CN116462727A - Preparation method of beta-nicotinamide riboside chloride - Google Patents
Preparation method of beta-nicotinamide riboside chloride Download PDFInfo
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- CN116462727A CN116462727A CN202310440342.4A CN202310440342A CN116462727A CN 116462727 A CN116462727 A CN 116462727A CN 202310440342 A CN202310440342 A CN 202310440342A CN 116462727 A CN116462727 A CN 116462727A
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- beta
- nicotinamide
- riboside chloride
- nicotinamide riboside
- ribose
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 78
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims abstract description 52
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims abstract description 52
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims abstract description 51
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 47
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 44
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000007787 solid Substances 0.000 claims abstract description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000003756 stirring Methods 0.000 claims abstract description 36
- 238000002156 mixing Methods 0.000 claims abstract description 26
- 235000005152 nicotinamide Nutrition 0.000 claims abstract description 24
- 239000011570 nicotinamide Substances 0.000 claims abstract description 24
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- 230000008569 process Effects 0.000 claims abstract description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 22
- 230000004224 protection Effects 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 162
- 239000002904 solvent Substances 0.000 claims description 41
- 238000001816 cooling Methods 0.000 claims description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000012295 chemical reaction liquid Substances 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- YABIFCKURFRPPO-IVOJBTPCSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyridin-1-ium-3-carboxamide;chloride Chemical compound [Cl-].NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 YABIFCKURFRPPO-IVOJBTPCSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 11
- DAYLJWODMCOQEW-TURQNECASA-N NMN zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)([O-])=O)O2)O)=C1 DAYLJWODMCOQEW-TURQNECASA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 229950006238 nadide Drugs 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 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 4
- 238000001035 drying Methods 0.000 description 4
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- 206010013663 drug dependence Diseases 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
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- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 206010039966 Senile dementia Diseases 0.000 description 2
- 239000004280 Sodium formate Substances 0.000 description 2
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- 230000000052 comparative effect Effects 0.000 description 2
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- 238000010438 heat treatment Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229920001296 polysiloxane Polymers 0.000 description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 2
- 235000019254 sodium formate Nutrition 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- ZHGFYHSIDIAPHL-WZBOVFFLSA-N (2S,3R,4R)-2,3-diacetyl-2,3,4,5-tetrahydroxy-6-oxoheptanoyl chloride Chemical compound ClC(=O)[C@](O)([C@](O)([C@H](O)C(O)C(C)=O)C(C)=O)C(C)=O ZHGFYHSIDIAPHL-WZBOVFFLSA-N 0.000 description 1
- 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 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 210000001789 adipocyte Anatomy 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 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 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 230000036996 cardiovascular health Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000032677 cell aging Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000235 effect on cancer Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 229940064982 ethylnicotinate Drugs 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- -1 nicotinic acid ester Chemical class 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003290 ribose derivatives Chemical class 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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Classifications
-
- 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
-
- 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
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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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 riboside chloride, belonging to the technical field of organic synthetic drugs. The invention discloses a preparation method of beta-nicotinamide riboside chloride, which comprises the following steps: s1: dissolving ribose with acetonitrile to prepare acetonitrile solution of ribose, adding nicotinamide solid into a reaction system, stirring, adding catalyst triphenylphosphine in the stirring process, mixing, and performing nitrogen protection after mixing; s2: after the nitrogen protection is finished, the concentrated hydrochloric acid is dripped, heat is generated in the dripping process, the temperature of the reaction system is controlled to be 20-25 ℃, and stirring reaction is continued after the dripping is finished. The invention solves the problems of more process steps, complex operation and lower yield of the beta-nicotinamide riboside chloride prepared by the prior method, and the preparation method has the advantages of less process steps, simple operation and higher yield.
Description
Technical Field
The invention relates to the technical field of organic synthetic medicaments, in particular to a preparation method of beta-nicotinamide riboside chloride.
Background
Nicotinamide mononucleotide (Nicotinamide Mononucleotide, NMN) is a biochemical substance inherent in biological cells, and is converted into nicotinamide adenine dinucleotide (NAD, also called coenzyme I) which is an important substance for survival of biological cells after being adenylated by nicotinamide nucleotide adenyltransferase, and thousands of reactions are involved in each cell. NMN is a direct precursor of NAD, is the most ideal way to supplement NAD at present, and its level in biological cells directly affects the concentration of NAD, plays an important role in biological cell energy generation, and is harmless to human body.
