CN113512079A - Preparation method of beta-nicotinamide mononucleotide - Google Patents
Preparation method of beta-nicotinamide mononucleotide Download PDFInfo
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- FZAQROFXYZPAKI-UHFFFAOYSA-N anthracene-2-sulfonyl chloride Chemical compound C1=CC=CC2=CC3=CC(S(=O)(=O)Cl)=CC=C3C=C21 FZAQROFXYZPAKI-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 239000000463 material Substances 0.000 claims abstract description 39
- 238000006482 condensation reaction Methods 0.000 claims abstract description 38
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- 238000006366 phosphorylation reaction Methods 0.000 claims abstract description 28
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims abstract description 26
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- 230000026731 phosphorylation Effects 0.000 claims abstract description 12
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- 238000000034 method Methods 0.000 claims description 32
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- 238000001704 evaporation Methods 0.000 claims description 21
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- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 claims description 4
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical class C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 claims description 4
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- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 2
- 239000003456 ion exchange resin Substances 0.000 claims description 2
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 2
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000391 magnesium silicate Substances 0.000 claims description 2
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 2
- 235000019792 magnesium silicate Nutrition 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
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- STCOOQWBFONSKY-UHFFFAOYSA-N tributyl phosphate Chemical compound CCCCOP(=O)(OCCCC)OCCCC STCOOQWBFONSKY-UHFFFAOYSA-N 0.000 claims description 2
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- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 2
- RXPQRKFMDQNODS-UHFFFAOYSA-N tripropyl phosphate Chemical compound CCCOP(=O)(OCCC)OCCC RXPQRKFMDQNODS-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 35
- 238000004519 manufacturing process Methods 0.000 abstract description 15
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- 230000006196 deacetylation Effects 0.000 abstract description 11
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- 238000007086 side reaction Methods 0.000 abstract description 10
- 230000035484 reaction time Effects 0.000 abstract description 9
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- 239000000047 product Substances 0.000 description 25
- 230000000052 comparative effect Effects 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 6
- IHNHAHWGVLXCCI-FDYHWXHSSA-N [(2r,3r,4r,5s)-3,4,5-triacetyloxyoxolan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O IHNHAHWGVLXCCI-FDYHWXHSSA-N 0.000 description 5
- 238000005086 pumping Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005265 energy consumption Methods 0.000 description 4
- 229940064982 ethylnicotinate Drugs 0.000 description 4
- 229950006238 nadide Drugs 0.000 description 4
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
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- 238000004128 high performance liquid chromatography Methods 0.000 description 3
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- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
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- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 229910001069 Ti alloy Inorganic materials 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
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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
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a preparation method of beta-nicotinamide mononucleotide. The preparation method comprises the following steps: s1: under the condition of existence of a catalyst and a first solvent, nicotinamide and D-ribose are subjected to condensation reaction in a first microchannel reactor to obtain a material A containing beta-nicotinamide-D-ribose; the temperature of the condensation reaction is 51-90 ℃, and the residence time of the condensation reaction is 0.5-10 min; s2: removing the first solvent from the mixture of the material A and the second solvent to obtain a material B; s3: and carrying out phosphorylation reaction on the material B and the phosphorylation auxiliary agent to obtain a material C containing the beta-nicotinamide mononucleotide. The preparation method can effectively shorten the reaction time, improve the production efficiency, reduce side reactions, improve the product yield, reduce the content of organic impurities in the product and reduce the occupied area of equipment; meanwhile, the steps of deacetylation and ammonolysis are reduced, and the reaction flow is shortened.
Description
Technical Field
The invention particularly relates to a preparation method of beta-nicotinamide mononucleotide.
