CN116514881A - Preparation method of beta-nicotinamide mononucleotide - Google Patents
Preparation method of beta-nicotinamide mononucleotide Download PDFInfo
- Publication number
- CN116514881A CN116514881A CN202310543311.1A CN202310543311A CN116514881A CN 116514881 A CN116514881 A CN 116514881A CN 202310543311 A CN202310543311 A CN 202310543311A CN 116514881 A CN116514881 A CN 116514881A
- Authority
- CN
- China
- Prior art keywords
- nicotinamide
- reaction
- catalyst
- stirring
- reaction solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 39
- 238000002360 preparation method Methods 0.000 title abstract description 18
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims abstract description 93
- 238000006243 chemical reaction Methods 0.000 claims abstract description 88
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 78
- 239000003054 catalyst Substances 0.000 claims abstract description 54
- 235000005152 nicotinamide Nutrition 0.000 claims abstract description 46
- 239000011570 nicotinamide Substances 0.000 claims abstract description 46
- 229960003966 nicotinamide Drugs 0.000 claims abstract description 46
- 238000003756 stirring Methods 0.000 claims abstract description 46
- 238000002156 mixing Methods 0.000 claims abstract description 36
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 32
- JLEBZPBDRKPWTD-TURQNECASA-O N-ribosylnicotinamide Chemical class NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 JLEBZPBDRKPWTD-TURQNECASA-O 0.000 claims abstract description 22
- 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 claims abstract description 21
- 239000002777 nucleoside Substances 0.000 claims abstract description 17
- 150000003833 nucleoside derivatives Chemical class 0.000 claims abstract description 17
- 238000001035 drying Methods 0.000 claims abstract description 13
- 239000005457 ice water Substances 0.000 claims abstract description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 11
- STCOOQWBFONSKY-UHFFFAOYSA-N tributyl phosphate Chemical compound CCCCOP(=O)(OCCCC)OCCCC STCOOQWBFONSKY-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 7
- 230000000850 deacetylating effect Effects 0.000 claims abstract description 6
- 150000007530 organic bases Chemical class 0.000 claims abstract description 5
- 239000013078 crystal Substances 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000005303 weighing Methods 0.000 claims description 15
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 12
- MISVBCMQSJUHMH-UHFFFAOYSA-N pyrimidine-4,6-diamine Chemical compound NC1=CC(N)=NC=N1 MISVBCMQSJUHMH-UHFFFAOYSA-N 0.000 claims description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 claims description 9
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 6
- 238000007789 sealing Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 239000012153 distilled water Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical group [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 238000009777 vacuum freeze-drying Methods 0.000 claims description 5
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000011347 resin Substances 0.000 claims description 2
- 229920005989 resin Polymers 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000003197 catalytic effect Effects 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 4
- 230000000052 comparative effect Effects 0.000 description 12
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) 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-O 0.000 description 3
- 239000003957 anion exchange resin Substances 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000011033 desalting Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000011897 Deaf-Blind disease Diseases 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 206010061296 Motor dysfunction Diseases 0.000 description 1
- 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 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 229930003537 Vitamin B3 Natural products 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940064982 ethylnicotinate Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229950006238 nadide Drugs 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 150000003698 vitamin B derivatives Chemical class 0.000 description 1
- 235000019160 vitamin B3 Nutrition 0.000 description 1
- 239000011708 vitamin B3 Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/06—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/02—Phosphorylation
-
- 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
- B01J2231/4283—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues using N nucleophiles, e.g. Buchwald-Hartwig amination
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention relates to a preparation method of beta-nicotinamide mononucleotide, which comprises the following steps: step (1), mixing nicotinamide and tetraacetylribose in chloroform, and adding a catalyst for reaction to obtain a solution of nicotinamide triacetyl nucleoside; step (2), adding organic base into the solution of nicotinamide triacetyl nucleoside, and deacetylating under stirring to obtain nicotinamide riboside salt; and (3) mixing nicotinamide riboside salt in tributyl phosphate, dropwise adding phosphorus oxychloride, stirring for reaction under the ice water bath condition, introducing ammonia gas for ammonolysis after the reaction is finished, and extracting, purifying and drying to obtain the beta-nicotinamide mononucleotide. The catalyst TMSH-pyrPOCs prepared by the invention is used for catalyzing nicotinamide triacetyl nucleoside, has high catalytic efficiency and is more stable, and the defects of low catalytic activity and excessive byproducts of the existing halosilane catalyst at low temperature are overcome.
