CN112457353A - Synthesis method of beta-nicotinamide riboside chloride - Google Patents
Synthesis method of beta-nicotinamide riboside chloride Download PDFInfo
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- CN112457353A CN112457353A CN202011618119.7A CN202011618119A CN112457353A CN 112457353 A CN112457353 A CN 112457353A CN 202011618119 A CN202011618119 A CN 202011618119A CN 112457353 A CN112457353 A CN 112457353A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
Abstract
The invention discloses a synthesis method of beta-nicotinamide riboside chloride, which uses TMSCl as a chlorination reagent and boron trifluoride diethyl etherate as a catalyst to catalyze the glycosylation reaction of tetraacetyl ribose and nicotinamide. The reaction condition is mild, and the product yield is high. The used reagent has low cost and easy obtaining, and is suitable for industrial production. The reaction conditions are relatively safe and environment-friendly, the reaction process is simple, and ion exchange reaction is not needed; the reaction product is relatively easy to purify and separate, and the high quality of the product can be ensured; the reagent used in the reaction process has low cost, and is beneficial to reducing the production cost.
Description
Technical Field
The invention relates to the field of compound synthesis, in particular to a synthesis method of beta-nicotinamide riboside chloride.
Background
Beta-nicotinamide riboside chloride is NR for short, is a nucleoside compound with CAS number 1341-23-7 and structural formula:
beta-nicotinamide riboside chloride (NR) is a precursor of Nicotinamide Adenine Dinucleotide (NAD) and represents a source of vitamin B3. Recent studies have shown that new health benefits can be obtained by ingesting larger amounts of nicotinamide riboside than naturally occurring in food products. Nicotinamide mononucleotide plays an important role in the cellular energy production of the human body, and it is involved in the synthesis of intracellular NAD (nicotinamide adenine dinucleotide, an important coenzyme for cellular energy conversion). NR has been implicated in increasing tissue NAD concentration and inducing insulin sensitivity as well as enhancing deacetylase (sirtuin) function. Its ability to increase NAD production suggests that NR can also improve mitochondrial health, stimulate mitochondrial function and induce the production of new mitochondria. Other studies with NR in alzheimer's models have shown that this molecule is bioavailable to the brain and may provide neuroprotection by stimulating brain NAD synthesis.
There are two conventional routes for the synthesis of NR: one is that TMSOTf is used as an activating reagent, and tetraacetyl ribose and nicotinamide or nicotinic acid ester are used as raw materials to carry out condensation reaction in solvent dichloromethane, acetonitrile or 1, 2-dichloroethane to generate the target product. The other method is to prepare 1' chloro-or bromo-sugar, directly react active halo-sugar with nicotinic acid derivative to generate target product, and then obtain the target product through deprotection and recrystallization.
However, both of these methods have major disadvantages, the first method requires at least more than equivalent TMSOTf, which results in a significant increase in production cost, and finally requires replacement of the triflate ion by a substitution reaction, which results in waste of resources. The second method has strong reaction activity, but has low yield, poor reaction stereoselectivity and a considerable part of alpha-configuration byproducts, thereby bringing a great deal of problems for later separation and purification.
Disclosure of Invention
The present invention aims to solve the above problems of the prior art by providing a method for synthesizing beta-nicotinamide riboside chloride.
In order to achieve the purpose, the invention provides the following technical scheme: a method for synthesizing beta-nicotinamide riboside chloride, which has the following reaction formula,
the method comprises the following specific steps:
the method comprises the following steps: condensation reaction: taking nicotinamide and 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose as initial raw materials, and taking TMSCl as a chlorinating agent under the catalytic action of boron trifluoride diethyl etherate to perform condensation reaction to obtain an intermediate 2;
step two: acetyl deprotection reaction: carrying out deprotection reaction on the intermediate 2 obtained in the step one to generate a crude product of beta-nicotinamide riboside chloride;
step three: and (3) purification reaction: and dissolving the crude product of the beta-nicotinamide riboside chloride in ethyl acetate for recrystallization, filtering and drying to obtain a finished product of the beta-nicotinamide riboside chloride.
As a preferred embodiment of the present invention, the reaction components in the first step further include: trifluoromethyl chlorosilane, boron trifluoride diethyl etherate and dichloromethane, wherein the solvent dichloromethane can be replaced by acetonitrile, 1, 2-dichloroethane.
In a preferred embodiment of the present invention, the 1,2, 3, 5-tetraacetyl- β -D-ribofuranose in the first step is dissolved in dichloromethane, and the solvent used is not limited to dichloromethane, but may be other similar solvents such as acetonitrile, 1, 2-dichloroethane, and the like.
In a preferred embodiment of the present invention, in the first step, the reaction equivalent of boron trifluoride diethyl etherate as a catalyst is 0.05 to 0.2 equivalent based on 1,2, 3, 5-tetraacetyl- β -D-ribofuranose.