Background
beta-Nicotinamide Mononucleotide (NMN) is a naturally occurring bioactive nucleotide that can be synthesized in the human body and ingested by everyday vegetables and meats, closely related to human immunity and metabolism. The function of beta-nicotinamide mononucleotide in vivo is mainly embodied by nicotinamide adenine dinucleotide, which is widely distributed in all cells and participates in thousands of biocatalytic reactions. In recent years, the anti-aging effect of nicotinamide adenine dinucleotide has attracted extensive attention of the scientific community, a large number of animal experiments show that after the content of nicotinamide adenine dinucleotide is increased, the aged organs can be restored to the young state, and the supplement of beta-nicotinamide mononucleotide is the best means for increasing nicotinamide adenine dinucleotide. At present, the cooperative study of the university of jujukui on celebration japan and the university of washington usa starts to perform the clinical study of β -nicotinamide mononucleotide to examine the effectiveness and safety of the substance to the human body, and various major health-care product manufacturers also start to release β -nicotinamide mononucleotide products.
Beta-nicotinamide mononucleotide is mainly prepared by 2 methods of biosynthesis and chemical synthesis, wherein the chemical synthesis mainly comprises the following three methods:
the first method comprises the following steps: the method takes tetraacetyl ribose and ethyl nicotinate as starting materials, and prepares beta-nicotinamide mononucleotide by main process steps of condensation, deacetylation protecting group, ammonolysis, activated carbon chromatographic separation, phosphorylation and the like, see Journal of Medicinal Chemistry,2007,50, 6458-6461; angewandte chemical Edition,2004,43, 4637-4640.
The second method comprises the following steps: the beta-nicotinamide mononucleotide is prepared by using tetraacetyl ribose and nicotinamide as starting materials through condensation, deacetylation of protecting groups, chromatographic separation with activated carbon, phosphorylation and other main process steps, see Bioorganic and Medicinal Chemistry Letters,2002,12, 1135-1137.
The third method comprises the following steps: chinese patent document CN109053838A discloses a method for preparing β -nicotinamide mononucleotide or β -nicotinamide mononucleotide, specifically discloses preparation of β -nicotinamide mononucleotide by using tetraacetyl ribose and ethyl nicotinate as starting materials and performing main process steps of condensation, deacetylation of protecting group, phosphorylation, ammonolysis and the like.
The beta-nicotinamide mononucleotide produced by the chemical method takes tetraacetyl ribose as a starting material, deacetylation protecting groups are needed in the reaction process, the reaction process is long, and the product yield is low. The reaction is a kettle type reaction, and the kettle type reaction has many defects: most of the traditional reaction equipment is formed by combining intermittent equipment, the occupied area is large, the mass transfer and heat transfer effects of the reaction are poor, the reaction time is long (the total reaction and treatment time exceeds 3 days), the efficiency is low, the energy consumption is high, the side reactions are increased, the product yield is low, and the impurity content is high. The kettle type reaction greatly restricts the production of the beta-nicotinamide mononucleotide on the aspects of energy consumption, production efficiency, environmental protection and cost.
Therefore, the development of a method for preparing beta-nicotinamide mononucleotide, which can effectively shorten the production process, improve the production efficiency, reduce side reactions, improve the yield, reduce the energy consumption, improve the product quality and reduce the occupied area of equipment, is urgently needed by those skilled in the art.
Disclosure of Invention
The technical problem solved by the invention is to solve the defects of long production flow, long reaction time, low efficiency, more side reactions, low product yield, high organic impurity content, high energy consumption and large equipment floor area of the method for preparing the beta-nicotinamide mononucleotide in the prior art, and provide the method for preparing the beta-nicotinamide mononucleotide. The preparation method can effectively shorten the reaction time, improve the production efficiency, reduce side reactions, improve the product yield, reduce the content of organic impurities in the product and reduce the occupied area of equipment; meanwhile, the steps of deacetylation and ammonolysis are reduced, and the reaction flow is shortened.
The invention adopts the following technical scheme to solve the technical problems:
the invention also provides a preparation method of the beta-nicotinamide mononucleotide, which comprises the following steps:
s1: under the condition of existence of a catalyst and a first solvent, nicotinamide and D-ribose are subjected to condensation reaction in a first microchannel reactor to obtain a material A containing beta-nicotinamide-D-ribose; the temperature of the condensation reaction is 51-90 ℃, and the residence time of the condensation reaction is 0.5-10 min;
s2: removing the first solvent from the mixture of the material A and the second solvent to obtain a material B;
s3: and carrying out phosphorylation reaction on the material B and the phosphorylation auxiliary agent to obtain a material C containing beta-nicotinamide mononucleotide.
