Synthesis method of melatonin intermediate N-acetyl-5-hydroxytryptamine

Abstract

The invention provides a synthesis method of a melatonin intermediate N-acetyl-5-hydroxytryptamine, which comprises the following steps: adding 5-hydroxytryptamine hydrochloride into an organic solvent and water, stirring for dissolving, adding inorganic alkali, dropwise adding acetyl chloride, controlling the temperature, stirring for reaction, and performing post-treatment after the reaction is finished to obtain a white N-acetyl-5-hydroxytryptamine solid. The melatonin intermediate obtained through the method is good in solid state and high in product yield, and the purity can reach 99.93% or above. Meanwhile, the method is simple and convenient to operate, saves materials and labor, avoids generation and treatment of waste water and waste residues, and is more suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of synthesis of pharmaceutical compounds, and particularly relates to a synthesis method of a melatonin intermediate. BACKGROUND

[0002] N-acetyl-5-methoxytryptamine (melatonin) belongs to B-indole propyl alanine derivatives, is an amine hormone produced by mammalian pineal gland after dark stimulation, and is an important antioxidant in vivo. Melatonin can improve the sleep quality of animals. With the growth of animal age, the secretion amount of N-acetyl-5-methoxytryptamine gradually decreases, thereby affecting the sleep quality of animals. More and more studies show that N-acetyl-5-methoxytryptamine has physiological functions such as anti-oxidation, anti-aging, immune regulation, and anti-cancer in addition to treating insomnia.

[0003] Patent WO2011047156 introduces a chemical synthesis method of melatonin. 5-hydroxytryptamine hydrochloride is used as a starting material, the amino group and phenolic hydroxyl group are acetylated by using acetyl chloride, then the acetyl group of the phenolic hydroxyl group is selectively hydrolyzed under alkaline conditions to obtain the melatonin intermediate N-acetyl-5-hydroxytryptamine, and finally the phenolic hydroxyl group is methylated by using dimethyl sulfate, so that melatonin is finally prepared by three reaction steps.

[0004] Patent CN113788780A also introduces a chemical synthesis method of melatonin. 5-hydroxytryptamine hydrochloride is also used as a starting material, acetylation is first performed, then methylation is performed by using dimethyl sulfate to obtain melatonin. The method of the patent is similar to the method of patent WO2011047156, only the selective hydrolysis of the second step is combined as a post-treatment step of the acetylation reaction of the first step, and the hydrolysis degree of the ester bond is determined by the length of the post-treatment time, so that the double acetylation by-product is easily left. In addition, the obtained reaction product is a melatonin intermediate solution, not a solid intermediate, so that the quality control of the intermediate is difficult to perform.

[0005] The process method introduced in the patent CN 113387868A is similar to CN 113788780A. In the acetylation process, organic base and inorganic base are added, dichloromethane is used as the reaction solvent, water is added after the reaction is completed, and stirring is carried out for 15 min. The selective ester hydrolysis reaction is carried out by using inorganic base, which is equivalent to combining the selective hydrolysis step as a post-treatment step of the acetylation reaction. The patent method needs to strictly control the water content of dichloromethane during the acetylation reaction, and the product is obtained by evaporating the solvent in the post-treatment, which is easy to leave residues, which is not conducive to quality control. The product is difficult to take out from the reaction kettle, which increases the difficulty of industrial production. The method needs to add triethylamine, which has the defects of toxicity, flammability and explosion. Special attention needs to be paid to operation and storage. In the scale-up production, a large amount of nitrogen source pollutants will be generated, which brings great difficulty to the treatment of waste liquid and waste gas, and violates the concept of green chemistry.

