CN110283221A - The preparation and purification method of heterocyclic compound - Google Patents
The preparation and purification method of heterocyclic compound Download PDFInfo
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- CN110283221A CN110283221A CN201810226169.7A CN201810226169A CN110283221A CN 110283221 A CN110283221 A CN 110283221A CN 201810226169 A CN201810226169 A CN 201810226169A CN 110283221 A CN110283221 A CN 110283221A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/048—Pyridine radicals
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
Abstract
The present invention relates to the synthesis of heterocyclic compound, and in particular to the preparation and purification method of nicotinamide riboside salt.The method includes the steps: it in the presence of a catalyst by compound B and ammonium salt, is dissolved in solvent 1, at appropriate temperatures, is passed through air containment reaction, filter out catalyst, the crude product obtained after reaction solution concentration after reaction；It is precipitated crystal after crude product is dissolved in solvent 2, filters, dries, obtain nicotinamide riboside salt shown in formula (I).Preparation and purification method process operation of the invention is simple, and reaction speed is fast, and product purity is high, and catalyst is recyclable to be applied, at low cost, environmental-friendly.It is suitable for commercially producing, has a good application prospect.
Description
Technical field
The present invention relates to the synthesis of heterocyclic compound, and in particular to the preparation and purification method of nicotinamide riboside salt.
Background technique
Nicotinamide riboside salt (structure is shown in Formulas I) has as natural, nutritional supplement tremendous potential, wherein chlorination
Nicotinamide riboside salt, English name Nicotinamide Riboside Chloride, abbreviation NR, CAS registration number 23111-00-
4, it is nicotinamide adenine dinucleotide (nicotinamideadenine dinucleotide, NAD+) pyridine-nucleosides before
Body.The forties in last century, people just had discovered that NR.Find that the promotion haemophilus influenzae purified from blood grows at that time
Growth factor (factorV) have 3 kinds of forms: nicotinamide adenine dinucleotide (NAD+), nicotinamide mononucleotide (NMN) and
Chlorination nicotinamide riboside salt (NR).And NR is so that substance (Gingrich, the W. " that this bacterial growth is most fast
Codehydrogenase I andotherpyridinium compounds as V factor for Haemophilus
Influenzae and Haemophilus parainfluenzae " .J.Bacteriol.1944,47,535-550.).
NAD+It is the essential multi-functional small molecules of organism, mainly as the important coenzyme and nucleosides of oxidoreducing enzyme
The source of Adenosine diphosphate glucoside (ADP ribosyl).It was found that many in experimental system be able to extend the albumen of life all
It is NAD+Dependence.NAD+Synthesis precursor think only niacin and nicotine (nicotinamide) always.Until 2004,
One new metabolic pathway is found.
A result of study (Bieganowki, P.and Brenner, C. " have been delivered on Cell in 2004
Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes
Establish a Preiss-Handler Independent Route to NAD+in Fungi and Humans"
.Cell, it 2004,117,495-502.), discloses in Yeast system, NR can be used as NAD+New precursor, moreover, people and
The nicotinamide riboside kinases of yeast can play a significant role in this metabolic pathway.All think all the time, NAD+It closes
It is NAD at enzyme+Necessary to synthesis, however experiment shows that NR can form NAD+The yeast growth of synzyme dependent/non-dependent.?
The discovery of NR in milk serum also prompts NR that may also contribute to NAD in human body+Horizontal rising.
It is published within 2012 article report (Canto, C.et.al. " the The NAD of Cell Metabolism+
Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects
Against High-Fat Diet-Induced Obesity " .CellMetabolism, 2012,15,838-847.), feeding
NR is supplemented in newborn zooblast and mouse tissue can increase NAD+Level activates silent message transcription regulatory factor 1 (SIRT1)
With silent message transcription regulatory factor 3 (SIRT3), oxidative metabolism speed is improved, the metabolism barrier for preventing high fat diet from inducing
Hinder.This article also indicates that NR can be used as nutritional supplement, improves metabolism and age-dependent disease.
S.Tanimori et al. report it is a kind of prepare nicotinamide riboside fluoroform sulphonate,
(Bioorg.Med.Chem.Lett.2002,12,1135–1137；J.Med.Chem.2007,50,6458–6461).This method
Using the sugar (1,2,3,5- tetra--O- acetyl group-β-D- ribofuranoside) and niacinamide of acetyl protection in acetonitrile solvent,
Under the conditions of TMSOTf, room temperature reaction prepares the nicotinamide riboside fluoroform sulphonate of acetyl protection, then again in methyl alcohol, alkalinity
Under the conditions of deprotection obtain nicotinamide riboside fluoroform sulphonate.Reaction process is as follows:
The document reports the method for preparing nicotinamide riboside fluoroform sulphonate, and obtained product is a pair of of various configuration
Mixture, α: β=13:87 of ratio, but the method for not reporting other anion salts.
