CN111377983B - Preparation method of beta-nicotinamide mononucleotide - Google Patents
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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Abstract
The invention relates to the technical field of medicines, and provides a preparation method of beta-nicotinamide mononucleotide, which comprises the following steps of: in alkaline aqueous solution with pH value of 8-10, under the condition that the temperature of a reaction system is 25-50 ℃, nicotinamide riboside salt and metaphosphate are subjected to phosphorylation reaction for 2-5 h to obtain an intermediate product of nicotinamide mononucleotide; b, acidification reaction: adding acid into the reaction solution, regulating the pH value to 3-5, reducing the temperature of the reaction system, and acidifying the intermediate product of nicotinamide mononucleotide salt to form beta-nicotinamide mononucleotide; and C, purifying the product, namely filtering the reaction solution obtained in the step B by using a protein membrane, concentrating by using a high-pressure desalination membrane, separating and purifying by using anion exchange resin, concentrating and crystallizing to obtain a beta-nicotinamide mononucleotide pure product.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to a preparation method of beta-nicotinamide mononucleotide.
Background
NMN (nicotinamide mononucleotide) is an organic molecule and also a nucleotide, and various nutrient sources of human beings contain the substance, so that the NMN (nicotinamide mononucleotide) is a revolutionary breakthrough which can obviously reverse aging and prolong service life through strict scientific verification in the world for the first time.
Nicotinamide mononucleotide anti-aging is primarily discovered by David Sinclair laboratories of Harvard university in 2014, and the remarkable effects of anti-aging and life prolonging are respectively confirmed in multiple angles and all directions by world top scientific research institutions such as Harvard medical college, washington university, japanese university of should celebration and the like in 2016-2018.
Currently, large scale synthesis of nicotinamide mononucleotide is mainly achieved by enzymatic reactions (Burgo, E.S et al, biochemistry,47:11086 (2008); rozenberg, A et al, J.org.chem.,73:9314 (2008)). However, the enzymatic reaction often involves various bottlenecks, such as high cost of the enzymatic method, harsh reaction conditions, unstable production process, large difference in product indexes of each batch, low reaction productivity, and the like. Early organic synthetic chemists have also made some efforts, but have had undesirable effects, low reaction yields, complex processes, high costs, and the use of some toxic reagents, all of which severely limit the large-scale application of these processes (Jaemoon, L et al chem. Commun.,729-730 (1999)). In addition, fermentation methods may involve relatively sensitive transgenic technology, and problems such as endotoxin overstandard may be brought about during the reaction, which brings about a number of hidden troubles for the final application of the product.
Therefore, the market has urgent need for developing a green, environment-friendly, efficient and stable nicotinamide mononucleotide synthesis process.
Disclosure of Invention
The invention aims to solve the problems, and aims to provide a preparation method of beta-nicotinamide mononucleotide, so as to solve the problems of unstable process, hidden danger of product safety, complex process and the like in the existing preparation process.
The preparation process of the beta-nicotinamide mononucleotide in the invention is summarized as follows: firstly, carrying out phosphorylation reaction on nicotinamide riboside salt (II) under alkaline condition to obtain nicotinamide mononucleotide (III), then, acidizing under acidic condition to obtain a target primary product (I), and purifying to obtain a target product pure product, wherein the reaction formula is as follows:
the preparation method of the beta-nicotinamide mononucleotide specifically comprises the following steps:
A. phosphorylation reaction
In alkaline aqueous solution with pH value of 8-10, under the condition that the temperature of a reaction system is 25-50 ℃, nicotinamide riboside salt with a structure of formula II and metaphosphate are subjected to phosphorylation reaction for 2-5 h, so as to obtain an intermediate product with a structure of formula III;
B. acidification reaction
Adding acid into the reaction solution, regulating the pH value to 3-5, reducing the temperature of the reaction system, and acidifying the intermediate product with the structure of formula III to form beta-nicotinamide mononucleotide with the structure of formula I;
C. purification of the product
And B, filtering the reaction solution obtained in the step B through a protein membrane, concentrating through a high-pressure desalting membrane, separating, purifying through anion exchange resin, concentrating and crystallizing to obtain a beta-nicotinamide mononucleotide pure product.
Preferably, in step A, M in formula (III) is sodium or potassium element, the metaphosphate is sodium metaphosphate or potassium metaphosphate, and the metaphosphate has a sodium trimetaphosphate content of P 2 O 5 The content is more than 68%, and the pH value of the 1% aqueous solution is 6.2.
The alkaline aqueous solution is any one of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and magnesium hydroxide aqueous solution.
