CN112028954B - Preparation method of nicotinamide ribose - Google Patents
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Abstract
The invention relates to the technical field of organic synthesis, in particular to a preparation method of nicotinamide ribose. The preparation method of nicotinamide riboside comprises the following steps: reacting nicotinamide triacetyl nucleoside or salt thereof in methanol at-20-30 ℃ for 6-30 h under the action of inorganic strong base and weak acid salt, and adding acid for neutralization treatment. The preparation method of nicotinamide riboside has the advantages of high product yield, low cost of raw materials and process, and simple and convenient operation; meanwhile, no toxic or harmful raw materials are used in the reaction process, no toxic or harmful substances are generated, and the environment friendliness is good.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of nicotinamide ribose.
Background
Nicotinamide Riboside (NR), which has the following structural formula.
Nicotinamide riboside is a derivative of vitamin B3 and is a precursor substrate for the important coenzyme NAD +. Coenzyme NAD + occurs in many metabolic reactions of cells, and is involved in the decomposition of compounds such as proteins, carbohydrates and fats, and the vital activity of the human body is not separated from coenzyme NAD +. And the amount of coenzyme NAD + is reduced with the aging or pathological changes of cells. By supplementing the precursor substrate nicotinamide ribose, the content of coenzyme NAD + can be improved, the metabolic activity of cells is improved, and the physiological functions of the human body in various aspects are ensured.
The existing preparation method of nicotinamide ribose has the defects of poor process controllability, poor environmental protection property and the like.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a preparation method of nicotinamide ribose, and the preparation method is used for solving the technical problems of poor controllability, poor environmental protection and the like of a preparation process of nicotinamide ribose in the prior art.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
the preparation method of nicotinamide riboside comprises the following steps:
reacting nicotinamide triacetyl nucleoside or salt thereof in methanol at-20-30 ℃ for 6-30 h under the action of inorganic strong base and weak acid salt, and adding acid for neutralization treatment.
The preparation method of nicotinamide riboside has the advantages of high product yield, low cost of raw materials and process, and simple and convenient operation; meanwhile, no toxic or harmful raw materials are used in the reaction process, no toxic or harmful substances are generated, and the environment friendliness is good.
Taking nicotinamide triacetyl nucleoside as an example, the synthetic route is as follows:
in a particular embodiment of the invention, the reaction is carried out under protective gas. Further, the shielding gas includes any one of nitrogen and argon.
In a specific embodiment of the present invention, the salt of nicotinamide triacetyl nucleoside comprises at least one of hydrochloride, sulfate, sulfonate and triflate of nicotinamide triacetyl nucleoside.
In a specific embodiment of the present invention, the inorganic strong and weak acid salt comprises any one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, trisodium phosphate, disodium hydrogen phosphate and sodium acetate. Further, the inorganic strong alkali weak acid salt comprises trisodium phosphate.
In a specific embodiment of the invention, the ratio of nicotinamide triacetylcucleoside or a salt thereof to methanol is 1 mmol/mL (0.8-1.2) mL, preferably 1 mmol/1 mL.
In a specific embodiment of the present invention, the amount of the inorganic strong base and weak acid salt is 1 to 5 times, preferably 2 to 4 times, and more preferably 3 times that of the nicotinamide triacetyl nucleoside.
In a specific embodiment of the present invention, the acid includes hydrochloric acid in the neutralization treatment by adding acid.
In the specific embodiment of the invention, after the neutralization treatment by adding acid, the liquid is collected by solid-liquid separation and concentrated. In actual practice, the concentration is carried out at normal temperature to remove the solvent and the like in the liquid.
In the specific embodiment of the invention, absolute ethyl alcohol is added into the concentrated material, and crystallization is carried out to obtain the crude product of nicotinamide riboside.
In a specific embodiment of the present invention, the crude nicotinamide riboside is subjected to a recrystallization process. Further, the recrystallization includes: dissolving the nicotinamide ribose crude product by water, adding alcohol, and standing for 1-72 hours at the temperature of-5-12 ℃; wherein the ratio of the crude product to the water to the alcohol is 1 g/mL (0.2-0.5) to 3-5 mL; the alcohol includes any one or more of methanol, ethanol, and isopropanol.