P.Franchetti et al. in 2004 delivered an article (Bioorg.Med.Chem.Lett.2004,14,
4655-4658) preparation method of nicotinamide riboside has been reported.This method has used the sugar of acetyl protection and benzyl protection respectively
Sugar, at the same it is more dominant in order to control beta comfiguration in two configurations of α and β, first niacinamide trimethyl silicon substrate is protected, then again
Synthesis of glycoside key, is finally deprotected.Equally, the document only reports the method for preparing nicotinamide riboside fluoroform sulphonate, but
The method of other anion salts is not reported.
United States Patent (USP) US8106184 reports above-mentioned similar preparation method, another United States Patent (USP) US20070117765
(CN101360421) more easy " one kettle way " is reported.This method replaces niacinamide using nicotinate, molten in methylene chloride
In agent, under the catalysis of TMSOTf (1 equivalent), the sugar with protection generates nucleosides, and yield is greater than 90%, the shape of stereoselectivity
At β-isomers.Then ammonia hydroxide/methanol carries out ammonolysis, obtains target product, using preparation liquid phase purifying.One of this method is excellent
Gesture is not need the silanization protection of experience niacinamide, after the completion of reaction, solvent is directly evaporated off, is used for subsequent reactions, realizes
Multistep reaction " one kettle way ".But gained target product needs to purify using preparation liquid phase, cannot achieve industrialization.
World patent WO2015014722 also reports the method for preparing a variety of anion salts of nicotinamide riboside, and route is such as
Under:
Then this method removes acetyl and protects first by restoring the fluoroform sulphonate of nicotinamide riboside under alkaline condition
Shield, anion salt required for finally being prepared under the catalyst of carbon load.Reaction solution is after filtering out catalyst through freezing
Drying directly obtains product.In the patent, final step reacts item from the embodiment of the method description that compound B prepares finished product
Part is room temperature, the lower 1 hour end of reaction of condition of normal pressure.We have under this condition by patent Example condition is repeated several times
A large amount of starting material lefts, will extend to 24 hours the reaction time can not fully reacting, with extend the reaction time, impurity
Increase therewith.
Since this product is to thermally labile, it is difficult to obtain product by the way that water is concentrated under reduced pressure.Therefore, document is by freeze-drying
Afterwards, the product purity obtained is less than 50% (HPLC), and no any purification process of description in the patent, obtained product purity
It can not further increase.In addition, patented method needs the freeze-drying of use condition harshness, production cost is expensive.To sum up, the patent
The method is unable to fully reacting, and no purification process, product purity is low, and freeze-drying method is at high cost, therefore is not suitable for business
Metaplasia produces.
Summary of the invention
The object of the present invention is to provide a kind of preparation and purification methods of nicotinamide riboside salt shown in formula (I).
To achieve the goals above, the present invention provides the preparations of nicotinamide riboside salt shown in a kind of formula (I) and pure
Change method,
Wherein, X is selected from Cl, Br；
The preparation and purification method of nicotinamide riboside salt shown in the formula (I), comprising the following steps:
1) preparation method: in the presence of a catalyst by compound B and ammonium salt, being dissolved in solvent 1, at appropriate temperatures, leads to
Enter air containment reaction, filters out catalyst, the crude product obtained after reaction solution concentration after reaction；
2) purification process: precipitating crystal after crude product is dissolved in solvent 2, filter, dry, and obtains nicotinoyl shown in formula (I)
Amine nucleosides salt.
Preferably,
In step 1),
The solvent 1 is selected from one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, amylalcohol or water or a variety of；
The ammonium salt is selected from ammonium chloride, ammonium bromide, ammonium sulfate, ammonium acetate or ammonium formate；
The catalyst is selected from the precious metal catalyst using carbon containing noble metal catalyst or carbon-free carrier appendix
Agent；Preferably, the carbon containing noble metal catalyst is selected from palladium carbon, platinum carbon, rhodium carbon, ruthenium carbon；Carbon-free carrier appendix
Noble metal catalyst be selected from the palladium of silica gel load, the platinum of silica gel load, the rhodium of silica gel load, the ruthenium of silica gel load, calcium carbonate
The palladium of load, the platinum of calcium carbonate load, the rhodium of calcium carbonate load or the ruthenium of calcium carbonate load；
The catalyst amount is 1~20%, further preferably the 5~10% of compound B weight；
The reaction temperature of the reaction is 0~60 DEG C, further preferably 20~50 DEG C；
The reaction pressure of the reaction is 0.2~3MPa, further preferably 0.8~1.2MPa.