[0006] The synthesis methods introduced in the above three patents are all based on 5-hydroxytryptamine hydrochloride as the starting material, acetylation is carried out by acetyl chloride in the presence of organic base in organic solvent. Under this condition, the phenolic hydroxyl group will also be acetylated to form an ester, which cannot be avoided. Subsequently, the acetyl group on the phenolic hydroxyl group needs to be selectively removed to obtain the melatonin intermediate N-acetyl-5-hydroxytryptamine. This method increases the reaction steps, reduces the yield of the intermediate, increases the cost of labor and materials, generates waste liquid and waste residue, and has poor atom economy, which is not conducive to the environment. We also found in the experimental process and tracking detection process that in the presence of organic base, on the basis of amino acetylation and phenolic hydroxyl acetylation, the secondary amine on the indole ring will also undergo acetylation reaction, which introduces an impurity and leads to poor reaction selectivity and low conversion rate.

[0007] The existing technology will produce phenolic hydroxyl acetylation by-products in the acetylation process, and subsequent selective hydrolysis reaction is also needed, which reduces the reaction yield, increases the cost of materials and labor, generates waste water and waste residue, and is not conducive to the environment. SUMMARY

[0008] In view of the shortcomings of the prior art, the present application provides a synthesis method of melatonin intermediate N-acetyl-5-hydroxytryptamine, which solves the problems of complex process, low yield and poor product quality in the prior art. The method is simple to operate and saves materials and labor; the post-treatment is simple and the product is in good condition, which is more conducive to quality control; the reaction selectivity is high, the atom economy is good, the generation and treatment of waste water and waste residue are avoided, and it is more suitable for industrial production.

[0009] The synthesis method of melatonin intermediate N-acetyl-5-hydroxytryptamine provided by the present application comprises the following steps:

[0010] 1. Add 5-hydroxytryptamine hydrochloride into organic solvent and water, stir to dissolve,

[0011] 2. Add inorganic base, stir to dissolve,

[0012] 3. Drop acetyl chloride, control temperature, stir to react, to obtain N-acetyl-5-hydroxytryptamine.

[0013] In the step 1, the organic solvent is tetrahydrofuran or acetonitrile.

[0014] Further, the inorganic base is one of sodium carbonate, potassium carbonate and sodium hydroxide.

[0015] Further, the mass-volume ratio of 5-hydroxytryptamine hydrochloride, organic solvent and water is 1g:2ml-10ml:5ml-20ml.

[0016] Preferably, the ratio of 5-hydroxytryptamine hydrochloride, organic solvent and water is 1g:5ml-8ml:8ml-15ml.

[0017] Further, the molar ratio of inorganic base to 5-hydroxytryptamine hydrochloride is 3.0-10.0:1.0.

[0018] Further, the temperature in step 3 is 5-30℃.

[0019] Further, the molar ratio of acetyl chloride to 5-hydroxytryptamine hydrochloride in step 3 is 1.5-3.0:1.0.

[0020] Further, the reaction time in step 3 is 1-2h.

[0021] In the present application, the synthesis method of melatonin intermediate N-acetyl-5-hydroxytryptamine further comprises step 4: after the reaction is completed, post-treatment is carried out to obtain N-acetyl-5-hydroxytryptamine fine product.

[0022] Further, the post-treatment method in step 4 is to add water and ethyl acetate to the reaction solution, stir and then stand to separate the layers, retain the organic phase, extract the aqueous phase with ethyl acetate, stand to separate the layers, remove the aqueous phase, combine the organic phases, evaporate the solvent, add acetonitrile, stir to crystallize at low temperature, filter, rinse, dry, to obtain N-acetyl-5-hydroxytryptamine white granular fine product.

[0023] Further, in step 4, the temperature is lowered to 5℃, and the stirring crystallization is 2h.

[0024] This invention, through exploration and understanding of the acetylation reaction of 5-hydroxytryptamine hydrochloride in existing technologies, combined with study and reflection on the Schotten-Baumann reaction, reveals that primary amines exhibit higher reactivity with acyl chlorides than secondary amines, tertiary amines, and phenolic hydroxyl groups. However, the presence of water may cause the reactive acyl chloride to undergo hydrolysis first, thereby losing its reactivity with the amino group. Through continuous experimentation and optimization, suitable solvents and inorganic bases for the selective acetylation of 5-hydroxytryptamine hydrochloride were finally identified, resulting in reaction conditions where acetylation occurs only on the primary amine group, without acetylation of the phenolic hydroxyl group.