The preparation method of the invention can have the following reactions:
in S1, the first solvent may be a solvent which is conventional in the art and can dissolve the nicotinamide and the D-ribose, and may be one or more of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, N-dimethylformamide, acetonitrile and 1, 4-dioxane, preferably tetrahydrofuran.
In S1, the catalyst may be conventional in the art, and is preferably one or more of halogenated trimethylsilane, trimethylsilyl trifluoromethanesulfonate and triethylsilyl trifluoromethanesulfonate.
Wherein, the halogenated trimethylsilane can be conventional in the field, and is preferably one or more of trimethylchlorosilane, trimethylbromosilane and trimethyliodosilane.
In S1, the molar ratio of nicotinamide to D-ribose is preferably 1 (0.5-2), more preferably 1 (0.8-1.2), for example 1: 1.
In S1, the amount of the catalyst added may be conventional in the art, and preferably, the molar ratio of the catalyst to the nicotinamide is (0.5-2): 1, more preferably (0.6-1): 1, such as 0.7:1, 0.8:1 or 0.9: 1.
In S1, the amount of the first solvent added may be conventional in the art, and preferably, the mass ratio of the first solvent to the D-ribose is (3-15): 1, more preferably (8-12): 1, such as 9:1, 10:1 or 11: 1.
At S1, the internal structure of the first microchannel reactor may be conventional in the art and may generally be one or more of heart-shaped, diamond-shaped, arc-shaped, dog-leg shaped, wave-shaped, and oval-shaped.
In S1, the condensation reaction temperature is preferably 60 to 85 ℃, for example, 65 ℃, 70 ℃, 75 ℃ or 80 ℃.
In the prior art, beta-nicotinamide mononucleotide is produced by taking tetraacetyl ribose and nicotinamide or ethyl nicotinate as raw materials to carry out condensation reaction, and then carrying out steps of deacetylation, phosphorylation, ammonolysis and the like, and the process flow is complex. The invention adopts nicotinamide and D-ribose as the initial raw materials for reaction, can save the steps of deacetylation and aminolysis, and greatly shortens the process flow.
By adopting the conventional kettle type reaction, because the reaction temperature is low and the reaction time is long, a large amount of side reactions exist in the condensation reaction of nicotinamide and D-ribose, if the reaction temperature is increased to be more than 50 ℃, the side reactions are more severe, and the product yield is very low. The invention creatively applies the microchannel reaction technology to the condensation reaction of nicotinamide and D-ribose, and a large amount of experimental researches show that the reaction temperature is increased to more than 50 ℃, the reaction retention time is greatly shortened, and the product yield can be effectively improved.
In S1, the retention time is preferably 1-7 min, more preferably 2-4 min.
In S1, preferably, the temperature of the condensation reaction is 51-60 ℃, and the residence time of the condensation reaction is 5-10 min.
In S1, preferably, the temperature of the condensation reaction is 60-90 ℃, and the residence time of the condensation reaction is 2-8 min.
In a preferred embodiment of the present invention, the residence time of the condensation reaction is 2min when the temperature of the condensation reaction is 80 ℃.
In a preferred embodiment of the present invention, the residence time of the condensation reaction is 4min at a temperature of 75 ℃.
In S1, the temperature of the outlet section of the first microchannel reactor is preferably 3 to 10 ℃ lower than the temperature of the condensation reaction, more preferably 4 to 7 ℃ lower, for example 5 ℃.
The temperature of the outlet section of the first microchannel reactor is set to be lower, so that the pressure at the outlet can be reduced, and the safety is improved.
In S2, the removing the first solvent can be performed by a conventional method in the art, preferably evaporation, more preferably thin film evaporation.
In the traditional evaporation, the retention time of the material A at a higher temperature is longer, the intermediate product is easy to generate side reaction, the retention time of the intermediate product in an evaporator can be effectively shortened by adopting film evaporation, the occurrence of side reaction is reduced, and the product yield is further improved.