The pH value of the reaction system is 9, the reaction temperature is preferably 30 ℃, the reaction time is 4 hours, the reaction is monitored by on-line reaction, and after 4 hours of reaction, the raw materials are consumed.
Preferably, in step B, the acid added is an inorganic or organic acid: inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or phosphoric acid; the organic acid includes p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, maleic acid, tartaric acid, fatty acid or long-chain fatty acid.
The reaction system temperature is 10 ℃, and the pH value of the reaction solution is 3.5 after the acid is added for adjustment. The reason for setting the reaction system temperature to 10 ℃ is that the alkaline environment is required in the step A, the acidic reaction environment is required in the step B, and the heat release amount of the acid-base reaction is large in the process of acid regulation, so that the intermediate product structure is easily damaged if the temperature is not reduced first.
Preferably, in the step C, the molecular weight of the protein membrane is 30000-50000, and the high-pressure desalination membrane is an 8040 nanofiltration membrane. Before desalination, the reaction solution is diluted by four times by adding water, and concentrated by eight times by adopting an 8040 nanofiltration membrane; water was then added to the concentrate to a pre-first desalination volume and concentrated eight times using an 8040 nanofiltration membrane, after which the desalination step was repeated at least once.
In the process of separating and purifying anion exchange resin, the adopted anion exchange resin is 201 x 7 type anion resin, after a sample is put on a column, the sample is rinsed once with clean water, then the product is eluted by 0.003M aqueous solution with the volume of twice that of the clean water, the eluting speed is controlled to be 1-1.5L/h, and the product is collected.
In the concentrating and crystallizing process, the adopted crystallization solution is any two mixed solutions of methanol, ethanol, isopropanol and acetone. Concentrating the collected product solution by adopting a low-temperature evaporation or nanofiltration membrane concentration mode before crystallization, then adding the concentrated product solution into the crystallization solution, stirring, and drying the precipitated solid to obtain the pure beta-nicotinamide mononucleotide.
Effects and effects of the invention
According to the preparation method of the beta-nicotinamide mononucleotide, nicotinamide riboside salt is used as a reaction primary raw material, only two main reaction steps of nicotinamide riboside salt phosphorylation reaction and nicotinamide mononucleotide acidification reaction are involved, the involved raw materials are mainly alkali liquor or acid liquor, enzyme catalysis is not needed in the reaction process, toxic reagents are not needed, and the transgenic technology in the fermentation method is not involved.
Therefore, compared with the enzymatic reaction, the preparation method of the beta-nicotinamide mononucleotide has the advantages of low raw material cost, mild, stable and easily controlled process conditions, and the product indexes of different batches are close, so that the improvement of the reaction productivity is facilitated; compared with a chemical synthesis method and a fermentation method, the product obtained by the preparation method has high safety, and the application prospect of the product is improved.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a β -nicotinamide mononucleotide prepared in example one of the present invention;
FIG. 2 is a beta-nicotinamide mononucleotide prepared in example one of the invention 13 C nuclear magnetic spectrogram.
Detailed Description
The present invention will be described in detail with reference to the following examples and the accompanying drawings. The following examples should not be construed as limiting the scope of the invention.
Example 1
Step A: preparation of nicotinamide mononucleotide sodium salt:
to a 2000mL three-necked flask was added nicotinamide riboside chloride (100 g,0.344 mol) and 1000mL of aqueous sodium hydroxide solution at ph=9. After the temperature was controlled to 30℃and stabilized, sodium Trimetaphosphate (STMP) (110.48 g,0.361 mol) was added to the mixture to react for 4 hours. HPLC monitors the progress of the reaction, and HPLC shows 85% of the starting material to be consumed after 4 hours, and the nicotinamide mononucleotide content of the product is 83%.
And (B) step (B): preparation of nicotinamide mononucleotide
Cooling the reaction system to 10 ℃, adding 1M hydrochloric acid, adjusting the pH value of the reaction system to 3.5, and acidifying nicotinamide mononucleotide sodium salt to obtain an inner salt form with a structure I.
Step C: nicotinamide mononucleotide purification
Adding 3L of water to dilute the concentration of the reaction solution, and filtering by adopting a protein film with the molecular weight of 30000-50000; then, the solution was concentrated to 500mL by using an 8040 nanofiltration membrane, diluted with 3L of water, concentrated to 500mL by using a high-pressure desalination membrane, and repeated 3 times, and the salt residue in the system was substantially removed.
After 3L dilution with water, 1M aqueous sodium hydroxide solution was added to adjust the pH to 8, and 10Kg of 201X 7 type anion resin was used for purification and separation. After the sample was put on the column, the product was eluted with 3L of clear water and then with 6L of 0.003M aqueous hydrogen chloride at a rate of 1 to 1.5L/h, and 1.8L of the fraction containing the product was collected.