The university of japanese celebration Ying Yi ju and university of washington in united states cooperate to conduct clinical trials on the anti-aging effect and safety of β -n m n, and up to the present studies have shown that β -Nicotinamide Mononucleotide (NMN) has the following effects: 1. delay senility: restoring the functions of aging cells, and recovering the vitality of weak human organs so as to achieve the aim of delaying aging; 2. improving cardiovascular health: improving the functions of myocardial cells and vascular cells, and reducing the blood lipid level in the cardiovascular system, so that the cardiovascular function can be improved; 3. improving brain health: the activity of brain cells and other nerve cells is improved, and the functions of the whole nervous system are improved, so that the brain health can be improved, the effect on senile dementia is better, the characteristic change of brain mitochondria of patients with mild cognitive dysfunction and Alzheimer disease can be realized, and the mitochondrial energy output can be reduced along with the development of diseases; 4. improving fat metabolism: reducing the absorption of lipid substances in food by human body, improving the consumption of fat in fat cells, and achieving the purpose of losing weight; 5. improving the resistance of human body to cancer cells: improving the functions of various immune cells in human body, enhancing the resistance to cancer cells, and having auxiliary treatment effect on cancer; 6. drug addiction stopping effect: the drug addiction can be relieved by taking a large amount of the medicine, and the medicine has better drug addiction stopping effect; 7. cosmetic effect: improving the functions of epidermis cells and other cells in human body, and keeping the skin bright. With the increase of the cognition of people on the medical and health-care effects of nicotinamide mononucleotide and the wide application of the nicotinamide mononucleotide as a reaction substrate in the chemical industry, the demand for nicotinamide mononucleotide in the market is increasing.
Beta-nicotinamide riboside chloride (beta-NAC) is a derivative of vitamin b3 that can be used both for the synthesis of NMN and as a substrate for NAD+ degradation reactions. The beta-NAC not only can enhance metabolism of organisms and delay cell aging, but also can be used as a nutritional supplement to play a role in neuroprotection and slow down neuronal death.
The synthesis method reported in the current literature basically comprises the steps of reacting substituted ribose with nicotinamide or nicotinic acid ester, and removing protecting groups to obtain beta-nicotinamide riboside chloride, wherein the method comprises the following steps:
the first method is as follows: starting from nicotinamide and tetraacetyl ribose
The second method is as follows: starting from nicotinamide and 2,3, 5-triacetyl-1-chlororibose
The third method is as follows: starting from ethyl nicotinate and tetraacetyl ribose
The beta-nicotinamide riboside chloride prepared by the method has the advantages of more process steps, complex operation and lower yield.
Disclosure of Invention
The invention aims to provide a preparation method of beta-nicotinamide riboside chloride, which has the advantages of few process steps, simple operation, higher yield and solves the problems in the prior art.
In order to achieve the above purpose, the present invention provides the following technical solutions:
the preparation method of the beta-nicotinamide riboside chloride comprises the following steps:
s1: dissolving ribose with acetonitrile to prepare acetonitrile solution of ribose, adding nicotinamide solid into a reaction system, stirring, adding catalyst triphenylphosphine in the stirring process, mixing, and performing nitrogen protection after mixing;
s2: after the nitrogen protection is finished, dropwise adding concentrated hydrochloric acid, wherein heat is generated in the dropwise adding process, the temperature of a reaction system is required to be controlled to be 20-25 ℃, and stirring reaction is continued after the dropwise adding is finished;
s3: the pre-cooled ethyl acetate solvent is prepared in advance, the pre-cooling temperature of the ethyl acetate is 0-5 ℃, after the reaction is finished, the reaction liquid is dripped into the pre-cooled ethyl acetate, because the polarity of nicotinamide riboside chloride is large, solids are separated out from the low-polarity solvent according to a similar compatibility principle, and the filtered solids are leached by the pre-cooled ethyl acetate and then dried to obtain the beta-nicotinamide riboside chloride.
