WO2021196349A1 - 烟酰胺核糖的有机酸盐及其组合物与制备方法 - Google Patents

烟酰胺核糖的有机酸盐及其组合物与制备方法 Download PDF

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WO2021196349A1
WO2021196349A1 PCT/CN2020/089566 CN2020089566W WO2021196349A1 WO 2021196349 A1 WO2021196349 A1 WO 2021196349A1 CN 2020089566 W CN2020089566 W CN 2020089566W WO 2021196349 A1 WO2021196349 A1 WO 2021196349A1
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acid
nicotinamide ribose
organic acid
organic
salt
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French (fr)
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杨超文
王蕾
宋家良
符定良
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Shenzhen Dieckmann Tech Co Ltd
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Shenzhen Dieckmann Tech Co Ltd
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Priority to ES20929580T priority Critical patent/ES3017586T3/es
Priority to KR1020227038347A priority patent/KR102591687B1/ko
Priority to NZ793910A priority patent/NZ793910B2/en
Priority to US17/595,192 priority patent/US11505570B2/en
Priority to EP20929580.7A priority patent/EP4130017B1/en
Priority to JP2022559562A priority patent/JP7319744B2/ja
Priority to CA3140065A priority patent/CA3140065C/en
Priority to AU2020440743A priority patent/AU2020440743B2/en
Publication of WO2021196349A1 publication Critical patent/WO2021196349A1/zh
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    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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    • C07C59/235—Saturated compounds containing more than one carboxyl group
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    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to an organic acid salt of nicotinamide ribose, a composition and a preparation method thereof.
  • Nicotinamide ribose is a derivative of vitamin B3 (also known as niacin).
  • NR has the functions of enhancing the body’s metabolism, preventing stem cell senescence, and maintaining stem cell function.
  • Supplementing NR through diet can prevent the development of liver cancer in mice and induce tumor regression, and no side effects have been found under high doses.
  • ⁇ -nicotinamide mononucleotide obtained by phosphorylation of ⁇ -nicotinamide ribose ( ⁇ -NR) is a synthetic substrate of coenzyme I in organisms.
  • ⁇ -NMN has anti-aging properties and regulates insulin It secretes and affects the activity of mRNA expression level. Therefore, ⁇ -NR and ⁇ -NMN have become hot compounds in the fields of drug development, regenerative medicine and skin care, and the market demand prospects are huge.
  • nicotinamide ribose exists in the form of cations (structure I), which is actually unstable and needs to form an ion pair with anions (structure II) to be stable.
  • the purpose of the present invention is to provide a novel organic acid salt of nicotinamide ribose that can exist stably.
  • Another object of the present invention is to provide a method for preparing the organic acid salt of nicotinamide ribose.
  • Another object of the present invention is to provide a composition containing an organic acid salt of nicotinamide ribose.
  • Another object of the present invention is to provide a method for preparing the composition.
  • An organic acid salt of nicotinamide ribose the organic acid selected from malic acid, tannic acid, eicosapentaenoic acid, docosahexaenoic acid, caffeic acid, trans-cinnamic acid, trans-4-hydroxy- Cinnamic acid, monosodium citrate, disodium citrate, citric acid, chlorogenic acid, gluconic acid, ferulic acid, royal jelly acid, nervonic acid, cichoric acid, rosmarinic acid, carnosic acid, niacin, adipic acid Acid, lauric acid, salicylic acid, monopotassium glycyrrhizinate, folic acid, chondroitin sulfate, potassium hydrogen tartrate, glutamic acid, aspartic acid.
  • the above organic acids are all organic acids or organic acid salts with at least one free carboxyl group and solid at room temperature.
  • the molar ratio of the nicotinamide ribose to the organic acid is 1:2.
  • the molar ratio of the nicotinamide ribose to the organic acid is 1:1.
  • organic acid is citric acid, malic acid, and royal jelly acid.
  • the preparation method of the organic acid salt of nicotinamide ribose under the protection of nitrogen, dissolve nicotinamide ribose in methanol, add organic acid, add methyl tert-butyl ether or ethyl acetate after stirring, continue to stir, filter, wash, Dry to obtain the product.
  • the composition of the organic acid salt of nicotinamide ribose includes the organic acid salt of nicotinamide ribose and a carrier.