After concentration to 300mL with nanofiltration membrane, methanol/isopropanol=1 was added: after 300mL of the mixed solution with a volume ratio of 1, the mixture was stirred for 10 minutes, and a white solid was precipitated. After filtration and drying 78g of white solid was obtained, the yield was 68% and the purity was 99.5%.
Subjecting the obtained product to nuclear magnetic hydrogen spectrum 13 And C, nuclear magnetic spectrum verification, wherein the specific result is as follows, and the spectrograms are respectively shown in fig. 1 and 2:
1 HNMR(D 2 O,400MHz)：δ9.36(s,1H),9.18(d,1H,J＝6.4Hz),8.87(d,1H,J＝8.0Hz),8.19(t,1H,J＝8.0Hz),6.11(d,1H,J＝5.6Hz)，4.54(s,1H，H-1’)，4.46(t,1H,J＝5.2Hz)，4.45-4.33(m,1H),4.23-4.03(m,2H)。
13 C NMR(D 2 O,100MHz):165.8,146.1,142.6,140.0,134.0,128.7,100.1,87.6,87.5,77.9,71.1,64.3。
example 2
Step A: preparation of nicotinamide mononucleotide potassium salt:
to a 2000mL three-necked flask was added nicotinamide riboside chloride (100 g,0.344 mol) and 1000mL of aqueous sodium hydroxide solution at ph=9. After the temperature was controlled to 30℃and stabilized, sodium Trimetaphosphate (STMP) (110.48 g,0.361 mol) was added to the mixture to react for 4 hours. HPLC monitors the progress of the reaction, and HPLC shows 79% of the starting material to be consumed after 4 hours, with a nicotinamide mononucleotide content of 76% being the product.
And (B) step (B): preparation of nicotinamide mononucleotide
Cooling the reaction system to 10 ℃, adding 1ML of phosphoric acid, adjusting the pH value of the reaction system to 3.5, and acidifying nicotinamide mononucleotide sodium salt to obtain an inner salt form with a structure I.
Step C: nicotinamide mononucleotide purification
Adding 3L of water to dilute the concentration of the reaction solution, and filtering by adopting a protein film with the molecular weight of 30000-50000; then, the solution was concentrated to 500mL by using an 8040 nanofiltration membrane, diluted with 3L of water, concentrated to 500mL by using a high-pressure desalination membrane, and repeated 3 times, and the salt residue in the system was substantially removed.
After 3L dilution with water, 1M aqueous sodium hydroxide solution was added to adjust the pH to 8, and 10Kg of 201X 7 type anion resin was used for purification and separation. After the sample was put on the column, the product was eluted with 3L of clear water and then with 6L of 0.003M aqueous hydrogen chloride at a rate of 1 to 1.5L/h, and 1.8L of the fraction containing the product was collected.
After concentration to 300mL with nanofiltration membrane, ethanol/acetone=1 was added: after 300mL of the mixed solution with a volume ratio of 1, the mixture was stirred for 10 minutes, and a white solid was precipitated. After filtration and drying, 68g of white solid was obtained, the yield was 62%, and the purity was 99.1%.
Subjecting the obtained product to nuclear magnetic hydrogen spectrum 13 And C, nuclear magnetic spectrum verification, wherein specific results and spectrograms are the same as those of the embodiment 1.
The foregoing has shown and described the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (9)
1. A method for preparing beta-nicotinamide mononucleotide, which is characterized by comprising the following steps:
A. phosphorylation reaction
In alkaline aqueous solution with pH value of 8-10, under the condition that the temperature of a reaction system is 25-50 ℃, nicotinamide riboside salt with a structure of formula II and metaphosphate are subjected to phosphorylation reaction for 2-5 h, and an intermediate product with a structure of formula III is obtained, wherein the reaction process is as follows:
wherein M is sodium or potassium element,
B. acidification reaction
Adding acid into the reaction solution, regulating the pH value to 3-5, reducing the temperature of the reaction system, and acidifying the intermediate product with the structure of formula III to form beta-nicotinamide mononucleotide with the structure of formula I:
C. purification of the product
And B, filtering the reaction solution obtained in the step B through a protein membrane, concentrating through a high-pressure desalting membrane, separating, purifying through anion exchange resin, concentrating and crystallizing to obtain a beta-nicotinamide mononucleotide pure product.
2. The method for producing a β -nicotinamide mononucleotide according to claim 1, wherein:
wherein in the step A, the metaphosphate is sodium metaphosphate or potassium metaphosphate,
the alkaline aqueous solution is sodium hydroxide or potassium hydroxide.