In a preferred embodiment of the present invention, in the first step, based on 1,2, 3, 5-tetraacetyl- β -D-ribofuranose, the reaction equivalent of nicotinamide reactant is 1:0.9 to 1: 2.
As a preferred technical scheme of the invention, the temperature of the condensation reaction in the first step is 10-40 ℃.
In a preferred embodiment of the present invention, the reaction component in the second step is methanol, but the reaction component is not limited to methanol, and may be other alcohols such as ethanol.
In the second step, 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose is used as a reference, and the equivalent weight of the reactant methanol is 1: 3-1: 10; the temperature of the deacetylation reaction is-10-5 ℃.
According to a preferable technical scheme of the invention, 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose is taken as a reference in the third step, and the equivalent weight of ethyl acetate is 1: 5-1: 20; the drying temperature is 20-50 ℃; the conversion rate of nicotinamide riboside is 89%, the yield is 78%, the purity of the finished product is 99.82%, the number of impurities is 2, and the content of each impurity is not higher than 0.1%.
The invention has the beneficial effects that: the reaction conditions are relatively safe and environment-friendly, the reaction process is simple, and ion exchange reaction is not needed; the reaction product is relatively easy to purify and separate, and the high quality of the product can be ensured; the reagent used in the reaction process has low cost, and is beneficial to reducing the production cost.
Detailed Description
The following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more readily understand the advantages and features of the present invention and to clearly define the scope of the invention.
The invention provides a technical scheme that: a method for synthesizing beta-nicotinamide riboside chloride, which has the following reaction formula,
the method comprises the following specific steps:
the method comprises the following steps: condensation reaction: taking nicotinamide and 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose as initial raw materials, and taking TMSCl as a chlorinating agent under the catalytic action of boron trifluoride diethyl etherate to perform condensation reaction to obtain an intermediate 2;
step two: acetyl deprotection reaction: carrying out deprotection reaction on the intermediate 2 obtained in the step one to generate a crude product of beta-nicotinamide riboside chloride;
step three: and (3) purification reaction: and dissolving the crude product of the beta-nicotinamide riboside chloride in ethyl acetate for recrystallization, filtering and drying to obtain a finished product of the beta-nicotinamide riboside chloride.
The reaction components in the first step further comprise: trifluoromethyl chlorosilane, boron trifluoride diethyl etherate and dichloromethane, wherein the solvent dichloromethane can be replaced by acetonitrile, 1, 2-dichloroethane. The 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose in the first step is dissolved in dichloromethane, and the solvent used is not limited to dichloromethane, and other similar solvents such as acetonitrile, 1, 2-dichloroethane and the like can also be used. In the first step, 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose is taken as a reference, and the reaction equivalent of boron trifluoride diethyl etherate serving as a catalyst is 0.05 to 0.2 equivalent. In the first step, 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose is used as a reference, and the reaction equivalent of nicotinamide reactant is 1: 0.9-1: 2. The temperature of the condensation reaction in the first step is 10-40 ℃. The reaction component in the second step is methanol, but it is not limited to methanol, and other alcohols such as ethanol may be used. In the second step, 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose is taken as a reference, and the equivalent weight of the reactant methanol is 1: 3-1: 10; the temperature of the deacetylation reaction is-10-5 ℃. In the third step, 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose is taken as a reference, and the equivalent weight of ethyl acetate is 1: 5-1: 20; the drying temperature is 20-50 ℃; the conversion rate of nicotinamide riboside is 89%, the yield is 78%, the purity of the finished product is 99.82%, the number of impurities is 2, and the content of each impurity is not higher than 0.1%.
Boron trifluoride ether activates ribose substrate, and after nicotinic acid derivative participates in the reaction, TMSCl is used for providing a chlorine source to form beta-nicotinamide riboside chloride. The by-product is stable trimethylsilanolate acetate.
Specifically, the preparation method comprises the following steps:
the method comprises the following steps: condensation: dissolving tetraacetyl ribose in a suitable solvent such as dichloromethane, controlling the temperature at 5-10 ℃, dropwise adding boron trifluoride diethyl etherate solution, activating ribose substrate, stirring for half an hour, adding nicotinamide derivative, controlling the temperature, dropwise adding TMSCl, heating to 30 ℃, and reacting until the raw material tetraacetyl ribose raw material point disappears.
Step two: deacetylation protecting group: and (3) after dichloromethane is distilled under reduced pressure, dissolving the product in an ammonia methanol solution, controlling the temperature to be lower than 0 ℃, stirring for 12 times to disappear, and after the reaction is finished, distilling under reduced pressure at a temperature of below 30 ℃ to remove ethanol and redundant ammonia gas to obtain a crude product of the beta-nicotinamide riboside chloride.