The invention makes nicotinamide triacetyl nucleoside or salt thereof react under the action of inorganic strong base weak acid salt, the post-treatment operation is simple, most impurities can be removed by recrystallization, and the purity of the prepared nicotinamide ribose can meet the requirement without complicated purification operations such as column chromatography and the like.
In a specific embodiment of the present invention, the preparation method specifically includes the following steps:
dissolving nicotinamide triacetyl nucleoside or salt thereof in methanol, cooling to-20-10 ℃, adding inorganic strong base weak acid salt, reacting at-10-0 ℃ for 6-20 h, and then dripping acid into the reaction system for neutralization treatment.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention carries out reaction treatment on nicotinamide triacetyl nucleoside or salt thereof under the action of inorganic strong base weak acid salt, has high product yield, low cost of raw materials and process and simple and convenient operation; meanwhile, no toxic or harmful raw materials are used in the reaction process, no toxic or harmful substances are generated, and the environment friendliness is good.
(2) The preparation method has simple post-treatment operation, can remove most impurities through recrystallization, does not need complicated purification operations such as column chromatography and the like, and can ensure that the purity of the prepared nicotinamide ribose meets the requirement; the purification steps are simplified, the production efficiency is improved, and the process cost is saved.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is an HPLC chart of a purified nicotinamide riboside product obtained in example 2 of the present invention;
FIG. 2 is an HPLC chart of the purified nicotinamide riboside product obtained in example 3 of the present invention;
wherein, the HPLC detection conditions refer to the existing detection conditions of nicotinamide ribose.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings and the detailed description, but those skilled in the art will understand that the following described embodiments are some, not all, of the embodiments of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The preparation method of nicotinamide riboside comprises the following steps:
reacting nicotinamide triacetyl nucleoside or salt thereof in methanol at-20-30 ℃ for 6-30 h under the action of inorganic strong base and weak acid salt, and adding acid for neutralization treatment.
The preparation method of nicotinamide riboside has the advantages of high product yield, low cost of raw materials and process, and simple and convenient operation; meanwhile, no toxic or harmful raw materials are used in the reaction process, no toxic or harmful substances are generated, and the environment friendliness is good.
Taking nicotinamide triacetyl nucleoside as an example, the synthetic route is as follows:
as in the different embodiments, the temperature of the reaction may be-20 ℃, -15 ℃, -10 ℃, -5 ℃, 0 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃ and the like; the reaction time may be 6h, 8h, 10h, 12h, 15h, 18h, 20h, 22h, 25h, 28h, 30h, and the like.
In a particular embodiment of the invention, the reaction is carried out under protective gas. Further, the shielding gas includes any one of nitrogen and argon.
In a specific embodiment of the present invention, the salt of nicotinamide triacetyl nucleoside comprises at least one of hydrochloride, sulfate, sulfonate and triflate of nicotinamide triacetyl nucleoside.
In a specific embodiment of the present invention, the inorganic strong and weak acid salt comprises any one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, trisodium phosphate, disodium hydrogen phosphate and sodium acetate. Preferably, the inorganic strong and weak acid salt comprises trisodium phosphate.
In a specific embodiment of the invention, the ratio of nicotinamide triacetylcucleoside or a salt thereof to methanol is 1 mmol/mL (0.8-1.2) mL, preferably 1 mmol/1 mL.
In various embodiments, the ratio of nicotinamide triacetyl nucleoside or salt thereof to methanol can be 1 mmol: 0.8mL, 1 mmol: 0.85mL, 1 mmol: 0.9mL, 1 mmol: 0.95mL, 1 mmol: 1mL, 1 mmol: 1.05mL, 1 mmol: 1.1mL, 1 mmol: 1.15mL, 1 mmol: 1.2mL, and the like.
In a specific embodiment of the present invention, the amount of the inorganic strong base and weak acid salt is 1 to 5 times, preferably 2 to 4 times, and more preferably 3 times that of the nicotinamide triacetyl nucleoside.
In a specific embodiment of the present invention, the acid includes hydrochloric acid in the neutralization treatment by adding acid.
In the specific embodiment of the invention, after the neutralization treatment by adding acid, the liquid is collected by solid-liquid separation and concentrated. In actual practice, the concentration is carried out at normal temperature to remove the solvent and the like in the liquid.
