CN114369128A - Process for preparing nicotinamide mononucleotide - Google Patents
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- CN114369128A CN114369128A CN202011099456.XA CN202011099456A CN114369128A CN 114369128 A CN114369128 A CN 114369128A CN 202011099456 A CN202011099456 A CN 202011099456A CN 114369128 A CN114369128 A CN 114369128A
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/048—Pyridine radicals
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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- C07H1/02—Phosphorylation
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- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
Abstract
The invention provides a preparation method of nicotinamide mononucleotide. The preparation method comprises the step of carrying out phosphorylation reaction on raw materials containing nicotinamide riboside salt, 1, 8-bis-dimethylamino-naphthalene, phosphorus oxychloride and a solvent to obtain a reaction solution containing nicotinamide mononucleotide. On one hand, 1, 8-bis-dimethylamino-naphthalene can inhibit phosphorus oxychloride from continuously attacking hydroxyl at the 2-position or the 3-position; on the other hand, one nitrogen atom of the 1, 8-bis-dimethylamino group is beneficial to the extraction of hydroxyl hydrogen at the 2-position, the other nitrogen atom is beneficial to the removal of chlorine in phosphorus oxychloride, and the removal of hydrogen chloride is beneficial under the synergistic action of the two N atoms. Meanwhile, because the two nitrogen atoms in the 1, 8-bis-dimethylamino naphthalene are closer to each other, a transition intermediate formed in the hydrogen chloride removal process of the 1, 8-bis-dimethylamino naphthalene is more stable, so that the hydrogen chloride removal process is prone to intramolecular reaction, and the selectivity of the phosphorylation reaction is further improved.
Description
Technical Field
The invention relates to the technical field of nicotinamide mononucleotide synthesis, and particularly relates to a preparation method of nicotinamide mononucleotide.
Background
Nicotinamide Mononucleotide (NMN), alias beta-nicotinamide mononucleotide, as NAD+The intermediate in the remedy pathway has the functions of resisting oxidation and reducing oxidative stress, and has good performance in the treatment of specific diseases, such as cerebral apoplexy, cardiac ischemia-reperfusion, Alzheimer disease, Parkinson disease, acute kidney injury, retinal degenerative disease, type 2 diabetes and the like. Particularly in the aspect of anti-aging, NMN can slow down physiological decline of organisms, enhance energy metabolism and prolong the life.
In 2018, in 5 months, Herbalmax, a U.S. dietary supplement enterprise, converted NMN (Nicotinamide monoglucoside Nicotinamide mononucleotide), which is experimentally confirmed to significantly delay aging and prolong life, into an actual product reinvigator (the Chinese name "reviotuo") and marketed. This message has attracted a wide range of attention.
At present, the production methods of beta-nicotinamide mononucleotide include chemical synthesis method and enzymatic synthesis method. For example, Journal of Biological Chemistry,1958(233), (493), and Analytical Biochemistry,2011(412), 18 report a method for enzymatically producing nicotinamide mononucleotide, in which nicotinamide ribose is used as a substrate and reacted with nicotinamide ribokinase or recombinant cells containing nicotinamide ribokinase in the presence of a phosphate donor such as ATP to produce beta-nicotinamide mononucleotide.
Chemical synthesis of nicotinamide mononucleotide is reported in many documents, and almost all methods of phosphorus oxychloride are used, for example, chem.Commun.1999, 729-730, CN102876759, Tetrahedron 65(2009) 8378-.
However, the enzyme used in the enzymatic synthesis method is expensive, which limits the use of the enzyme in industrial production. The phosphorus oxychloride is independently used as a phosphorylation reagent in the chemical method preparation, the reaction selectivity is not high, the hydroxyl groups at other sites are easy to be chlorinated, the product is easy to degrade under the phosphorus oxychloride, the post-treatment needs to use ion exchange resin for further purification due to more impurities, the operation is complicated, and the purity and the yield of the obtained product are low.
Disclosure of Invention
The invention mainly aims to provide a preparation method of nicotinamide mononucleotide, which solves the problem of low selectivity of a synthetic method of nicotinamide mononucleotide in the prior art.
In order to achieve the above object, according to one aspect of the present invention, there is provided a method for preparing nicotinamide mononucleotide, comprising: step S1, carrying out phosphorylation reaction on raw materials containing nicotinamide riboside salt, 1, 8-bis-dimethylamino naphthalene, phosphorus oxychloride and a solvent to obtain a reacted system; step S2, hydrolyzing the reacted system to obtain a reaction solution containing nicotinamide mononucleotide.