Description
Technical Field
The invention relates to the field of nucleotide synthesis, in particular to a preparation method of beta-nicotinamide mononucleotide.
Background
Beta-nicotinamide mononucleotide, also known as NMN, is a naturally occurring biologically active nucleoside. Because nicotinamide belongs to vitamin B3, NMN belongs to the category of vitamin B derivatives, and is widely involved in multiple biochemical reactions of human body and is closely related to immunity and metabolism. NMN is a precursor of nad+ (Nicotinamide adenine dinucleotide), whose function is also predominantly reflected by nad+. With age, NMN and NAD+ levels tended to decrease, while NAD+ metabolite NAM tended to rise. The decline in nad+ during aging is believed to be a major cause of diseases and disabilities, such as hearing and vision loss, cognitive and motor dysfunction, immunodeficiency, arthritis caused by autoimmune inflammatory response disorders, metabolic disorders, and cardiovascular diseases. Therefore, the NMN supplementation can increase the NAD+ content in the body, thereby delaying, improving, preventing aging and the like, or improving age-induced metabolic disorders, senile diseases and the like, and has important significance.
At present, the main synthesis method of the beta-nicotinamide mononucleotide is to use tetraacetylribose and nicotinamide or ethyl nicotinate as starting materials, and finally obtain the beta-nicotinamide mononucleotide through the process steps of condensation, deacetylation protecting group, phosphorylation, ammonolysis and the like. However, the reaction process for synthesizing the beta-nicotinamide mononucleotide has the defects of long reaction flow, long reaction time, low reaction efficiency, more side reactions, low product yield and high impurity content.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a preparation method of beta-nicotinamide mononucleotide.
The aim of the invention is realized by adopting the following technical scheme:
a method for preparing beta-nicotinamide mononucleotide, comprising the following steps:
step (1), weighing nicotinamide and tetraacetylribose, mixing in chloroform, fully dissolving, and adding a catalyst for reaction to obtain a solution of nicotinamide triacetyl nucleoside;
step (2), adding organic base into the solution of nicotinamide triacetyl nucleoside, deacetylating under stirring, then adjusting the pH of the reaction solution to 5-6, and removing the solvent under reduced pressure to obtain nicotinamide riboside salt;
and (3) mixing nicotinamide riboside salt in tributyl phosphate, fully dissolving, dropwise adding phosphorus oxychloride, stirring for reaction under the ice water bath condition, introducing ammonia gas for ammonolysis after the reaction is finished, and extracting, purifying and drying to obtain the beta-nicotinamide mononucleotide.
Preferably, in the step (1), the molar ratio of nicotinamide to tetraacetylribose is 1:1.2-1.6.
Preferably, in the step (1), the reaction process is reflux stirring reaction for 1.5-2.5h under the condition of 4-50 ℃ in a water bath.
Preferably, in the step (1), the addition amount of chloroform is 5-6 times of the total mass of nicotinamide and tetraacetylribose.
Preferably, in the step (1), the catalyst is TMSH-pyrPOCs, and the adding amount of the catalyst is 1% -5% of the mass of nicotinamide.
Preferably, the TMSH-PyrPOCs comprise TMSCl-PyrPOCs, TMSBr-PyrPOCs and TMSI-PyrPOCs according to different raw materials.
Preferably, in the step (2), the organic base is sodium ethoxide solution, and the concentration is 0.1-0.3g/mL.
Preferably, in the step (2), the reaction condition is ice-water bath, and the reaction is stirred for 1-2h.
Preferably, in the step (3), the molar ratio of the nicotinamide riboside salt to the phosphorus oxychloride is 1:1.5-2.5, and the tributyl phosphate is added in an amount which is 5-6 times of the sum of the masses of the nicotinamide riboside salt and the phosphorus oxychloride.
Preferably, in the step (3), the stirring reaction time of the ice water bath is 5-10h.
Preferably, in the step (3), the flow rate of the ammonia gas is 0.1-0.3L/min, and the flow time is 1-2h.
Preferably, in the step (3), the reaction solution is poured into distilled water to be stirred, then ethyl acetate is added to be stirred continuously, and the oil phase layer is removed after standing and layering; the purification is to use resin exchange method to remove salt and purify the water phase layer; the drying is vacuum drying or freeze drying.