The second solvent and the material A are mixed and then evaporated to remove the first solvent, so that the material can keep a good flowing state in evaporation equipment, and the flowing is not influenced by the fact that the viscosity of the material is increased due to the evaporation of the first solvent.
Wherein the temperature of the evaporation can be conventional in the art, preferably 0-30 ℃, more preferably 15-25 ℃, for example 20 ℃.
Wherein, the vacuum degree of the evaporation can be conventional in the field, and is preferably 0.06 MPa-0.1 MPa.
When the evaporation is the film evaporation, the residence time of the material A is preferably 0.5-5 min, for example, 2 min.
In S2, the second solvent may be a solvent that is conventional in the art and can dissolve the material B and the phosphorylation aid, and is preferably a phosphate.
Wherein the phosphate ester can be conventional in the art, and preferably is one or more of trimethyl phosphate, triethyl phosphate, tripropyl phosphate and tributyl phosphate.
In S2, the amount of the second solvent may be conventional in the art, and preferably, the mass ratio of the second solvent to the material a is (0.5-1.5): 1, for example, 0.6:1 or 0.8: 1.
In S3, the phosphorylation assistant is conventional in the art, and preferably is phosphorus oxychloride.
In S3, the mass ratio of the phosphorylation assistant to the material B may be conventional in the art, and is preferably (0.1-1): 1, more preferably (0.2-0.5): 1, such as 0.25:1, 0.3:1 or 0.4: 1.
In S3, the temperature of the phosphorylation reaction is preferably-25 to 5 ℃, more preferably-5 to 5 ℃, for example, 0 ℃.
In S3, preferably, the phosphorylation reaction is performed in a second microchannel reactor. In the second microchannel reactor, the residence time of the phosphorylation reaction is preferably 0.5 to 20min, and more preferably 0.5 to 5 min.
The phosphorylation reaction is carried out in the tank reactor to release a large amount of heat, and the reaction time needs to be greatly prolonged in order to better dissipate heat.
The first microchannel reactor and the second microchannel reactor may be made of one or more of silicon carbide, glass, stainless steel, titanium alloy, hastelloy, copper, silver and tantalum.
In the method for producing β -nicotinamide mononucleotide of the present invention, preferably, the phosphorylation reaction is followed by a purification step.
Wherein, the purification can be performed by the conventional method in the field, preferably comprises extraction and chromatography.
The extraction can be carried out by adopting a method which is conventional in the field, and generally, the material C, the third solvent and water are uniformly mixed, then are kept stand for layering, and are taken as an aqueous phase.
In the extraction step, the third solvent may be a solvent which is conventional in the art and is capable of dissolving organic impurities and is immiscible with water, and preferably one or more of dichloromethane, ethyl acetate and chloroform.
The beta-nicotinamide mononucleotide obtained after phosphorylation reaction is easy to dissolve in water, and the water and the third solvent are respectively used as a water phase and an organic phase to separate the beta-nicotinamide mononucleotide and organic substances in the material C.
In the purification step, the chromatography may be performed by a method conventional in the art, and generally, the diluted aqueous phase is passed through a chromatography column packed with a stationary phase.
Wherein, the concentration of the diluted water phase is preferably 3-10%, for example 5%.
Wherein, the stationary phase can be conventional in the field, and preferably is one or more of silica gel, macroporous ion exchange resin, non-ionic adsorption resin, alumina and magnesium silicate.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
1. the preparation method of the invention can reduce the steps of deacetylation and ammonolysis, greatly shorten the reaction flow and improve the safety and environmental protection of production;
2. the reaction time is greatly shortened, the production efficiency is improved, the reaction time is shortened by dozens of hours compared with the traditional kettle type reaction, and in the better implementation, the reaction time can be even as low as several minutes or dozens of minutes;
3. the side reaction is reduced, the product yield is improved, and when the product purity reaches more than 90%, the product yield can still be kept more than 45%, even can be as high as 52%, which is obviously higher than that of a kettle type reaction;
4. the content of organic impurities in the product is greatly reduced and can be less than 0.2 percent and even less than 0.1 percent;
5. the production equipment used in the invention occupies a much smaller area than the traditional kettle type reaction scheme, and has the advantages of small size and high precision.