  • the carrier is malic acid, tannic acid, eicosapentaenoic acid, docosahexaenoic acid, caffeic acid, Trans-cinnamic acid, trans-4-hydroxy-cinnamic acid, lactic acid, monosodium citrate, disodium citrate, citric acid, chlorogenic acid, gluconic acid, ferulic acid, royal jelly acid, nervonic acid, cichoric acid, Rosmarinic acid, carnosic acid, niacin, adipic acid, lauric acid, monopotassium glycyrrhizinate, folic acid, chondroitin sulfate, potassium bitartrate, salicylic acid, glycine, glutamic acid, alanine, arginine Acid, leucine,
  • the carrier is niacin, glutamic acid, royal jelly acid, and nervonic acid.
  • organic acid salt is malate of nicotinamide ribose.
  • the molar ratio of the organic acid salt of nicotinamide ribose to the carrier is 1:1.
  • the composition of the organic acid salt of nicotinamide ribose includes the organic acid salt of nicotinamide ribose and a carrier.
  • the carrier is microcrystalline cellulose or apple cider vinegar powder;
  • the molar ratio of acid is 1:2 or 1:1.
  • organic acid salt is malate or citrate of nicotinamide ribose.
  • the mass ratio of the organic acid salt of nicotinamide ribose and the carrier is 1:1.
  • the preparation method of the composition of the organic acid salt of nicotinamide ribose under the protection of nitrogen, the organic acid salt of nicotinamide ribose is ground and mixed with the carrier.
  • the organic acid salt of nicotinamide ribose of the present invention adopts more acidic organic acids. These organic acids have free carboxyl groups, which can provide lone pairs of electrons and form close ion pairs with the nitrogen positive ions of nicotinamide ribose.
  • the hydrophobicity of nicotinamide ribose has a very good stability effect on nicotinamide ribose, which improves the stability of nicotinamide ribose organic acid salt.
  • nicotinamide ribose and organic acid exist in a molar ratio of 1:2, one molecule of NR and two molecules of organic acid can exist stably. First, one molecule of organic acid forms an ion pair with NR, and then the other molecule of organic The acid and the basic amide in NR form a hydrogen bond due to the action of acid-base to carry out acid-base pairing, and the stability of nicotinamide ribose organic acid salt is further improved.
  • the organic acid salt of nicotinamide ribose is compounded with microcrystalline cellulose.
  • the microcrystalline cellulose has hydrophobicity and heat resistance, which can prevent the penetration of water and improve the stability of the organic acid salt to water.
  • Nicotinamide ribose can be converted into coenzyme nicotinamide adenine dinucleotide (NAD + , also called coenzyme I) that can transfer protons in the body.
  • NAD + participates in the body and energy metabolism, synthesizes ATP, repairs DNA and inhibits cell apoptosis. It is involved in many physiological reactions such as the decomposition of proteins, carbohydrates and fats.
  • the invention selects organic acids and apple cider vinegar powder that can participate in the above-mentioned metabolism and other physiological activities, and is compounded with nicotinamide ribose to form a composite nutritional additive, and each component can be complementary and coordinated to produce superimposed effects. Tests have proved that adding organic acid and apple cider vinegar powder as a carrier does not significantly affect the stability of NR organic acid salt, and this compound nutritional additive has potential application value.
  • nicotinamide ribose (0.0220mol, 1eq) in 60mL methanol, add anhydrous citric acid (0.0264mol, 1.2eq), stir for 2h to dissolve, add 75mL without Water methyl tert-butyl ether, continue to stir for 30 minutes, filter under nitrogen protection, rinse with anhydrous ether, and dry below -5°C to obtain the product (0.0123mol).
  • the product NRX contains nicotinamide ribose (NR) and citric acid (X). The molar ratio is 1:1; the yield: 55.91%.
  • NRX 2 contains nicotinamide ribose (NR) and citric acid (X) The molar ratio is 1:2; yield: 56.82%.
  • the amount of nicotinamide ribose and anhydrous citric acid is charged according to the molar ratio of 1:3.3, and the characterization data of the obtained product is the same, indicating that the product obtained is a product with a molar ratio of nicotinamide ribose (NR) to citric acid (X) of 1:2 NRX 2 .
  • NRX contains nicotinamide ribose (NR) and malic acid (X). The molar ratio is 1:1; the yield: 57%.
  • NRX 2 contains nicotinamide ribose (NR) and malic acid (X) The molar ratio is 1:2; yield: 60.51%.
