阅读说明：本技术 一种以对甲氧基苯胺为原料合成褪黑素中间体的方法 (Method for synthesizing melatonin intermediate by taking p-methoxyaniline as raw material ) 是由 常宏宏 张娟 延秀银 李学金 刘强 高文超 于 2021-09-07 设计创作，主要内容包括：本发明属于化合物合成技术领域,为了解决目前合成褪黑素的方法中需要昂贵的还原剂,成本高、存在安全风险等问题,提供了一种以对甲氧基苯胺为原料合成褪黑素中间体的方法。以对甲氧基苯胺和乙二醇为原料,以负载型催化剂Pt/Al-(2)O-(3),一步水热法合成5-甲氧基吲哚,然后通过3步水热反应获得褪黑素前体5-甲氧基色胺。以乙二醇和对甲氧基苯胺为原料,首先合成5-甲氧基吲哚,随后经过3步反应得到了5-甲氧基色胺,反应总收率为14.0%。最后一步合成褪黑素将继续探索。设计了一条新的褪黑素合成路线,实现了应用结构简单且廉价的原料苯胺衍生物和乙二醇合成了褪黑素前体5-甲氧基色胺。(The invention belongs to the technical field of compound synthesis, and provides a method for synthesizing a melatonin intermediate by taking p-methoxyaniline as a raw material in order to solve the problems of high cost, safety risk and the like caused by the need of expensive reducing agents in the conventional method for synthesizing melatonin. Taking p-anisidine and glycol as raw materials and taking a supported catalyst Pt/Al 2 O 3 Synthesizing 5-methoxyindole by a one-step hydrothermal method, and then obtaining melatonin precursor 5-methoxytryptamine by 3-step hydrothermal reaction. The method comprises the steps of firstly synthesizing 5-methoxyindole by using ethylene glycol and p-methoxyaniline as raw materials, and then carrying out 3-step reaction to obtain 5-methoxytryptamine, wherein the total reaction yield is 14.0%. The final step of synthesizing melatonin will continue to be explored. A new melatonin synthesis route is designed, and the synthesis of the melatonin precursor 5-methoxytryptamine by using the aniline derivative and the ethylene glycol which have simple structures and low prices is realized.)

1. A method for synthesizing a melatonin intermediate by taking p-methoxyaniline as a raw material is characterized by comprising the following steps: taking p-anisidine and glycol as raw materials and taking a supported catalyst Pt/Al₂O₃Synthesizing 5-methoxyindole by a one-step hydrothermal method, and then obtaining melatonin precursor 5-methoxytryptamine by 3-step hydrothermal reaction.

2. The method for synthesizing the melatonin intermediate by taking p-methoxyaniline as the raw material as the claim 1 is characterized in that: the method comprises the following specific steps:

(1) synthesis of 5-methoxyindole: based on the content of the effective metal catalyst, 0.15 mmol and 3 wt percent of supported catalyst Pt/Al₂O₃As a catalyst, sequentially adding 54mmol of ethylene glycol and 1 mmol of p-anisidine, and stirring at the constant temperature of 190 ℃ for reaction for 24 hours; after the reaction is finished, taking out and cooling to room temperature, adding water, extracting with ethyl acetate, distilling under reduced pressure to recover the solvent and unreacted ethylene glycol, and carrying out column chromatography separation on residual liquid to obtain 5-methoxyindole;

(2) synthesizing an intermediate 5-methoxy-3- (2-formaldehyde) -indole: 0.68 mmol of 5-methoxyindole is dissolved in 200. mu.L of DMF for further use; cooling 340 μ L DMF to 0 deg.C in ice water bath, introducing nitrogen gas for protection, and addingAdding 100 mu L of phosphorus oxychloride POCl₃Injecting the mixture into the reactor, fully dissolving the mixture, adding the mixture into DMF (dimethyl formamide) solution of 5-methoxyindole within 10 min, heating the mixture to 35 ℃ under the protection of nitrogen, and stirring the mixture for reaction for 1 h; after the reaction is finished, adding ice water for quenching, sequentially adding NaOH solution and water, then extracting by using ethyl acetate, carrying out reduced pressure distillation to recover the solvent, and carrying out column chromatography separation on residual liquid to obtain an intermediate 3-aldehyde-5-methoxyindole;

