CN116063359A - Preparation method of coenzyme I related substances - Google Patents
Preparation method of coenzyme I related substances Download PDFInfo
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- CN116063359A CN116063359A CN202111277994.8A CN202111277994A CN116063359A CN 116063359 A CN116063359 A CN 116063359A CN 202111277994 A CN202111277994 A CN 202111277994A CN 116063359 A CN116063359 A CN 116063359A
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- resin
- reaction
- adenine dinucleotide
- nicotinamide adenine
- coenzyme
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- 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 title claims abstract description 27
- 229950006238 nadide Drugs 0.000 title claims abstract description 27
- 239000000126 substance Substances 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 239000011347 resin Substances 0.000 claims abstract description 34
- 229920005989 resin Polymers 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 10
- 150000001450 anions Chemical class 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 11
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- 230000001105 regulatory effect Effects 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000008346 aqueous phase Substances 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- 125000000129 anionic group Chemical group 0.000 description 2
- 230000002210 biocatalytic effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000006479 redox reaction Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 1
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108010035289 Glucose Dehydrogenases Proteins 0.000 description 1
- 101001110310 Lentilactobacillus kefiri NADP-dependent (R)-specific alcohol dehydrogenase Proteins 0.000 description 1
- 108010028658 Leucine Dehydrogenase Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000008558 metabolic pathway by substance Effects 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 108010028584 nucleotidase Proteins 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000275 quality assurance Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000019491 signal transduction 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
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
-
- 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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- 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 method for preparing related substances of coenzyme I. The invention takes aqueous solution of nicotinamide adenine dinucleotide as raw material, and the raw material is stirred and reacts in the presence of alkaline anion resin, and the high-purity related substance A is obtained after post-treatment. The preparation method disclosed by the invention has the advantages of no need of using organic solvent in the whole process of aqueous phase reaction, high yield and simple post-treatment, and related substances are directly prepared.
Description
Technical field:
the invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of related substances of coenzyme I.
The background technology is as follows:
nicotinamide adenine dinucleotide (coenzyme I, english name: nicotinamide adenine dinucleotide, NAD) is an indispensable small molecular compound in organisms, and participates in oxidation-reduction reaction, energy transfer, substance metabolism, signal transduction and other processes.
NAD is one of the indispensable coenzymes in modern biocatalytic reactions. Modern biocatalytic techniques mimic reactions in vivo that are performed using enzymes, the conditions of which are strictly based on metabolic characteristics in vivo, so chiral reduction as catalyzed by common leucine dehydrogenases, glucose dehydrogenases, and partial ketoreductases all require the assistance of NAD to complete the entire reaction. In the fields of foods and pharmaceuticals, redox reactions (in particular chiral reduction) are the most numerous, intensive and mature reactions, and therefore the demand for NAD is enormous.
The quality of food and medicine is directly related to the health and life safety of people, is a precondition guarantee for the safety, effectiveness and stability of food and medicine, and is one of key elements for quality assurance in impurity research and control. Therefore, intensive studies on the quality of the product and related substances are necessary, NAD is also important as an important substance participating in the reaction, and its own quality study is also important, and especially it may be degraded in the reaction to produce related substance A, so that it is necessary to be able to synthesize the substance for quality analysis study.
The preparation of a related substance A is disclosed in Chemistry-A European Journal,2019,25 (17), 4379-4389, the route being shown in Scheme 1.
The process uses NAD as raw material, and related substance A is required to be obtained under the action of nicotinamide adenine dinucleotide nucleotidase, and adenosine diphosphate can be produced by the process, and is difficult to separate and purify from related substance A.
Therefore, the synthesis method of the related substance A, which has higher product purity, simple preparation method and low cost, has very important application value in the process research of NAD and the quality control of the product.
The invention comprises the following steps:
the invention aims at overcoming the defects of the prior art and providing a preparation method of related substances A in coenzyme I, which is easy to operate and prepare.
The technical scheme adopted by the invention is as follows:
the method comprises the following specific steps: and (3) stirring the nicotinamide adenine dinucleotide aqueous solution in the presence of alkaline anion resin, and after the reaction is finished, carrying out post-treatment on the reaction solution to obtain the high-purity related substance A.