Drawings
FIG. 1 shows reaction systems used in examples 1 to 2 of the present invention and comparative example 2.
Reference numerals
1-a first microchannel reactor; 11-a second feed port; 12-a first feed port; 2-a mixer; 3-a thin film evaporator; 4-a second microchannel reactor; 41-a third feed port; 42-a fourth feed port; 5-an extraction separator; 6-chromatographic column.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
The following reaction or separation steps are carried out in the reaction system shown in FIG. 1:
s1: condensation reaction
Uniformly mixing 38 parts of nicotinamide, 48 parts of D-ribose and 400 parts of tetrahydrofuran in a feeding tank, adding 70 parts of triethylsilyl trifluoromethanesulfonate into the other feeding tank, respectively pumping the liquid in the two feeding tanks into a first microchannel reactor 1 from a first feeding port 12 and a second feeding port 11, setting the temperature of the first nine microchannel modules of the first microchannel reactor 1 to be 80 ℃, the temperature of the tenth microchannel module to be 75 ℃, setting the total residence time to be 2 minutes, and carrying out condensation reaction to obtain a material A.
S2: thin film evaporator evaporation
Mixing the material A and triethyl phosphate in a mass ratio of 5:3 in the mixer 2, continuously pumping into a thin film evaporator 3 for evaporating tetrahydrofuran, wherein the area of the thin film evaporator 3 is 1m2The medium temperature in the film evaporator 3 is 20 ℃, the evaporation vacuum degree is 0.098MPa, and the retention time of the material in the film evaporator 3 is 1 minute, so that the material B is obtained.
S3: phosphorylation reactions
And continuously pumping the material B and the phosphorus oxychloride into a second microchannel reactor 4 from a third feeding port 41 and a fourth feeding port 42 respectively to perform rapid phosphorylation reaction, wherein the mass ratio of the material B to the phosphorus oxychloride is 4:1, the mass flow ratio of the third feeding port 41 to the fourth feeding port 42 is also 4:1, the temperature of the second microchannel reactor 4 is set to be 0 ℃, and the retention time of the phosphorylation reaction is 4 minutes to obtain a material C.
S4: purification of
Mixing the material C, dichloromethane and water, feeding the mixture into an extraction separator 5, extracting, discharging an organic layer, diluting an obtained water layer to the concentration of about 5% by using water, carrying out chromatographic separation by using a chromatographic column 6, and obtaining a purified beta-nicotinamide mononucleotide aqueous solution by using a non-ionic adsorption resin as a stationary phase in the chromatographic column 6.
Example 2
S1: condensation reaction
Uniformly mixing 38 parts of nicotinamide, 48 parts of D-ribose and 500 parts of tetrahydrofuran in a feeding tank, adding 70 parts of triethylsilyl trifluoromethanesulfonate into the other feeding tank, respectively pumping the liquid in the two feeding tanks into a first microchannel reactor 1 from a first feeding port 12 and a second feeding port 11, setting the temperature of the first nine microchannel modules of the first microchannel reactor 1 to be 75 ℃, the temperature of the tenth microchannel module to be 70 ℃, setting the total residence time to be 4 minutes, and carrying out condensation reaction to obtain a material A.
S2: thin film evaporator evaporation
The material A and triethyl phosphate were mixed in the mixer 2 at a mass ratio of 5:4 and continuously fed into the thin film evaporator 3, and the other steps were the same as those of S2 of example 1.
S3 and S4 are the same as those in example 1.
Comparative example 1
S1: condensation reaction
Adding 50 parts of ethyl nicotinate, 100 parts of tetraacetyl-D-ribose and 400 parts of dichloromethane into the bottom of a reaction kettle, stirring and mixing uniformly, heating to a boiling point, keeping reflux, slowly dropwise adding 80 parts of triethyl silyl trifluoromethanesulfonate into the reaction kettle for 1 hour, and keeping reflux for 4 hours after dropwise adding.