Preferably, the preparation method of the catalyst comprises the following steps:
s1, weighing 2,4, 6-trihydroxy-1, 3, 5-benzene tricaldehyde and chloroform, mixing in a flask, uniformly stirring, adding anhydrous magnesium sulfate as a catalyst, and fully mixing and stirring to form a first reaction solution;
s2, weighing 4, 6-pyrimidinediamine and mixing with chloroform in a beaker, and fully mixing and stirring to form a second reaction solution;
s3, dropwise adding the second reaction solution into the continuously stirred first reaction solution, simultaneously adding halosilane TMSH into the first reaction solution, sealing a flask after the dropwise adding is finished, and placing the flask in an indoor dark and cool place for 3-5 days, wherein a large number of crystals grow on the inner wall of the flask to obtain a third reaction solution;
s4, shaking the reaction bottle until crystals on the inner wall fall off, filtering out the crystals, washing the crystals at least three times by using chloroform, and drying the crystals to obtain the TMSH-pyrPOCs.
Preferably, the mass volume ratio of the 2,4, 6-trihydroxy-1, 3, 5-benzene tricaldehyde and the chloroform of the S1 is 1g: (10-20) mL.
Preferably, the anhydrous magnesium sulfate of S1 is added in an amount of 2% -6% of the mass of 2,4, 6-trihydroxy-1, 3, 5-benzene tricaldehyde.
Preferably, the mass volume ratio of the 4, 6-pyrimidinediamine of S2 to chloroform is 1g: (15-25) mL.
Preferably, the volume ratio of the second reaction solution to the first reaction solution of the S3 is 1.25-1.5:1.
Preferably, the halosilane TMSH of S3 includes at least one of trimethylchlorosilane tmcl, trimethylbromosilane tmbr, and trimethyliodosilane TMSI.
Preferably, the molar ratio of the halosilane TMSH of S3 to the 2,4, 6-trihydroxy-1, 3, 5-benzenetricaldehyde of S1 is 1:1-2.
Preferably, the drying of S4 is a drying process in a vacuum oven at 60 ℃.
The beneficial effects of the invention are as follows:
1. in the existing synthesis process of beta-nicotinamide mononucleotide, nicotinamide and tetraacetylribose are subjected to condensation reaction to generate nicotinamide triacetyl nucleoside, the step requires catalytic reaction of a catalyst, and a common catalyst is a halosilane catalyst such as TMSCl, TMSBr, TMSI, and the catalyst has poor thermal stability, so that the catalytic reaction is required to be carried out at a low temperature, and the defects of overlong catalytic reaction, low reaction efficiency and excessive byproducts of the reaction can occur.
2. The catalyst used for synthesizing nicotinamide triacetyl nucleoside in the first step is TMSH-pyrPOCs, and the catalyst is prepared by taking pyrimidinyl porous organic cage pyrPOCs as a carrier and taking halosilane TMSH as the carrier. The supported pyrPOCs take 2,4, 6-trihydroxy-1, 3, 5-benzene tricaldehyde and 4, 6-pyrimidine diamine as raw materials, so that the porous organic cage containing pyrimidine groups is prepared.
3. The catalyst TMSH-pyrPOCs prepared by the invention is used for catalyzing nicotinamide triacetyl nucleoside, has high catalytic efficiency and is more stable, and the defects of low catalytic activity and excessive byproducts of the existing halosilane catalyst at low temperature are overcome.
Drawings
The invention will be further described with reference to the accompanying drawings, in which embodiments do not constitute any limitation of the invention, and other drawings can be obtained by one of ordinary skill in the art without inventive effort from the following drawings.
FIG. 1 is an SEM image of TMSCl-pyrPOCs of the catalyst prepared in comparative example 1 of the invention;
FIG. 2 is an SEM image of porous organic cage PyrPOCs prepared in comparative example 4 of the present invention.
Detailed Description
The technical features, objects and advantages of the present invention will be more clearly understood from the following detailed description of the technical aspects of the present invention, but should not be construed as limiting the scope of the invention.
The invention is further described with reference to the following examples.
