CN111377983A - Preparation method of β -nicotinamide mononucleotide - Google Patents
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Abstract
The invention relates to the technical field of medicines, and provides a preparation method of β -nicotinamide mononucleotide, which comprises the steps of A phosphorylation reaction, adding acid into a reaction solution, adjusting the pH value to 3-5, reducing the temperature of the reaction system, acidifying the intermediate product of nicotinamide mononucleotide to form β -nicotinamide mononucleotide, B product purification, and sequentially carrying out protein membrane filtration, high-pressure desalting membrane concentration, anion exchange resin separation purification, concentration and crystallization on the reaction solution obtained in the step B to obtain a pure product of β -nicotinamide mononucleotide.
Description
Technical Field
The invention belongs to the field of biological medicine, and particularly relates to a preparation method of β -nicotinamide mononucleotide.
Background
NMN (nicotinamide mononucleotide) is an organic molecule and also a nucleotide, contains the substance from many human nutritional sources, and is the first revolutionary breakthrough in the world that aging can be remarkably reversed and the life can be prolonged through rigorous scientific verification.
The effect of nicotinamide mononucleotide on aging inhibition is preliminarily found in 2014 by David Sinclair laboratories of Harvard university, and the remarkable effects of aging inhibition and life prolonging are comprehensively proved by world top research institutions such as Harvard medical college, Washington university, Japan Chongqing university and the like from multiple angles of improving physical ability, inhibiting cognitive decline caused by aging, reversing vascular death, protecting cardiovascular and cerebrovascular functions and the like in 2016 and 2018.
Currently, large scale synthesis of nicotinamide mononucleotide is achieved mainly by enzymatic reactions (Burgos, E.S et al, Biochemistry, 47:11086 (2008); Rozenberg, A et al, J.org.chem.,73:9314 (2008)). However, enzymatic reactions often involve various bottlenecks, such as high cost of enzymatic methods, harsh reaction conditions, unstable production process, large difference of product indexes of each batch, low reaction yield and the like. Previous organic synthetic chemists have made some efforts, but the results are not ideal, the reaction yields are low, the process is complex, the cost is high, some toxic reagents are used, all of which severely limit the large-scale application of these processes (Jaemoon, L et al, chem. Commun., 729-. In addition, the fermentation method may involve a relatively sensitive transgenic technology, and the problems of excessive endotoxin and the like may be brought in the reaction process, which brings many hidden dangers to the final application of the product.
Therefore, the market has urgent need for developing a process for synthesizing nicotinamide mononucleotide, which is green, environment-friendly, efficient and stable.
Disclosure of Invention
The invention aims to solve the problems and provide a preparation method of β -nicotinamide mononucleotide, so as to solve the problems of unstable process, potential safety hazard of products, complex process and the like in the existing preparation process.
Firstly, carrying out phosphorylation reaction on nicotinamide riboside (II) under alkaline conditions to obtain nicotinamide mononucleotide salt (III), then acidifying under acidic conditions to obtain a target primary product (I), and then carrying out purification steps to obtain a target product pure product, wherein the reaction formula is as follows:
the preparation method of the β -nicotinamide mononucleotide specifically comprises the following steps:
A. phosphorylation reactions
Carrying out phosphorylation reaction on nicotinamide riboside with a structure shown in a formula II and metaphosphate for 2-5 h in an alkaline aqueous solution with a pH value of 8-10 and at a reaction system temperature of 25-50 ℃ to obtain an intermediate product with a structure shown in a formula III;
B. acidification reaction
Adding acid into the reaction solution, adjusting the pH value to 3-5, reducing the temperature of the reaction system, and acidifying the intermediate product with the structure of the formula III to form β -nicotinamide mononucleotide with the structure of the formula I;
C. purification of the product
And D, sequentially carrying out protein membrane filtration, high-pressure desalting membrane concentration, anion exchange resin separation and purification, concentration and crystallization on the reaction solution obtained in the step B to obtain a pure product of β -nicotinamide mononucleotide.
