1. A novel method of synthesizing the dietary supplement melatonin, comprising the steps of:

(1) adding N-acetyl serotonin into ethanol water solution under nitrogen protection, adding phase transfer catalyst quaternary ammonium salt, and stirring for 10-15 min;

(2) then simultaneously dripping sodium hydroxide solution and a methylating agent, controlling the dripping temperature at 20-25 ℃, controlling the pH of the system to be 11-11.5 in the dripping process, controlling the dripping time at 30-40min, keeping the temperature at 20-25 ℃ after finishing dripping, continuously reacting for 3-4h, sampling, carrying out controlled detection, and adding dilute sulfuric acid into the system to neutralize until the pH of the system is 6-6.5, wherein the residual amount of the N-acetyl serotonin is less than or equal to 0.1 g/kg;

(3) starting a vacuum device, keeping the vacuum degree of-0.095 to-0.097 Mpa, setting the water bath temperature at 60-70 ℃, distilling ethanol water under reduced pressure, stopping distilling under reduced pressure when the temperature of distilled gas phase reaches 50 ℃ at most, and closing vacuum;

(4) rapidly cooling cold saline water to 0-3 deg.C, crystallizing for 15-20min, and filtering;

(5) and leaching the filter cake with purified water, compacting, pumping to obtain a wet melatonin product, and drying to obtain a melatonin product, wherein the yield is more than or equal to 98.5%, and the HPLC purity is more than or equal to 99.5%.

2. The novel method according to claim 1, wherein the mass ratio of the N-acetyl serotonin to the ethanol aqueous solution in the step (1) is 1:4-1:5, and the weight of the quaternary ammonium salt catalyst added is 0.3-0.6% of the mass of the N-acetyl serotonin.

3. The novel method of claim 1, wherein the methylating agent in step (2) is one of dimethyl sulfate, dimethyl carbonate and methyl halide, and the molar ratio of the methylating agent to the N-acetyl serotonin is 1.1:1-1.2: 1.

4. The method as claimed in claim 1, wherein the temperature in step (4) is reduced to 0-3 ℃.

5. The novel process according to claim 1, characterized in that in step (4) the crystallization is carried out for 15-20 min.

Background

Melatonin, also known as melatonin, is chemically known as N-acetyl-5-methoxytryptamine, is an indole hormone secreted by the pineal body of the human brain, has the main function of maintaining the circadian rhythm of the human body per se, is beneficial to sleep, has the functions of enhancing the immunologic function of the human body and inhibiting the growth of tumor cells, and can also have an inhibiting effect on the central nervous system; is a more effective peroxide-based scavenger than vitamin E, and in addition it has a regulatory effect on growth and development, sexual function and many organs.

Different processes exist for the synthesis of melatonin, and two main process routes exist at present:

1. 5-methoxytryptamine is obtained by multi-step chemical synthesis, and melatonin is obtained by acetylation reaction. In patent CN110229092A, 5-methoxyindole is used as an initiator, oxalyl chloride is used for acylation, dechlorination and amination are carried out, lithium aluminum hydride is used for reduction to obtain 5-methoxytryptamine, and finally acetylation is carried out for 4 steps to obtain the melatonin. The method has the defects of complex process, harsh reaction conditions, large harm of used raw materials to the environment, low yield and high cost.

2. Cheap 4-aminobutyric acid is used as a raw material, 4-acetamido butyraldehyde dimethyl acetal is obtained through esterification of carboxyl, acylation of amino, reduction of ester, oxidation of hydroxyl and protection of aldehyde group, and finally, the 4-acetamido butyraldehyde dimethyl acetal and p-methoxyphenylhydrazine are subjected to ring closing reaction to obtain the melatonin. Patent CN110229092A discloses a secondary synthesis method. The method has the defects of long process route, use of various chemical raw materials and organic solvents, low yield and high cost.

The technique described in WO2011047156A1 is similar to that of the present patent, but its yield is low at 61.4%, and the work-up is complicated by operations such as extraction with a solvent.