Example 1
A method for preparing beta-nicotinamide mononucleotide, comprising the following steps:
step (1), weighing nicotinamide and tetraacetylribose, mixing in chloroform, wherein the molar ratio of the nicotinamide to the tetraacetylribose is 1:1.4, the adding amount of the chloroform is 5 times of the sum of the masses of the nicotinamide and the tetraacetylribose, adding a catalyst TMSCl-pyrPOCs after the nicotinamide and the tetraacetylribose are fully dissolved, and carrying out reflux stirring reaction for 2 hours at 45 ℃ under the condition that the adding amount of the catalyst is 3% of the mass of the nicotinamide to obtain a solution of the nicotinamide triacetyl nucleoside;
step (2), adding 0.2g/mL sodium ethoxide solution into the solution of nicotinamide triacetyl nucleoside, deacetylating under the stirring condition of an ice-water bath, stirring for 2h for reaction, adjusting the pH value of the reaction solution to be 5-6, and removing the solvent under reduced pressure to obtain nicotinamide riboside salt;
mixing nicotinamide riboside salt in tributyl phosphate, fully dissolving, dripping phosphorus oxychloride, stirring under ice water bath condition for reaction for 8h, wherein the molar ratio of nicotinamide riboside salt to phosphorus oxychloride is 1:2, the adding amount of tributyl phosphate is 5 times of the sum of the mass of nicotinamide riboside salt and phosphorus oxychloride, introducing ammonia gas for ammonolysis after the reaction is finished, introducing ammonia gas for 1.5h at a flow rate of 0.2L/min, pouring the reaction solution into distilled water for stirring, adding ethyl acetate for continuous stirring, standing for layering, removing an oil phase layer, eluting a water phase layer by a filter filled with anion exchange resin D202 for desalting, and vacuum drying or freeze drying to obtain beta-nicotinamide mononucleotide.
The preparation method of the catalyst TMSCl-pyrPOCs (scanning electron microscope image is shown as figure 1) comprises the following steps:
s1, weighing 2,4, 6-trihydroxy-1, 3, 5-benzene tricaldehyde and chloroform, mixing in a flask, uniformly stirring, adding anhydrous magnesium sulfate as a catalyst, and fully mixing and stirring to form a first reaction solution; wherein the mass volume ratio of the 2,4, 6-trihydroxy-1, 3, 5-benzaldehyde to the chloroform is 1g:15mL of anhydrous magnesium sulfate was added in an amount of 4% by mass of 2,4, 6-trihydroxy-1, 3, 5-benzenetricaldehyde.
S2, weighing 4, 6-pyrimidinediamine and mixing with chloroform in a beaker, and fully mixing and stirring to form a second reaction solution; wherein the mass volume ratio of the 4, 6-pyrimidinediamine to the chloroform is 1g:20mL.
S3, dropwise adding the second reaction solution into the continuously stirred first reaction solution, simultaneously adding trimethylchlorosilane TMSCl into the first reaction solution, sealing a flask after the dropwise adding is finished, and placing the flask in an indoor dark and cool place for 4 days, wherein a large number of crystals grow on the inner wall of the flask to obtain a third reaction solution; wherein the volume ratio of the second reaction solution to the first reaction solution is 1.5:1, and the molar ratio of the trimethylchlorosilane TMSCl to the 2,4, 6-trihydroxy-1, 3, 5-benzene tricaldehyde is 1:1.5.
S4, shaking the reaction bottle until crystals on the inner wall fall off, filtering out the crystals, washing the crystals at least three times by using chloroform, and drying the crystals in a vacuum box at 60 ℃ to obtain TMSCl-pyrPOCs.
Example 2
A method for preparing beta-nicotinamide mononucleotide, comprising the following steps:
step (1), mixing nicotinamide and tetraacetylribose in chloroform, wherein the molar ratio of the nicotinamide to the tetraacetylribose is 1:1.2, the adding amount of the chloroform is 5 times of the sum of the masses of the nicotinamide and the tetraacetylribose, after the nicotinamide and the tetraacetylribose are fully dissolved, adding a catalyst TMSCl-pyrPOCs, wherein the preparation method of the catalyst TMSCl-pyrPOCs is the same as that of the example 1, and the adding amount of the catalyst is 3% of the mass of the nicotinamide, and carrying out reflux stirring reaction for 1.5 hours at 40 ℃ to obtain a solution of the nicotinamide triacetyl nucleoside;
step (2), adding 0.1g/mL sodium ethoxide solution into the solution of nicotinamide triacetyl nucleoside, deacetylating under the stirring condition of an ice-water bath, stirring for reacting for 1h, then adjusting the pH value of the reaction solution to be 5-6, and removing the solvent under reduced pressure to obtain nicotinamide riboside salt;
mixing nicotinamide riboside salt in tributyl phosphate, fully dissolving, dripping phosphorus oxychloride, stirring under ice water bath condition for reaction for 5h, wherein the molar ratio of nicotinamide riboside salt to phosphorus oxychloride is 1:1.5, adding tributyl phosphate with the addition amount being 5 times of the sum of the mass of nicotinamide riboside salt and phosphorus oxychloride, introducing ammonia gas for ammonolysis after the reaction is finished, introducing ammonia gas with the flow rate of 0.1L/min for 1h, pouring the reaction solution into distilled water for stirring, adding ethyl acetate for continuous stirring, standing for layering, removing an oil phase layer, eluting an aqueous phase layer by a filter filled with anion exchange resin D202 for desalting, and vacuum drying or freeze drying to obtain beta-nicotinamide mononucleotide.