In the specific embodiment of the invention, absolute ethyl alcohol is added into the concentrated material, and crystallization is carried out to obtain the crude product of nicotinamide riboside.
In a specific embodiment of the present invention, the crude nicotinamide riboside is subjected to a recrystallization process. Further, the recrystallization includes: dissolving the nicotinamide ribose crude product by water, adding alcohol, and standing for 1-72 hours at the temperature of-5-12 ℃; wherein the ratio of the crude product to the water to the alcohol is 1 g/mL (0.2-0.5) to 3-5 mL; the alcohol includes any one or more of methanol, ethanol, and isopropanol.
In a specific embodiment of the present invention, the preparation method specifically includes the following steps:
dissolving nicotinamide triacetyl nucleoside or salt thereof in methanol, cooling to-20-10 ℃, adding inorganic strong base weak acid salt, reacting at-10-0 ℃ for 6-20 h, and then dripping acid into the reaction system for neutralization treatment.
Example 1
This example provides a method for preparing nicotinamide riboside, comprising the following steps:
(1) dissolving nicotinamide triacetyl nucleoside (3.81g, 10mmol) in 10mL of methanol, cooling to-15 ℃, adding anhydrous sodium carbonate (3.28g, 30mmol), reacting at constant temperature of-10 to-5 ℃ for 6h, protecting under nitrogen in the reaction process, and monitoring the completion of the reaction by a TLC point plate;
(2) then, dripping hydrochloric acid into the reacted materials at the temperature of-15 ℃ for neutralization, filtering after neutralization, removing filter residues, leaching filter cakes by adopting 5mL of methanol, collecting filtrate, concentrating the filtrate at normal temperature to be dry, and adding absolute ethyl alcohol for crystallization to obtain light yellow solid which is a nicotinamide ribose crude product;
(3) dissolving the crude product of nicotinamide ribose by pure water, adding absolute ethyl alcohol, standing for 24 hours at the temperature of-5-12 ℃, and carrying out recrystallization treatment; wherein the ratio of the crude product to the pure water to the absolute ethyl alcohol is 1 g/0.2 mL/4 mL, and the white solid nicotinamide riboside is obtained by recrystallization treatment, namely 1.80g (62% yield).
Example 2
This example provides a method for preparing nicotinamide riboside, comprising the following steps:
(1) dissolving nicotinamide triacetyl nucleoside (3.81g, 10mmol) in 10mL of methanol, cooling to-15 ℃, adding anhydrous potassium carbonate (4.15g, 30mmol), reacting at-10 ℃ for 6h at constant temperature after the addition is finished, protecting under nitrogen in the reaction process, and monitoring the completion of the reaction through a TLC point plate;
(2) then, dripping hydrochloric acid into the reacted materials at the temperature of-15 ℃ for neutralization, filtering after neutralization, removing filter residues, leaching filter cakes by adopting 5mL of methanol, collecting filtrate, concentrating the filtrate at normal temperature to be dry, and adding absolute ethyl alcohol for crystallization to obtain light yellow solid which is a nicotinamide ribose crude product;
(3) dissolving the crude product of nicotinamide ribose by pure water, adding absolute ethyl alcohol, standing for 24 hours at the temperature of-5-12 ℃, and carrying out recrystallization treatment; wherein the ratio of the crude product to the pure water to the absolute ethyl alcohol is 1 g/0.2 mL/4 mL, and the white solid nicotinamide riboside pure product is obtained after recrystallization treatment (yield is 68%).
Example 3
This example provides a method for preparing nicotinamide riboside, comprising the following steps:
(1) dissolving nicotinamide triacetyl nucleoside (3.81g, 10mmol) in 10mL of methanol, cooling to-10 ℃, adding anhydrous trisodium phosphate (4.92g, 30mmol), reacting at a constant temperature of 0 ℃ for 20h, protecting under nitrogen in the reaction process, and monitoring the completion of the reaction through a TLC point plate;
(2) then, dripping hydrochloric acid into the reacted materials at the temperature of minus 5 ℃ for neutralization, filtering after neutralization, removing filter residues, leaching filter cakes by adopting 5mL of methanol, collecting filtrate, concentrating the filtrate at normal temperature to be dry, and adding absolute ethyl alcohol for crystallization to obtain light yellow solid which is a nicotinamide ribose crude product;
(3) dissolving the crude product of nicotinamide ribose by pure water, adding absolute ethyl alcohol, standing for 24 hours at the temperature of-5-12 ℃, and carrying out recrystallization treatment; wherein the ratio of the crude product to the pure water to the absolute ethyl alcohol is 1 g/0.2 mL/4 mL, and the white solid nicotinamide riboside pure product is obtained after recrystallization treatment (yield 80%).