Further, the concentration of the aqueous solution of nicotinamide adenine dinucleotide is 1% -30%.
Further, the basic anionic resin is selected from the group consisting of WDA-OH powdered resin, D201 resin, D202 resin, D213 resin, JK206 resin, preferably WDA-OH powdered resin, D202 resin, JK206 resin.
Still further, the basic anionic resin is used in an amount of 20% to 400%, preferably 50% to 200% by weight of nicotinamide adenine dinucleotide.
Further, the reaction time of the reaction is 10 to 18 hours.
Further, the reaction temperature of the reaction is 40 to 50 ℃.
After the reaction is finished, the filtrate after the reaction liquid is filtered is eluted by water through a HZ-818 macroporous resin column and is concentrated.
Still further, the concentrate should be adjusted to a pH of 3.0.
Furthermore, the concentrated solution needs to be dripped into precooled absolute ethyl alcohol to separate out solid, and the precooling temperature is 5-10 ℃.
The preparation method disclosed by the invention has the beneficial effects that the whole process of aqueous phase reaction is carried out, an organic solvent is not needed, and related substances with high purity are directly prepared, so that the yield is high, and the post-treatment is simple.
Drawings
FIG. 1 LC-MS spectrum of example 1
FIG. 2 example 1 1 HNMR spectrogram
FIG. 3 HPLC profile of example 1
Detailed Description
The technical content of the present invention will be further described with reference to specific embodiments, for better understanding of the content of the present invention, but the scope of the present invention is not limited thereto.
EXAMPLE 1 catalytic preparation of related substance A with WDA-OH powdered resin
A500 mL reaction flask was charged with 20g of nicotinamide adenine dinucleotide and 300g of deionized water, and stirring was started. After the materials are dissolved, 10 percent sodium hydroxide solution is added dropwise to adjust the pH value to be between 8.0 and 9.0. Heating to 30 ℃, adding 15g of WDA-OH powdery resin, uniformly mixing, continuously heating to 40-45 ℃, and carrying out heat preservation reaction for 10 hours.
The reaction liquid is filtered, the filter cake is WDA-OH powdery resin, and the next batch of the resin is reused after the reaction liquid is recovered and activated. Passing the filtrate through HZ-818 macroporous resin column, eluting with water, tracking and detecting by HPLC, and collecting the filtrate with purity higher than that of the macroporous resin column98% of the elution solution is concentrated into 100mL, 10% of hydrochloric acid is used for adjusting the pH to 3.0, the solution is dripped into 1000mL of absolute ethanol precooled to 5-10 ℃, a large amount of solid is separated out, after stirring for 1h, the solution is filtered by suction, and vacuum drying is carried out at 30 ℃ for 20h, thus obtaining 15.2g of white solid product with the purity of 99.4%. The LC-MS spectrum is shown in figure 1, 1 HNMR spectra are shown in FIG. 2 and HPLC spectra are shown in FIG. 3.
EXAMPLE 2 catalytic preparation of related substance A with D202 resin
A1000 mL reaction flask was charged with 20g of nicotinamide adenine dinucleotide and 800g of deionized water, and stirring was started. After the materials are dissolved, 10% sodium hydroxide solution is added dropwise to adjust the pH value to 9.0-9.5. 15g of D202 resin is added, the temperature is raised to 45-50 ℃ and the reaction is carried out for 18h.
The reaction liquid is filtered, the filter cake is D202 resin, and the next batch of the reaction liquid is reused after being recovered and activated. Passing the filtrate through a HZ-818 macroporous resin column, eluting with water, tracking and detecting by HPLC, collecting the eluting solution with the purity higher than 98%, concentrating to 100mL, adjusting the pH to 3.0 by 10% hydrochloric acid, dripping into 1000mL of absolute ethyl alcohol precooled to 5-10 ℃, precipitating a large amount of solid, stirring for 1h, filtering, vacuum drying at 30 ℃ for 20h, and obtaining 13.2g of white solid product with the purity of 99.5%.
EXAMPLE 3 catalytic preparation of related substance A with JK206 resin
A1000 mL reaction flask was charged with 20g of nicotinamide adenine dinucleotide and 500g of deionized water, and stirring was started. After the materials are dissolved, 10 percent sodium hydroxide solution is added dropwise to adjust the pH value to be between 8.5 and 9.0. Heating to 30 ℃, adding 15g of JK206 resin, mixing uniformly, heating to 40-45 ℃ and reacting for 15h at a constant temperature.