  • the amount of nicotinamide ribose and anhydrous malic acid is charged according to the molar ratio of 1:3.3, and the characterization data of the obtained product is the same, indicating that the obtained product is a product with a molar ratio of nicotinamide ribose (NR) to malic acid (X) of 1:2 NRX 2 .
  • nicotinamide ribose (0.0400mol, 1eq) in 60mL methanol, add royal jelly acid (0.0860mol, 2.15eq), stir for 2h, slowly add 120mL anhydrous ethyl acetate Ester, continue to stir for 30min, filter under nitrogen protection, rinse with anhydrous ether, and dry below -5°C to obtain 12.5g of product (0.02mol).
  • the molar ratio of nicotinamide ribose (NR) to royal jelly acid (X) in product NRX 2 is 1:2; Yield: 50%.
  • nicotinamide ribose malate of Example 4 Under the protection of nitrogen, add 0.01 mol of nicotinamide ribose malate of Example 4 to 0.01 mol of niacin, and grind at low temperature (about 16°C, the same below) for about 10 minutes until the material is about 200 meshes, and 6.4 g of NR malic acid is obtained. A mixture of nicotinates.
  • nicotinamide ribose malate of Example 4 was added to 0.01 mol of glutamic acid, and ground at low temperature for about 10 minutes until the material was about 200 mesh, to obtain 6.65 g of a mixture of NR malate glutamate.
  • nicotinamide ribose malate of Example 4 was added to 0.01 mol of royal jelly acid, and ground at low temperature for about 10 minutes until the material was about 200 meshes to obtain 7.05 g of NR royal jelly malate mixture.
  • nicotinamide ribose malate of Example 4 was added to 0.01 mol of nervonic acid, and ground at low temperature for about 10 minutes until the material was about 200 meshes, and 8.85 g of NR malate nervate mixture was obtained.
  • nicotinamide ribose malate of Example 4 was added to 1 g of microcrystalline cellulose, and ground at low temperature for about 10 minutes until the material was about 200 mesh, to obtain 2 g of NR malate microcrystalline cellulose mixture.
  • nicotinamide ribose malate of Example 3 was added to 1 g of microcrystalline cellulose, and the mixture was ground at low temperature for about 10 minutes until the material was about 200 meshes to obtain 2 g of NR malate microcrystalline cellulose mixture.
  • nicotinamide ribose citrate of Example 2 was added to 1 g of microcrystalline cellulose, and the mixture was ground for about 10 minutes at low temperature until the material was about 200 meshes to obtain 2 g of NR citrate microcrystalline cellulose mixture.
  • nicotinamide ribose citrate of Example 1 Under the protection of nitrogen, 1 g of nicotinamide ribose citrate of Example 1 was added to 1 g of microcrystalline cellulose, and the mixture was ground at low temperature for about 10 minutes until the material was about 200 meshes to obtain 2 g of NR citrate microcrystalline cellulose mixture.
  • a nicotinamide ribose chloride salt with microcrystalline cellulose as a carrier was prepared.
  • Example 1 Example 2
  • Example 3 Example 4 Comparison 0 98.930 98.471 98.573 98.818 98.525 1 98.828 98.317 98.691 98.547 98.284 2 98.450 98.079 98.310 98.629 98.087 3 98.190 98.168 98.288 98.316 97.701 4 98.252 97.933 98.076 98.207 97.449 5 97.978 97.806 97.912 98.081 97.575 6 97.814 97.788 97.645 98.100 97.210 Decomposition rate 1.13% 0.69% 0.94% 0.73% 1.33%
  • Example 1 Example 2
  • Example 3 Example 4 Comparison 0 98.930 98.471 98.573 98.818 98.525 1 98.198 98.492 98.482 98.424 98.171 2 98.409 98.240 98.185 98.360 98.206 3 98.171 98.097 98.270 98.298 97.540 4 97.957 97.626 97.946 98.239 97.612 5 97.823 97.704 97.592 97.707 97.384 6 97.670 97.498 97.337 97.816 97.109 Decomposition rate 1.27% 0.99% 1.25% 1.01% 1.44%
  • Example 1 Comparing Example 1 with Example 2, Example 3 with Example 4, it is found that the molar ratio of NR and organic acid at 1:2 is more stable than the molar ratio of NR with organic acid at 1:1.