Preferably, in the step S1, the molar ratio of ribose to nicotinamide in the ribose solution is (1-1.2): 1.
preferably, in the step S1, the mass-volume ratio of nicotinamide to acetonitrile is 1: (4-6).
Preferably, in S1, the solvent is DMSO, DMF, NMP or acetonitrile.
Preferably, in the S1, the molar ratio of triphenylphosphine to nicotinamide is (0.5-1): 1.
preferably, in S2, the molar ratio of ribose in the ribose solution to hydrochloric acid in the concentrated hydrochloric acid is 1:1.1.
preferably, in S3, the volume ratio of ethyl acetate to acetonitrile is 1:1.
compared with the prior art, the invention has the beneficial effects that:
according to the preparation method of the beta-nicotinamide riboside chloride, an acetonitrile solution of ribose, nicotinamide and a catalyst are mixed, concentrated hydrochloric acid is dripped after the dripping is finished, the temperature is raised, the mixture is stirred for reaction, crystals are separated out after the reaction is finished, the crystals are dripped into ethyl acetate, and the crystals are filtered and dried to obtain the beta-nicotinamide riboside chloride.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In order to solve the problems of more process steps, complex operation and lower yield of the existing preparation method of the beta-nicotinamide riboside chloride, the embodiment provides the following technical scheme:
example 1
Dissolving 150g of ribose with 600ml of acetonitrile to prepare acetonitrile solution of ribose, adding 122g of nicotinamide solid into a reaction system, stirring, adding 262g of triphenylphosphine catalyst in the stirring process, mixing, and performing nitrogen protection after the mixing is finished;
after the nitrogen protection is finished, dropwise adding 36% concentrated hydrochloric acid, wherein heat is generated in the dropwise adding process, the temperature of a reaction system is required to be controlled to be 20-25 ℃, and stirring reaction is continued after the dropwise adding is finished;
pre-cooling 600ml of ethyl acetate solvent, wherein the pre-cooling temperature of the ethyl acetate is 0-5 ℃, after the reaction is finished, the reaction liquid is dripped into the ethyl acetate which is finished in a pre-cooling way to separate out solid, the filtered solid is leached by the pre-cooling ethyl acetate, and then is dried to obtain 265g of beta-nicotinamide riboside chloride, and the yield is 91.3%.
Example two
Dissolving 150g of ribose with 500ml of acetonitrile to prepare acetonitrile solution of ribose, adding 122g of nicotinamide solid into a reaction system, stirring, adding 262g of triphenylphosphine catalyst in the stirring process, mixing, and performing nitrogen protection after the mixing is finished;
after the nitrogen protection is finished, dropwise adding 36% concentrated hydrochloric acid, wherein heat is generated in the dropwise adding process, the temperature of a reaction system is required to be controlled to be 20-25 ℃, and stirring reaction is continued after the dropwise adding is finished;
pre-cooling 500ml of ethyl acetate solvent, wherein the pre-cooling temperature of the ethyl acetate is 0-5 ℃, after the reaction is finished, the reaction liquid is dripped into the ethyl acetate which is finished in a pre-cooling way to separate out solid, the filtered solid is leached by the pre-cooling ethyl acetate, and then the filtered solid is dried to obtain 269g of beta-nicotinamide riboside chloride, and the yield is 92.7%.
Example III
Dissolving 160g of ribose with 500ml of acetonitrile to prepare acetonitrile solution of ribose, adding 122g of nicotinamide solid into a reaction system, stirring, adding 262g of triphenylphosphine catalyst in the stirring process, mixing, and performing nitrogen protection after the mixing is finished;
after the nitrogen protection is finished, dropwise adding 36% concentrated hydrochloric acid, wherein heat is generated in the dropwise adding process, the temperature of a reaction system is required to be controlled to be 20-25 ℃, and stirring reaction is continued after the dropwise adding is finished;
pre-cooling 500ml of ethyl acetate solvent, wherein the pre-cooling temperature of the ethyl acetate is 0-5 ℃, after the reaction is finished, the reaction liquid is dripped into the ethyl acetate which is finished in a pre-cooling way to separate out solid, the filtered solid is leached by the pre-cooling ethyl acetate, 273g of beta-nicotinamide riboside chloride is obtained after drying, and the yield is 94.1%.
