阅读说明：本技术 一种5,6-二羟基吲哚及其衍生物的合成方法 (Synthesis method of 5, 6-dihydroxyindole and derivatives thereof ) 是由 陈瑨 申志浩 刘长春 周洋 田之涯 代本才 于 2021-10-11 设计创作，主要内容包括：本发明公开了一种5,6-二羟基吲哚及其衍生物的合成方法,属于有机合成技术领域。该方法以三氟甲基磺酸铜为催化剂,(4,5-二甲氧基苯基)乙酰胺类化合物为原料,在无机碱的存在下发生成环反应,接着在氢卤酸水溶液中脱去保护基,反应液后处理之后得到5,6-二羟基吲哚及其衍生物。该方法避免了硝化或高压催化加氢反应过程,减少了副反应,提高了反应的安全性及收率；使用三氟甲基磺酸铜为催化剂,便宜易得,后处理简单,降低了成本,减少了三废排放,易于大规模生产应用。(The invention discloses a method for synthesizing 5, 6-dihydroxyindole and derivatives thereof, belonging to the technical field of organic synthesis. The method takes copper trifluoromethanesulfonate as a catalyst and takes a (4, 5-dimethoxyphenyl) acetamide compound as a raw material, a ring reaction is generated in the presence of inorganic base, then a protecting group is removed in a hydrohalic acid aqueous solution, and the 5, 6-dihydroxyindole and the derivatives thereof are obtained after the post-treatment of a reaction solution. The method avoids the nitration or high-pressure catalytic hydrogenation reaction process, reduces side reactions, and improves the safety and yield of the reaction; the copper trifluoromethanesulfonate is used as a catalyst, is cheap and easy to obtain, has simple post-treatment, reduces the cost, reduces the discharge of three wastes, and is easy for large-scale production and application.)

1. a method for synthesizing 5, 6-dihydroxyindole and derivatives thereof is characterized by comprising the following steps:

(1) taking a (4, 5-dimethoxyphenyl) acetamide compound as a raw material, adding a copper trifluoromethanesulfonate catalyst and an inorganic alkaline compound, and carrying out a cyclization reaction in an organic solvent;

(2) cooling the reaction liquid to room temperature, and removing the solvent by rotary evaporation to obtain solid powder which is directly used for reaction;

(3) adding a halogen acid aqueous solution, heating and refluxing to react and remove a protecting group;

(4) cooling the reaction liquid to room temperature, removing the aqueous solution in the reaction by rotary evaporation, dissolving the obtained solid in methanol, filtering, and concentrating the mother liquid under reduced pressure again to obtain a product 5, 6-dihydroxyindole and a derivative thereof;

the structural general formulas of the (4, 5-dimethoxyphenyl) acetamide compound and the 5, 6-dihydroxyindole derivative are respectively as follows:

wherein R is in H, methyl or ethylOne kind of (1); r₁Is one of H, methyl, ethyl and methoxyl; r₂Is one of H, methyl, ethyl, isopropyl and carboxyl; x is one of Cl and Br;

in the step (1), the inorganic basic compound is any one of alkali metal hydroxide and alkali metal carbonate.

2. The method for synthesizing 5, 6-dihydroxyindole and derivatives thereof according to claim 1, wherein the molar ratio of the catalyst to the starting compound I in step (1) is (0.05-0.5): 1.

3. the method for synthesizing 5, 6-dihydroxyindole and derivatives thereof according to claim 1, wherein the molar ratio of the inorganic basic compound to the starting compound I in step (1) is (0.05-0.5): 1.

Technical Field

The invention relates to a synthesis method of 5, 6-dihydroxyindole and derivatives thereof, belonging to the technical field of organic synthesis.