  • NR and organic acid exist in a molar ratio of 1:1, they prefer to exist in the form of ion pairs according to the electronic effect; when NR and organic acid are fed in a molar ratio of 1:2, according to HNMR, it is found that one molecule of NR and two molecules The organic acid of NR exists stably.
  • one molecule of organic acid forms an ion pair with NR, and then the other molecule of organic acid forms a hydrogen bond with the basic amide in NR due to the action of acid-base, and the acid-base pairing is helpful to improve The stability of the salt.
  • two molecules of acid can provide a stronger acidic environment, and the stronger the acidity, the better the stability of NR.
  • the acidity of NMN (nicotinamide mononucleotide) is stronger than NR, and the stability is much higher than that of NR.
  • NR and organic acid exist in a molar ratio of 1:2, the content of NR decreases, the influence of free hydroxyl and amide functional groups between molecules is weakened, and the stability increases.
  • Example 14 0 58.585 97.487 91.719 97.812 97.086 1 58.918 96.170 90.593 96.397 95.776 2 58.755 96.818 92.279 97.108 96.931 3 59.925 96.836 91.762 96.870 96.510 4 57.507 96.504 90.745 96.607 96.208 5 58.363 96.701 90.329 95.914 96.350 6 57.150 95.257 90.140 95.128 95.601 Decomposition rate 2.45% 2.29% 1.72% 2.74% 1.53%
  • organic acid salt of nicotinamide ribose is compounded with another organic acid or apple cider vinegar powder, although the stability is reduced, it is still acceptable. Therefore, the addition of organic acid and apple cider vinegar powder as a carrier does not significantly affect NR The stability of organic acid salts.
  • Organic acid or apple cider vinegar powder and nicotinamide ribose are compounded to form a compound nutritional additive. Each component can be complementary and coordinated to produce superimposed effects, which has potential application value.
  • Example 10 Example 11
  • Example 12 Example 13 Comparison 0 98.759 98.550 98.316 98.694 97.917 1 98.632 98.180 98.440 98.633 97.874 2 98.714 98.442 98.259 98.441 97.656 3 98.557 98.395 98.213 98.527 97.326 4 98.324 98.308 98.007 98.372 97.470 5 98.491 98.273 98.110 98.393 97.319 6 98.425 98.112 98.041 98.238 97.277 Decomposition rate 0.34% 0.45% 0.28% 0.46% 0.65%
  • Example 10 Example 11
  • Example 12 Example 13 Comparison 0 98.759 98.550 98.316 98.694 97.917 1 98.691 98.339 98.282 98.625 97.776
  • the stability of the NR organic acid salt with microcrystalline cellulose as the carrier is higher (Examples 10 to 13 are compared with Examples 1 to 4). Because microcrystalline cellulose has hydrophobicity and heat resistance, it can prevent the penetration of moisture. Although microcrystalline cellulose is added, the molar ratio of NR to organic acid is 1:2 (Examples 10, 12) is more stable than the molar ratio of NR to organic acid is 1:1 (Examples 11, 13); NR The stability of the malate or citrate compounded with microcrystalline cellulose is also better than the corresponding NR chloride salt compounded with microcrystalline cellulose (comparative example), which further supports the previous conclusion.