Step three: and (3) recrystallization: dissolving the crude product of the beta-nicotinamide riboside chloride in ethyl acetate, controlling the dissolving temperature below 40 ℃, filtering to remove mechanical substances and other insoluble impurities after complete dissolution, cooling to 5 ℃ for crystallization, controlling the crystallization time to be 3-5 hours, filtering to remove the solvent, and drying by blowing air to obtain the target product, namely the high-purity white solid.
The solvent for the condensation reaction is dichloromethane, but is not limited to dichloromethane, and can also be one or a mixture of chloroform, acetonitrile, 1, 2-dichloromethane and tetrahydrofuran. The solvent used in the deacetylation reaction of (1) is methanol, but is not limited to methanol, and may be a polar solvent such as ethanol, tetrahydrofuran, isopropanol, or the like. The purification solvent of (2) is ethyl acetate, but not limited to ethyl acetate, and one or a mixture of plural kinds of polar solvents such as ethanol, acetone, acetonitrile, DMF and the like may be used. The material drying method of (1) is forced air drying, but vacuum drying and freeze drying can also be used. The amount of boron trifluoride diethyl etherate used as the catalyst is 0.05-0.2 equivalent of tetraacetyl ribose. The amount of TMSCl (b) is 1.05 to 2 equivalents based on tetraacetylribose. The amount of the methanol is 3-10 times of the weight ratio of the tetraacetyl ribose. The amount of ethyl acetate is 5-20 times by weight of the tetraacetyl ribose.
Example 1:
a method for synthesizing beta-nicotinamide riboside chloride comprises the following reaction steps:
the method comprises the following steps: condensation reaction:
weighing 240g of tetraacetyl ribose, dissolving the tetraacetyl ribose in 1.2L of dichloromethane, dripping 48g of 48% boron trifluoride ether, controlling the temperature to be about 5 ℃, adding 100g of nicotinamide, stirring for 20 minutes, controlling the temperature to be below 5 ℃, dripping 180g of trimethylchlorosilane in 1 hour, controlling the temperature to be 30 ℃ after finishing dripping, and reacting for 8 hours, wherein a point plate shows that the tetraacetyl ribose as a raw material reacts completely. After unreacted nicotinamide salt was removed by filtration, the filtrate was distilled under reduced pressure to remove methylene chloride to obtain a pale yellow oil.
Step two: reaction of deacetylation:
and adding 2L of 4N ammonia methanol solution into the light yellow oily substance, controlling the temperature to be below 0 ℃, reacting for 12 hours, dotting the plate to show that the raw materials are completely reacted, and stopping the reaction when HPLC (high performance liquid chromatography) monitors that the ratio of the product is more than 90%. Excess ammonia and methanol were distilled off at a temperature below 30 ℃ to give a yellow oil.
Step three: and (3) recrystallization:
dissolving the yellow oily substance in 2.4L ethyl acetate, heating to 40 ℃ for dissolving and clarifying, slowly cooling to separate out a white solid, controlling the temperature to be 5 ℃ for continuous crystallization for 3 hours, filtering to remove the solvent, washing a filter cake with 500mL ethyl acetate, and drying by blowing at 35 ℃ to remove the solvent to obtain the target product, namely 184g of beta-nicotinamide riboside chloride, wherein the mass yield is 77%, and the purity is 99.5%.
Example 2:
the beta-nicotinamide riboside chloride is prepared by ten times of amplification, and the steps are as follows:
the method comprises the following steps: condensation reaction:
weighing 2.4Kg of tetraacetyl ribose, dissolving in 12L of dichloromethane, dripping 480g of 48% boron trifluoride ether, controlling the temperature to be about 5 ℃, adding 1Kg of nicotinamide, stirring for 20 minutes, controlling the temperature to be below 5 ℃, dripping 1.8Kg of trimethylchlorosilane in 1 hour, controlling the temperature to be 30 ℃ after finishing dripping, and reacting for 8 hours, and displaying that the raw material of tetraacetyl ribose reacts completely by a point plate. After unreacted nicotinamide salt was removed by filtration, the filtrate was distilled under reduced pressure to remove methylene chloride to obtain a pale yellow oil.
Step two: reaction of deacetylation:
and (3) adding 20L of 4N ammonia methanol solution into the light yellow oily substance, controlling the temperature to be-5-0 ℃, reacting for 12 hours, monitoring the complete reaction of the raw materials by a TLC point plate, and stopping the reaction when the HPLC monitoring shows that the ratio of the product is more than 90%. Excess ammonia and methanol were distilled off at a temperature below 30 ℃ to give a yellow oil.