S2: evaporation of
And (3) removing the dichloromethane solvent in the reaction kettle by reduced pressure distillation, basically finishing the solvent evaporation after 5 hours, and adding 200 parts of methanol to completely dissolve the solvent evaporated material.
S3: deacetylation and ammonolysis reactions
And (3) pumping the solution obtained in the step (S2) into an ammoniation reaction kettle, cooling to-5 ℃, introducing 100 parts of ammonia gas into 200 parts of methanol at the temperature of-2 ℃ to dissolve the ammonia gas into an ammonia methanol solution, dropwise adding the ammonia methanol solution into the ammoniation reaction kettle for 2 hours, and reacting for 70 hours while maintaining the temperature in the reaction kettle at-2 ℃.
S4: evaporation of
The ammoniated reaction product obtained in S3 is distilled under reduced pressure to remove methanol and excess ammonia for about 12 hours.
S5: phosphorylation reactions
Dissolving an ammoniated product obtained by distilling S4 with 600 parts of trimethyl phosphate, adding the ammoniated product into a reaction kettle after dissolving, cooling the temperature to minus 10 ℃, slowly dripping 200 parts of phosphorus oxychloride for 3 hours, controlling the reaction temperature below minus 3 ℃ in the dripping process, and keeping the temperature for 24 hours.
S6: purification of
S6 is the same as S4 of example 1.
Comparative example 2
S1: condensation reaction
The total residence time was 10S, and the other steps were the same as in S1 of example 1.
S2 to S4 are the same as S2 to S4 in example 1.
Effects of the embodiment
The purity, yield and total content of organic impurities of β -nicotinamide mononucleotide obtained in examples 1-2 and comparative example 1 were determined by High Performance Liquid Chromatography (HPLC), and the results are shown in table 2.
The specific conditions and methods of HPLC detection are shown in Table 1.
TABLE 1 specific conditions and methods for HPLC detection
TABLE 2 test results of products obtained in examples 1 to 2 and comparative examples 1 to 2
| Sample (I) | NMN purity/%) | Total content of organic impurities/%) | Total yield/% |
| Example 1 | 92 | 0.2 | 48 |
| Example 2 | 91.5 | 0.1 | 52 |
| Comparative example 1 | 91.5 | 0.4 | 35 |
| Comparative example 2 | 91.3 | 0.7 | 18 |
From the data in table 2, it can be seen that the NMN obtained in examples 1 and 2 both have a purity of greater than 90% and a low content of organic impurities, both less than 0.2%, especially in example 2 where the content of organic impurities is only 0.1%, and the reduction of the content of organic impurities in the product can meet the downstream high purity requirements for the NMN product. The product yield of the examples 1-2 is higher than 45%, which is much higher than 35% of that of the comparative example 1, especially the product yield of the example 2 is as high as 52%. Meanwhile, the total production time of the NMN provided by the embodiment of the invention is only ten minutes or less than ten minutes, which is greatly shortened compared with nearly one hundred hours of the comparative ratio 1, and the production efficiency is greatly improved. The invention omits the conventional steps of deacetylation and ammonolysis, greatly shortens the production flow, and improves the production safety and environmental protection.
The residence time of the condensation reaction of comparative example 2 was 10s, and the other steps were the same as in example 1, and the product yield was significantly reduced, and the organic impurity content was significantly increased, indicating that the choice of residence time in the first microchannel reactor had a significant effect on product yield and product purity, etc.
Claims (10)
1. A method for preparing beta-nicotinamide mononucleotide, which comprises the following steps:
s1: under the condition of existence of a catalyst and a first solvent, nicotinamide and D-ribose are subjected to condensation reaction in a first microchannel reactor to obtain a material A containing beta-nicotinamide-D-ribose; the temperature of the condensation reaction is 51-90 ℃, and the residence time of the condensation reaction is 0.5-10 min;
s2: removing the first solvent from the mixture of the material A and the second solvent to obtain a material B;
s3: and carrying out phosphorylation reaction on the material B and the phosphorylation auxiliary agent to obtain a material C containing beta-nicotinamide mononucleotide.