[0025] Beneficial Effects: This invention, through screening and optimization of the types of bases and reaction solvents used in the first-step acetylation reaction, ultimately found a method for selective acetylation, namely, acetylation of only primary amines without producing phenolic hydroxyl acetylated products. This eliminates the need for a selective deacetylation reaction step, resulting in good atom economy, saving materials and labor, and avoiding the generation and treatment of wastewater and waste residue. The N-acetyl-5-hydroxytryptamine prepared by this method has a good product condition, making post-processing operations more suitable for scale-up production, and greatly improving the product yield with a purity of over 99.93%. It avoids the large amount of nitrogen source pollutants generated during the scale-up production of triethylamine, making it more suitable for industrial production. Attached Figure Description

[0026] Figure 1 The chromatogram is of N-acetyl-5-hydroxytryptamine prepared in Example 1 of this invention. Detailed Implementation

[0027] Example 1

[0028] Add 5 g of 5-hydroxytryptamine hydrochloride (23 mmol), 25 ml of tetrahydrofuran, and 50 ml of water to a reaction flask, stir until dissolved, then add 10 g of sodium carbonate solid (92 mmol) and stir to dissolve at room temperature. Slowly add 3.69 g of acetyl chloride (46 mmol) dropwise, maintaining the temperature at 25 °C. After the addition is complete, stir the reaction for 1 h, and monitor the reaction progress by HPLC. When the 5-hydroxytryptamine concentration is ≤1.0%, add 100 ml of water and 50 ml of ethyl acetate to the reaction solution, stir for 10 min, allow to stand and separate the layers, retain the organic phase, extract the aqueous phase with 50 ml of ethyl acetate, allow to stand and separate the layers, remove the aqueous phase, and combine the organic phases. Evaporate the solvent from the organic phase, add 50 ml of acetonitrile, cool to 5 °C, stir to crystallize for 2 h, filter, wash with 10 ml of acetonitrile, and dry to obtain 4.98 g of white granular solid N-acetyl-5-hydroxytryptamine, yield 99.0%, purity 99.96%.

[0029] Example 2

[0030] Add 1 g of 5-hydroxytryptamine hydrochloride (4.7 mmol), 5 ml of acetonitrile, and 10 ml of water to a reaction flask, stir until dissolved, then add 2.6 g of potassium carbonate solid (18.8 mmol) and stir to dissolve at room temperature. Slowly add 0.74 g of acetyl chloride (9.4 mmol) dropwise, maintaining the temperature at 5 °C. After the addition is complete, stir the reaction for 1 h, and monitor the reaction progress by HPLC. When the 5-hydroxytryptamine concentration is ≤1.0%, add 20 ml of water and 10 ml of ethyl acetate to the reaction solution, stir for 10 min, allow to stand and separate the layers, retain the organic phase, extract the aqueous phase with 10 ml of ethyl acetate, allow to stand and separate the layers, remove the aqueous phase, and combine the organic phases. Evaporate the solvent from the organic phase, add 10 ml of acetonitrile, cool to 5 °C, stir to crystallize for 2 h, filter, wash with 2 ml of acetonitrile, and dry to obtain 1 g of white granular solid N-acetyl-5-hydroxytryptamine, yield 99.1%, purity 99.95%.