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Abstract

一种烟酰胺核糖的有机酸盐，所述有机酸选自苹果酸、柠檬酸、王浆酸等，烟酰胺核糖与有机酸的摩尔比为1：2或1：1。烟酰胺核糖的有机酸盐与载体复配的组合物，所述载体选自烟酸、谷氨酸、王浆酸、神经酸、微晶纤维素或苹果醋粉。采用了酸性更强的有机酸，这些有机酸与烟酰胺核糖形成紧密离子对，具有一定的疏水性，使得烟酰胺核糖的稳定性提升；载体可以防止水分渗入，提高有机酸盐对水的稳定性。

Description

烟酰胺核糖的有机酸盐及其组合物与制备方法 技术领域
本发明属于医药技术领域，具体涉及烟酰胺核糖的有机酸盐及其组合物与制备方法。
背景技术
烟酰胺核糖(NR)是维生素B3(也称为烟酸)的一种衍生物，大量研究表明NR具有增强机体的新陈代谢、防止干细胞衰老、维持干细胞功能等作用；在肝癌研究方面，结果显示，通过饮食补充NR能够阻止小鼠肝癌的发展，诱使肿瘤退缩，且在高剂量使用下尚未发现任何副作用。此外，β-烟酰胺核糖(β-NR)经磷酸化后得到的β-烟酰胺单核苷酸(NMN)是生物体内辅酶I的合成底物，研究表明β-NMN具有抗衰老、调节胰岛素分泌、并影响mRNA表达水平的活性，因此，β-NR和β-NMN已经成为药物开发、再生医学和护肤领域的热点化合物，市场需求前景巨大。
烟酰胺核糖的游离形式是以阳离子(结构I)形式存在，实际上是不稳定的，需要与阴离子形成离子对(结构II)才稳定。
Figure PCTCN2020089566-appb-000001
已有文献公开了烟酰胺核糖的氯盐，但是仍然不是很稳定，其对水、光、温度比较敏感。因此，为了方便NR的使用，拓展其用途范围，需要研究NR更稳定存在的形式。此外，目前NR的使用方式较为单一，不能与其他化合物起到互补作用。
发明内容
本发明的目的是提供一类新颖的能稳定存在的烟酰胺核糖的有机酸盐。
本发明的另一目的是提供烟酰胺核糖的有机酸盐的制备方法。
本发明的另一目的是提供一种包含烟酰胺核糖的有机酸盐的组合物。
本发明的另一目的是提供该组合物的制备方法。
为达到上述目的之一，本发明采用以下技术方案：
烟酰胺核糖的有机酸盐，所述有机酸选自苹果酸、鞣酸、二十碳五烯酸、二十二碳六烯酸、咖啡酸、反式肉桂酸、反式-4-羟基-肉桂酸、柠檬酸一钠、柠檬酸二钠、柠檬酸、绿原酸、葡萄糖酸、阿魏酸、王浆酸、神经酸、菊苣酸、迷迭香酸、鼠尾草酸、烟酸、己二酸、月桂 酸、水杨酸、甘草酸一钾、叶酸、硫酸软骨素、酒石酸氢钾、谷氨酸、天门冬氨酸。
以上有机酸都是带有至少一个游离羧基、而且常温下为固态的有机酸或者有机酸盐。
进一步地，所述烟酰胺核糖与有机酸的摩尔比为1：2。
进一步地，所述烟酰胺核糖与有机酸的摩尔比为1：1。
进一步地，所述有机酸为柠檬酸、苹果酸、王浆酸。
烟酰胺核糖的有机酸盐的制备方法：在氮气保护下，将烟酰胺核糖溶于甲醇，加入有机酸，搅拌后加入甲基叔丁基醚或乙酸乙酯，继续搅拌，经过滤、洗涤、干燥得到产物。
烟酰胺核糖的有机酸盐的组合物，包括烟酰胺核糖的有机酸盐和载体，所述载体为苹果酸、鞣酸、二十碳五烯酸、二十二碳六烯酸、咖啡酸、反式肉桂酸、反式-4-羟基-肉桂酸、乳酸、柠檬酸一钠、柠檬酸二钠、柠檬酸、绿原酸、葡萄糖酸、阿魏酸、王浆酸、神经酸、菊苣酸、迷迭香酸、鼠尾草酸、烟酸、己二酸、月桂酸、甘草酸一钾、叶酸、硫酸软骨素、酒石酸氢钾、水杨酸、甘氨酸、谷氨酸、丙氨酸、精氨酸、亮氨酸、异亮氨酸、缬氨酸、胱氨酸、半胱氨酸、甲硫氨酸、苏氨酸、丝氨酸、苯丙氨酸、酪氨酸、色氨酸、脯氨酸、羟脯氨酸、天门冬氨酸；所述有机酸盐如前所述，烟酰胺核糖与有机酸的摩尔比为1：2或1：1。
进一步地，所述载体为烟酸、谷氨酸、王浆酸、神经酸。
进一步地，所述有机酸盐为烟酰胺核糖的苹果酸盐。
进一步地，所述烟酰胺核糖的有机酸盐和载体的摩尔比为1：1。
烟酰胺核糖的有机酸盐的组合物，包括烟酰胺核糖的有机酸盐和载体，所述载体为微晶纤维素或苹果醋粉；所述有机酸盐如前所述，烟酰胺核糖与有机酸的摩尔比为1：2或1：1。
进一步地，所述有机酸盐为烟酰胺核糖的苹果酸盐或柠檬酸盐。
