CN115974756A - Method for purifying melatonin and crystallization mother liquor thereof - Google Patents
Method for purifying melatonin and crystallization mother liquor thereof Download PDFInfo
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- CN115974756A CN115974756A CN202310012510.XA CN202310012510A CN115974756A CN 115974756 A CN115974756 A CN 115974756A CN 202310012510 A CN202310012510 A CN 202310012510A CN 115974756 A CN115974756 A CN 115974756A
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Abstract
The invention discloses a method for purifying melatonin and a crystallization mother liquor thereof, wherein the purity and the recovery rate of the melatonin are greatly improved by adding deoxygenated water and carrying out nitrogen filling protection in the whole process in the ethanol purification process; and the melatonin and self-condensed impurities thereof are reduced into the synthetic precursor 5-methoxytryptamine by the crystallization mother liquor through alkaline hydrolysis, and the synthetic precursor is acylated to obtain a mother liquor material product with the purity equivalent to that of a crude melatonin product, so that the recovery rate and the total purification yield of the melatonin in the mother liquor can be effectively improved, the treatment capacity of the final mother liquor is reduced, the three-waste treatment pressure is relieved, and the product competitiveness is favorably improved.
Description
Technical Field
The invention relates to the technical field of chemical separation, in particular to a method for purifying melatonin and a crystallization mother liquor thereof.
Background
Melatonin, also known as pineal hormone and melatonin, has strong neuroendocrine immunoregulation activity and free radical scavenging antioxidant capacity, and is the strongest endogenous free radical scavenger discovered so far; has obvious effects of preventing pathological changes, regulating circadian rhythm and delaying aging, and simultaneously, the melatonin has obvious regulating effect on the central nervous system, the immune system and the cardiovascular system.
The melatonin has various chemical synthesis methods, and a better route finally adopts 5-methoxytryptamine as a raw material to obtain a crude melatonin product through acylation reaction, and the crude melatonin product is recrystallized to obtain a fine melatonin product. At present, in industrial production, the crystallization method of melatonin mainly uses ethanol as a solvent for crystallization, and a mother liquor is necessarily generated in the crystallization process. In the prior art, ethanol is mostly adopted as a solvent for the purification treatment of melatonin, but the purification yield is low. Therefore, the crude melatonin is purified by using an ethanol water solution, for example, the ethanol water solution with the concentration of 15-20%, the purification yield is 90-93%, the product purity can reach more than 99.5%, but the impurity content of the peak after the retention time is 12.398 minutes is 0.13%, the requirement that USP is less than or equal to 0.1% is exceeded, and the USP43 standard is not met; and the ethanol aqueous solution with low concentration is used, so that the subsequent mother liquor treatment capacity is large, and the treatment energy consumption is high. As another example, animal pineal bodies are used to extract melatonin from the crystallization mother liquor, but the source of the raw animal pineal bodies is the biggest problem.
In addition, the ethanol solvent adopted in the existing melatonin purification technology has higher solubility in ethanol, and the melatonin ethanol mother liquor can be decomposed in the concentration process to generate a self-condensation impurity which can not be purified by ethanol, so that the single impurity is more than 0.1 percent (USP 43 standard: the single impurity is less than or equal to 0.1 percent) and the USP standard is not met. Therefore, how to extract the melatonin dissolved in the ethanol mother liquor is the key point for improving the total yield of the melatonin purification technology. Meanwhile, how to remove the self-condensation impurities generated in the concentration of the melatonin ethanol mother liquor so as to improve the purity of the melatonin extracted from the mother liquor is beneficial to the increase of the competitiveness of the product.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a method for purifying melatonin and a crystallization mother liquor thereof, so as to solve the problems that the yield of the existing melatonin ethanol purification process is low, the melatonin residue in the crystallization mother liquor is large, impurities caused by melatonin self-condensation are generated in the mother liquor treatment process, and the like.
The purpose of the invention is realized by the following technical scheme:
the invention provides a method for purifying melatonin and a crystallization mother liquor thereof, which comprises 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; preferably, 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;
(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; preferably, the temperature is reduced to 0-5 ℃;
(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 a solid fraction, adding acid to adjust the pH value to 1-4, preferably 1-2, and stirring until the solid is completely dissolved to obtain an 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, preferably 12-13, centrifugally separating to obtain melatonin precursor 5-methoxytryptamine, and acylating 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.