(3) synthesizing an intermediate 5-methoxy-3- (2-nitrovinyl) indole: dissolving 0.6 mmol of 3-aldehyde-5-methoxyindole and 1.65 mmol of ammonium acetate in 2 mL of nitromethane; sealing and filling nitrogen for protection, heating to 80 ℃, and stirring for reaction for 2.5 h; cooling the reaction mixture to room temperature, adding 3 mL of water, carrying out reduced pressure distillation to recover the solvent, and separating the residual liquid by column chromatography; obtaining an intermediate 4;

(4) synthesizing an intermediate 5-methoxytryptamine: dissolving 0.6 mmol of the intermediate 4 in 6 mL of tetrahydrofuran THF, adding 0.36 mmol of 10% Pd/C catalyst, vacuumizing, sequentially replacing with nitrogen and hydrogen for three times, connecting a hydrogen balloon, introducing hydrogen, and stirring at 25 ℃ for reaction for 7 h; filtering the reaction solution, and performing rotary evaporation and column chromatography separation on a liquid phase to obtain 5-methoxytryptamine; (PE: EtOAc =90: 10); the isolation yield was 32.2%.

3. The method for synthesizing the melatonin intermediate by taking p-methoxyaniline as the raw material as claimed in claim 2, wherein the method comprises the following steps: eluent used in column chromatography in the step (1) and the step (2) is petroleum ether according to volume ratio: ethyl acetate = 97: 3; the eluent used in the column chromatography in the step (3) is petroleum ether according to the volume ratio: ethyl acetate =95: 5; the eluent used in the column chromatography in the step (4) is petroleum ether according to the volume ratio: ethyl acetate =90: 10.

4. The method for synthesizing the melatonin intermediate by taking p-methoxyaniline as the raw material as claimed in claim 2, wherein the method comprises the following steps: the supported catalyst Pt/Al₂O₃The preparation method comprises the following steps: firstly, carrying acid carrier Al₂O₃Placing the mixture in a muffle furnace, roasting the mixture for 4 hours at 500 ℃, and naturally cooling the mixture to room temperature; weighing1 g of the carrier was immersed in 30 mL of chloroplatinic acid H having a mass concentration of 3%₂PtCl₆·6H₂Stirring the mixture in an O aqueous solution for 24 hours at normal temperature, fully and uniformly mixing reaction liquid, filtering, drying a solid filter cake for 12 hours at 120 ℃, grinding the solid, roasting the ground solid in a muffle furnace for 4 hours at 500 ℃, and naturally cooling to obtain the Pt/Al with the Pt loading of 3 wt%₂O₃A catalyst; the catalyst is activated after being recycled for 4 times: the solid catalyst is washed by water, filtered, roasted for 5 hours at 500 ℃, and cooled for recycling.

Technical Field

The invention belongs to the technical field of compound synthesis, and particularly relates to a method for synthesizing a melatonin intermediate by taking p-methoxyaniline as a raw material.

Background

Besides being commonly used for treating insomnia, researchers also find that melatonin has the effect of inhibiting tumors, and the main manifestation of the melatonin is as follows: (1) can delay the aging of T cells so as to improve the lethality of the T cells to tumor cells; (2) can inhibit mitosis of hormone-dependent tumor cells; (2) can improve the activity of the antitumor drug and reduce the side effect. The melatonin structure is shown in figure 1.

The synthesis methods of melatonin are reported more, and most of the synthesis methods use indole, 5-methoxyindole and 4-methoxyphenylhydrazine as raw materials, need to undergo multi-step reactions, and have low total yield. Two synthetic routes for synthesizing melatonin by using 5-methoxyindole as a raw material are shown in the scheme 1 and the scheme 2. The reaction routes are all subjected to the reaction steps of indole three-position substitution and modification, and expensive lithium aluminum hydride is used as a reducing agent, so that the cost is high. In the first route, virulent potassium cyanide is used, so that a large safety risk exists; in the second route, anhydrous ether is used as a solvent, so that the catalyst is flammable and explosive, and is not easy to apply to actual production.

5-methoxyindole is a medical intermediate and is often used for synthesizing 5-methoxytryptamine, melatonin and other drug molecules. However, the reaction of aniline with ethylene glycol has been reported to be a reaction for synthesizing 5-methoxyindole from p-methoxyaniline.