Preferably, in step A, M in formula (III) is sodium or potassium element, metaphosphate is sodium metaphosphate or potassium metaphosphate, and sodium trimetaphosphate in metaphosphate has content of P2O5Calculated by the content of more than 68 percent, the pH value of 1 percent 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, and the raw materials are consumed after 4 hours of reaction through on-line reaction monitoring.
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 temperature of the reaction system is 10 ℃, and the pH value of the reaction solution is 3.5 after the acid is added for adjustment. The reason why the temperature of the reaction system is set to 10 ℃ is that the step a is an alkaline environment, the step B requires an acidic reaction environment, and the exothermic amount of the acid-base reaction is large during the acid adjustment process, so that the structure of the intermediate product is easily damaged if the temperature is not lowered first.
Preferably, in the step C, the molecular weight of the protein membrane adopted is 30000-50000, and the high-pressure desalination membrane is 8040 nanofiltration membrane. Before desalting, adding water into the reaction solution to dilute by four times, and concentrating by eight times by adopting an 8040 nanofiltration membrane; water was then added to the concentration to the pre-first desalting volume and concentrated eight times using 8040 nanofiltration membranes, and the desalting step was repeated at least once.
In the process of separating and purifying the anion exchange resin, the adopted anion exchange resin is 201 x 7 type anion resin, after a sample is loaded on a column, the sample is washed by clean water for one time, then a product is eluted by 0.003M aqueous solution of hydrogen chloride with the volume twice that of the clean water, the elution speed is controlled to be 1-1.5L/h, and the product is collected.
Before crystallization, the collected product solution is concentrated by adopting a low-temperature evaporation or nanofiltration membrane concentration mode, then the product solution is added into the crystallization solution to be stirred, and the separated solid is dried, so that the pure β -nicotinamide mononucleotide is obtained.
Action and Effect of the invention
According to the preparation method of β -nicotinamide mononucleotide provided by the invention, nicotinamide riboside is taken as a reaction initial raw material, only two main reaction steps of nicotinamide riboside phosphorylation reaction and nicotinamide mononucleotide acidification reaction are involved, the involved raw material is mainly alkaline solution or acid solution, enzyme catalysis is not needed in the reaction process, no toxic reagent is used, and no transgenic technology in a fermentation method is involved.
Therefore, compared with the enzymatic reaction, the preparation method of β -nicotinamide mononucleotide has the advantages of low raw material cost, mild, stable and easily controlled process conditions, and similar product indexes of different batches, and is beneficial to improving the reaction capacity.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of β -nicotinamide mononucleotide prepared in the first embodiment of the invention;
FIG. 2 shows β -nicotinamide mononucleotide prepared in the first embodiment of the invention13C nuclear magnetic spectrum.
Detailed Description
The present invention will be described in detail below with reference to 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, nicotinamide ribochloride (100g, 0.344mol) was added, and 1000mL of an aqueous sodium hydroxide solution having a ph of 9 was added. After temperature control to 30 ℃ until stabilization, Sodium Trimetaphosphate (STMP) (110.48g, 0.361mol) was added and reacted for 4 hours. The reaction progress was monitored by high performance liquid chromatography, HPLC showed 85% of the starting material was consumed after 4 hours and the product nicotinamide mononucleotide content was 83%.
And 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 the nicotinamide mononucleotide sodium salt to obtain an inner salt form with a structure I.
And C: nicotinamide mononucleotide purification
Adding 3L of water to dilute the concentration of the reaction solution, and filtering by adopting a protein membrane with the molecular weight of 30000-50000; and then desalting and concentrating to 500mL by using an 8040 nanofiltration membrane at high pressure, adding 3L of water for dilution, continuously concentrating to 500mL by using a high-pressure desalting membrane, and repeating for 3 times to basically remove residual salt in the system.