Background

5, 6-dihydroxyindole is an important intermediate of melanogen, is originally found in one plant in the nature and has no toxic or side effect on the human body. The common effective black dyeing component in the hair dye is aniline compound which has harmful effects of carcinogenesis, teratogenicity, allergy and the like on human body and has great harm to the health of people. 5, 6-dihydroxyindole is used as an effective substitute for aniline compounds because of its low irritation to human skin. It is also a good antioxidant, and can be used as intermediate for synthesizing some amino acids, alkaloids and tryptamine. 5, 6-dihydroxyindole was developed by some big foreign companies in the early 90 s of the last century and some patents were filed; in recent years, some research is carried out in China, but the methods are still in the research stage, are all produced in small quantities and cannot be applied to large-scale industrial production. At present, the main domestic supplier of the chemical is German Pasteur company, which has high price and is almost monopolized.

At present, there are several common methods for synthesizing 5, 6-dihydroxyindole, which can be classified into benzaldehyde method (US4595765, 1986; Synthetic Communications, 1985, 15 (4): 321-329), phenylacetonitrile method (fine petrochemical, 2007, (2): 53-55), phenethylamine method (EP1820491, 2007; CN110981782, 2020), etc. according to the difference of the starting materials, and the synthesis is generally carried out by several steps of hydroxyl protection, nitration, cyclization, deprotection, etc.; in addition, it is reported in the literature that electrochemical methods (29 th academic annual meeting of the chinese chemical society, 2014) can synthesize the substance.

Because the existing processes of 5, 6-dihydroxyindole all need nitration or high-pressure catalytic hydrogenation reaction, the process is difficult to control, side reactions are more, the separation and purification processes are complex, and the finally obtained final product has extremely unstable properties, thereby becoming a great difficulty in the synthesis of the existing 5, 6-dihydroxyindole and also becoming a reason for few domestic production. Therefore, research and development of a high-yield synthesis method of 5, 6-dihydroxyindole to synthesize a high-purity product are problems to be solved at present, and the industrial production requirements can be met.

Disclosure of Invention

Aiming at the defects that the existing domestic production method has low yield, high synthesis and separation difficulty and is difficult to obtain high-purity products, the invention aims to provide a novel synthesis route of 5, 6-dihydroxyindole and derivatives thereof, which has high yield, mild reaction conditions, simple post-treatment and easy large-scale production.

The technical scheme for solving the technical problems is as follows:

the method for synthesizing the 5, 6-dihydroxyindole and the derivatives thereof comprises the steps of taking a (4, 5-dimethoxyphenyl) acetamide compound I (self-made) as a raw material, adopting copper trifluoromethanesulfonate as a catalyst, carrying out a ring-forming reaction in the presence of an inorganic base, and then removing a protecting group in a hydrohalic acid aqueous solution to obtain a target product III. The specific reaction route is as follows:

R＝H,Me,Et X＝Cl,Br

R₁＝H,Me,Et,OCH₃

R₂＝H,Me,Et,i-Pr,COOH

wherein R is one of H, methyl and ethyl; r₁Is one of H, methyl, ethyl and methoxyl; r₂Is one of H, methyl, ethyl, isopropyl and carboxyl; x is one of Cl and Br.

The synthesis method of the 5, 6-dihydroxyindole and the derivatives thereof comprises the following steps:

(1) taking a (4, 5-dimethoxyphenyl) acetamide compound I (self-made) as a raw material, adding a copper trifluoromethanesulfonate catalyst and an inorganic alkaline compound, and carrying out a cyclization reaction in an organic solvent;

(2) cooling the reaction liquid to room temperature, and removing the solvent by rotary evaporation to obtain solid powder II which is directly used for reaction;

(3) adding a halogen acid aqueous solution, heating and refluxing to react and remove a protecting group;

(4) and cooling the reaction liquid to room temperature, removing the aqueous solution in the reaction by rotary evaporation, dissolving the obtained solid in methanol, filtering, and concentrating the mother liquid under reduced pressure again to obtain a product III.

In the synthesis method, the molar ratio of the copper trifluoromethanesulfonate catalyst to the raw material compound I in the step (1) is (0.05-0.5): 1, preferably (0.1 to 0.3): 1.

in step (1), the inorganic basic compound is any one of an alkali metal hydroxide and an alkali metal carbonate, and is preferably sodium hydroxide or potassium hydroxide. The molar ratio of the inorganic alkaline compound to the raw material compound I is (0.05-0.5): 1, preferably (0.1 to 0.3): 1.

further, in the step (1), the organic solvent is an organic solvent such as N, N-dimethylformamide, 1, 4-dioxane, xylene, toluene, or the like, and preferably an aprotic solvent such as toluene, xylene, or the like.