Further, the molar ratio of the 1, 8-bis-dimethylamino naphthalene, nicotinamide riboside salt and phosphorus oxychloride is 1-2: 1: 4-6, preferably 1.5:1: 5.
Further, the anion in the above nicotinamide riboside salt is trifluoromethanesulfonate ion or chloride ion.
Further, the solvent is a polar aprotic solvent, preferably trimethyl phosphate or triethyl phosphate.
Further, the temperature of the phosphorylation reaction is-20 to 0 ℃, and preferably-10 to 0 ℃.
Further, the time of the phosphorylation reaction is 12 to 48 hours, preferably 18 to 36 hours.
Further, the preparation method further comprises the following steps: crystallizing the reaction solution containing nicotinamide mononucleotide, wherein the process of crystallizing comprises dissolving the reaction solution containing nicotinamide mononucleotide in water to obtain an aqueous solution; mixing the aqueous solution with the organic solvent and stirring to precipitate the nicotinamide mononucleotide.
Further, the temperature of the crystallization treatment is-10 to 0 ℃, preferably-10 to-5 ℃, and the time of the crystallization treatment is preferably 1 to 6 hours, and more preferably 2 to 4 hours.
Further, the volume ratio of the water to the organic solvent is 1:5 to 20, preferably 1:10 to 15.
Further, the organic solvent is selected from one or more of ethanol, n-propanol, isopropanol, acetonitrile and acetone.
By applying the technical scheme of the invention, 2-hydroxy on the five-membered heterocycle of the nicotinamide riboside salt is primary hydroxy, 3-hydroxy and 4-hydroxy belong to secondary hydroxy, and because the reaction activity of the primary hydroxy is stronger than that of the secondary hydroxy, when the phosphorylation reaction occurs, 1, 8-bis-dimethylamino naphthalene preferentially forms a compound with 2-hydroxy of the nicotinamide riboside salt, and on one hand, because 1, 8-bis-dimethylamino naphthalene is a rigid structure containing two aromatic rings, the volume is larger, and the phosphorus oxychloride can be inhibited from continuously attacking 2-hydroxy or 3-hydroxy; on the other hand, during the phosphorylation reaction, one nitrogen atom of the 1, 8-bis-dimethylamino is beneficial to the removal of 2-hydroxyl hydrogen, the other nitrogen atom is beneficial to the removal of chlorine in phosphoryl chloride, and the removal of hydrogen chloride is beneficial to the synergistic effect of the two N atoms, meanwhile, because the two nitrogen atoms in the 1, 8-bis-dimethylamino naphthalene are closer to each other, the excessive intermediate formed in the hydrogen chloride removal process of the 1, 8-bis-dimethylamino naphthalene is more stable, so that the hydrogen chloride removal process is prone to intramolecular reaction, and the selectivity of the phosphorylation reaction is further improved.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
figure 1 shows a nuclear magnetic resonance hydrogen spectrum of β -nicotinamide mononucleotide provided according to example 1 of the invention;
FIG. 2 shows an infrared spectrum of β -nicotinamide mononucleotide provided according to example 1 of the invention.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail below with reference to the embodiments with reference to the attached drawings.
As analyzed by the background art, the problem of low selectivity of the synthetic method of nicotinamide mononucleotide exists in the prior art, and in order to solve the problem, the invention provides a preparation method of nicotinamide mononucleotide.
In an exemplary embodiment of the present application, there is provided a method for preparing nicotinamide mononucleotide, comprising: step S1, carrying out phosphorylation reaction on raw materials containing nicotinamide riboside salt, 1, 8-bis-dimethylamino naphthalene, phosphorus oxychloride and a solvent to obtain a reacted system; step S2, hydrolyzing the reacted system to obtain a reaction solution containing nicotinamide mononucleotide.