Example IV
Dissolving 150g of ribose with 600ml of DMSO to prepare a DMSO solution of ribose, adding 122g of nicotinamide solid into a reaction system, stirring, adding 262g of triphenylphosphine serving as a catalyst in the stirring process, mixing, and performing nitrogen protection after the mixing is finished;
after the nitrogen protection is finished, dropwise adding 36% concentrated hydrochloric acid, wherein heat is generated in the dropwise adding process, the temperature of a reaction system is required to be controlled to be 20-25 ℃, and stirring reaction is continued after the dropwise adding is finished;
pre-cooling 600ml of ethyl acetate solvent, wherein the pre-cooling temperature of the ethyl acetate is 0-5 ℃, after the reaction is finished, the reaction liquid is dripped into the ethyl acetate which is finished in a pre-cooling way to separate out solid, the filtered solid is leached by the pre-cooling ethyl acetate, and then dried to obtain 221g of beta-nicotinamide riboside chloride, and the yield is 76.2%.
Example five
Dissolving 150g of ribose with 600ml of DMF to prepare DMF solution of ribose, adding 122g of nicotinamide solid into a reaction system, stirring, adding 262g of triphenylphosphine catalyst in the stirring process, mixing, and performing nitrogen protection after the mixing is finished;
after the nitrogen protection is finished, dropwise adding 36% concentrated hydrochloric acid, wherein heat is generated in the dropwise adding process, the temperature of a reaction system is required to be controlled to be 20-25 ℃, and stirring reaction is continued after the dropwise adding is finished;
pre-cooling 600ml of ethyl acetate solvent, wherein the pre-cooling temperature of the ethyl acetate is 0-5 ℃, after the reaction is finished, the reaction liquid is dripped into the ethyl acetate which is finished in a pre-cooling way to separate out solid, the filtered solid is leached by the pre-cooling ethyl acetate, and then the filtered solid is dried to obtain 229g of beta-nicotinamide riboside chloride, and the yield is 78.9%.
Example six
Dissolving 150g of ribose with 600ml of NMP to prepare NMP solution of ribose, adding 122g of nicotinamide solid into a reaction system, stirring, adding 262g of triphenylphosphine serving as a catalyst in the stirring process, mixing, and performing nitrogen protection after the mixing is finished;
after the nitrogen protection is finished, dropwise adding 36% concentrated hydrochloric acid, wherein heat is generated in the dropwise adding process, the temperature of a reaction system is required to be controlled to be 20-25 ℃, and stirring reaction is continued after the dropwise adding is finished;
pre-cooling 600ml of ethyl acetate solvent, wherein the pre-cooling temperature of the ethyl acetate is 0-5 ℃, after the reaction is finished, the reaction liquid is dripped into the ethyl acetate which is finished in a pre-cooling way to separate out solid, the filtered solid is leached by the pre-cooling ethyl acetate, and then the filtered solid is dried to obtain 220g of beta-nicotinamide riboside chloride, and the yield is 75.8%.
Example seven
Dissolving 150g of ribose with 600ml of acetonitrile to prepare acetonitrile solution of ribose, adding 122g of nicotinamide solid into a reaction system, stirring, adding 131g of triphenylphosphine serving as a catalyst in the stirring process, mixing, and performing nitrogen protection after the mixing is finished;
after the nitrogen protection is finished, dropwise adding 36% concentrated hydrochloric acid, wherein heat is generated in the dropwise adding process, the temperature of a reaction system is required to be controlled to be 20-25 ℃, and stirring reaction is continued after the dropwise adding is finished;
pre-cooling 600ml of ethyl acetate solvent, wherein the pre-cooling temperature of the ethyl acetate is 0-5 ℃, dropwise adding the reaction liquid into the pre-cooled ethyl acetate after the reaction is finished to separate out solid, leaching the filtered solid by the pre-cooled ethyl acetate, and drying to obtain 259g of beta-nicotinamide riboside chloride, wherein the yield is 89.3%.