Step three: and (3) recrystallization:
dissolving the yellow oily substance in 24L of ethyl acetate, heating to 40 ℃, dissolving and clarifying, slowly cooling to separate out a white solid, controlling the temperature to be 5 ℃, continuously crystallizing for 3 hours, filtering to remove the solvent, washing a filter cake by using 5L of ethyl acetate, and carrying out forced air drying at 35 ℃ to remove the solvent to obtain a target product, so that 1.88Kg of beta-nicotinamide riboside chloride is obtained, the mass yield is 78%, and the purity is 99.8%.
Example 3:
a synthetic method for preparing beta-nicotinamide riboside chloride comprises the following steps:
the method comprises the following steps: condensation reaction:
weighing 2.4Kg of tetraacetyl ribose, dissolving in 12L of dichloromethane, dripping 240g of 48% boron trifluoride ether, controlling the temperature to be about 5 ℃, adding 1Kg of methyl nicotinate, stirring for 20 minutes, controlling the temperature to be below 5 ℃, dripping 1.8Kg of trimethylchlorosilane in 1 hour, controlling the temperature to be 30 ℃ after dripping is finished, and reacting for 8 hours, and counting plates to show that the raw material tetraacetyl ribose is completely reacted. The methylene chloride was distilled off under reduced pressure to obtain a pale yellow oil.
Step two: reaction of deacetylation:
and adding 20L of 4N ammonia methanol solution into the light yellow oily substance, controlling the temperature below 0 ℃, reacting for 24 hours, dotting the plate to show that the raw materials are completely reacted, and stopping the reaction when the HPLC (high performance liquid chromatography) monitor shows that the content of the product is more than 88%. Excess ammonia and methanol were distilled off at a temperature below 30 ℃ to give a yellow oil.
Step three: and (3) recrystallization:
dissolving the yellow oily substance in 24L ethyl acetate, heating to 40 ℃ for dissolving and clarifying, slowly cooling to separate out a white solid, controlling the temperature to be 5 ℃ for continuous crystallization for 5 hours, filtering to remove the solvent, washing the filter cake with 5L ethyl acetate, and drying by blowing at 35 ℃ to remove the solvent to obtain the target product, namely 1.62Kg of beta-nicotinamide riboside chloride, with the mass yield of 67% and the purity of 99.2%.
The above examples only show some embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (9)
1. A method for synthesizing beta-nicotinamide riboside chloride, which is characterized by comprising the following steps: the reaction formula is as follows,
the method comprises the following specific steps:
the method comprises the following steps: condensation reaction: taking nicotinamide and 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose as initial raw materials, and taking TMSCl as a chlorinating agent under the catalytic action of boron trifluoride diethyl etherate to perform condensation reaction to obtain an intermediate 2;
step two: acetyl deprotection reaction: carrying out deprotection reaction on the intermediate 2 obtained in the step one to generate a crude product of beta-nicotinamide riboside chloride;
step three: and (3) purification reaction: and dissolving the crude product of the beta-nicotinamide riboside chloride in ethyl acetate for recrystallization, filtering and drying to obtain a finished product of the beta-nicotinamide riboside chloride.
2. The method of claim 1, wherein said step of synthesizing comprises: the reaction components in the first step further comprise: trifluoromethyl chlorosilane, boron trifluoride diethyl etherate and dichloromethane, wherein the solvent dichloromethane can be replaced by acetonitrile, 1, 2-dichloroethane.
3. The method of claim 1, wherein said step of synthesizing comprises: in the first step, the 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose is dissolved in dichloromethane, and the solvent used is not limited to dichloromethane, and other similar solvents such as acetonitrile, 1, 2-dichloroethane and the like can be used.
4. The method of claim 1, wherein said step of synthesizing comprises: in the first step, 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose is taken as a reference, and the reaction equivalent of boron trifluoride diethyl etherate serving as a catalyst is 0.05-0.2 equivalent.
5. The method of claim 1, wherein said step of synthesizing comprises: in the first step, 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose is used as a reference, and the reaction equivalent of nicotinamide reactant is 1: 0.9-1: 2.
6. The method of claim 1, wherein said step of synthesizing comprises: the temperature of the condensation reaction in the first step is 10-40 ℃.
7. The method of claim 1, wherein said step of synthesizing comprises: the reaction component in the second step is methanol, but the reaction component is not limited to methanol, and other alcohols such as ethanol may be used.
8. The method of claim 1, wherein said step of synthesizing comprises: in the second step, 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose is taken as a reference, and the equivalent weight of the reactant methanol is 1: 3-1: 10; the temperature of the deacetylation reaction is-10-5 ℃.
9. The method of claim 1, wherein said step of synthesizing comprises: in the third step, 1,2, 3, 5-tetraacetyl-beta-D-ribofuranose is taken as a reference, and the equivalent weight of ethyl acetate is 1: 5-1: 20; the drying temperature is 20-50 ℃; the conversion rate of nicotinamide riboside is 89%, the yield is 78%, the purity of the finished product is 99.82%, the number of impurities is 2, and the content of each impurity is not higher than 0.1%.
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