The 2-hydroxyl on the five-membered heterocyclic ring of the nicotinamide riboside salt is primary hydroxyl, the 3-hydroxyl and the 4-hydroxyl belong to secondary hydroxyl, and the reactivity of the primary hydroxyl is stronger than that of the secondary hydroxyl, so that 1, 8-bis-dimethylamino naphthalene preferentially forms a compound with the 2-hydroxyl of the nicotinamide riboside salt when the phosphorylation reaction occurs, and on one hand, the 1, 8-bis-dimethylamino naphthalene is a rigid structure containing two aromatic rings, so that the volume is larger, and the phosphorus oxychloride can be inhibited from continuously attacking the 2-hydroxyl or the 3-hydroxyl; on the other hand, during the phosphorylation reaction, one nitrogen atom of the 1, 8-bis-dimethylamino is beneficial to the removal of 2-hydroxyl hydrogen, the other nitrogen atom is beneficial to the removal of chlorine in phosphoryl chloride, and the removal of hydrogen chloride is beneficial to the synergistic effect of the two N atoms, meanwhile, because the two nitrogen atoms in the 1, 8-bis-dimethylamino naphthalene are closer to each other, the excessive intermediate formed in the hydrogen chloride removal process of the 1, 8-bis-dimethylamino naphthalene is more stable, so that the hydrogen chloride removal process is prone to intramolecular reaction, and the selectivity of the phosphorylation reaction is further improved.
Specifically, the process of the above reaction is as follows:
in order to promote the reaction of the raw materials as completely as possible and improve the efficiency of the reaction, the molar ratio of the 1, 8-bis-dimethylamino naphthalene, nicotinamide riboside salt and phosphorus oxychloride is preferably 1-2: 1: 4-6, and more preferably 1.5:1: 5.
In one embodiment of the present application, the anion in the above nicotinamide riboside salt is triflate ion or chloride ion.
Nicotinamide riboside salts herein are a source of the nicotinamide riboside moiety of nicotinamide mononucleotide, and for the purposes of improving solubility of nicotinamide riboside salts in solvents and reducing costs, the aforementioned nicotinamide riboside salts are preferred.
The preparation method of the nicotinamide riboside salt can be synthesized according to the prior art, and in order to improve the synthesis efficiency of the nicotinamide riboside salt, the following synthesis methods are preferably adopted to sequentially synthesize the nicotinamide riboside triacetate trifluoromethanesulfonate and the nicotinamide riboside chloride:
taking a clean reaction bottle (1L), adding 20g of tetraacetyl ribose, 11.2g of nicotinamide and 400mL of acetonitrile, and starting stirring; keeping the temperature at 25 ℃, adding 27.6g of trimethylsilyl trifluoromethanesulfonate, and dissolving the solution to be clear; after 20min, TLC detection, the reaction of tetraacetyl ribose is complete. Adding 8mL of methanol into the reaction solution, concentrating under reduced pressure after 5min, adding 100mL of dichloromethane into the concentrated oil, filtering under reduced pressure, and concentrating the mother liquor under reduced pressure to obtain nicotinamide riboside triacetate trifluoromethanesulfonate, which is weighed as 37.5 g.
Nicotinamide riboside triacetate triflate (37.5g) is added into a 500mL reaction bottle and placed in an ice bath, then 200mL ammonia methanol solution (4M) is added, and after reaction stirring is carried out for 6h, reduced pressure concentration is carried out, thus obtaining 13.5g nicotinamide riboside triflate.
10g of nicotinamide riboside triflate is dissolved in 30mL of water, and then concentrated to dryness under reduced pressure by using a perchloride type anion exchange resin, and then added with 50mL of absolute ethyl alcohol, stirred, crystallized and filtered to obtain 6.5g of nicotinamide riboside chloride.
In order to improve the solubility of the raw materials in the solvent and thus the reaction efficiency, the solvent is preferably a polar aprotic solvent, and the polar aprotic solvent is preferably trimethyl phosphate or triethyl phosphate.
In one embodiment of the present application, the temperature of the phosphorylation reaction is-20 to 0 ℃, preferably-10 to 0 ℃.
In order to reduce the occurrence of side reactions in the above reaction, it is preferable that the above reaction is carried out at the above reaction temperature range.
In order to achieve both the reaction efficiency and the conversion rate of the reaction raw materials, the time of the phosphorylation reaction is preferably 12 to 48 hours, and preferably 18 to 36 hours.
In an embodiment of the present application, the above preparation method further includes: crystallizing the reaction solution containing nicotinamide mononucleotide, wherein the process of crystallizing comprises dissolving the reaction solution containing nicotinamide mononucleotide in water to obtain an aqueous solution; mixing the aqueous solution with the organic solvent and stirring to precipitate the nicotinamide mononucleotide.