In step 2),
The solvent 2 includes one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, amylalcohol or water or a variety of；
The compound B and 2 mass volume ratio of solvent is about 1g:(3~30) mL, further preferably about 1g:(5~
10)mL。
In a preferred embodiment, the preparation of compound B is referred to patent WO2015014722 by following technique
Route preparation:
Using niacinamide and 1,2,3,5-Tetra-O-Acetyl-D-Ribose as starting material, in acetonitrile solvent, in Trimethylsilyl trifluoromethanesulfonate
(TMSOTf) under catalysis, the intermediate 1 of the formation beta comfiguration of stereoselectivity；
The intermediate 1 restores to obtain intermediate 2 by sodium hydrosulfite,
Intermediate 2 continue under the alkaline condition of sodium hydroxide deacetylation to get compound B.
Beneficial effect
The method provided in present patent application, reaction condition is mild, and aftertreatment technology is easy to operate, at low cost, the present invention
By closed compressive reaction method, make reaction conversion faster, reaction solution purity is higher.Literature method reaction is incomplete, reaction solution
It is more complicated；It is difficult to purify by crystallization.
Post-processing is avoided using being concentrated under reduced pressure using freeze-drying described in document.Purification process uses the side of direct crystallization
Method, product purity can be improved to 98% (HPLC) or more；Further, product purity reaches 99% or more.
The present invention passes through compressive reaction, and product purity is high in gained reaction solution, and post-processing can avoid column layer reported in the literature
Analysis or freeze-drying, purification process refining effect is good, only can obtain 98% (HPLC) or more by conventional crystallization technique
High purity product, suitable for commercially producing needs.
Specific embodiment
The following examples can make those skilled in the art that the present invention be more fully understood, but it is not limited in any way
The present invention.
Sample data is by following Instrument measuring: mass spectrographic measurement uses 6120 type mass spectrograph of Agilent；Nuclear magnetic resonance spectroscopy
(1HNMR 400 Nuclear Magnetic Resonance of BrukerAvance III) is used, using TMS as internal standard, chemical shift unit is ppm；Colour developing makes
Smart section WFH-203B ultraviolet analysis instrument for three purposed, wavelength are 254nm and 365nm.
Column chromatography silica gel (100-200 mesh, 300-400 mesh) is Haiyang Chemical Plant, Qingdao's production；TLC silica gel plate is Yantai
The HSGF-254 type tlc silica gel plate of plant produced, the chromatoplate that thin-layer chromatography uses are prefabricated with a thickness of 0.2 ± 0.03mm
The standby pre-prepared plate thickness of thin-layer chromatography used is 0.4-0.5mm；Ethyl alcohol, the reagents such as isopropanol are that analysis is pure purchased from An Naiji
Chemical Co., Ltd., agents useful for same and solvent unless otherwise indicated, are not specially treated.
Wherein the preparation method of compound B is referring to WO2015014722.
The preparation and purification of 1. chlorination nicotinamide riboside salt crude product of embodiment
50g compound B is dissolved in 500mL isopropanol, 10g ammonium chloride is then added, (wet product contains 5% palladium carbon of 1g
About 50%) water, is passed through air, control pressure to about 0.2MPa is stirred to react, about 20 hours in 20 DEG C, and monitoring is to having reacted
At.It is filtered to remove palladium carbon, filtrate adds active carbon decoloring, is concentrated under reduced pressure, and 500mL ethyl alcohol is added in obtained crude product, and stirring and crystallizing is taken out
Filter, filtration cakes torrefaction obtain 50g chlorination nicotinamide riboside salt solid, yield 89%, purity 99.4%.
1H-NMR(D2O,400MHz),9.46(s,1H),9.12(m,1H),8.83(m,1H),8.13(m,1H),6.11(d,
1H), 4.37 (t, 1H), 4.21 (m, 1H), 4.10 (m, 1H), 3.92 (m, 1H), 3.75 (m, 1H), mass spectrum m/z (ESI): 255.