Example 3
A method for preparing beta-nicotinamide mononucleotide, comprising the following steps:
step (1), mixing nicotinamide and tetraacetylribose in chloroform, wherein the molar ratio of the nicotinamide to the tetraacetylribose is 1:1.6, the adding amount of the chloroform is 6 times of the sum of the masses of the nicotinamide and the tetraacetylribose, after the nicotinamide and the tetraacetylribose are fully dissolved, adding a catalyst TMSCl-pyrPOCs, wherein the preparation method of the catalyst TMSCl-pyrPOCs is the same as that of the example 1, and the adding amount of the catalyst is 3% of the mass of the nicotinamide, and carrying out reflux stirring reaction for 2.5 hours at 50 ℃ to obtain a solution of the nicotinamide triacetyl nucleoside;
step (2), adding 0.3g/mL sodium ethoxide solution into the solution of nicotinamide triacetyl nucleoside, deacetylating under the stirring condition of an ice-water bath, stirring for 2h for reaction, adjusting the pH value of the reaction solution to be 5-6, and removing the solvent under reduced pressure to obtain nicotinamide riboside salt;
mixing nicotinamide riboside salt in tributyl phosphate, fully dissolving, dripping phosphorus oxychloride, stirring under ice water bath condition for reaction for 10h, wherein the molar ratio of nicotinamide riboside salt to phosphorus oxychloride is 1:2.5, adding tributyl phosphate with the addition amount of 6 times of the sum of the mass of nicotinamide riboside salt and phosphorus oxychloride, introducing ammonia gas for ammonolysis after the reaction is finished, introducing ammonia gas with the flow rate of 0.3L/min for 2h, pouring the reaction solution into distilled water for stirring, adding ethyl acetate for continuous stirring, standing for layering, removing an oil phase layer, eluting an aqueous phase layer by a filter filled with anion exchange resin D202 for desalting, and vacuum drying or freeze drying to obtain beta-nicotinamide mononucleotide.
Example 4
A preparation method of beta-nicotinamide mononucleotide is the same as the preparation process of the example 1, except that the catalyst is different, the catalyst of the comparative example is TMSBr-PyrPOCs, and the preparation method of the catalyst comprises the following steps:
s1, weighing 2,4, 6-trihydroxy-1, 3, 5-benzene tricaldehyde and chloroform, mixing in a flask, uniformly stirring, adding anhydrous magnesium sulfate as a catalyst, and fully mixing and stirring to form a first reaction solution; wherein the mass volume ratio of the 2,4, 6-trihydroxy-1, 3, 5-benzaldehyde to the chloroform is 1g:10mL of anhydrous magnesium sulfate was added in an amount of 2% by mass of 2,4, 6-trihydroxy-1, 3, 5-benzenetricaldehyde.
S2, weighing 4, 6-pyrimidinediamine and mixing with chloroform in a beaker, and fully mixing and stirring to form a second reaction solution; wherein the mass volume ratio of the 4, 6-pyrimidinediamine to the chloroform is 1g:15mL.
S3, dropwise adding the second reaction solution into the continuously stirred first reaction solution, simultaneously adding trimethylbromosilane TMSBr into the first reaction solution, sealing a flask after the dropwise adding is finished, and placing the flask in an indoor dark and cool place for 3 days, wherein a large number of crystals grow on the inner wall of the flask to obtain a third reaction solution; wherein the volume ratio of the second reaction liquid to the first reaction liquid is 1.25:1; the molar ratio of trimethylbromosilane TMSBr to 2,4, 6-trihydroxy-1, 3, 5-benzene tricaldehyde is 1:1.
S4, shaking the reaction bottle until crystals on the inner wall fall off, filtering out the crystals, washing the crystals at least three times by using chloroform, and drying the crystals in a vacuum box at 60 ℃ to obtain TMSBr-pyrPOCs.