Further, in the step (2-1), the basic catalyst is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium tert-butoxide or triethylamine; preferably, the pH value of the system is 12-13, the reflux temperature is 70-75 ℃, and the reflux time is 4-5 h;
in the scheme, the purity of the melatonin crude product in the step (1-1) is more than 99.50%. 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%. The purity of the mother liquor material in the step (2-4) is more than 99.50%.
The invention has the following beneficial effects:
(1) In the process of purifying melatonin, ethanol is mostly adopted as a solvent in the prior art, the solubility of the melatonin in the ethanol is high and can reach about 20 percent at most, and therefore, the purification yield is low. The method has the advantages that the deoxygenated water is added in the purification process, and the nitrogen is protected in the whole process, so that the solubility of the melatonin in the ethanol can be reduced due to the fact that the melatonin is slightly soluble in the water, the content of the melatonin in the crystallization mother liquor is reduced, and the recovery rate in the melatonin purification technology is greatly improved; meanwhile, by reducing the oxygen content in the purification system, the self-condensation impurities generated in the purification process are reduced, and the purity of the refined melatonin product is improved, so that the purity of the refined melatonin product is more than 99.7 percent, and the single impurity is less than 0.1 percent.
(2) The method reduces the melatonin and self-condensed impurities thereof in the melatonin crystallization mother liquor into the melatonin synthesis precursor 5-methoxytryptamine in an alkaline hydrolysis reduction mode, the synthesis precursor is subjected to secondary purification such as acidification and alkali, and finally, acylation is carried out to obtain a mother liquor material with the purity equivalent to that of a crude melatonin product, the purity of the mother liquor material can reach more than 99.5%, the recovery rate of the melatonin in the mother liquor is improved, the total purification yield can reach more than 95%, the mother liquor treatment capacity is reduced, and the three-waste treatment pressure is reduced.
Drawings
The invention will now be described in further detail with reference to the following examples and the accompanying drawings:
FIG. 1 is a process flow diagram of an embodiment of the invention;
fig. 2 is a melatonin extract purity detection spectrum according to the first embodiment of the invention;
fig. 3 is a detection spectrum of the purity of the mother liquor material obtained after the melatonin crystallization mother liquor treatment in the first embodiment of the invention;
fig. 4 is a detection spectrum of the material purity of the mother liquor obtained by the melatonin crystallization mother liquor according to the prior art (concentration, crystallization and recrystallization).
Detailed Description
The first embodiment is as follows:
the present embodiment relates to a method for purifying melatonin and a crystallization mother liquor thereof, as shown in fig. 1, the steps are as follows:
(1) Purification of crude melatonin
(1-1) mixing 300g of a melatonin crude product with the purity of 99.63% with 900g of an ethanol water solution with the concentration of 40% to obtain a dissolved solution, wherein water used in the ethanol water solution is deoxygenated water;
(1-2) adding 5g of activated carbon into the dissolved solution, replacing system air with nitrogen, heating to 70 ℃, dissolving and decolorizing the obtained decolorized solution for 30min, and filtering and separating the activated carbon to obtain melatonin filtrate;
(1-3) cooling the melatonin filtrate to 5 ℃ at the speed of 10 ℃/h, and then continuously crystallizing for 4h to obtain a crystallization liquid, and performing centrifugal separation to obtain 280g of melatonin fine wet material and 913g of melatonin crystallization mother liquor; after the refined wet melatonin material is dried in vacuum, 273g of refined melatonin product with the purity of 99.87 percent and the single impurity content of 0.04 percent (shown in figure 2) is obtained, and the yield is 91.0 percent;
(2) Melatonin crystallization mother liquor treatment
(2-1) mixing the melatonin crystallization mother liquor with sodium methoxide, controlling the pH value of the system to be 12, and refluxing at 70 ℃ for 4 hours to obtain alkaline hydrolysis liquid;
(2-2) concentrating the alkaline hydrolysis liquid in vacuum to obtain 411g of solid fraction, adding acid to adjust the pH value to 2, and stirring for 20min until the solid is completely dissolved to obtain an acidified liquid;
(2-3) adding 0.5g of activated carbon into the acidified solution to decolorize the acidified solution to obtain a decolorized solution, and separating the activated carbon to obtain a filtrate;
(2-4) adding alkali into the filtrate to adjust the pH value to 12, performing centrifugal separation to obtain 18g of melatonin precursor 5-methoxytryptamine, performing acylation to obtain 18.7g of mother liquor material with the purity of 99.57%, and circularly adding the mother liquor material into a crude product of melatonin for purification.