The preparation and purification of 2. chlorination nicotinamide riboside salt of embodiment
10g compound B is dissolved in 200mL water, 2g ammonium chloride is then added, (wet product, water content is about for 5% platinum carbon of 1g
50%) it, is passed through air, pressure about 2.0MPa is stirred in 40 DEG C, and monitoring to reaction is completed, and about 20 hours.It is filtered to remove catalysis
Agent, filtrate add active carbon decoloring, are concentrated under reduced pressure, and 100mL isopropanol is added in obtained crude product, and stirring and crystallizing filters, and filter cake is dry
It is dry, obtain 8.9g chlorination nicotinamide riboside salt solid, yield 79%, purity 99.2%.
1H-NMR(D2O,400MHz),9.46(s,1H),9.12(m,1H),8.83(m,1H),8.13(m,1H),6.11(d,
1H), 4.37 (t, 1H), 4.21 (m, 1H), 4.10 (m, 1H), 3.92 (m, 1H), 3.75 (m, 1H), mass spectrum m/z (ESI): 255.
The preparation and purification of 3. chlorination nicotinamide riboside salt of embodiment
10g compound B is dissolved in 200mL methanol, 2g ammonium chloride, 1g 5% platinum carbon (wet product, water content is then added
About 50%), it is passed through air, until about 1.0MPa, is stirred in 30 DEG C, monitoring to reaction is completed, about 20 hours.Filtering, filtrate decompression
100mL ethyl alcohol is added in concentration, obtained crude product, and stirring and crystallizing filters, and filtration cakes torrefaction obtains 9.2g chlorination nicotinamide riboside
Salt solid, yield 82%, purity 98.5%.
1H-NMR(D2O,400MHz),9.46(s,1H),9.12(m,1H),8.83(m,1H),8.13(m,1H),6.11(d,
1H), 4.37 (t, 1H), 4.21 (m, 1H), 4.10 (m, 1H), 3.92 (m, 1H), 3.75 (m, 1H), mass spectrum m/z (ESI): 255.
The preparation and purification of 4. chlorination nicotinamide riboside salt of embodiment
10g compound B is dissolved in 200mL ethyl alcohol, 2g ammonium chloride, 1g 5% platinum carbon (wet product, water content is then added
About 50%), it is passed through air, until about 1.5MPa, is stirred in 50 DEG C, monitoring to reaction is completed, about 20 hours.Filtering, filtrate decompression
100mL isopropanol is added in concentration, obtained crude product, and stirring and crystallizing filters, and filtration cakes torrefaction obtains 6.9g chlorination nicotinamide riboside
Salt solid, yield 62%, purity 99.3%.
1H-NMR(D2O,400MHz),9.46(s,1H),9.12(m,1H),8.83(m,1H),8.13(m,1H),6.11(d,
1H), 4.37 (t, 1H), 4.21 (m, 1H), 4.10 (m, 1H), 3.92 (m, 1H), 3.75 (m, 1H), mass spectrum m/z (ESI): 255.
The preparation and purification of 5. bromination nicotinamide riboside salt of embodiment
10g compound B is dissolved in 200mL ethyl alcohol, then addition 3.7g ammonium bromide, and 5% platinum carbon of 1g (wet product, it is aqueous
About 50%) amount, is passed through air, until about 1.5MPa, is stirred in 20 DEG C, monitoring to reaction is completed.Filtering, filtrate decompression concentration, obtains
100mL isopropanol is added in the crude product arrived, and stirring and crystallizing filters, filtration cakes torrefaction, and it is solid to obtain 7.9g chlorination nicotinamide riboside salt
Body, yield 61%, purity 98.6%.
1H-NMR(D2O,400MHz),9.46(s,1H),9.12(m,1H),8.83(m,1H),8.13(m,1H),6.11(d,
1H), 4.37 (t, 1H), 4.21 (m, 1H), 4.10 (m, 1H), 3.92 (m, 1H), 3.75 (m, 1H), mass spectrum m/z (ESI): 255.
The preparation of 1. chlorination nicotinamide riboside salt of comparative example
1g compound B is dissolved in 100mL water, 2g ammonium chloride, 0.2g 5% platinum carbon (wet product, water content is then added
About 50%), it being passed through air bubbling to be reacted, stirring 24 hours or more, monitoring shows the generation of 37% product in HPLC, remaining
For unreacted raw material compound B.It needs to remove water by freeze-drying mode according to document.
The preparation of 2. chlorination nicotinamide riboside salt of comparative example
1g compound B is dissolved in 100mL methanol, then addition 2g ammonium chloride, and 5% platinum carbon of 0.2g (wet product, it is aqueous
About 50%) amount, is passed through air bubbling and is reacted, stirring 24 hours or more, monitoring showed the generation of 39% product in HPLC,
Remaining is unreacted compound B.Reaction solution is concentrated, grease is obtained, is added in ethyl alcohol and stirs, no solid is precipitated.