Example 5
A preparation method of beta-nicotinamide mononucleotide is the same as the preparation process of the example 1, except that catalysts are different, the catalysts of the comparative example are TMSI-PyrPOCs, and the preparation method of the catalysts comprises the following steps:
s1, weighing 2,4, 6-trihydroxy-1, 3, 5-benzene tricaldehyde and chloroform, mixing in a flask, uniformly stirring, adding anhydrous magnesium sulfate as a catalyst, and fully mixing and stirring to form a first reaction solution; wherein the mass volume ratio of the 2,4, 6-trihydroxy-1, 3, 5-benzaldehyde to the chloroform is 1g:20mL of anhydrous magnesium sulfate was added in an amount of 6% by mass of 2,4, 6-trihydroxy-1, 3, 5-benzenetricaldehyde.
S2, weighing 4, 6-pyrimidinediamine and mixing with chloroform in a beaker, and fully mixing and stirring to form a second reaction solution; wherein the mass volume ratio of the 4, 6-pyrimidinediamine to the chloroform is 1g:25mL.
S3, dropwise adding the second reaction solution into the continuously stirred first reaction solution, simultaneously adding the trimethyliodosilane TMSI into the first reaction solution, sealing the flask after the dropwise adding is finished, and placing the flask in an indoor dark and cool place for 5 days, wherein a large number of crystals grow on the inner wall of the flask to obtain a third reaction solution; wherein the volume ratio of the second reaction liquid to the first reaction liquid is 1.5:1; the molar ratio of trimethylbromosilane TMSI to 2,4, 6-trihydroxy-1, 3, 5-benzenetricaldehyde is 1:2.
S4, shaking the reaction bottle until crystals on the inner wall fall off, filtering out the crystals, washing the crystals at least three times by using chloroform, and drying the crystals in a vacuum box at 60 ℃ to obtain the TMSI-pyrPOCs.
Example 6
A method for preparing beta-nicotinamide mononucleotide is the same as the preparation process of example 1, except that in step (1), the catalyst is added in an amount of 1% by mass of nicotinamide.
Example 7
A method for preparing beta-nicotinamide mononucleotide is the same as the preparation process of example 1, except that in step (1), the catalyst is added in an amount of 5% by mass of nicotinamide.
Comparative example 1
A method for preparing beta-nicotinamide mononucleotide is the same as in example 1, except that:
the catalysts were different, the catalyst of this comparative example was TMSCl, and the addition was 3% of the mass of nicotinamide.
Comparative example 2
A method for preparing beta-nicotinamide mononucleotide is the same as in example 1, except that:
the catalysts are different, the catalyst of the comparative example is TMSBr, and the addition amount of the catalyst is 3% of the mass of nicotinamide.
Comparative example 3
A method for preparing beta-nicotinamide mononucleotide is the same as in example 1, except that:
the catalysts were different, the catalyst of this comparative example was TMSI, added in an amount of 3% of the mass of nicotinamide.
Comparative example 4
A scanning electron microscope diagram of the porous organic cage PyrPOCs is shown in figure 2, and the preparation method comprises the following steps:
s1, weighing 2,4, 6-trihydroxy-1, 3, 5-benzene tricaldehyde and chloroform, mixing in a flask, uniformly stirring, adding anhydrous magnesium sulfate as a catalyst, and fully mixing and stirring to form a first reaction solution; wherein the mass volume ratio of the 2,4, 6-trihydroxy-1, 3, 5-benzaldehyde to the chloroform is 1g:15mL of anhydrous magnesium sulfate was added in an amount of 4% by mass of 2,4, 6-trihydroxy-1, 3, 5-benzenetricaldehyde.
S2, weighing 4, 6-pyrimidinediamine and mixing with chloroform in a beaker, and fully mixing and stirring to form a second reaction solution; wherein the mass volume ratio of the 4, 6-pyrimidinediamine to the chloroform is 1g:20mL.
S3, dropwise adding the second reaction solution into the continuously stirred first reaction solution, sealing the flask after dropwise adding, and standing in a dark and cool place indoors for 4 days, wherein a large number of crystals grow on the inner wall of the flask to obtain a third reaction solution; wherein the volume ratio of the second reaction liquid to the first reaction liquid is 1.5:1.
S4, shaking the reaction bottle until crystals on the inner wall fall off, filtering out the crystals, washing the crystals at least three times by using chloroform, and drying the crystals in a vacuum box at 60 ℃ to obtain the pyrPOCs.