Currently, most reports on the synthesis of 5-methoxyindole adopt a synthesis method using p-methoxynitrobenzene as a raw material, and synthesize indole by using a synthesis method using L-B indole and using nitrostyrene analogues as a raw material. Few studies on the synthesis of 5-methoxyindole have been found in the field of aniline ethylene glycol synthesis of indole.

Disclosure of Invention

The invention provides a method for synthesizing a melatonin intermediate by taking p-methoxyaniline as a raw material, aiming at solving the problems that an expensive reducing agent is needed, the cost is high, the safety risk exists and the like in the conventional method for synthesizing melatonin.

The invention is realized by the following technical scheme: a method for synthesizing melatonin intermediate by taking p-methoxyaniline as raw material comprises the steps of taking p-methoxyaniline and ethylene glycol as raw materials and taking a supported catalyst Pt/Al₂O₃Synthesizing 5-methoxyindole by a one-step hydrothermal method, and then obtaining melatonin precursor 5-methoxytryptamine by 3-step hydrothermal reaction.

The method comprises the following specific steps:

(1) synthesis of 5-methoxyindole: based on the content of the effective metal catalyst, 0.15 mmol and 3 wt percent of supported catalyst Pt/Al₂O₃As a catalyst, sequentially adding 54mmol of ethylene glycol and 1 mmol of p-anisidine, and stirring at the constant temperature of 190 ℃ for reaction for 24 hours; after the reaction is finished, taking out and cooling to room temperature, adding water, extracting with ethyl acetate, distilling under reduced pressure to recover the solvent and unreacted ethylene glycol, and carrying out column chromatography separation on residual liquid to obtain 5-methoxyindole;

(2) synthesizing an intermediate 5-methoxy-3- (2-formaldehyde) -indole: 0.68 mmol of 5-methoxyindole is dissolved in 200. mu.L of DMF for further use; cooling 340 μ L DMF to 0 deg.C with ice water bath, introducing nitrogen gas for protection, and adding 100 μ L phosphorus oxychloride POCl₃Injecting the mixture into the reactor, fully dissolving the mixture, adding the mixture into DMF (dimethyl formamide) solution of 5-methoxyindole within 10 min, heating the mixture to 35 ℃ under the protection of nitrogen, and stirring the mixture for reaction for 1 h; after the reaction is finished, adding ice water for quenching, sequentially adding NaOH solution and water, then extracting by using ethyl acetate, carrying out reduced pressure distillation to recover the solvent, and carrying out column chromatography separation on residual liquid to obtain an intermediate 3-aldehyde-5-methoxyindole;

(3) synthesizing an intermediate 5-methoxy-3- (2-nitrovinyl) indole: dissolving 0.6 mmol of 3-aldehyde-5-methoxyindole and 1.65 mmol of ammonium acetate in 2 mL of nitromethane; sealing and filling nitrogen for protection, heating to 80 ℃, and stirring for reaction for 2.5 h; the reaction mixture was cooled to room temperature, 3 mL of water was added, the solvent was recovered by distillation under reduced pressure, and the residue was separated by column chromatography. Obtaining an intermediate 4;

(4) synthesizing an intermediate 5-methoxytryptamine: dissolving 0.6 mmol of the intermediate 4 in 6 mL of tetrahydrofuran THF, adding 0.36 mmol of 10% Pd/C catalyst, vacuumizing, sequentially replacing with nitrogen and hydrogen for three times, connecting a hydrogen balloon, introducing hydrogen, and stirring at 25 ℃ for reaction for 7 h; filtering the reaction solution, and performing rotary evaporation and column chromatography separation on a liquid phase to obtain the 5-methoxytryptamine.

Eluent used in column chromatography in the step (1) and the step (2) is petroleum ether according to volume ratio: ethyl acetate = 97: 3; the eluent used in the column chromatography in the step (3) is petroleum ether according to the volume ratio: ethyl acetate =95: 5; the eluent used in the column chromatography in the step (4) is petroleum ether according to the volume ratio: ethyl acetate =90: 10.