N-acetyl serotonin is an endogenous synthetic intermediate from serotonin to melatonin. With the rapid development of synthetic biology, the enzymatic conversion of glucose to N-acetyl serotonin is realized in cell factories. The melatonin is obtained by taking the N-acetyl serotonin as the initial raw material through one-step methylation, the synthesis process is simple, the yield is high and is more than 98.5%, the quality is good, the content is more than 99.5%, and the standard of USP42 is completely met.

Disclosure of Invention

The method takes N-acetyl serotonin as a starting raw material, obtains the melatonin through one-step methylation reaction, has simple synthesis process, mild synthesis process conditions, high yield of over 98.5 percent, good quality and content of over 99.5 percent, and completely meets the standard of USP 42.

In order to achieve the above object, the present invention provides the following technical solutions:

a novel method for synthesizing a dietary supplement melatonin comprises the following specific steps:

1. adding N-acetyl serotonin into the ethanol water solution under the protection of nitrogen, adding one of phase transfer catalyst quaternary ammonium salts such as benzyl trimethyl ammonium chloride and hexadecyl tributyl ammonium bromide, and keeping for 10-15min under stirring, wherein the mass ratio of the N-acetyl serotonin to the ethanol water solution is 1:4-1:5, and the weight of the added quaternary ammonium salt catalyst is 0.3-0.6% of the mass of the N-acetyl serotonin.

2. Simultaneously dropwise adding sodium hydroxide solution and one of methylating agents such as dimethyl sulfate, dimethyl carbonate and methyl halide, wherein the molar ratio of the methylating agent to the N-acetyl serotonin is 1.1:1-1.2:1, the dropwise adding temperature is controlled to be 20-25 ℃, the pH value of the system is controlled to be 11-11.5 in the dropwise adding process, the dropwise adding time is controlled to be 30-40min, after the dropwise adding is finished, the temperature is kept to be 20-25 ℃, the reaction is continued for 3-4h, the sampling is carried out, the detection is controlled, the residual quantity of the N-acetyl serotonin is less than or equal to 0.1g/kg, and then adding dilute sulfuric acid into the system to neutralize until the pH value of the system is 6-6.5.

3. Starting a vacuum device, keeping the vacuum degree of-0.095 to-0.097 Mpa, setting the water bath temperature at 60-70 ℃, distilling ethanol water under reduced pressure, stopping distilling under reduced pressure when the temperature of the distilled gas phase reaches 50 ℃ at most, and closing vacuum. Rapidly cooling to 0-3 ℃ with cold water, keeping the temperature of 0-3 ℃, stirring for 15-20min, then filtering, leaching a filter cake with purified water, compacting, pumping to obtain a melatonin wet product, and then drying for 3-4h at 70-80 ℃ to obtain a melatonin product, wherein the molar yield is more than or equal to 98.5%, and the HPLC purity is more than 99.5%.

The reaction route of the preparation method of the invention is as follows:

compared with the prior art, the invention has the following beneficial effects:

the method takes the N-acetyl serotonin as the initial raw material, obtains the melatonin through one-step methylation reaction, has simple synthesis process, mild synthesis process conditions, high yield of over 98.5 percent, good quality and content of more than 99.5 percent, and completely meets the standard of USP 42. The production method of the melatonin provided by the invention saves the cost and is easy for industrial production.

Detailed Description

The invention discloses a novel method for synthesizing a dietary supplement melatonin, which can be realized by appropriately improving process parameters by a person skilled in the art by taking the contents into consideration. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.

The reagents or apparatus used in the present invention are commercially available.