进一步地，所述烟酰胺核糖的有机酸盐和载体的质量比为1：1。
烟酰胺核糖的有机酸盐的组合物的制备方法：在氮气保护下，将烟酰胺核糖的有机酸盐与载体研磨混合即得。
本发明具有以下有益效果：
1、本发明的烟酰胺核糖的有机酸盐采用了酸性更强的有机酸，这些有机酸带有游离羧基，可以提供孤对电子，与烟酰胺核糖的氮正离子形成紧密离子对，具有一定的疏水性，对烟酰胺核糖起到非常好的稳定性效果，使得烟酰胺核糖有机酸盐的稳定性提升。
2、当烟酰胺核糖与有机酸以摩尔比1：2存在时，一分子的NR与两分子的有机酸可以稳定存在，首先一分子的有机酸与NR形成离子对，然后另一分子的有机酸与NR中呈碱性的酰胺由于酸碱作用形成氢键，进行酸碱配对，烟酰胺核糖有机酸盐的稳定性进一步提高。
3、将烟酰胺核糖的有机酸盐与微晶纤维素复配，微晶纤维素具有疏水性和耐热性，可以 防止水分渗入，提高有机酸盐对水的稳定性。
4、烟酰胺核糖在体内能转换成转递质子的辅酶烟酰胺腺嘌呤二核苷酸(NAD +，也称辅酶Ⅰ)，NAD +参与机体及能量代谢、合成ATP、修复DNA、抑制细胞凋亡，参与蛋白质、碳水化合物和脂肪等化合物的分解等众多的生理反应。本发明选择能够参与以上代谢等生理活动的有机酸、苹果醋粉，与烟酰胺核糖复配成复合营养添加剂，各组分可以互补、协调，产生叠加的效果。经试验证实，加入有机酸、苹果醋粉作为载体没有显著影响NR有机酸盐的稳定性，这种复合营养添加剂具有潜在的应用价值。
具体实施方式
下面结合具体实施例对本发明做进一步的说明。以下份数，均指重量份。
实施例1
烟酰胺核糖柠檬酸盐(1：1)的制备
在氮气保护下，温度为-10～-5℃，将烟酰胺核糖(0.0220mol，1eq)溶于60mL甲醇，加入无水柠檬酸(0.0264mol，1.2eq)，搅拌2h溶清，加入75mL无水甲基叔丁基醚，继续搅拌30min,氮气保护下过滤、无水乙醚漂洗，-5℃以下干燥得产物(0.0123mol)，产物NRX中烟酰胺核糖(NR)与柠檬酸(X)的摩尔比为1：1；收率：55.91％。
表征数据：
HNMR(400MHz,MeOD):δ9.72(s,1H),9.42-9.43(d,1H),9.01-9.03(d,1H),8.25-8.30(m,1H),6.18-6.19(d,1H),4.42-4.464(m,2H),4.30-4.32(t,1H),4.01-4.05(dd,1H)，3.85-3.89(dd,1H),2.67-2.79(q,4H)；
MS(ESI+):254.96【M-1】,MS(ESI-):191.12【M-1】；
IR(KBr)ν max 3412,2940,2375,1692,1612,1516,1395,1232,1098,894,677,622cm -1。
实施例2
烟酰胺核糖柠檬酸盐(1：2)的制备
在氮气保护下，温度为-10～-5℃，将烟酰胺核糖(0.0220mol，1eq)溶于60mL甲醇，加入无水柠檬酸(0.0495mol.2.25eq)，搅拌2h溶清，加入150mL无水甲基叔丁基醚，继续搅拌30min,氮气保护下过滤、无水乙醚漂洗，-5℃以下干燥得产物(0.0125mol)，产物NRX 2中烟酰胺核糖(NR)与柠檬酸(X)的摩尔比为1：2；收率：56.82％。
表征数据：
HNMR(400MHz,MeOD):δ9.73(s,1H),9.43-9.45(d,1H),9.04-9.06(d,1H),8.27-8.32(m,1H),6.20-6.21(d,1H),4.43-4.45(m,2H),4.30-4.33(t,1H),4.02-4.05(d,1H)，3.85-3.89(d,1H),2.74-2.86(q,8H)；
MS(ESI+):254.97【M-1】,MS(ESI-):191.16【M-1】；
IR(KBr)ν max 3425,2929,2370,1697,1624,1516,1394,1219,1097,893,678,623cm -1。
将烟酰胺核糖与无水柠檬酸的用量按照摩尔比1:3.3投料，所得产物的表征数据一样，说明得到的是烟酰胺核糖(NR)与柠檬酸(X)摩尔比为1：2的产物NRX 2。
实施例3
烟酰胺核糖苹果酸盐(1：1)的制备