Comparative example one
Dissolving 350g of tetraacetylribose with 600ml of acetonitrile to prepare acetonitrile solution of ribose, adding 122g of nicotinamide solid into a reaction system to stir, adding 2220g of catalyst trifluoromethane sulfonate trimethyl silicone grease into the reaction system to mix, performing nitrogen protection after mixing, controlling the temperature to be 20-25 ℃, stirring to react, adding methanol and sodium formate to continue the reaction after the reaction is finished, and adding hydrochloric acid to wash after the reaction is finished;
pre-cooling 600ml of ethyl acetate solvent, wherein the pre-cooling temperature of the ethyl acetate is 0-5 ℃, the reaction liquid is dripped into the ethyl acetate which is pre-cooled, the solid is separated out after the reaction, the filtered solid is leached by the pre-cooled ethyl acetate, and the filtered solid is dried to obtain 213g of beta-nicotinamide riboside chloride, and the yield is 73.3%.
Comparative example two
Dissolving 400g of tetraacetylribose with 500ml of acetonitrile to prepare acetonitrile solution of ribose, adding 122g of nicotinamide solid into a reaction system to stir, adding 2220g of catalyst trifluoromethane sulfonate trimethyl silicone grease into the reaction system to mix, performing nitrogen protection after mixing, controlling the temperature to be 20-25 ℃, stirring to react, adding methanol and sodium formate to continue the reaction after the reaction is finished, and adding hydrochloric acid to wash after the reaction is finished;
pre-cooling 600ml of ethyl acetate solvent, wherein the pre-cooling temperature of the ethyl acetate is 0-5 ℃, the reaction liquid is dripped into the ethyl acetate which is pre-cooled, the solid is separated out after the reaction, the filtered solid is leached by the pre-cooled ethyl acetate, and then the filtered solid is dried to obtain 222g of beta-nicotinamide riboside chloride, and the yield is 76.3%.
The yield of the beta-nicotinamide riboside chloride prepared by the preparation method provided by the invention is shown in table 1:
table 1: yield of beta-nicotinamide riboside chloride
According to the first and fourth embodiments, when the solvent amount, ribose amount, triphenylphosphine amount and ethyl acetate solvent amount are the same, the solvent for dissolving ribose is changed to obtain the amount and yield of beta-nicotinamide riboside chloride with different mass, wherein when the solvent for dissolving ribose is acetonitrile, the amount and yield of beta-nicotinamide riboside chloride are higher than when the solvent is DMSO;
according to the first and fifth embodiments, when the solvent amount, ribose amount, triphenylphosphine amount and ethyl acetate solvent amount are the same, the amount and yield of beta-nicotinamide riboside chloride with different mass can be obtained by changing the solvent for dissolving ribose, wherein when the solvent for dissolving ribose is acetonitrile, the amount and yield of beta-nicotinamide riboside chloride are higher than when the solvent is DMF;
according to the first and sixth embodiments, when the solvent amount, ribose amount, triphenylphosphine amount and ethyl acetate solvent amount are the same, the amount and yield of beta-nicotinamide riboside chloride with different mass can be obtained by changing the solvent for dissolving ribose, wherein when acetonitrile is used as the solvent for dissolving ribose, the amount and yield of beta-nicotinamide riboside chloride are higher than when NMP is used as the solvent;
according to the first and seventh embodiments, when the solvent, the solvent amount, the ribose amount and the ethyl acetate solvent amount are the same, the triphenylphosphine amount is changed to obtain the beta-nicotinamide riboside chloride amount and the yield of different qualities, wherein when the triphenylphosphine amount is 262g, the beta-nicotinamide riboside chloride amount and the yield are higher than when the triphenylphosphine amount is 131 g;
according to the second and third examples, when the solvent, the solvent amount, the triphenylphosphine amount and the ethyl acetate solvent amount are the same, the amount of ribose is changed to obtain the amount and the yield of beta-nicotinamide riboside chloride with different mass, wherein the amount of ribose is 160g, and the amount and the yield of beta-nicotinamide riboside chloride are higher than those of ribose when the amount of ribose is 150 g.
Therefore, by changing the solvent for dissolving ribose, the triphenylphosphine amount and the ribose amount, the amount and the yield of the beta-nicotinamide riboside chloride can be improved.