Experimental example
For the determination of the final yield and the High Performance Liquid Chromatography (HPLC) purity of the products β -nicotinamide mononucleotide prepared in inventive example 1, example 4, example 5, and comparative examples 1-3, the results of the detection were then counted, and the statistical results are shown in Table 1:
TABLE 1 yield and purity of beta-nicotinamide mononucleotide obtained with different catalysts
From the comparison of the above table 1, it can be seen that the yields of the embodiments 1, 4 and 5 of the present invention can reach more than 80% and the purity can reach 98%, which means that the efficiency of the catalyst of the present invention is higher under the conventional reaction temperature and time, and the purity of the product is also higher under the same purification process conditions; the catalysts of examples 1, 4, 5 of the present invention are shown to have a stronger catalytic activity than conventional halosilane catalysts, while also reacting fewer by-products from the side and being easier to purify.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. A method for preparing beta-nicotinamide mononucleotide, which is characterized by comprising the following steps:
step (1), weighing nicotinamide and tetraacetylribose, mixing in chloroform, fully dissolving, and adding a catalyst for reaction to obtain a solution of nicotinamide triacetyl nucleoside;
step (2), adding organic base into the solution of nicotinamide triacetyl nucleoside, deacetylating under stirring, then adjusting the pH of the reaction solution to 5-6, and removing the solvent under reduced pressure to obtain nicotinamide riboside salt;
and (3) mixing nicotinamide riboside salt in tributyl phosphate, fully dissolving, dropwise adding phosphorus oxychloride, stirring for reaction under the ice water bath condition, introducing ammonia gas for ammonolysis after the reaction is finished, and extracting, purifying and drying to obtain the beta-nicotinamide mononucleotide.
2. The method for producing β -nicotinamide mononucleotide according to claim 1, wherein in step (1), the molar ratio of nicotinamide to tetraacetylribose is 1:1.2-1.6; the addition amount of the chloroform is 5-6 times of the sum of the masses of the nicotinamide and the tetraacetylribose.
3. The method for preparing β -nicotinamide mononucleotide according to claim 1, wherein in step (1), the reaction is performed under reflux and stirring at 4-50 ℃ in a water bath for 1.5-2.5h.
4. The method for preparing β -nicotinamide mononucleotide according to claim 1, wherein in the step (1), the catalyst is TMSH-PyrPOCs, and the catalyst is added in an amount of 1% -5% of the mass of nicotinamide.
5. The method for preparing β -nicotinamide mononucleotide according to claim 1, wherein in step (2), the organic base is sodium ethoxide solution with a concentration of 0.1-0.3g/mL; the reaction condition is ice water bath, and the reaction is stirred for 1-2h.
6. The method for producing a β -nicotinamide mononucleotide according to claim 1, wherein in the step (3), the molar ratio of nicotinamide riboside salt to phosphorus oxychloride is 1:1.5-2.5, and the amount of tributyl phosphate added is 5-6 times the sum of the masses of nicotinamide riboside salt and phosphorus oxychloride.
7. The method for preparing β -nicotinamide mononucleotide according to claim 1, wherein in the step (3), the reaction time is 5-10h with stirring in an ice water bath; the flow rate of the ammonia gas is 0.1-0.3L/min, and the flow time is 1-2h.
8. The method for preparing β -nicotinamide mononucleotide according to claim 1, wherein in the step (3), the reaction solution is poured into distilled water and stirred, ethyl acetate is added and stirred continuously, and the oil phase layer is removed after standing and layering; the purification is to use resin exchange method to remove salt and purify the water phase layer; the drying is vacuum drying or freeze drying.
9. The method for preparing the beta-nicotinamide mononucleotide according to claim 1, wherein the method for preparing the catalyst comprises the following steps:
s1, weighing 2,4, 6-trihydroxy-1, 3, 5-benzene tricaldehyde and chloroform, mixing in a flask, uniformly stirring, adding anhydrous magnesium sulfate as a catalyst, and fully mixing and stirring to form a first reaction solution;
s2, weighing 4, 6-pyrimidinediamine and mixing with chloroform in a beaker, and fully mixing and stirring to form a second reaction solution;
s3, dropwise adding the second reaction solution into the continuously stirred first reaction solution, simultaneously adding halosilane TMSH into the first reaction solution, sealing a flask after the dropwise adding is finished, and placing the flask in an indoor dark and cool place for 3-5 days, wherein a large number of crystals grow on the inner wall of the flask to obtain a third reaction solution;
s4, shaking the reaction bottle until crystals on the inner wall fall off, filtering out the crystals, washing the crystals at least three times by using chloroform, and drying the crystals to obtain the TMSH-pyrPOCs.