Compared with the prior art, the post-treatment process avoids the step of purifying the ion exchange resin of the reaction liquid containing the nicotinamide mononucleotide, thereby reducing the reaction steps and lowering the production cost.
In order to improve the efficiency of the crystallization treatment, the temperature of the crystallization treatment is preferably-10 to 0 ℃, preferably-10 to-5 ℃, and the time of the crystallization treatment is preferably 1 to 6 hours, and more preferably 2 to 4 hours.
In one embodiment of the present invention, the volume ratio of the water to the organic solvent is 1:5 to 20, preferably 1:10 to 15.
Preferably, the water and the organic solvent in the above ratio are more favorable for the precipitation of nicotinamide mononucleotide.
In order to improve the efficiency of the crystallization treatment, it is preferable that the organic solvent is selected from any one or more of ethanol, n-propanol, isopropanol, acetonitrile, and acetone.
The advantageous effects of the present application will be described below with reference to specific examples and comparative examples.
Example 1
Weighing 10g of nicotinamide riboside chloride (34.4mmol), adding into a 100mL reaction bottle, adding 50mL of trimethyl phosphate, cooling to-20-10 ℃, adding 11.06g of 1, 8-bis-dimethylamino-naphthalene (51.6mmol), then dropwise adding 26.4g of phosphorus oxychloride (172mmol), reacting for 24h, carrying out vacuum filtration on the reaction solution, and concentrating the filtrate under reduced pressure to obtain a concentrated product.
Adding 20mL of purified water into the concentrated product at the temperature of-10 to-5 ℃, slowly dripping 200mL of acetonitrile after dissolving, stirring and crystallizing for 4h, and filtering to obtain 8.62g of beta-nicotinamide mononucleotide, wherein the nuclear magnetic resonance hydrogen spectrum of the beta-nicotinamide mononucleotide product is shown in the attached drawing 1, and the nuclear magnetic resonance hydrogen spectrum data is as follows:1H-NMR(600MHz,D2o) delta ppm9.31(1H, s, Ar),9.095-9.105(1H, d, Ar),8.771-8.785(1H, d, Ar),8.079-8.103(1H, t, Ar),5.991-6.001(1H, d, H-1),4.405-4.420(1H, m, H-2),4.388-4.396(1H, t, H-3),4.249(1H, d, H-4),4.045-4.046(1H, d, H-5),3.876-3.896(1H, d, H-5). As can be seen from FIG. 1, the product after crystallization is beta-nicotinamide mononucleotide and has almost no impurities. The infrared spectrum of the beta-nicotinamide mononucleotide product is shown in figure 2, wherein 3437.15 is the stretching vibration of hydroxyl on a sugar ring; 3221.42 nitrogen-hydrogen stretching vibration of amide; 3118.9 is the stretching vibration of the hydroxyl on phosphoryl; 3068.75 is the stretching vibration of the hydroxyl on the pyridine ring; 2873.94 is a hydrocarbon extension of sugar ring No. 5Performing contraction vibration; 1670.35 is the stretching vibration of carbon and oxygen on amide carbonyl; 1573.91 is the stretching vibration of carbon-carbon double bond on pyridine ring; 1402.25 is amide carbon nitrogen stretching vibration; 1215.15 is phosphorus oxygen double bond stretching vibration on phosphoryl; 1105.21,1087.85 is carbon-oxygen single bond stretching vibration; 775.38,765.74 shows bending vibration of hydrogen single bond of pyridine ring.
Example 2
Example 2 differs from example 1 in that,
the molar ratio of 1, 8-bis-dimethylaminonaphthalene, nicotinamide ribochloride (34.4mmol) and phosphorus oxychloride is 1:1:5, and 8.05g of beta-nicotinamide mononucleotide is finally obtained.
Example 3
Example 3 differs from example 1 in that,
the molar ratio of 1, 8-bis-dimethylaminonaphthalene, nicotinamide ribochloride (34.4mmol) and phosphorus oxychloride is 2:1:5, and 8.03g of beta-nicotinamide mononucleotide is finally obtained.
Example 4
Example 4 differs from example 1 in that,
1, 8-Dimethylaminonaphthalene, nicotinamide ribochloride (34.4mmol) and phosphorus oxychloride in a molar ratio of 1.5:1:4, to obtain 8.33g of beta-nicotinamide mononucleotide.