After diluting with 3L of water, 1M aqueous sodium hydroxide solution was added to adjust the pH to 8, and then 10Kg of 201X 7 type anion resin was used for purification and separation. After loading the sample on the column, the sample was rinsed once with 3L of clear water, and then the product was eluted with 6L of 0.003M aqueous hydrogen chloride solution at a rate of 1-1.5L/h, and 1.8L of the product-containing fraction was collected.
After concentration to 300mL with nanofiltration membrane, methanol/isopropanol-1: after 300mL of the mixture at a volume ratio of 1, the mixture was stirred for 10 minutes to precipitate a white solid. 78g of white solid is obtained after filtration and drying, the yield is 68 percent, and the purity is 99.5 percent.
Subjecting the obtained product to nuclear magnetic hydrogen spectrum and13c nuclear magnetic spectrum verification, wherein the specific result is as follows, and the spectrograms are respectively shown in figure 1 and figure 2:
1HNMR(D2O,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)。
13C NMR(D2O,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, nicotinamide ribochloride (100g, 0.344mol) was added, and 1000mL of an aqueous sodium hydroxide solution having a ph of 9 was added. After temperature control to 30 ℃ until stabilization, Sodium Trimetaphosphate (STMP) (110.48g, 0.361mol) was added and reacted for 4 hours. The reaction progress was monitored by high performance liquid chromatography, HPLC showed 79% of the starting material was consumed after 4 hours and the product nicotinamide mononucleotide content was 76%.
And B: preparation of Nicotinamide mononucleotide
Cooling the reaction system to 10 ℃, adding 1ML phosphoric acid, adjusting the pH value of the reaction system to 3.5, and acidifying the nicotinamide mononucleotide sodium salt to obtain an inner salt form with a structure I.
And C: nicotinamide mononucleotide purification
Adding 3L of water to dilute the concentration of the reaction solution, and filtering by adopting a protein membrane with the molecular weight of 30000-50000; and then desalting and concentrating to 500mL by using an 8040 nanofiltration membrane at high pressure, adding 3L of water for dilution, continuously concentrating to 500mL by using a high-pressure desalting membrane, and repeating for 3 times to basically remove residual salt in the system.
After diluting with 3L of water, 1M aqueous sodium hydroxide solution was added to adjust the pH to 8, and then 10Kg of 201X 7 type anion resin was used for purification and separation. After loading the sample on the column, the sample was rinsed once with 3L of clear water, and then the product was eluted with 6L of 0.003M aqueous hydrogen chloride solution at a rate of 1-1.5L/h, and 1.8L of the product-containing fraction was collected.
After concentration to 300mL with nanofiltration membrane, ethanol/acetone ═ 1: after 300mL of the mixture at a volume ratio of 1, the mixture was stirred for 10 minutes to precipitate a white solid. After filtering and drying, 68g of white solid is obtained, the yield is 62 percent, and the purity is 99.1 percent.
Subjecting the obtained product to nuclear magnetic hydrogen spectrum and13and C, nuclear magnetic spectrum verification, wherein the specific result and the spectrogram are the same as those of the example 1.
The foregoing shows and describes the general principles, essential 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, which are given by way of illustration of the principles of the present invention, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (9)
1. A method for preparing β -nicotinamide mononucleotide, which is characterized by comprising the following steps:
A. phosphorylation reactions
In an alkaline aqueous solution with the pH value of 8-10, carrying out phosphorylation reaction on nicotinamide riboside with a structure shown in a formula II and metaphosphate for 2-5 h at the temperature of a reaction system of 25-50 ℃ to obtain an intermediate product with a structure shown in a formula III, wherein the reaction process is as follows:
B. acidification reaction
Adding acid into the reaction solution, adjusting the pH value to 3-5, reducing the temperature of the reaction system, and acidifying the intermediate product with the structure of the formula III to form β -nicotinamide mononucleotide with the structure of the formula I:
C. purification of the product
And D, sequentially carrying out protein membrane filtration, high-pressure desalting membrane concentration, anion exchange resin separation and purification, concentration and crystallization on the reaction solution obtained in the step B to obtain a pure product of β -nicotinamide mononucleotide.