2. The method of claim 1, wherein said first solvent is one or more of dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, N-dimethylformamide, acetonitrile and 1, 4-dioxane, preferably tetrahydrofuran;
and/or the catalyst is one or more of halogenated trimethylsilane, trimethylsilyl trifluoromethanesulfonate and triethylsilyl trifluoromethanesulfonate; the halogenated trimethylsilane is preferably one or more of trimethylchlorosilane, trimethylbromosilane and trimethyliodosilane.
3. The method of claim 1, wherein the molar ratio of nicotinamide to D-ribose in S1 is 1 (0.5-2), preferably 1 (0.8-1.2), such as 1: 1;
and/or, in S1, the molar ratio of the catalyst to the nicotinamide is (0.5-2): 1, preferably (0.6-1): 1, such as 0.7:1, 0.8:1 or 0.9: 1;
and/or in S1, the mass ratio of the first solvent to the D-ribose is (3-15): 1, preferably (8-12): 1, such as 9:1, 10:1 or 11: 1;
and/or, in S1, the condensation reaction temperature is 60-85 ℃, such as 65 ℃, 70 ℃, 75 ℃ or 80 ℃;
and/or in S1, the residence time is 1-7 min, preferably 2-4 min.
4. The method of claim 1, wherein in S1, when the temperature of the condensation reaction is 51 to 60 ℃, the residence time of the condensation reaction is 5 to 10 min;
or in S1, when the temperature of the condensation reaction is 60-90 ℃, the residence time of the condensation reaction is 2-8 min.
5. The method of claim 1, wherein the residence time of said condensation reaction is 2min when the temperature of said condensation reaction is 80 ℃ in S1;
or when the temperature of the condensation reaction is 75 ℃, the residence time of the condensation reaction is 4 min.
6. The method of claim 1, wherein in S1, the temperature of the outlet section of the first microchannel reactor is 3 to 10 ℃ lower than the temperature of the condensation reaction, preferably 4 to 7 ℃ lower, for example 5 ℃.
7. The method of claim 1, wherein in S2, said removing said first solvent is by evaporation, preferably by thin film evaporation;
and/or, in S2, the second solvent is a phosphate ester;
and/or in S2, the mass ratio of the second solvent to the material A is (0.5-1.5): 1, such as 0.6:1 or 0.8: 1.
8. The method of claim 7, wherein the temperature of evaporation is 0-30 ℃, preferably 15-25 ℃, e.g. 20 ℃;
and/or the vacuum degree of the evaporation is 0.06MPa to 0.1 MPa;
and/or the residence time of the film evaporation is 0.5-5 min, such as 2 min;
and/or the phosphate is one or more of trimethyl phosphate, triethyl phosphate, tripropyl phosphate and tributyl phosphate.
9. The method of claim 1, wherein in S3, said phosphorylation aid is phosphorus oxychloride;
and/or in S3, the mass ratio of the phosphorylation assistant to the material B is (0.1-1): 1, preferably (0.2-0.5): 1, such as 0.25:1, 0.3:1 or 0.4: 1;
and/or, in S3, the temperature of the phosphorylation reaction is-25 to 5 ℃, preferably-5 to 5 ℃, for example, 0 ℃;
and/or, in S3, the phosphorylation reaction is performed in a second microchannel reactor; the residence time in the second microchannel reactor is preferably 0.5 to 20min, more preferably 0.5 to 5 min.
10. The method of claim 1, wherein said phosphorylation reaction is followed by a purification step; the purification preferably comprises extraction and chromatography;
the extraction is preferably carried out by uniformly mixing the material C, the third solvent and water, standing for layering and taking an aqueous phase; the third solvent is preferably one or more of dichloromethane, ethyl acetate and chloroform;
the chromatography method is preferably that the diluted water phase passes through a chromatographic column filled with a stationary phase; the concentration of the diluted aqueous phase is preferably 3-10%, for example 5%; the stationary phase is preferably one or more of silica gel, macroporous ion exchange resin, non-ionic adsorption resin, alumina and magnesium silicate.
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