As a comparison, we also according to patent WO2015014722 carried out chlorination nicotinamide riboside salt preparation (see
Comparative example 1 and comparative example 2), the results showed that, according to reaction condition described in WO2015014722, reaction speed is very slow, raw
At product it is considerably less.And cannot be purified by crystallization, it is unable to get qualified products.And Examples 1 to 5 is added by closed
Reaction method to be pressed, makes reaction conversion faster, reaction solution purity is higher, also, post-processes and can avoid column chromatography or freeze-drying,
Purification process refining effect is good, and the high purity product of 98% (HPLC) or more can be only obtained by conventional crystallization technique, is fitted
For commercially producing needs.
Claims (10)
1. a kind of preparation and purification method of nicotinamide riboside salt shown in formula (I),
Wherein, X is selected from Cl, Br；
The preparation and purification method the following steps are included:
1) it preparation method: in the presence of a catalyst by compound B and ammonium salt, is dissolved in solvent 1, at appropriate temperatures, is passed through sky
Gas confined reaction filters out catalyst, the crude product obtained after reaction solution concentration after reaction；
2) purification process: precipitating crystal after crude product is dissolved in solvent 2, filter, dry, and obtains niacinamide core shown in formula (I)
Glycosides salt.
2. the preparation and purification method of nicotinamide riboside salt according to claim 1, which is characterized in that in step 1),
The solvent 1 is selected from one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, amylalcohol or water or a variety of.
3. the preparation and purification method of nicotinamide riboside salt according to claim 1, which is characterized in that in step 1),
The ammonium salt is selected from ammonium chloride, ammonium bromide, ammonium sulfate, ammonium acetate or ammonium formate.
4. the preparation and purification method of nicotinamide riboside salt according to claim 1, which is characterized in that in step 1),
The catalyst is selected from the noble metal catalyst using carbon containing noble metal catalyst or carbon-free carrier appendix.
5. the preparation and purification method of nicotinamide riboside salt according to claim 4, which is characterized in that in step 1),
The carbon containing noble metal catalyst is selected from palladium carbon, platinum carbon, rhodium carbon, ruthenium carbon；The noble metal of carbon-free carrier appendix is urged
Agent is selected from palladium, the carbon that the palladium of silica gel load, the platinum of silica gel load, the rhodium of silica gel load, the ruthenium of silica gel load, calcium carbonate load
The ruthenium of the platinum of sour calcium load, the rhodium of calcium carbonate load or calcium carbonate load.
6. the preparation and purification method of nicotinamide riboside salt according to claim 1, which is characterized in that in step 1),
The reaction temperature of the reaction is 0~60 DEG C, preferably 20~50 DEG C.
7. the preparation and purification method of nicotinamide riboside salt according to claim 1, which is characterized in that in step 1),
The reaction pressure of the reaction is 0.2~3MPa, preferably 0.8~1.2MPa.
8. the preparation and purification method of nicotinamide riboside salt according to claim 1, which is characterized in that in step 1),
The catalyst amount is 1~20%, preferably the 5~10% of compound B weight.
9. the preparation and purification method of nicotinamide riboside salt according to claim 1, which is characterized in that in step 2),
The solvent 2 includes one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, amylalcohol or water or a variety of.
10. the preparation and purification method of nicotinamide riboside salt according to claim 1, which is characterized in that in step 2),
The compound B and 2 mass volume ratio of solvent is 1:3~1:30g/mL, preferably 1:5~1:10g/mL.
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| CN111808156A (en) * | 2020-07-15 | 2020-10-23 | 许昌远志生物科技有限公司 | Beta-nicotinamide riboside chloride crystal form 1A and crystal form 1B and preparation method thereof |
| CN111848710A (en) * | 2020-08-20 | 2020-10-30 | 深圳市迪克曼科技开发有限公司 | Preparation method of nicotinamide ribose and reduction state and salt thereof |
| CN114276393A (en) * | 2022-01-27 | 2022-04-05 | 南京诺云生物科技有限公司 | Preparation process of beta-nicotinamide riboside chloride |
| CN116139928A (en) * | 2022-11-28 | 2023-05-23 | 上海巧坤化工科技有限公司 | Composite catalyst and preparation method and application thereof |
| CN116139928B (en) * | 2022-11-28 | 2024-02-13 | 上海巧坤化工科技有限公司 | Composite catalyst and preparation method and application thereof |
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