2. The method of β -nicotinamide mononucleotide according to claim 1, wherein:
wherein, in the step A, M is sodium or potassium element, metaphosphate is sodium metaphosphate or potassium metaphosphate,
the alkaline aqueous solution is any one of aqueous solutions of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and magnesium hydroxide.
3. The method of β -nicotinamide mononucleotide according to claim 1, wherein:
wherein, in the step A, the pH value of the reaction system is 9, the reaction temperature is 30 ℃, and the reaction time is 4 hours.
4. The method of β -nicotinamide mononucleotide according to claim 1, wherein:
in the step A, the content of sodium trimetaphosphate in the metaphosphate is P2O5Calculated by the content of more than 68 percent, the pH value of 1 percent aqueous solution is 6.2.
5. The method of 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 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.
6. The method of β -nicotinamide mononucleotide according to claim 1, wherein:
in the step B, the temperature of the reaction system is 10 ℃, and the pH value of the reaction solution is 3.5 after the reaction system is adjusted by adding acid.
7. The method of 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 desalting membrane is an 8040 nanofiltration membrane, before desalting, the reaction solution is diluted by four times by adding water, and the reaction solution is concentrated by eight times by adopting the 8040 nanofiltration membrane; water was then added to the concentration to the pre-first desalination volume and concentrated eight times using the 8040 nanofiltration membrane, and the desalination step was repeated at least once.
8. The method of β -nicotinamide mononucleotide according to claim 1, wherein:
wherein, in the process of separating and purifying the anion exchange resin in the step C, the adopted anion exchange resin is 201 by 7 type anion resin,
after the sample is loaded on the column, the sample is rinsed once with clear water, then the product is eluted by 0.003M aqueous hydrogen chloride solution with the volume twice that of the clear water, the elution speed is controlled to be 1-1.5L/h, and the product is collected.
9. The method of claim 8, wherein said β -nicotinamide mononucleotide is prepared by:
wherein, in the concentration and crystallization process in the step C, the adopted crystallization solution is any two mixed solutions of methanol, ethanol, isopropanol and acetone,
before crystallization, the collected product solution is concentrated by adopting a low-temperature evaporation or nanofiltration membrane concentration mode, then the product solution is added into the crystallization solution to be stirred, and the separated solid is dried to obtain the pure β -nicotinamide mononucleotide.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112225759A (en) * | 2020-10-22 | 2021-01-15 | 闵令涛 | Preparation and purification method of beta-nicotinamide mononucleotide solution |
| 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 |
| CN113121629A (en) * | 2021-03-25 | 2021-07-16 | 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 |
| WO2022033589A1 (en) * | 2020-08-13 | 2022-02-17 | 常州博海威医药科技股份有限公司 | NEW CRYSTAL FORM OF β-NICOTINAMIDE MONONUCLEOTIDE, PREPARATION METHOD THEREFOR AND USE THEREOF |
| 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 |
| 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 |
| 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 |
| 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 |
| CN114933621A (en) * | 2022-04-13 | 2022-08-23 | 深圳市迪克曼生物科技有限公司 | Organic acid salt of nicotinamide ribose, and crystal form, preparation method and application thereof |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022033589A1 (en) * | 2020-08-13 | 2022-02-17 | 常州博海威医药科技股份有限公司 | NEW CRYSTAL FORM OF β-NICOTINAMIDE MONONUCLEOTIDE, PREPARATION METHOD THEREFOR AND USE 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 |
| CN113121629A (en) * | 2021-03-25 | 2021-07-16 | 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 |
| CN114933621A (en) * | 2022-04-13 | 2022-08-23 | 深圳市迪克曼生物科技有限公司 | Organic acid salt of nicotinamide ribose, and crystal form, preparation method and application thereof |
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