Example two:
the present embodiment relates to a method for purifying melatonin and a crystallization mother liquor thereof, as shown in fig. 1, the steps are as follows:
(1) Purification of crude melatonin
(1-1) mixing 300g of a melatonin crude product with the purity of 99.58% with 720g of an ethanol aqueous solution with the concentration of 50% to obtain a dissolved solution, wherein water used in the ethanol aqueous solution is deoxygenated water;
(1-2) adding 5g of activated carbon into the dissolved solution, replacing system air with nitrogen, heating to 65 ℃, dissolving and decolorizing the obtained decolorized solution for 30min, and filtering and separating the activated carbon to obtain melatonin filtrate;
(1-3) cooling the melatonin filtrate to 0 ℃ at the speed of 10 ℃/h, and then continuously crystallizing for 5h to obtain a crystallization liquid, and centrifugally separating to obtain 272g of melatonin refined wet material and 729g of melatonin crystallization mother liquor; after the refined wet melatonin material is dried in vacuum, 268g of refined melatonin with the purity of 99.81 percent and the single impurity content of 0.03 percent is obtained, and the yield is 89.3 percent;
(2) Melatonin crystallization mother liquor treatment
(2-1) mixing the melatonin crystallization mother liquor with sodium tert-butoxide, controlling the pH value of a system to be 13, and refluxing at the temperature of 75 ℃ for 4 hours to obtain alkaline hydrolysis liquid;
(2-2) carrying out vacuum concentration on the alkaline hydrolysis liquid to obtain 380g of solid fraction, adding acid to adjust the pH value to 1, and stirring for 20min until the solid is completely dissolved to obtain an acidified liquid;
(2-3) adding 0.5g of activated carbon into the acidified solution to decolorize the acidified solution to obtain a decolorized solution, and separating the activated carbon to obtain a filtrate;
(2-4) adding alkali into the filtrate to adjust the pH value to 13, performing centrifugal separation to obtain 21.8g of melatonin precursor 5-methoxytryptamine, performing acylation to obtain 22.5g of a mother liquor material with the purity of 99.62%, and circularly adding the mother liquor material into a crude product of melatonin for purification.
Example three:
the present embodiment relates to a method for purifying melatonin and a crystallization mother liquor thereof, as shown in fig. 1, the steps are as follows:
(1) Purification of crude melatonin
(1-1) mixing 300g of a melatonin crude product with the purity of 99.60% with 600g of an ethanol aqueous solution with the concentration of 60% to obtain a dissolved solution, wherein water used in the ethanol aqueous solution is deoxygenated water;
(1-2) adding 5g of activated carbon into the dissolved solution, replacing system air with nitrogen, heating to 60 ℃, dissolving and decolorizing the obtained decolorized solution for 30min, and filtering and separating the activated carbon to obtain melatonin filtrate;
(1-3) cooling the melatonin filtrate to-5 ℃ at the speed of 10 ℃/h, and then continuously crystallizing for 8h to obtain a crystallization liquid, and centrifugally separating to obtain 265g of a melatonin refined wet material and 611g of a melatonin crystallization mother liquor; after the refined wet melatonin material is dried in vacuum, 266g of refined melatonin with the purity of 99.83 percent and the single impurity content of 0.03 percent is obtained, and the yield is 88.6 percent;
(2) Melatonin crystallization mother liquor treatment
(2-1) mixing the melatonin crystallization mother liquor with potassium hydroxide, controlling the pH value of a system to be 14, and refluxing at the temperature of 75 ℃ for 6 hours to obtain alkaline hydrolysis liquid;
(2-2) concentrating the alkaline hydrolysis liquid in vacuum to obtain 375g of solid fraction, adding acid to adjust the pH value to 1, and stirring for 20min until the solid is completely dissolved to obtain an acidified liquid;
(2-3) adding 0.5g of activated carbon into the acidified solution to decolorize the acidified solution to obtain a decolorized solution, and separating the activated carbon to obtain a filtrate;
(2-4) adding alkali into the filtrate to adjust the pH value to 14, performing centrifugal separation to obtain 23.0g of melatonin precursor 5-methoxytryptamine, performing acylation to obtain 24.1g of a mother liquor material with the purity of 99.67%, and circularly adding the mother liquor material into a crude product of melatonin for purification.
The method is based on the detection method of the purity and impurities of the melatonin in the United states pharmacopoeia USP43, and the product quality of the melatonin crystallization mother liquor purification process is superior to that of the conventional purification process in 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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