[0031] Example 3

[0032] 1 g of 5-hydroxytryptamine hydrochloride (4.7 mmol), 2 ml of tetrahydrofuran, and 5 ml of water were added to a reaction flask and stirred until dissolved. Then, 1.9 g of sodium hydroxide solid (47 mmol) was added and stirred at room temperature until dissolved. 1.1 g of acetyl chloride (14.1 mmol) was slowly added dropwise at 10 °C. After the addition was complete, the mixture was stirred for 1.5 h, and the reaction progress was monitored by HPLC. When the 5-hydroxytryptamine concentration was ≤1.0%, 20 ml of water and 10 ml of ethyl acetate were added to the reaction solution, and the mixture was stirred for 10 min. The mixture was allowed to stand and separate into layers, and the organic phase was retained. The aqueous phase was extracted with 10 ml of ethyl acetate, allowed to stand and separate into layers, and the aqueous phase was removed. The organic phases were combined. The solvent was evaporated from the organic phase, and 10 ml of acetonitrile was added. The mixture was cooled to 5 °C and stirred to crystallize for 2 h. After filtration, the crystals were washed with 2 ml of acetonitrile and dried to obtain 0.9 g of white granular solid N-acetyl-5-hydroxytryptamine, with a yield of 98.2% and a purity of 99.93%.

[0033] Example 4

[0034] Add 1 g of 5-hydroxytryptamine hydrochloride (4.7 mmol), 10 ml of tetrahydrofuran, and 20 ml of water to a reaction flask, stir until dissolved, then add 1.5 g of sodium carbonate solid (14.1 mmol) and stir to dissolve at room temperature. Slowly add 0.55 g of acetyl chloride (7.1 mmol) dropwise, maintaining the temperature at 20 °C. After the addition is complete, stir the reaction for 2 h, and monitor the reaction progress by HPLC. When the 5-hydroxytryptamine concentration is ≤1.0%, add 20 ml of water and 10 ml of ethyl acetate to the reaction solution, stir for 10 min, allow to stand and separate the layers, retain the organic phase, extract the aqueous phase with 10 ml of ethyl acetate, allow to stand and separate the layers, remove the aqueous phase, and combine the organic phases. Evaporate the solvent from the organic phase, add 10 ml of acetonitrile, cool to 5 °C, stir to crystallize for 2 h, filter, wash with 2 ml of acetonitrile, and dry to obtain 0.98 g of white granular solid N-acetyl-5-hydroxytryptamine, yield 99.1%, purity 99.95%.

[0035] Example 5

[0036] 1 g of 5-hydroxytryptamine hydrochloride (4.7 mmol), 8 ml of acetonitrile, and 15 ml of water were added to a reaction flask and stirred until dissolved. Then, 2.49 g of sodium carbonate solid (23.5 mmol) was added and stirred at room temperature until dissolved. 0.92 g of acetyl chloride (11.75 mmol) was slowly added dropwise. After the addition was complete, the temperature was maintained at 10 °C, and the reaction was stirred for 1 h. The reaction progress was monitored by HPLC. When the 5-hydroxytryptamine concentration was ≤1.0%, 20 ml of water and 10 ml of ethyl acetate were added to the reaction solution, and the mixture was stirred for 10 min. The mixture was allowed to stand and separate into layers, and the organic phase was retained. The aqueous phase was extracted with ethyl acetate, allowed to stand and separate into layers, and the aqueous phase was removed. The organic phases were combined. The solvent was evaporated from the organic phase, and 10 ml of acetonitrile was added. The mixture was cooled to 5 °C, stirred, and crystallized for 2 h. The crystals were filtered, washed with 2 ml of acetonitrile, and dried to obtain 0.97 g of white granular solid N-acetyl-5-hydroxytryptamine, with a yield of 98.5% and a purity of 99.96%.