Comparative example 1
Comparative example 1 the preparation process of example 1 was referenced, with the following differences: anhydrous sodium carbonate was not added.
The reaction is carried out without adding anhydrous sodium carbonate, and after the reaction is carried out for 30 hours, no corresponding product is generated.
The process was repeated 3 times, and no corresponding product was formed.
This is mainly because: nicotinamide triacetyl nucleoside contains three acetyl groups, one of which is easy to react, and under the condition of not adding anhydrous sodium carbonate, the three acetyl groups can not be completely reacted, so that a corresponding product can not be obtained.
Comparative example 2
The preparation is carried out by adopting the existing mode of introducing ammonia into the system.
In operation, the ammonia cylinder is used, so that potential safety hazards exist; in addition, unstable airflow can cause suck-back when ammonia gas is introduced, and the ammonia gas is not metered well.
Experimental example 1
To illustrate the difference between the methods of preparing nicotinamide ribose by the examples and the comparative examples of the present invention, the yield and product purity (HPLC) of nicotinamide ribose prepared by the examples and the comparative examples are tested, and the test results are shown in Table 1.
TABLE 1 results of the yield and purity test of nicotinamide riboside product of different preparation methods
| Numbering | Yield (%) | Purity (%) |
| Example 1 | 62 | ＞99 |
| Example 2 | 68 | ＞99 |
| Example 3 | 80 | ＞99 |
| Comparative example 1 | 0 | — |
Remarking: in the comparative example, since no product was obtained, the purity could not be checked
The purity test of nicotinamide riboside prepared in example 2 and example 3 is illustrated, and the pure nicotinamide riboside prepared in example 2 and example 3 is tested under the conventional conditions for detecting nicotinamide riboside by HPLC, and the test results are shown in FIGS. 1 and 2, respectively.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (8)
1. The preparation method of nicotinamide riboside is characterized by comprising the following steps:
dissolving nicotinamide triacetyl nucleoside or salt thereof in methanol, cooling to-20-10 ℃, adding inorganic strong base weak acid salt, reacting at-10-0 ℃ for 6-20 h, and then, dropwise adding acid into a reaction system for neutralization treatment;
the reaction is carried out under the protection of protective gas;
the inorganic strong base weak acid salt is trisodium phosphate;
the amount of the inorganic strong base weak acid salt is 2-4 times that of the nicotinamide triacetyl nucleoside;
the dosage ratio of the nicotinamide triacetyl nucleoside or the salt thereof to the methanol is 1 mmol/0.8-1.2 mL.
2. The method for producing nicotinamide ribose according to claim 1, wherein the shielding gas includes any one of nitrogen and argon.
3. The method of preparing nicotinamide riboside according to claim 1, wherein the salt of nicotinamide triacetyl nucleoside includes at least one of hydrochloride, sulfate, sulfonate, and triflate of nicotinamide triacetyl nucleoside.
4. The method for producing nicotinamide ribose according to claim 1, wherein the acid includes hydrochloric acid in the neutralization treatment by adding acid.
5. The method for producing nicotinamide ribose according to claim 1, further comprising, after the acid neutralization treatment: and (4) performing solid-liquid separation to collect liquid, and performing concentration treatment.
6. The method of claim 5, wherein the concentration of nicotinamide riboside is performed by adding absolute ethanol to the concentrated material and crystallizing to obtain a crude product of nicotinamide riboside.
7. The method of claim 6, wherein the crude nicotinamide ribose is recrystallized.
8. The method for producing nicotinamide ribose according to claim 7, wherein the recrystallization includes: dissolving the nicotinamide ribose crude product by water, adding alcohol, and standing for 1-72 hours at the temperature of-5-12 ℃; wherein the ratio of the crude product to the water to the alcohol is 1 g/mL (0.2-0.5) to 3-5 mL; the alcohol includes any one or more of methanol, ethanol, and isopropanol.
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