The preparation method of the beta-nicotinamide riboside chloride comprises the steps of mixing acetonitrile solution of ribose, nicotinamide and a catalyst, dropwise adding concentrated hydrochloric acid after mixing, heating and stirring for reaction after the dropwise adding, dropwise adding the mixture into ethyl acetate after the reaction is finished to separate out crystals, filtering and drying to obtain the beta-nicotinamide riboside chloride, wherein the reaction process comprises the following steps:
the yields of β -nicotinamide riboside chloride prepared using the preparation method provided by the prior art are shown in table 2:
table 2: yield of beta-nicotinamide riboside chloride
The comparison shows that the raw material used by the beta-nicotinamide riboside chloride prepared by the preparation method is ribose, and the beta-nicotinamide riboside chloride prepared by the existing preparation method is deoxyribose, so that compared with the quality of the raw material used by the raw material, the beta-nicotinamide riboside chloride prepared by the existing preparation method is deoxyribose, the consumption of ribose is small, and the cost of the used material can be reduced.
The catalyst used by the beta-nicotinamide riboside chloride prepared by the preparation method is triphenylphosphine, the equivalent number is 1 equivalent, and the catalyst used by the beta-nicotinamide riboside chloride prepared by the existing preparation method is trifluoromethylsilicone triflate, and the equivalent number is 10 times of the equivalent, so that the cost of the beta-nicotinamide riboside chloride prepared by the preparation method is greatly reduced.
The yield of the beta-nicotinamide riboside chloride prepared by the preparation method is improved by more than ten percent compared with the yield of the beta-nicotinamide riboside chloride prepared by the existing preparation method, and the preparation method has great advantages.
In summary, the preparation method of the beta-nicotinamide riboside chloride provided by the invention comprises the steps of mixing acetonitrile solution of ribose, nicotinamide and a catalyst, dropwise adding concentrated hydrochloric acid after the mixing, heating and stirring to react after the dropwise adding, dropwise adding the mixture into ethyl acetate after the reaction is finished to precipitate crystals, filtering and drying to obtain the beta-nicotinamide riboside chloride, and the preparation method provided by the invention has the advantages of few process steps, simplicity in operation and higher yield.
It is noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (7)
1. The preparation method of the beta-nicotinamide riboside chloride is characterized by comprising the following steps of:
s1: dissolving ribose with solvent to prepare solvent solution of ribose, adding nicotinamide solid into the reaction system, stirring, adding catalyst triphenylphosphine in the stirring process, mixing, and performing nitrogen protection after mixing;
s2: after the nitrogen protection is finished, dropwise adding concentrated hydrochloric acid, wherein heat is generated in the dropwise adding process, the temperature of a reaction system is required to be controlled to be 20-25 ℃, and stirring reaction is continued after the dropwise adding is finished;
s3: the pre-cooled ethyl acetate solvent is prepared in advance, the pre-cooling temperature of the ethyl acetate is 0-5 ℃, after the reaction is finished, the reaction liquid is dripped into the pre-cooled ethyl acetate, because the polarity of nicotinamide riboside chloride is large, solids are separated out from the low-polarity solvent according to a similar compatibility principle, and the filtered solids are leached by the pre-cooled ethyl acetate and then dried to obtain the beta-nicotinamide riboside chloride.
2. The method for preparing the beta-nicotinamide riboside chloride according to claim 1, wherein the method comprises the following steps: in the S1, the molar ratio of ribose to nicotinamide in ribose solution is (1-1.2): 1.
3. the method for preparing the beta-nicotinamide riboside chloride according to claim 2, wherein the method comprises the following steps: in the S1, the mass volume ratio of nicotinamide to solvent is 1: (4-6).
4. The method for preparing the beta-nicotinamide riboside chloride according to claim 2, wherein the method comprises the following steps: in the step S1, the solvent is DMSO, DMF, NMP or acetonitrile.
5. A process for the preparation of β -nicotinamide riboside chloride according to claim 3, wherein: in the S1, the molar ratio of triphenylphosphine to nicotinamide is (0.5-1): 1.
6. the method for preparing beta-nicotinamide riboside chloride according to claim 4, wherein the method comprises the following steps: in the S2, the molar ratio of ribose in ribose solution to hydrochloric acid in concentrated hydrochloric acid is 1:1.1.
7. the method for preparing beta-nicotinamide riboside chloride according to claim 5, wherein the method comprises the following steps: in the step S3, the volume ratio of the ethyl acetate to the solvent is 1:1.
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