The supported catalyst Pt/Al₂O₃The preparation method comprises the following steps: firstly, carrying acid carrier Al₂O₃Placing the mixture in a muffle furnace, roasting the mixture for 4 hours at 500 ℃, and naturally cooling the mixture to room temperature; weighing 1 g of carrier, and soaking in 30 mL of chloroplatinic acid H with the mass concentration of 3%₂PtCl₆·6H₂Stirring the mixture in an O aqueous solution for 24 hours at normal temperature, fully and uniformly mixing reaction liquid, filtering, drying a solid filter cake for 12 hours at 120 ℃, grinding the solid, roasting the ground solid in a muffle furnace for 4 hours at 500 ℃, and naturally cooling to obtain the Pt/Al with the Pt loading of 3 wt%₂O₃A catalyst; the catalyst is activated after being recycled for 4 times: the solid catalyst is washed by water, filtered, roasted for 5 hours at 500 ℃, and cooled for recycling.

The invention researches a reaction system for synthesizing 5-methoxyindole by one step by taking p-methoxyaniline as a raw material, screens various commonly used noble metal compounds and supported catalysts, and has poor catalytic effect of most metal catalysts, most of which even have no reaction. And Pt/Al is used₂O₃Relatively good yield can be obtained by the reaction, and the yield of the 5-methoxyindole can reach 49.6%.

The method comprises the steps of firstly synthesizing 5-methoxyindole by using ethylene glycol and p-methoxyaniline as raw materials, and then carrying out 3-step reaction to obtain 5-methoxytryptamine, wherein the total reaction yield is 14.0%. The final step of synthesizing melatonin will continue to be explored. A new melatonin synthesis route is designed, and the synthesis of the melatonin precursor 5-methoxytryptamine by using the aniline derivative and the ethylene glycol which have simple structures and low prices is realized.

Drawings

Fig. 1 is a structural formula of melatonin;

fig. 2 is a first route for synthesizing melatonin by using 5-methoxyindole as a raw material;

fig. 3 is a second route for synthesizing melatonin by using 5-methoxyindole as a raw material;

FIG. 4 is a gas chromatography standard curve for p-anisidine;

FIG. 5 is a gas chromatographic standard curve for 5-methoxyindole;

FIG. 6 is a reaction equation of p-methoxyaniline and ethylene glycol to synthesize 5-methoxyindole;

fig. 7 is a route for synthesizing melatonin by using 5-methoxyindole as a raw material;

fig. 8 is a reaction equation for synthesizing melatonin by using p-anisidine and ethylene glycol as raw materials; in the figure: 1 is p-anisidine; 2 is 5-methoxyindole; 3 is 5-methoxy-3- (2-carboxaldehyde) -indole; 4 is intermediate 5-methoxy-3- (2-nitrovinyl) indole; 5 is intermediate 5-methoxy tryptamine;

FIG. 9 is a nuclear magnetic spectrum of 5-methoxyindole;

FIG. 10 is a nuclear magnetic spectrum of 3-aldehyde-5-methoxyindole;

FIG. 11 is a nuclear magnetic spectrum of 5-methoxy-3- (2-nitrovinyl) indole;

FIG. 12 is a nuclear magnetic spectrum of 5-methoxytryptamine.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are some embodiments of the present invention, but not all embodiments; all other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1: in order to explore the reason and find a catalyst system with a good catalytic effect in the reaction for synthesizing the melatonin intermediate by taking p-anisidine as a raw material, a supported catalyst is selected for screening the catalyst system. The catalyst for one-step synthesis of indole from aniline and ethylene glycol mainly comprises metal palladium, platinum, rhodium, ruthenium, and metal catalysts such as copper and silver under high temperature. Therefore, attempts have been made to select a suitable catalyst reaction system by separately attempting to use these metal catalysts under relatively low temperature and atmospheric pressure conditions.

1. Laboratory instruments and reagents: the laboratory instruments used are shown in Table 1 and the reagents used are shown in Table 2.

TABLE 1 Experimental apparatus

TABLE 2 test reagents

2. Procedure of experiment

Preparation of the supported catalyst: preparing a supported catalyst by adopting an impregnation method, firstly roasting a catalyst carrier in a muffle furnace at 500 ℃ for 4 hours, and then naturally cooling to obtain a pretreated carrier for later use; soaking 1 g of the roasted carrier in a metal salt solution to be loaded with a certain concentration, stirring for 24h at normal temperature, carrying out suction filtration and washing on the solid, placing the solid in a 120 ℃ drying oven for drying for 12 h, taking out the solid, grinding the solid, placing the solid in a muffle furnace for roasting at 500 ℃ for 4h, and cooling the solid for reaction.

The reaction process is as follows: a25 mL pressure-resistant test tube was charged with 0.15 mmol of the main catalyst (based on the content of the effective metal catalyst), 0.45 mmol of the cocatalyst a, and 0.45 mmol of the cocatalyst b, and 54mmol (3 mL) of ethylene glycol and 1 mmol (108. mu.L) of p-anisidine were measured by a microsyringe and charged into the reaction tube. The reaction tube is placed in a constant temperature oil bath kettle at 190 ℃ and reacts for 24 hours under magnetic stirring. After the reaction is finished, the reaction tube is taken out and cooled to room temperature, thin layer chromatography is firstly used for analysis, then the reaction liquid is diluted by 10 times by absolute ethyl alcohol, anhydrous sodium sulfate is added for drying, then the reaction liquid is placed in a 1 mL centrifuge tube for 1800 r/s for centrifugation for 3 min, and then gas chromatography detection is carried out.

The detection method comprises the following steps: the conversion rate of p-methoxyaniline and the yield of 5-methoxyindole are detected by adopting a gas chromatography external standard method. The GC-2010 gas chromatograph, whose instrument is Shimadzu, Japan, was used. The chromatographic column is an Agilent HP-5 capillary column (30 m multiplied by 0.25 mm multiplied by 0.25 mu m), the temperature of the column is set as the temperature programming, the initial column temperature is 60 ℃, and the temperature is increased to 180 ℃ at the temperature increasing speed of 6 ℃/min. The standard curves of the p-methoxyaniline as the raw material and the 5-methoxyindole as the product are respectively established by the analysis method, and are shown in fig. 4 and fig. 5.

3. Results of the experiment

Experiments research the catalytic effects of various catalysts in the reaction of synthesizing 5-methoxyindole from ethylene glycol and p-methoxyaniline, and the reaction formula of synthesizing 5-methoxyindole from p-methoxyaniline and ethylene glycol is shown in figure 6. The designed and prepared palladium, platinum, rhodium and ruthenium, supported catalysts loaded by different carriers and a multi-component catalytic system formed by combining the metal compound and the auxiliary agent are mainly considered, and the experimental results are shown in tables 3 and 4. Reaction conditions are as follows: 0.015mmol of catalyst, 3 mL of glycol and 1 mmol of p-anisidine, and reacting at 190 ℃ for 24 hours, wherein the loading of the catalyst is 3 wt%.

Table 3: screening of Supported catalysts

The reaction conditions of the multi-component catalytic system are as follows: 0.015mmol of catalyst, 3 mL of glycol and 1 mmol of p-anisidine, and reacting at 190 ℃ for 24 hours, wherein the proportion of the cocatalyst is 1.5 percent and 4.5 percent.

Table 4: screening of multicomponent catalytic systems

Through screening of compounds of various metals and supported catalysts, the effect of the commonly used noble metal catalyst in the reaction is not good. And Pt/Al₂O₃The catalyst can obtain better yield of 49%. The catalytic system is used for the next synthesis of a drug intermediate. P-methoxyaniline is more difficult to perform in this reaction than aniline ethylene glycol, presumably because the electron cloud density on the benzene ring is increased by the para-methoxy group, and the amino group is difficult to dehydrate and condense with the alcoholic hydroxyl group, resulting in difficulty in the reaction. And the supported catalyst Pt/Al₂O₃The platinum has strong hydrogen absorption function, and the acidic alumina can help the dehydration process to normally carry out the reaction.

Example 2: the 5-methoxyindole obtained according to example 1 was used for the synthesis of melatonin, exploring its possible applications in the field of pharmaceutical synthesis. Melatonin (Meldonin, MT) is one of hormones secreted by the pineal gland, belongs to indole heterocyclic compounds, and has the chemical name ofN-acetyl-5-methoxytryptamine, also known as pinecone, melatonin. Melatonin is commonly used as a health-care medicine for regulating sleep and improving sleep quality, and researches show that the melatonin has a certain anti-aging effect and shows a certain inhibition effect on certain cancers such as breast cancer, lung cancer, melanoma and the like. P-methoxyaniline and ethylene glycol are used as raw materials, 5-methoxyindole is firstly synthesized, and then a synthesis process route of melatonin is further explored.

1. Synthesis of melatonin by using 5-methoxyindole as raw material

The reaction pathway as shown in scheme 7 was designed: firstly, formaldehyde is used as a source of three-position aldehyde group of an intermediate 3, ammonia water is used as alkali, FeCl₃As a catalyst, an isolated yield of 28.8% was obtained. Under the action of ammonium acetate, nitromethane and aromatic aldehyde are subjected to a nitro-alcohol condensation reaction and are dehydrated to obtain a target product, and the separation yield is 97.9%. Finally using LiAlH₄The double bond and the nitro group are reduced simultaneously, and the yield of the step is lower.

The specific test process is as follows: synthesis of intermediate 3: 0.5 mmol (74 mg) of 5-methoxyindole was dissolved in 2 mL of DMF, followed by addition of 0.5 mmol (40. mu.L) of aqueous formaldehyde (37%), 0.07 mmol (5. mu.L) of aqueous ammonia (25%), 0.01 mmol (16.2 mg) of FeCl₃. Reflux open to room temperature for 1 h. After the reaction is finished, using ethyl acetate to reactEster extraction, solvent recovery by distillation under reduced pressure followed by column chromatography (PE: EtOAc = 97:3) gave intermediate 3.

Synthesis of intermediate 4: 0.6 mmol (105 mg) of intermediate 3 and 1.65 mmol (127 mg) of ammonium acetate were dissolved in 2 mL of nitromethane. Sealing and filling nitrogen for protection, heating to 80 ℃, and stirring for reaction for 2.5 h. The reaction mixture was cooled to room temperature, the reaction solution was extracted with ethyl acetate, and the solvent was recovered by distillation under the reduced pressure and separated by column chromatography (PE: EtOAc =95:5) to give intermediate 4.

Synthesis of intermediate 5: 0.5 mmol (95 mg) of intermediate 4 was reacted with 2 mmol of LiAlH₄(76 mg) was added to 2 mL of tetrahydrofuran and the reaction was refluxed for 2 h. Thin layer chromatography showed low reaction yield (PE: EtOAc = 75:25) so no further synthesis of the product of step 4 could be carried out. The exploration experiment shows that: firstly, the yield is lower, phosphorus oxychloride which is more commonly used in the reaction is tried, and H at C3 is substituted into formaldehyde group, so that higher yield is obtained; thirdly, the reaction is hardly carried out, and thin-layer chromatography observation shows that a large amount of byproducts with extremely high polarity exist in the system, and the content of the intermediate 5 for reducing double bonds and nitro groups is extremely low, which is probably caused by LiAlH₄The reducibility is too strong, and double bonds of pyrrole rings and methoxyl groups on benzene rings are destroyed. The improved route adopts a milder hydrogen Pd/C system to finish the step reduction. The specific reaction equation is shown in FIG. 8.

The above route has five reactions, and the specific experimental process is as follows:

synthesis of intermediate 2: 1 mmol (123 mg) of p-anisidine, 54mmol (3 mL) of ethylene glycol (both as reactant and solvent), 0.015mmol (98 mg) of 3 wt% Pt/Al₂O₃Mixing, placing in a pressure-resistant tube, heating to 190 ℃, and stirring for reaction for 24 hours. After the reaction, the reaction mixture was cooled to room temperature, an appropriate amount of water was added, the mixture was extracted with ethyl acetate, the solvent and unreacted ethylene glycol were recovered by distillation under reduced pressure, and the residual liquid column chromatography gave 5-methoxyindole (PE: EtOAc = 97:3) in an isolated yield of 49.6%.