Further, the reaction temperature in the step (1) is 80-120 ℃, and the reaction time is 10-18 h. Preferably 100 ℃ and 110 ℃ for 12-14 h. The incomplete reaction can be caused by too low reaction temperature or too short reaction time, and the increase of byproducts and the reduction of yield can be caused by too high reaction temperature or too long reaction time.

In the synthesis method, the hydrohalic acid in the step (3) is hydrochloric acid or hydrobromic acid, and the molar ratio of the hydrohalic acid to the raw material is (1-3): 1. The mass concentration of the hydrochloric acid aqueous solution is more than 20 percent, and the mass concentration of the hydrochloric acid aqueous solution is preferably 35 to 37 percent sold in the market; the aqueous hydrobromic acid solution has a mass concentration of 20% or more, preferably 40% to 48% mass concentration (saturated concentration of hydrobromic acid).

Further, the reaction temperature in the step (3) is 80-120 ℃, and the reaction time is 2-5 h. Preferably at reflux temperature for 3-4 h.

Compared with the prior art, the invention has the advantages that: (1) the reaction condition is mild, the nitration or high-pressure catalytic hydrogenation reaction process is avoided, the side reaction is reduced, the reaction safety and yield are improved, and the yield reaches more than 90%; (2) the copper trifluoromethanesulfonate is used as the catalyst, so that the dosage is small, the selectivity is good, the post-treatment is simple, the cost is reduced, the discharge of three wastes is reduced, and the requirement of industrial production can be well met.

Detailed Description

The present invention will be described in further detail with reference to examples. Synthesis of (4, 5-dimethoxyphenyl) acetamide Compound I was synthesized according to the literature (Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972) 1999), 1981 (1): 290-.

Example 1

30.1g (0.1mol) of N- (2-bromo-4, 5-dimethoxyphenethyl) acetamide, 3.6g (0.01mol) of copper trifluoromethanesulfonate and 0.6g (0.01mol) of potassium hydroxide are added into 100mL of toluene, and the mixture is reacted for 12 hours at 100 ℃, the progress of the reaction is tracked by thin-layer chromatography, and the reaction is stopped when all the raw material points disappear. The reaction solution was cooled to room temperature and the solvent was removed by rotary evaporation to obtain 20.8g of a crude N-acetyl-5, 6-dimethoxyindoline as a white solid with a yield of 94.1%. 40g of hydrobromic acid aqueous solution with the mass concentration of 48% is added, the mixture is stirred for 0.5h at room temperature and heated to reflux for reaction for 3h, and the reaction liquid is detected by liquid chromatography until the reaction raw materials are completely converted. Cooling the reaction liquid to room temperature, removing most of the water solution in the reaction by rotary evaporation, dissolving the solid in methanol, filtering, and concentrating the mother liquid under reduced pressure to obtain a white solid, namely the product 5, 6-dihydroxyindole. The crude product was dried in a vacuum oven for 4-5 hours, and 12.7g was weighed, giving a yield of 91.4%. Analyzing data:¹HNMR(400MHz,DMSO-d⁶):δ10.21(s,1H),8.75(s,1H),8.47(s,1H),7.14-6.96(m,1H),6.81(s,1H),5.67-5.33(m,2H)ppm。