[0037] Example 6

[0038] Add 1 g of 5-hydroxytryptamine hydrochloride (4.7 mmol), 5 ml of tetrahydrofuran, and 8 ml of water to a reaction flask, stir until dissolved, then add 1.5 g of sodium carbonate solid (14.1 mmol) and stir to dissolve at room temperature. Slowly add 0.74 g of acetyl chloride (9.4 mmol) dropwise. After the addition is complete, maintain the temperature at 30 °C and stir for 1 h. Monitor the reaction progress by HPLC. When the 5-hydroxytryptamine concentration is ≤1.0%, add 20 ml of water and 10 ml of ethyl acetate to the reaction solution, stir for 10 min, allow to stand and separate the layers, retain the organic phase, extract the aqueous phase with ethyl acetate, allow to stand and separate the layers, remove the aqueous phase, and combine the organic phases. Evaporate the solvent from the organic phase, add 10 ml of acetonitrile, cool to 5 °C, stir to crystallize for 2 h, filter, wash with 2 ml of acetonitrile, and dry to obtain 0.98 g of white granular solid N-acetyl-5-hydroxytryptamine, yield 99.1%, purity 99.94%.

[0039] Comparative Example 1

[0040] Add 1 g of 5-hydroxytryptamine hydrochloride (4.7 mmol), 5 ml of methanol, and 10 ml of water to a reaction flask, stir until dissolved, then add 2 g of sodium carbonate solid (18.8 mmol), stir to dissolve at room temperature, and slowly add 0.74 g of acetyl chloride (9.4 mmol). After the addition is complete, maintain the temperature at 25 °C and stir for 1 h. Monitor the reaction progress by HPLC. A large amount of starting material remains. Add 20 ml of water and 10 ml of ethyl acetate to the reaction solution, stir for 10 min, allow to stand and separate the layers, retain the organic phase, extract the aqueous phase with 10 ml of ethyl acetate, allow to stand and separate the layers, remove the aqueous phase, and combine the organic phases. Evaporate the solvent from the organic phase, add 10 ml of acetonitrile, cool to 5 °C, stir to crystallize for 2 h, filter, wash with 2 ml of acetonitrile, and dry to obtain 0.6 g of white solid N-acetyl-5-hydroxytryptamine, yield 58%, purity 98.5%.

[0041] Comparative Example 2

[0042] Add 1 g of 5-hydroxytryptamine hydrochloride (4.7 mmol), 5 ml of dichloromethane, and 10 ml of water to a reaction flask, stir until dissolved, then add 2 g of sodium carbonate solid (18.8 mmol). Stir at room temperature, and insoluble matter precipitates. Slowly add 0.74 g of acetyl chloride (9.4 mmol). After addition, maintain the temperature at 25 °C and stir for 1 h. Monitor the reaction progress by HPLC. A large amount of starting material remains. Add 20 ml of water and 10 ml of ethyl acetate to the reaction solution, stir for 10 min, allow to stand and separate the layers, retain the organic phase, extract the aqueous phase with 10 ml of ethyl acetate, allow to stand and separate the layers, remove the aqueous phase, and combine the organic phases. Evaporate the solvent from the organic phase, add 10 ml of acetonitrile, cool to 5 °C, stir and crystallize for 2 h, filter, wash with 2 ml of acetonitrile, and dry to obtain 0.62 g of white solid N-acetyl-5-hydroxytryptamine, yield 60%, purity 98.8%.

[0043] Comparative Example 3

[0044] 1 g of 5-hydroxytryptamine hydrochloride (4.7 mmol) and 15 ml of tetrahydrofuran were added to a reaction flask. 2 g of sodium carbonate solid (18.8 mmol) was added with stirring. The mixture was stirred at room temperature, and 0.74 g of acetyl chloride (9.4 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 25 °C for 1 h, and the reaction progress was monitored by HPLC. When the 5-hydroxytryptamine concentration was ≤1.0%, the reaction solution was evaporated to dryness. 20 ml of water and 10 ml of ethyl acetate were added to the oily mixture, and the mixture was stirred for 10 min. The mixture was allowed to stand and separate into layers, and the organic phase was retained. The aqueous phase was extracted with 10 ml of ethyl acetate, allowed to stand and separate into layers, and the aqueous phase was removed. The organic phases were combined. The solvent was evaporated from the organic phase, and 10 ml of acetonitrile was added. The mixture was cooled to 5 °C and stirred to induce crystallization for 2 h. The crystals were filtered, washed with 2 ml of acetonitrile, and dried to obtain 0.82 g of white solid N-acetyl-5-hydroxytryptamine, with a yield of 80% and a purity of 67.5%, containing a large amount of diacetylated byproducts.