Example 5
Example 5 differs from example 1 in that,
the molar ratio of 1, 8-bis-dimethylaminonaphthalene, nicotinamide ribochloride (34.4mmol) and phosphorus oxychloride is 1.5:1:6, and 8.60g of beta-nicotinamide mononucleotide is finally obtained.
Example 6
Example 6 differs from example 1 in that,
weighing 5g of nicotinamide riboside trifluoromethanesulfonate (12.4mmol), adding into a 50mL reaction bottle, adding 25mL of trimethyl phosphate, cooling to-10-0 ℃, adding 2.66g of 1, 8-bis-dimethylamino-naphthalene (12.4mmol), dropwise adding 10.5g of phosphorus oxychloride (68.6mmol), reacting for 18h, carrying out vacuum filtration on the reaction solution, and concentrating the filtrate under reduced pressure to obtain a concentrated product.
Adding 10mL of purified water into the concentrated product at the temperature of-10 to-5 ℃, slowly dripping 100mL of acetonitrile after dissolving, stirring and crystallizing for 3h, and filtering to obtain 8.05g of beta-nicotinamide mononucleotide.
Example 7
Example 7 differs from example 1 in that,
1, 8-Dimethylaminonaphthalene, nicotinamide ribochloride (34.4mmol) and phosphorus oxychloride in a molar ratio of 0.5:1:5, to obtain 7.97g of beta-nicotinamide mononucleotide.
Example 8
Example 8 and example 1 difference is, phosphorylation reaction temperature is-10 ~ 0 ℃, finally obtain 8.82g beta-nicotinamide mononucleotide.
Example 9
Example 9 differs from example 1 in that the time of the phosphorylation reaction was 18h, and 8.59g of β -nicotinamide mononucleotide was finally obtained.
Example 10
Example 10 differs from example 1 in that the time of the phosphorylation reaction was 36h, and 8.59g of β -nicotinamide mononucleotide was finally obtained.
Example 11
Example 11 differs from example 1 in that the time of the phosphorylation reaction was 12h, and 8.30g of β -nicotinamide mononucleotide was finally obtained.
Example 12
Example 12 differs from example 1 in that the time of the phosphorylation reaction was 48h, and 8.35g of β -nicotinamide mononucleotide was finally obtained.
Example 13
Example 13 differs from example 1 in that the time of the phosphorylation reaction was 10h, and 8.07g of β -nicotinamide mononucleotide was finally obtained.
Example 14
Example 14 and example 1 difference, in the crystallization treatment temperature is-5 ~ 0 ℃, finally obtain 8.19g beta-nicotinamide mononucleotide.
Example 15
Example 15 differs from example 1 in that the time of crystallization treatment was 2 hours, and 8.64g of β -nicotinamide mononucleotide was finally obtained.
Example 16
Example 16 differs from example 1 in that the time of crystallization treatment was 1 hour, and 8.28g of β -nicotinamide mononucleotide was finally obtained.
Example 17
Example 17 differs from example 1 in that the time of crystallization treatment was 6 hours, and 8.34g of β -nicotinamide mononucleotide was finally obtained.
Example 18
Example 18 differs from example 1 in that the time of crystallization treatment was 0.5h, and 8.11g of β -nicotinamide mononucleotide was finally obtained.
Example 19
Example 19 differs from example 1 in that the volume ratio of water to acetonitrile is 1:15, resulting in 8.64g of β -nicotinamide mononucleotide.
Example 20
Example 20 differs from example 1 in that the volume ratio of water to acetone was 1:5, and 8.20g of β -nicotinamide mononucleotide was finally obtained.
Example 21
Example 21 differs from example 1 in that the volume ratio of water to acetone was 1:20, and 8.23g of β -nicotinamide mononucleotide was finally obtained.
Example 22
Example 22 differs from example 1 in that the volume ratio of water to acetone was 1:3, and 8.03g of β -nicotinamide mononucleotide was finally obtained.
Comparative example 1
Comparative example 1 differs from example 1 in that 4.25g of β -nicotinamide mononucleotide was obtained without the addition of 1, 8-bis-dimethylaminonaphthalene.
Comparative example 2
Comparative example 2 differs from example 1 in that triethylamine was used instead of 1, 8-bisdimethylaminonaphthalene to give 5.85g of β -nicotinamide mononucleotide.
Comparative example 3
Comparative example 3 differs from example 1 in that diisopropylethylamine was used instead of 1, 8-bisdimethylaminonaphthalene to give 5.90g of β -nicotinamide mononucleotide.
The yields and purities of β -nicotinamide mononucleotide prepared in examples 1 to 22 and comparative examples 1 to 3 are shown in table 1.
TABLE 1
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
the 2-hydroxyl on the five-membered heterocyclic ring of the nicotinamide riboside salt is primary hydroxyl, the 3-hydroxyl and the 4-hydroxyl belong to secondary hydroxyl, and the reactivity of the primary hydroxyl is stronger than that of the secondary hydroxyl, so that 1, 8-bis-dimethylamino naphthalene preferentially forms a compound with the 2-hydroxyl of the nicotinamide riboside salt when the phosphorylation reaction occurs, and on one hand, the 1, 8-bis-dimethylamino naphthalene is a rigid structure containing two aromatic rings, so that the volume is larger, and the phosphorus oxychloride can be inhibited from continuously attacking the 2-hydroxyl or the 3-hydroxyl; on the other hand, during the phosphorylation reaction, one nitrogen atom of the 1, 8-bis-dimethylamino is beneficial to the removal of 2-hydroxyl hydrogen, the other nitrogen atom is beneficial to the removal of chlorine in phosphoryl chloride, and the removal of hydrogen chloride is beneficial to the synergistic effect of the two N atoms, meanwhile, because the two nitrogen atoms in the 1, 8-bis-dimethylamino naphthalene are closer to each other, the excessive intermediate formed in the hydrogen chloride removal process of the 1, 8-bis-dimethylamino naphthalene is more stable, so that the hydrogen chloride removal process is prone to intramolecular reaction, and the selectivity of the phosphorylation reaction is further improved.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for producing nicotinamide mononucleotide, comprising:
step S1, carrying out phosphorylation reaction on raw materials containing nicotinamide riboside salt, 1, 8-bis-dimethylamino naphthalene, phosphorus oxychloride and a solvent to obtain a reacted system;
step S2, hydrolyzing the reacted system to obtain a reaction solution containing nicotinamide mononucleotide.
2. The method of claim 1, wherein the molar ratio of 1, 8-bis-dimethylaminonaphthalene to nicotinamide riboside salt to phosphorus oxychloride is 1-2: 1: 4-6, preferably 1.5:1: 5.
3. The method of claim 1, wherein the anion of nicotinamide riboside salt is triflate or chloride.
4. Preparation process according to claim 1, characterized in that the solvent is a polar aprotic solvent, preferably the polar aprotic solvent is trimethyl phosphate or triethyl phosphate.
5. The method according to claim 1, wherein the temperature of the phosphorylation reaction is-20 to 0 ℃, preferably-10 to 0 ℃.
6. The preparation method according to claim 1, wherein the time of the phosphorylation reaction is 12-48 h, preferably 18-36 h.
7. The method of manufacturing according to claim 1, further comprising:
carrying out crystallization treatment on the reaction liquid containing nicotinamide mononucleotide, wherein the crystallization treatment process comprises the steps of dissolving the reaction liquid containing nicotinamide mononucleotide in water to obtain an aqueous solution; and mixing and stirring the aqueous solution and the organic solvent to precipitate the nicotinamide mononucleotide.
8. The preparation method according to claim 7, wherein the temperature of the crystallization treatment is-10 to 0 ℃, preferably-10 to-5 ℃, and the time of the crystallization treatment is preferably 1 to 6 hours, and more preferably 2 to 4 hours.
9. The preparation method according to claim 7, wherein the volume ratio of the water to the organic solvent is 1:5 to 20, preferably 1:10 to 15.
10. The method according to claim 9, wherein the organic solvent is selected from any one or more of ethanol, n-propanol, isopropanol, acetonitrile, and acetone.
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| SEELA, FRANK，等: "Syntheses of pyrrolo[2,3-d]pyrimidine 2\',3\'-dideoxyribonucleosides related to 2\',3\'-dideoxyadenosine and 2\',3\'-dideoxyguanosine and inhibitory activity of 5\'-triphosphates on HIV-1 reverse transcriptase", 《HELVETICA CHIMICA ACTA》, vol. 74, no. 3, pages 554 - 564 * |
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