The reaction liquid is filtered, the filter cake is JK206 resin, and the next batch of the filter cake is recycled after the filter cake is activated. Passing the filtrate through a HZ-818 macroporous resin column, eluting with water, tracking and detecting by HPLC, collecting the eluting solution with the purity higher than 98%, concentrating to 100mL, adjusting the pH to 3.0 by 10% hydrochloric acid, dripping into 1000mL of absolute ethyl alcohol precooled to 5-10 ℃, precipitating a large amount of solid, stirring for 1h, filtering, and vacuum drying at 30 ℃ for 20h to obtain 14.5g of white solid product.
Claims (5)
1. A method for preparing a coenzyme I related substance A, which is characterized by comprising the following reaction formula:
the reaction steps are as follows: and (3) stirring and reacting the nicotinamide adenine dinucleotide aqueous solution for 10-18 hours in the presence of alkaline anion resin, and then carrying out post-treatment on the reaction solution to obtain the related substance A. The alkaline anion resin is selected from WDA-OH powdery resin, D202 resin and JK206 resin, and the post-treatment is that the reaction liquid is eluted and concentrated by a HZ-818 macroporous resin column, the pH value is regulated, and then the reaction liquid is added into precooled absolute ethyl alcohol to separate out solid.
2. The method of manufacturing according to claim 1, wherein: the concentration of the aqueous solution of nicotinamide adenine dinucleotide is 1% -30%.
3. The method of manufacturing according to claim 1, wherein: the dosage of the alkaline anion resin is 20-400% of the weight of nicotinamide adenine dinucleotide.
4. The method of manufacturing according to claim 1, wherein: the reaction temperature of the reaction is 40-50 ℃.
5. The method of manufacturing according to claim 1, wherein: the pH of the concentrate is adjusted to 3.0.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111277994.8A CN116063359A (en) | 2021-10-30 | 2021-10-30 | Preparation method of coenzyme I related substances |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111277994.8A CN116063359A (en) | 2021-10-30 | 2021-10-30 | Preparation method of coenzyme I related substances |
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| CN116063359A true CN116063359A (en) | 2023-05-05 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102876759A (en) * | 2012-10-29 | 2013-01-16 | 尚科生物医药（上海）有限公司 | Preparation method of nicotinamide adenine dinucleotide |
| CN105481923A (en) * | 2015-12-30 | 2016-04-13 | 平光制药股份有限公司 | Preparation method of nicotinamide adenine dinucleotide |
| CN109575028A (en) * | 2018-12-21 | 2019-04-05 | 新乡医学院 | A method of adenosine is hydrolyzed using catalyzing cation exchange resin-separation coupling technology |
-
2021
- 2021-10-30 CN CN202111277994.8A patent/CN116063359A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102876759A (en) * | 2012-10-29 | 2013-01-16 | 尚科生物医药（上海）有限公司 | Preparation method of nicotinamide adenine dinucleotide |
| CN105481923A (en) * | 2015-12-30 | 2016-04-13 | 平光制药股份有限公司 | Preparation method of nicotinamide adenine dinucleotide |
| CN109575028A (en) * | 2018-12-21 | 2019-04-05 | 新乡医学院 | A method of adenosine is hydrolyzed using catalyzing cation exchange resin-separation coupling technology |
Non-Patent Citations (3)
| Title |
|---|
| BRUCE G. ET AL.,: "One-Step, Nonenzymatic Synthesis of O-Acetyl-ADP-ribose and Analogues from NAD and Carboxylates", THE JOURNAL OF ORGANIC CHEMISTRY, no. 72, 31 December 2011 (2011-12-31), pages 6465 - 6474 * |
| 夏笃祎: "《离子交换树脂》", 30 June 1983, 化学工业出版社, pages: 12 - 13 * |
| 李敏等: "强碱性阴离子树脂去除水体中邻苯二甲酸酯类", 云南地质, vol. 36, no. 4, 31 December 2017 (2017-12-31), pages 425 - 428 * |
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