10. The method for preparing β -nicotinamide mononucleotide according to claim 1, wherein the halosilane TMSH of S3 comprises at least one of trimethylchlorosilane tmcl, trimethylbromosilane tmbr, and trimethyliodosilane TMSI.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310543311.1A CN116514881B (en) | 2023-05-15 | 2023-05-15 | Preparation method of beta-nicotinamide mononucleotide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310543311.1A CN116514881B (en) | 2023-05-15 | 2023-05-15 | Preparation method of beta-nicotinamide mononucleotide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116514881A true CN116514881A (en) | 2023-08-01 |
| CN116514881B CN116514881B (en) | 2024-05-17 |
Family
ID=87400915
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310543311.1A Active CN116514881B (en) | 2023-05-15 | 2023-05-15 | Preparation method of beta-nicotinamide mononucleotide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116514881B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109053838A (en) * | 2018-07-26 | 2018-12-21 | 四川大学 | Prepare β-nicotinamide mononucleotide or β-niacinamide ribose method |
| US20220363704A1 (en) * | 2020-06-19 | 2022-11-17 | Bontac Bio-Engineering(Shenzhen) Co., Ltd. | Method for preparing nicotinamide mononucleotide by using nicotinamide as raw material |
-
2023
- 2023-05-15 CN CN202310543311.1A patent/CN116514881B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109053838A (en) * | 2018-07-26 | 2018-12-21 | 四川大学 | Prepare β-nicotinamide mononucleotide or β-niacinamide ribose method |
| US20220363704A1 (en) * | 2020-06-19 | 2022-11-17 | Bontac Bio-Engineering(Shenzhen) Co., Ltd. | Method for preparing nicotinamide mononucleotide by using nicotinamide as raw material |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116514881B (en) | 2024-05-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101307015B (en) | Process for preparing cilastatin sodium | |
| CN106566851B (en) | Preparation method of chloramphenicol compound | |
| CN113214239B (en) | Tedizolid refining process and preparation method of tedizole phosphate | |
| CN102286046A (en) | Preparation method of ribavirin | |
| CN109574869A (en) | A kind of preparation method of Oseltamivir phosphate | |
| CN116514881B (en) | Preparation method of beta-nicotinamide mononucleotide | |
| JP2012533618A (en) | Process for producing fluorocytidine derivatives | |
| CN108822112B (en) | Preparation method of tofacitinib compound | |
| CN101050217A (en) | Method for synthesizing Vardenafil hydrochloric acid | |
| CN101321770A (en) | Scalable process for the preparation of a rapamycin 42-ester from a rapamycin 42-ester boronate | |
| CN111393243B (en) | Synthesis method of phosphorus chiral nucleoside drug and drug obtained by method | |
| CN102627286A (en) | Method for manufacturing zeolite and method for manufacturing epsilon-caprolatam | |
| CN109161577B (en) | Levo Corey lactone diol intermediate, preparation method and pharmaceutical application thereof | |
| CN109096129B (en) | Preparation method of L-carnitine tartrate | |
| CN111944855B (en) | Method for synthesizing (R) -1- (4- (benzyloxy) -3-nitrophenyl) -2-bromoethanol | |
| CN101928304B (en) | Preparation method of D-ribose | |
| CN111849959B (en) | Method for preparing cycloastragaloside by using co-immobilized double-enzyme catalytic astragaloside IV | |
| CN111841618B (en) | Preparation method and application of catalyst for synthesizing 2, 4-trimethyl-1, 3-pentanediol diisobutyrate | |
| CN113549075A (en) | Synthesis method of tofacitinib citrate diastereoisomer impurity | |
| CN112521421A (en) | Preparation method of pharmaceutical compound | |
| CN112480172A (en) | Use of borane-pyridine complexes for the preparation of pharmaceutical compounds | |
| CN110714043A (en) | Method for preparing guanosine triphosphate by immobilized enzyme method | |
| CN109053797A (en) | A kind of improvement synthetic method of oxygen phosphoric acid-l-tyrosine | |
| CN112940022A (en) | Preparation method of dimethylamine borane | |
| CN114057813B (en) | Method for synthesizing citicoline sodium |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |