CN115974756A - A kind of purification method of melatonin and its crystallization mother liquor - Google Patents

Abstract

The invention discloses a method for purifying melatonin and its crystallization mother liquor. The purity and recovery rate of melatonin are greatly improved by adding deoxygenated water and full nitrogen protection during the ethanol purification process; and the crystallization mother liquor is passed through Alkaline hydrolysis reduces melatonin and its self-condensed impurities to the synthetic precursor 5-methoxytryptamine, and the synthetic precursor is acylated to obtain a mother liquor material product with a purity equivalent to that of the crude melatonin, which can not only effectively improve the melatonin in the mother liquor The recovery rate and total purification yield of the element are improved, and the treatment volume of the final mother liquor is reduced, the pressure of the three wastes treatment is reduced, and it is beneficial to increase the competitiveness of the product.

Description

A kind of purification method of melatonin and its crystallization mother liquor

technical field

The invention relates to the technical field of chemical separation, in particular to a method for purifying melatonin and its crystallization mother liquor.

Background technique

Melatonin, also known as pineal gland and melatonin, has strong neuroendocrine immune regulation activity and free radical scavenging antioxidant capacity, and is the strongest endogenous free radical scavenger found so far; Circadian rhythm and delaying aging have significant effects. At the same time, melatonin has obvious regulatory effects on the central nervous system, immune system, and cardiovascular system.

Melatonin has a variety of chemical synthesis methods, and the better route is finally to use 5-methoxytryptamine as raw material to obtain crude melatonin through acylation reaction, and the crude melatonin is recrystallized to obtain fine melatonin white. At present, the crystallization method of melatonin in industrial production mainly uses ethanol as a solvent for crystallization, and the crystallization process will inevitably produce mother liquor. For the purification treatment of melatonin in the prior art, ethanol is mostly used as a solvent, but the purification yield is low. For this reason, there is also the use of ethanol aqueous solution, such as the use of 15-20% ethanol aqueous solution to purify the crude melatonin, the purification yield is 90-93%, and the product purity can reach more than 99.5%, but the retention time is 12.398 minutes The impurity content of the peak is 0.13%, which exceeds the requirement of USP ≤ 0.1%, and does not meet the USP43 standard; and the use of ethanol aqueous solution with too low concentration will cause a large amount of subsequent mother liquor treatment and high energy consumption. As another example, the pineal gland of animals is used to extract melatonin in the crystallization mother liquor, but the source of the pineal gland of the raw material animal is the biggest problem.

In addition, the ethanol solvent used in the existing melatonin purification technology, due to the relatively high solubility of melatonin in ethanol, and the ethanol mother liquor of melatonin will decompose during the concentration process, resulting in a melatonin that cannot be purified by ethanol Self-condensation impurities, resulting in simple impurities > 0.1% (USP43 standard: simple impurities ≤ 0.1%), which did not reach the USP standard. Therefore, how to extract the melatonin dissolved in the ethanol mother liquor will be the key to improving the total yield of the melatonin purification technology. At the same time, how to remove the self-condensation impurities produced in the concentration of melatonin ethanol mother liquor will help increase the competitiveness of the product to improve the purity of melatonin extracted from the mother liquor.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies in the prior art, to provide a method for purifying melatonin and its crystallization mother liquor, to solve the low yield of melatonin ethanol purification process, the relatively large residual melatonin in the crystallization mother liquor, Moreover, the mother liquor treatment process causes problems such as impurities caused by the self-condensation of melatonin.

The purpose of the present invention is achieved through the following technical solutions:

A method for purifying melatonin and its crystallization mother liquor provided by the invention comprises the following steps:

(1) Purification of crude melatonin

(1-1) The crude melatonin is mixed with the aqueous ethanol solution with a concentration of 30-95% according to the mass ratio of crude melatonin: aqueous ethanol=1:1-5 to obtain a solution, wherein the aqueous ethanol uses water It is deoxygenated water; preferably, the concentration of ethanol aqueous solution is 40-60%, according to the mass ratio of melatonin crude product: ethanol aqueous solution=1: 2-3;

(1-2) Add active carbon with an amount of 1 to 3 wt% of crude melatonin to the dissolving liquid, replace the air in the system with nitrogen, heat up to 50 to 75° C. to dissolve the decolorized solution obtained after decolorization, and separate the active carbon by filtration to obtain Obtain melatonin filtrate;

(1-3) The melatonin filtrate is cooled to -10-10°C at a rate of 10°C/h, and then the crystallization liquid obtained by continuing to crystallize for 4-8 hours is centrifuged to obtain melatonin fine-quality wet material and melatonin Melatonin crystallization mother liquor; the melatonin refined product wet material is vacuum-dried to obtain the melatonin refined product; preferably, the temperature is lowered to 0-5°C;

(2) Melatonin crystallization mother liquor treatment

(2-1) Mix the melatonin crystallization mother liquor with an alkaline catalyst, control the pH value of the system to 10-14, and reflux at a temperature of 60-80° C. for 2-8 hours to obtain an alkaline hydrolysis solution;

(2-2) Concentrating the alkali hydrolysis solution in vacuum to separate solid fractions, adding acid to adjust the pH value to 1-4, preferably, the pH value is 1-2, and stirring until the solid is completely dissolved to obtain an acidified solution;

(2-3) adding activated carbon in an amount of 0.1 to 0.3 wt% of the acidified solution to the acidified solution to decolorize the obtained decolorized solution, and separating the activated carbon to obtain a filtrate;

(2-4) Add alkali to the filtrate to adjust the pH value to 10-14, preferably, the pH value is 12-13, obtain the melatonin precursor 5-methoxytryptamine after centrifugation, and acylate Afterwards, a mother liquor material with a purity of >99.5% is obtained; the mother liquor material is recycled and added to crude melatonin for purification.

Further, the basic catalyst in the step (2-1) of the present invention is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium tert-butoxide, triethylamine; preferably, the pH value of the system is 12-13, and the reflux The temperature is 70~75℃, and the reflux time is 4~5h;

In the above scheme, the purity of the crude melatonin in step (1-1) of the present invention is above 99.50%. The purity of the refined melatonin in the step (1-3) is more than 99.70%, less than 0.05% of simple impurities, and the yield is more than 88%. The purity of the mother liquor material in the step (2-4) is above 99.50%.

The present invention has the following beneficial effects:

(1) In the purification process of melatonin, ethanol is mostly used as a solvent in the prior art, and the solubility of melatonin in ethanol is relatively large, up to about 20%, so the purification yield is low. In the present invention, by adding deoxygenated water in the purification process and nitrogen protection throughout the whole process, since melatonin is slightly soluble in water, the solubility of melatonin in ethanol can be reduced, thereby reducing the content of melatonin in the crystallization mother liquor, which helps It is used to greatly improve the recovery rate of melatonin purification technology; at the same time, by reducing the oxygen content in the purification system, it reduces the self-condensation impurities generated during the purification process, which helps to improve the purity of melatonin products and makes melatonin The purity of the prime products is above 99.7%, and the purity of simple and impurity is less than 0.1%.

(2) The present invention reduces melatonin and its self-condensed impurities in the melatonin crystallization mother liquor to melatonin synthesis precursor 5-methoxytryptamine by means of alkaline hydrolysis reduction, and the synthesis precursor is acidified, alkali Medium secondary purification, and finally carry out acylation to obtain the mother liquor material with the same purity as the crude melatonin. The purity of the mother liquor material can reach more than 99.5%, which improves the recovery rate of melatonin in the mother liquor, and the total purification yield can reach more than 95%. , and reduced the amount of mother liquor treatment, reducing the pressure on the treatment of three wastes.

Description of drawings

The present invention will be described in further detail below in conjunction with embodiment and accompanying drawing:

Fig. 1 is the processing flow chart of the embodiment of the present invention;

Fig. 2 is the melatonin high-quality goods purity detection collection of illustrative plates of the embodiment of the present invention;

Fig. 3 is the detection spectrum of the material purity of the mother liquor obtained after the treatment of the melatonin crystallization mother liquor of Embodiment 1 of the present invention;

Fig. 4 is the detection spectrum of the material purity of the mother liquor obtained by the prior art (concentration, crystallization, recrystallization) of the melatonin crystallization mother liquor.

Detailed ways

Embodiment one:

A kind of purification method of melatonin and crystallization mother liquor thereof of the present embodiment, as shown in Figure 1, its steps are as follows:

(1) Purification of crude melatonin

(1-1) 300 g of crude melatonin with a purity of 99.63% was mixed with 900 g of a 40% aqueous ethanol solution to obtain a solution, wherein the water used in the aqueous ethanol solution was deoxygenated water;

(1-2) Add 5 g of activated carbon to the above solution, replace the air in the system with nitrogen, heat up to 70° C. to dissolve the decolorized solution obtained after 30 minutes of decolorization, and separate the activated carbon by filtration to obtain the melatonin filtrate;

(1-3) The above-mentioned melatonin filtrate was cooled to 5°C at a rate of 10°C/h, and then the crystallization liquid obtained by continuing to crystallize for 4 hours was centrifuged to obtain 280g of melatonin high-quality wet material and 913g of melatonin crystallization mother liquor The melatonin high-quality goods wet material obtains the melatonin high-quality goods 273g that purity is 99.87%, single impurity 0.04% (seeing Fig. 2) after vacuum drying, and yield is 91.0%;

(2) Melatonin crystallization mother liquor treatment

(2-1) Mix the above-mentioned melatonin crystallization mother liquor with sodium methoxide, control the pH value of the system to 12, and reflux at a temperature of 70°C for 4 hours to obtain an alkaline solution;

(2-2) Vacuum-concentrate the alkaline solution to obtain 411 g of solid fraction, add acid to adjust the pH value to 2, stir for 20 minutes until the solid is completely dissolved, and then obtain the acidified solution;

(2-3) adding 0.5 g of activated carbon to the above-mentioned acidified solution to decolorize the decolorized solution obtained, and obtain the filtrate through separation of the activated carbon;

(2-4) Add alkali to the above-mentioned filtrate to adjust the pH to 12, obtain 18 g of melatonin precursor 5-methoxytryptamine after centrifugation, and obtain 18.7 g of mother liquor material with a purity of 99.57% after acylation, The mother liquor material is recycled and added to the crude melatonin for purification.

Embodiment two:

A kind of purification method of melatonin and crystallization mother liquor thereof of the present embodiment, as shown in Figure 1, its steps are as follows:

(1) Purification of crude melatonin

(1-1) 300 g of crude melatonin with a purity of 99.58% was mixed with 720 g of a 50% aqueous ethanol solution to obtain a solution, wherein the water used in the aqueous ethanol solution was deoxygenated water;

(1-2) Add 5 g of activated carbon to the above solution, replace the air in the system with nitrogen, heat up to 65° C. to dissolve the decolorized solution obtained after decolorization for 30 minutes, and separate the activated carbon by filtration to obtain the melatonin filtrate;

(1-3) The above-mentioned melatonin filtrate was cooled to 0°C at a rate of 10°C/h, and then the crystallization liquid obtained by continuing to crystallize for 5 hours was centrifuged to obtain 272g of melatonin high-quality wet material and 729g of melatonin crystallization mother liquor 268g of melatonin fine-quality product with a purity of 99.81% and 0.03% of simple impurities were obtained after vacuum drying the wet material of melatonin fine-quality product, and the yield was 89.3%;

(2) Melatonin crystallization mother liquor treatment

(2-1) Mix the above-mentioned melatonin crystallization mother liquor with sodium tert-butoxide, control the pH value of the system to 13, and reflux at a temperature of 75° C. for 4 hours to obtain an alkaline solution;

(2-2) Vacuum-concentrate the alkaline solution to obtain 380 g of solid fraction, add acid to adjust the pH value to 1, stir for 20 minutes until the solid is completely dissolved, and then obtain the acidified solution;

(2-3) adding 0.5 g of activated carbon to the above-mentioned acidified solution to decolorize the decolorized solution obtained, and obtain the filtrate through separation of the activated carbon;

(2-4) Add alkali to the above filtrate to adjust the pH value to 13, obtain 21.8 g of melatonin precursor 5-methoxytryptamine after centrifugation, and obtain 22.5 g of mother liquor material with a purity of 99.62% after acylation , the mother liquor material is recycled into the crude melatonin for purification.

Embodiment three:

A kind of purification method of melatonin and crystallization mother liquor thereof of the present embodiment, as shown in Figure 1, its steps are as follows:

(1) Purification of crude melatonin

(1-1) 300 g of crude melatonin with a purity of 99.60% was mixed with 600 g of an aqueous ethanol solution with a concentration of 60% to obtain a solution, wherein the water used in the aqueous ethanol solution was deoxygenated water;

(1-2) Add 5 g of activated carbon to the above solution, replace the air in the system with nitrogen, heat up to 60° C. to dissolve the decolorized solution obtained after decolorization for 30 minutes, and separate the activated carbon by filtration to obtain the melatonin filtrate;

(1-3) The above-mentioned melatonin filtrate was cooled to -5°C at a rate of 10°C/h, and then the crystallization liquid obtained by continuing to crystallize for 8 hours was centrifuged to obtain 265g of melatonin high-quality wet material and melatonin crystallization mother liquor 611g; the high-quality melatonin wet material obtained after vacuum drying has a purity of 99.83%, 0.03% pure melatonin 266g, and a yield of 88.6%;

(2) Melatonin crystallization mother liquor treatment

(2-1) Mix the above-mentioned melatonin crystallization mother liquor with potassium hydroxide, control the pH value of the system to 14, and reflux for 6 hours at a temperature of 75° C. to obtain an alkaline solution;

(2-2) Vacuum-concentrate the alkaline hydrolysis solution to obtain 375 g of solid fraction, add acid to adjust the pH value to 1, stir for 20 minutes until the solid is completely dissolved, and obtain an acidified solution;

(2-3) adding 0.5 g of activated carbon to the above-mentioned acidified solution to decolorize the decolorized solution obtained, and obtain the filtrate through separation of the activated carbon;

(2-4) Add alkali to the above filtrate to adjust the pH value to 14, obtain 23.0 g of melatonin precursor 5-methoxytryptamine after centrifugation, and obtain 24.1 g of mother liquor material with a purity of 99.67% after acylation , the mother liquor material is recycled into the crude melatonin for purification.

The present invention detects based on the detection method of melatonin purity and impurities in the United States Pharmacopoeia USP43, and the product quality of the purification process of the melatonin crystallization mother liquor of the present invention is superior to the conventional purification process of the prior art (see Figure 3 and Figure 4).

Claims (10)

1. A method for purifying melatonin and a crystallization mother liquor thereof is characterized by comprising the following steps:

(1) Purification of crude melatonin

(1-1) mixing the melatonin crude product with an ethanol water solution with the concentration of 30-95% according to the mass ratio of the melatonin crude product to the ethanol water solution = 1: 1-5 to obtain a dissolved solution, wherein the water used in the ethanol water solution is deoxygenated water;

(1-2) adding activated carbon with the amount of 1-3 wt% of the melatonin crude product into the dissolved solution, replacing system air with nitrogen, heating to 50-75 ℃, dissolving and decolorizing to obtain decolorized solution, and filtering and separating the activated carbon to obtain melatonin filtrate;

(1-3) cooling the melatonin filtrate to-10 ℃ at the speed of 10 ℃/h, then continuously crystallizing for 4-8 h to obtain a crystallization liquid, and performing centrifugal separation to obtain a melatonin refined wet material and a melatonin crystallization mother liquor; vacuum drying the melatonin refined wet material to obtain melatonin refined product;

(2) Melatonin crystallization mother liquor treatment

(2-1) mixing the melatonin crystallization mother liquor with an alkaline catalyst, controlling the pH value of the system to be 10-14, and refluxing at the temperature of 60-80 ℃ for 2-8 h to obtain alkaline hydrolysis liquid;

(2-2) concentrating the alkaline hydrolysis liquid in vacuum to separate out solid fraction, adding acid to adjust the pH value to 1-4, and stirring until the solid is completely dissolved to obtain acidified liquid;

(2-3) adding activated carbon with the use amount of 0.1-0.3 wt% of the acidified liquid into the acidified liquid for decolorization to obtain decolorized liquid, and separating the activated carbon to obtain filtrate;

(2-4) adding alkali into the filtrate to adjust the pH value to 10-14, performing centrifugal separation to obtain melatonin precursor 5-methoxytryptamine, and performing acylation to obtain a mother liquor material with the purity of more than 99.5%; and circularly adding the mother liquor material into the melatonin crude product for purification.

2. The method of purifying melatonin and the crystallization mother liquor thereof as claimed in claim 1, wherein: in the step (1-1), the concentration of the ethanol water solution is 40-60%, and the mass ratio of the melatonin crude product to the ethanol water solution is = 1: 2-3.

3. The method of purifying melatonin and the crystallization mother liquor thereof as claimed in claim 1, wherein: the crystallization temperature in the step (1-3) is 0-5 ℃.

4. The method of purifying melatonin and the crystallization mother liquor thereof as claimed in claim 1, wherein: and (3) in the step (2-1), the basic catalyst is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium tert-butoxide or triethylamine.

5. The method of purifying melatonin and crystallization mother liquor thereof as claimed in claim 1 or 4, wherein: the pH value of the system in the step (2-1) is 12-13, the reflux temperature is 70-75 ℃, and the reflux time is 4-5 h.

6. The method of purifying melatonin and the crystallization mother liquor thereof as claimed in claim 1, wherein: the pH value in the step (2-2) is 1-2.

7. The method of purifying melatonin and the crystallization mother liquor thereof as claimed in claim 1, wherein: the pH value in the step (2-4) is 12-13.

8. The method of purifying melatonin and the crystallization mother liquor thereof as claimed in claim 1, wherein: the purity of the melatonin crude product in the step (1-1) is more than 99.50%.

9. The method of purifying melatonin and the crystallization mother liquor thereof as claimed in claim 1, wherein: the purity of the refined melatonin in the step (1-3) is more than 99.70%, the purity of the refined melatonin is less than 0.05%, and the yield is more than 88.0%.

10. The method of purifying melatonin and the crystallization mother liquor thereof as claimed in claim 1, wherein: the purity of the mother liquor material in the step (2-4) is more than 99.50%.

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