example 2

31.5g (0.1mol) of compound N- (1- (2-bromo-4, 5-dimethoxyphenyl) propyl) acetamide, 5.4g (0.015mol) of copper trifluoromethanesulfonate and 0.6g (0.015mol) of sodium hydroxide are added into 100mL of toluene, and the mixture is reacted at 100 ℃ for 12 hours, the progress of the reaction is tracked by thin-layer chromatography, and the reaction is stopped when all the raw material points disappear. The reaction solution was cooled to room temperature and the solvent was removed by rotary evaporation to obtain 21.2g of a crude N-acetyl-2-methyl-5, 6-dimethoxyindoline as a white solid in a yield of 90.2%. Adding40g of hydrobromic acid aqueous solution with the mass concentration of 48 percent is added, stirred for 0.5h at room temperature and heated to reflux for reaction for 3h, and the reaction liquid is detected by liquid chromatography until the reaction raw materials are completely converted. Cooling the reaction liquid to room temperature, removing most of the water solution in the reaction by rotary evaporation, dissolving the solid in methanol, filtering, and concentrating the mother liquid under reduced pressure to obtain a white solid, namely the product 2-methyl-5, 6-dihydroxyindole. The crude product was dried in a vacuum oven for 4-5 hours, and 13.1g was weighed, giving a yield of 89.7%. Analyzing data:¹HNMR(400MHz,DMSO-d⁶⁾:δ10.11(s,1H),8.66(s,1H),8.38(s,1H),6.81-6.67(m,1H),5.67-5.33(m,2H),2.42(s,3H)ppm。

example 3

25.7g (0.1mol) of the compound N- (2-chloro-4, 5-dimethoxyphenethyl) acetamide, 7.2g (0.02mol) of copper trifluoromethanesulfonate and 0.8g (0.015mol) of potassium hydroxide are added into 100mL of xylene, and the mixture is reacted at 100 ℃ for 12 hours, the reaction progress is tracked by thin layer chromatography, and the reaction is stopped when all the raw material points disappear. The reaction solution was cooled to room temperature and the solvent was removed by rotary evaporation to obtain 20.4g of a crude N-acetyl-5, 6-dimethoxyindoline as a white solid in a yield of 92.3%. Adding 30g of hydrochloric acid aqueous solution with the mass concentration of 37%, stirring at room temperature for 0.5h, heating to reflux and reacting for 3h, and detecting the reaction liquid by liquid chromatography until the reaction raw materials are completely converted. Cooling the reaction liquid to room temperature, removing most of the water solution in the reaction by rotary evaporation, dissolving the solid in methanol, filtering, and concentrating the mother liquid under reduced pressure to obtain a white solid, namely the product 5, 6-dihydroxyindole. The crude product was dried in a vacuum oven for 4-5 hours, and 12.9g was weighed, giving a yield of 94.2%. Analyzing data:¹HNMR(400MHz,DMSO-d⁶):δ10.15(s,1H),8.77(s,1H),8.50(s,1H),7.21-6.93(m,1H),6.75(s,1H),5.61-5.39(m,2H)ppm。

example 4

34.5g (0.1mol) of compound 2-acetamido-3- (2-bromo-4, 5-dimethoxyphenyl) propionic acid, 7.2g (0.02mol) of copper trifluoromethanesulfonate and 0.8g (0.02mol) of sodium hydroxide are added into 100mL of xylene, the mixture is reacted at 100 ℃ for 12 hours, the progress of the reaction is tracked by thin-layer chromatography, and the reaction is stopped when all the raw material points disappear. The reaction solution is cooled to room temperature and the solvent is removed by rotary evaporation to obtain 23.9g of crude white solid N-acetyl-2-carboxyl-5, 6-dimethoxy indoline with the yield of90.2 percent. Adding 30g of hydrochloric acid aqueous solution with the mass concentration of 37%, stirring at room temperature for 0.5h, heating to reflux and reacting for 3h, and detecting the reaction liquid by liquid chromatography until the reaction raw materials are completely converted. Cooling the reaction liquid to room temperature, removing most of the water solution in the reaction by rotary evaporation, dissolving the solid in methanol, filtering, and concentrating the mother liquid under reduced pressure to obtain a white solid, namely the product 2-carboxyl-5, 6-dihydroxyindole. The crude product was dried in a vacuum oven for 4-5 hours, and 15.5g was weighed, giving a yield of 89.6%. Analyzing data:¹HNMR(400MHz,DMSO-d⁶):δ12.33(s,1H),11.25(s,1H),8.62(s,1H),8.11(s,1H),6.87-6.64(m,3H)ppm。