The invention is further illustrated by the following examples:

example 1:

21.8g of N-acetyl serotonin is added into a 150ml flask under the protection of nitrogen, 88g of 15% ethanol water solution is added, 100mg of hexadecyl tributyl ammonium bromide serving as a catalyst is added, and stirring is carried out for 10 min. And then simultaneously dropwise adding 14.49g of 30% sodium hydroxide solution and dimethyl sulfate, controlling the dropwise adding temperature to be 20-23 ℃, keeping the pH of the reaction system between 11 and 11.3 in the dropwise adding process, keeping the temperature to be 20-23 ℃ for continuously reacting for 4 hours after the dropwise adding is finished, sampling, performing controlled detection, keeping the residual amount of the N-acetyl serotonin at 0.09g/kg, and then adding 20% dilute sulfuric acid into the system to neutralize the pH of the system to be 6.5. Opening vacuum, keeping vacuum degree at-0.095 to-0.097 Mpa, setting water bath temperature at 60-70 deg.C, distilling under reduced pressure to obtain ethanol water, stopping reduced pressure distillation when distillation gas phase temperature reaches 50 deg.C, and closing vacuum. Rapidly cooling to 0-3 ℃ with cold water, keeping the temperature at 0-3 ℃, stirring for 20min, filtering, leaching a filter cake with purified water, compacting, pumping to obtain a melatonin wet product, and drying at 70-75 ℃ for 4h to obtain 22.99g of a melatonin product, wherein the yield is 99.1%, and the HPLC content is 99.7%.

Example 2:

21.8g of N-acetyl serotonin is added into a 150ml flask under the nitrogen atmosphere, then 95g of 15% ethanol water solution is added, 130mg of catalyst benzyl trimethyl ammonium chloride is added, and stirring is carried out for 10 min. And then simultaneously dropwise adding 30% sodium hydroxide solution and 15.12g dimethyl sulfate, controlling the dropwise adding temperature to be 22-25 ℃, keeping the pH value of the reaction system to be 11.1-11.5 in the dropwise adding process, keeping the temperature to be 20-25 ℃ for continuously reacting for 3.5h after the dropwise adding is finished, sampling, performing controlled detection, keeping the residual amount of the N-acetyl serotonin to be 0.1g/kg, and then adding 20% dilute sulfuric acid into the system to neutralize the pH value of the system to be 6.2. Opening vacuum, keeping vacuum degree at-0.095 to-0.097 Mpa, setting water bath temperature at 60-70 deg.C, distilling under reduced pressure to obtain ethanol water, stopping reduced pressure distillation when distillation gas phase temperature reaches 48 deg.C, and closing vacuum. Rapidly cooling to 0 ℃ with cold water, keeping the temperature at 0-3 ℃, stirring for 20min, filtering, leaching a filter cake with purified water, compacting, pumping to dry to obtain a melatonin wet product, and drying at 70-75 ℃ for 4h to obtain 22.94g of a melatonin product, wherein the yield is 98.9%, and the HPLC content is 99.6%.

Example 3:

21.8g of N-acetyl serotonin is added into a 150ml flask under nitrogen atmosphere, then 15% ethanol water solution 105g is added, and catalyst hexadecyl tributyl ammonium bromide 66mg is added, and stirring is kept for 10 min. And then simultaneously dropwise adding 14.12g of 30% sodium hydroxide solution and dimethyl sulfate, controlling the dropwise adding temperature to be 20-25 ℃, keeping the pH of the reaction system to be 11.0-11.5 in the dropwise adding process, keeping the temperature to be 20-25 ℃ for continuously reacting for 4h after the dropwise adding is finished, sampling, carrying out controlled detection, and adding 20% dilute sulfuric acid into the system to neutralize until the pH of the system is 6.4, wherein the residual amount of the N-acetyl serotonin is less than 0.1 g/kg. Opening vacuum, keeping vacuum degree at-0.095 to-0.097 Mpa, setting water bath temperature at 60-70 deg.C, distilling under reduced pressure to obtain ethanol water, stopping reduced pressure distillation when distillation gas phase temperature reaches 50 deg.C, and closing vacuum. Rapidly cooling to 0 ℃ with cold water, keeping the temperature at 0-3 ℃, stirring for 20min, filtering, leaching a filter cake with purified water, compacting, pumping to dry to obtain a melatonin wet product, and drying at 70-75 ℃ for 4h to obtain 22.85g of a melatonin product, wherein the yield is 98.5%, and the HPLC content is 99.5%.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.