Synthesis of intermediate 3: 0.68 mmol (147 mg) of 5-methoxyindole was dissolved in 200. mu.L of DMF. Cooling 340 μ L DMF to 0 deg.C in ice water bath, introducing nitrogen gas for protection, and addingMixing 100 mu L of OCl₃Injecting the mixture into the reactor, slowly adding the mixture into DMF (dimethyl formamide) solution of 5-methoxyindole after fully dissolving, heating to 35 ℃ under the protection of nitrogen, and stirring for reacting for 1 h. After the reaction is finished, ice water is added for quenching, NaOH solution and water are sequentially added, then ethyl acetate is used for extraction, reduced pressure distillation is carried out to recover the solvent, and column chromatography separation is adopted (PE: EtOAc = 97:3), so that the intermediate 3-aldehyde-5-methoxyindole is obtained, and the separation yield is 89.5%.

Synthesis of intermediate 4: 0.6 mmol (105 mg) of 3-formyl-5-methoxyindole and 1.65 mmol (127 mg) of ammonium acetate were dissolved in 2 mL of nitromethane. The reaction bottle is sealed and filled with nitrogen for protection, and the mixture is heated to 80 ℃ and stirred for reaction for 2.5 h. After the reaction mixture was cooled to room temperature, a small amount of water was added, and the solvent was recovered by column chromatography by distillation under the reduced pressure (PE: EtOAc =95: 5). Intermediate 4 was obtained in 97.9% isolated yield.

Synthesis of intermediate 5: 0.6 mmol (114 mg) of intermediate 4 was dissolved in 6 mL of THF, 0.36 mmol (381 mg) of 10% Pd/C catalyst was added, vacuum was applied, nitrogen and hydrogen were sequentially substituted three times, hydrogen was bubbled through a hydrogen balloon, and the reaction was stirred at 35 ℃ for 7 h. The reaction solution is filtered, and the liquid phase is subjected to rotary evaporation and column chromatography separation (PE: EtOAc =90: 10) to obtain the intermediate 5-methoxytryptamine, wherein the separation yield is 32.2%.

Synthesis of product 6 (melatonin): 1 mmol (208 mg) of intermediate 5 was dissolved in 3 mL of dichloromethane, 1.4 mmol (0.1 mL) of acetyl chloride was added, and the reaction was stirred at room temperature for 2 h. This step does not lead to the product melatonin and still requires further attempts.

The invention researches a reaction system for synthesizing 5-methoxyindole by one step by taking p-methoxyaniline as a raw material, screens various commonly used noble metal compounds and supported catalysts, and has poor catalytic effect of most metal catalysts, most of which even have no reaction. And Pt/Al is used₂O₃Relatively good yield can be obtained by the reaction, and the yield of the 5-methoxyindole can reach 49.6%.

The method comprises the steps of firstly synthesizing 5-methoxyindole by using ethylene glycol and p-methoxyaniline as raw materials, and then carrying out 3-step reaction to obtain 5-methoxytryptamine, wherein the total reaction yield is 14.0%. Although the yield is low at present, the reduction process of the fourth step still has a large optimization space, and the last step is also continuously explored. In a word, a new melatonin synthesis route is designed, and the synthesis of the melatonin precursor 5-methoxytryptamine by using the aniline derivative and the ethylene glycol which are simple in structure and low in price is realized.

The structure of the resulting compound is characterized as follows:

1. 5-methoxyindole：¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 7.18(d, J = 8.8 Hz, 1H), 7.08 (t, J = 2.9 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.8, 2.5 Hz, 1H), 6.39 (t, J = 2.5 Hz, 1H), 3.76 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 154.2, 130.9, 128.2, 124.8, 112.3, 111.7, 102.4, 102.3, 55.8。

2. 5-methoxy-3- (2-carboxaldehyde) -indoles：¹H NMR (400 MHz, DMSO-d ₆) δ 11.91 (s, 1H), 9.78 (s, 1H), 8.08 (d, J = 2.7 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 6.76 (dd, J = 8.8, 2.5 Hz, 1H), 3.66 (s, 3H)。

3. 5-methoxy-3- (2-nitrovinyl) indoles：¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 8.29 (d, J = 13.5 Hz, 1H), 7.74 (d, J = 13.5 Hz, 1H), 7.63 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.99 (dd, J = 8.9, 2.3 Hz, 1H), 3.92 (s, 3H)。

4. 5-methoxy tryptamine：¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 7.28 (s, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.89 (dd, J = 8.8, 2.4 Hz, 1H), 4.66 (t, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.46 (td, J = 7.3, 0.8 Hz, 2H), 1.56 (s, 2H)。

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.