[0045] Comparative Example 4

[0046] 1 g of 5-hydroxytryptamine hydrochloride (4.7 mmol), 5 ml of tetrahydrofuran, and 10 ml of water were added to a reaction flask. 1.9 g of triethylamine (18.8 mmol) was added with stirring at room temperature, followed by slow dropwise addition of 0.74 g of acetyl chloride (9.4 mmol). After the addition was complete, the reaction mixture was stirred at 25 °C for 2 h, and the reaction progress was monitored by HPLC. When the 5-hydroxytryptamine concentration was ≤1.0%, the reaction solution was evaporated to dryness. 20 ml of water and 10 ml of ethyl acetate were added to the oily mixture, and the mixture was stirred for 10 min. The mixture was allowed to stand and separate into layers, retaining the organic phase. The aqueous phase was extracted with 10 ml of ethyl acetate, allowed to stand and separate into layers, and the aqueous phase was removed. The organic phases were combined. The solvent was evaporated from the organic phase, and 10 ml of acetonitrile was added. The mixture was cooled to 5 °C and stirred to induce crystallization for 2 h. The crystals were filtered, washed with 2 ml of acetonitrile, and dried to obtain 0.9 g of white solid N-acetyl-5-hydroxytryptamine, with a yield of 88% and a purity of 40.9%, containing a large amount of diacetylated and triacetylated byproducts.

Claims

1. A method for synthesizing a melatonin intermediate, N-acetyl-5-hydroxytryptamine, comprising the following steps: (1) adding 5-hydroxytryptamine hydrochloride into an organic solvent and water, and stirring to dissolve; (2) adding an inorganic base, and stirring to dissolve; (3) adding acetyl chloride dropwise, controlling temperature, stirring to react, and obtaining N-acetyl-5-hydroxytryptamine. The organic solvent in step (1) is tetrahydrofuran or acetonitrile.

2. The method of synthesis of claim 1, wherein, The inorganic base is one of sodium carbonate, potassium carbonate, and sodium hydroxide.

3. The method of synthesis of claim 2, wherein, The mass-volume ratio of the 5-hydroxytryptamine hydrochloride, the organic solvent, and water is 1 g: 2 ml-10 ml: 5 ml-20 ml.

4. The method of synthesis of claim 3, wherein, The molar ratio of the inorganic base to the 5-hydroxytryptamine hydrochloride ranges from 3.0-10.0: 1.

0.

5. The method of synthesis according to any of claim 4, wherein, The temperature in step (3) is 5-30°C.

6. The method of synthesis of claim 5, wherein, The molar ratio of the acetyl chloride to the 5-hydroxytryptamine hydrochloride in step (3) ranges from 1.5-3.0: 1.

0.

7. The method of synthesis of claim 6, wherein, The reaction time in step (3) is 1-2 h.

8. The synthesis method according to claim 1, further comprising the following step: (4) after the reaction, performing post-treatment to obtain N-acetyl-5-hydroxytryptamine fine product.

9. The method of synthesis of claim 8, wherein, The post-treatment method in step (4) is adding water and ethyl acetate into the reaction solution, stirring, and then standing to separate into layers, leaving the organic phase, extracting the aqueous phase with ethyl acetate, standing to separate into layers, removing the aqueous phase, combining the organic phases, evaporating the solvent, adding acetonitrile, stirring to crystallize under cooling, filtering, washing, drying, and obtaining the N-acetyl-5-hydroxytryptamine fine product.

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