3. The method for producing a β -nicotinamide mononucleotide according to claim 1, wherein:
in the step A, the pH value of a reaction system is 9, the reaction temperature is 30 ℃, and the reaction time is 4 hours.
4. The method for producing a β -nicotinamide mononucleotide according to claim 1, wherein:
wherein in the step A, the content of sodium trimetaphosphate in the metaphosphate is expressed as P 2 O 5 The content is more than 68%, and the pH value of the 1% aqueous solution is 6.2.
5. The method for producing a β -nicotinamide mononucleotide according to claim 1, wherein:
wherein in the step B, the added acid is inorganic acid or organic acid,
the inorganic acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or phosphoric acid; the organic acid comprises p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, maleic acid, tartaric acid, fatty acid or long chain fatty acid.
6. The method for producing a β -nicotinamide mononucleotide according to claim 1, wherein:
in the step B, the temperature of a reaction system is 10 ℃, and the pH value of a reaction solution is 3.5 after the reaction system is regulated by adding acid.
7. The method for producing a β -nicotinamide mononucleotide according to claim 1, wherein:
in the step C, the molecular weight of the adopted protein membrane is 30000-50000, the high-pressure desalination membrane is an 8040 nanofiltration membrane, the reaction solution is diluted four times by adding water before desalination, and the 8040 nanofiltration membrane is adopted to concentrate the reaction solution eight times; water was then added to the concentrate to a pre-first desalination volume and concentrated eight times using the 8040 nanofiltration membrane, after which the desalination step was repeated at least once.
8. The method for producing a β -nicotinamide mononucleotide according to claim 1, wherein:
wherein, in the separation and purification process of the anion exchange resin in the step C, the adopted anion exchange resin is 201 x 7 type anion resin,
after the sample is put on the column, the sample is rinsed once by clean water, then the product is eluted by 0.003M hydrogen chloride water solution with the volume of twice that of the clean water, the eluting speed is controlled to be 1-1.5L/h, and the product is collected.
9. The method for producing a β -nicotinamide mononucleotide according to claim 8, wherein:
wherein, in the concentration and crystallization process of the step C, the adopted crystallization solution is any two mixed solutions of methanol, ethanol, isopropanol and acetone,
concentrating the collected product solution by adopting a low-temperature evaporation or nanofiltration membrane concentration mode before crystallization, then adding the concentrated product solution into the crystallization solution, stirring, and drying the precipitated solid to obtain the beta-nicotinamide mononucleotide pure product.
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| CN112538101A (en) * | 2020-08-13 | 2021-03-23 | 常州博海威医药科技股份有限公司 | Novel crystal form of beta nicotinamide mononucleotide, preparation method and application thereof |
| CN112225759A (en) * | 2020-10-22 | 2021-01-15 | 闵令涛 | Preparation and purification method of beta-nicotinamide mononucleotide solution |
| CN114507263A (en) * | 2020-11-16 | 2022-05-17 | 尚科生物医药（上海）有限公司 | Desalting method of beta-nicotinamide mononucleotide |
| CN114660187A (en) * | 2020-12-23 | 2022-06-24 | 安徽古特生物科技有限公司 | Preparation method of beta-nicotinamide mononucleotide |
| CN112961197A (en) * | 2021-02-23 | 2021-06-15 | 成都西域从容生物科技有限公司 | Chemical synthesis method of NMN |
| CN113121629B (en) * | 2021-03-25 | 2023-07-21 | 沁浩膜技术(厦门)有限公司 | Method for extracting nicotinamide mononucleotide from fermentation liquor |
| CN113402570A (en) * | 2021-05-25 | 2021-09-17 | 天尔生物医药(湖北)有限公司 | Crystallization method of nicotinamide mononucleotide |
| CN114213486A (en) * | 2021-12-31 | 2022-03-22 | 浙江拓普药业股份有限公司 | Method for extracting and purifying nicotinamide mononucleotide from broccoli |
| CN114632087A (en) * | 2022-01-26 | 2022-06-17 | 华中科技大学同济医学院附属同济医院 | Application of NMN in preparing medicine for preventing and treating vascular endothelial cell senility, vascular aging and vascular atherosclerosis |
| CN116621898A (en) * | 2022-04-13 | 2023-08-22 | 深圳市迪克曼科技开发有限公司 | Organic acid salt of nicotinamide riboside and crystal form, preparation method and application thereof |
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| CN110054658A (en) * | 2019-04-24 | 2019-07-26 | 鲁东大学 | A kind of synthetic method of niacinamide ribose |
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