 90%. Nuclear magnetic resonance analysis confirmed that the product structure was 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

[0082] (3) Reduction-cyclization reaction: Synthesis of 5,6-dihydroxyindoline

[0083] In a 2-liter pressure reactor, 88 g (0.2 mol) of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene prepared in the above reaction process, 10 g (20% Pd / C) catalyst, 1.5 g (0.03 mol) of cuprous chloride, 64 g (0.6 mol) of sodium carbonate, and 1000 g of water were added. The reaction was carried out at 110 °C for 5 hours under 10 kg hydrogen pressure. After the reaction was completed, the mixture was cooled, and the reaction solution was neutralized to pH 5 with dilute hydrochloric acid. Ethyl acetate (500 mL) was added, and the mixture was stirred for 30 minutes. The mixture was filtered (to recover the catalyst), and the extract was decolorized with activated carbon and evaporated to dryness to obtain a crystalline product. Recrystallization from isopropyl ether to n-hexane yielded 20.5 g of white crystals, with a yield of 68%. Melting point: 230-232 °C.

[0084] The purity of the product was determined to be 99.7% by liquid chromatography.

[0085] Example 5

[0086] (1) Bromination reaction: Synthesis of 3,4-dibenzyloxy-6-bromobenzaldehyde

[0087] In a 1500 mL three-necked flask, 159 g (0.5 mol) of 3,4-dibenzyloxybenzaldehyde was dissolved in 650 mL of dichloroethane under mechanical stirring. Then, 206.8 g (0.55 mol) of phenyltrimethylammonium tribromide was added in portions over 40 minutes at room temperature. The reaction was maintained at 45 °C for 5 h (TLC was used to determine the reaction endpoint). After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the product was recrystallized from isopropanol and dried under vacuum to obtain 178.6 g of product, with a yield of 92%. Nuclear magnetic resonance analysis confirmed that the product structure was 3,4-dibenzyloxy-6-bromobenzaldehyde.

[0088] (2) Condensation reaction: Synthesis of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene

[0089] 3,4-Dibenzyloxy-6-bromobenzaldehyde (198.5 g, 0.5 mol), formic acid-diethanolamine (300 g), and nitromethane (50.2 g, 0.75 mol) were added to a 1000 mL three-necked flask. The mixture was heated to 80 °C with stirring and maintained at this temperature for 4 h (TLC was used to determine the reaction endpoint). After the reaction was completed, the temperature was lowered to 20 °C. The reaction solution was transferred to 800 mL of water, filtered, recrystallized from methanol, and dried under vacuum to obtain 200 g of product, with a yield of 91%. Nuclear magnetic resonance analysis confirmed that the product structure was 3,4-dibenzyloxy-6-bromo-β-nitrostyrene.

[0090] (3) Reduction-cyclization reaction: Synthesis of 5,6-dihydroxyindoline

[0091] In a 5-liter pressure reactor, 220 g (0.5 mol) of 3,4-dibenzyloxy-6-bromo-β-nitrostyrene prepared in the above reaction process, 50 g of 10% Pd / C catalyst, 6 g (0.06 mol) of cuprous chloride, 220.8 g (1.6 mol) of sodium carbonate, and 25000 g of water were added. The reaction was carried out at 100 °C for 7 hours under 10 kg hydrogen pressure. After the reaction was completed, the mixture was cooled, and the reaction solution was neutralized to pH 5 with dilute hydrochloric acid. Ethyl acetate (3 x 500 mL) was added, and the mixture was stirred for 30 minutes. The mixture was filtered (catalyst recovery), and the extract was decolorized with activated carbon and evaporated to dryness to obtain a crystalline product. Recrystallization from isopropyl ether and n-hexane yielded 52.8 g of white crystals, with a yield of 70%. Melting point: 230-232 °C.

[0092] The purity of the product was determined to be 99.5% by liquid chromatography.

Claims

1. A method for preparing 5,6-dihydroxyindoline, characterized in that, Includes the following steps: (1) Dissolve 3,4-dibenzyloxybenzaldehyde in a reaction solvent, add a brominating reagent, and after the bromination reaction is completed, concentrate under reduced pressure to remove the reaction solvent. After recrystallization and drying, 3,4-dibenzyloxy-6-bromobenzaldehyde is obtained; the brominating reagent is bromine, phenyltrimethylammonium tribromide or 1-methyl-3-butylimidazole tribromide. (2) The 3,4-dibenzyloxy-6-bromobenzaldehyde obtained in step (1) is mixed with ammonium formate and nitromethane and then stirred and heated. After the condensation reaction is completed, it is recrystallized and dried to obtain 3,4-dibenzyloxy-6-bromo-β-nitrostyrene; the ammonium formate is formic acid-ethanolamine, formic acid-diethanolamine or formic acid-triethanolamine; (3) Under the action of a catalyst, cuprous halide and base, 3,4-dibenzyloxy-6-bromo-β-nitrostyrene obtained in step (2) is subjected to hydrogenation reduction, cyclization and debenzylation reaction with water as the reaction solvent to obtain the target product 5,6-dihydroxyindoline; the catalyst is a palladium catalyst supported on activated carbon; the base is sodium carbonate or potassium carbonate; the reaction pressure is 5 to 80 atmospheres; the reaction temperature is 30 to 150℃.

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

3. The method for preparing 5,6-dihydroxyindoline according to claim 2, characterized in that: In step (2), the reaction temperature is 20 to 120°C.

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

5. The method for preparing 5,6-dihydroxyindoline according to claim 4, 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.

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