在氮气保护下，温度为-10～-5℃，将烟酰胺核糖(0.0195mol,1eq)溶于60mL甲醇，加入无水苹果酸(0.0234mol，1.2eq)，搅拌2h溶清，加入100mL无水甲基叔丁基醚，继续搅拌30min,氮气保护下过滤、无水乙醚漂洗，-5℃以下干燥得产物(0.01334mol)，产物NRX中烟酰胺核糖(NR)与苹果酸(X)的摩尔比为1：1；收率：57％。
表征数据：
HNMR(400MHz,MeOD):δ9.72(s,1H),9.42-9.44(d,1H),9.02-9.04(d,1H),8.25-8.29(t,1H),6.18-6.19(d,1H),4.41-4.44(m,2H),4.26-4.30(m,2H),3.99-4.03(dd,1H)，3.83-3.87(dd,1H),2.49-2.80(dd,2H)；
MS(ESI+):254.96【M-1】,MS(ESI-):133.04【M-1】；
IR(KBr)ν max3379,2937,1691,591,1100,677,6cm -1。
实施例4
烟酰胺核糖苹果酸盐(1：2)的制备
在氮气保护下，温度为-10～-5℃，将烟酰胺核糖(0.0195mol,1eq)溶于45mL甲醇，加入无水苹果酸(0.043875mol，2.25eq)，搅拌2h溶清，加入80mL无水甲基叔丁基醚，继续搅拌30min,氮气保护下过滤、无水乙醚漂洗，-5℃以下干燥得产物(0.0118mol)，产物NRX 2中烟酰胺核糖(NR)与苹果酸(X)的摩尔比为1：2；收率：60.51％。
表征数据：
HNMR(400MHz,MeOD):δ9.73(s,1H),9.43-9.45(d,1H),9.04-9.06(d,1H),8.27-8.31(m,1H),6.19-6.20(d,1H),4.43-4.45(m,2H),4.31-4.34(m,3H),4.01-4.05(dd,1H)，3.85-3.89(dd,1H),2.53-2.83(dd,4H)；
MS(ESI+):254.94【M-1】,MS(ESI-):133.03【M-1】；
IR(KBr)ν max3409，2940，1698，1580，1411，1293，1181，1098，1028，658cm -1。
将烟酰胺核糖与无水苹果酸的用量按照摩尔比1:3.3投料，所得产物的表征数据一样，说明得到的是烟酰胺核糖(NR)与苹果酸(X)摩尔比为1：2的产物NRX 2。
实施例5
烟酰胺核糖王浆酸盐(1：2)的制备
在氮气保护下，温度为-10～-5℃，将烟酰胺核糖(0.0400mol,1eq)溶于60mL甲醇，加入王浆酸(0.0860mol,2.15eq)，搅拌2h，缓慢加入120mL无水乙酸乙酯，继续搅拌30min,氮气保护下过滤、无水乙醚漂洗，-5℃以下干燥得12.5g产物(0.02mol)，产物NRX 2中烟酰胺核糖(NR)与王浆酸(X)的摩尔比为1：2；收率：50％。
表征数据：
HNMR(400MHz,MeOD):δ9.73(s,1H),9.44(s,1H),9.04-9.05(d,1H),8.30(m,1H),6.58-6.66(m,2H),6.18(m,1H),5.81-5.85(d,2H),4.92(m,2H),4.31-4.43(t,1H),3.85-4.05(dd,2H),3.54-3.57(t,4H),2.13-2.18(m,4H),1.51-1.56(m,4H),1.45-1.49(m,4H),1.37(m,12H)；
MS(ESI+):254.96【M-】,MS(ESI-):185.23【M-1】；
IR(KBr)ν max3384，2924，1705，1654，1555，1421，1389，1187，1098，1053，977，869，677cm -1。
实施例6
以烟酸为载体的烟酰胺核糖苹果酸盐的制备
在氮气保护下，将0.01mol实施例4的烟酰胺核糖苹果酸盐加入0.01mol烟酸中，低温(大约16℃，下同)研磨10min左右，至物料大约200目，得到6.4g NR苹果酸烟酸盐的混合物。
IR(KBr)ν max3409，2927，1695，1584，1398，1319，1101，1028，747，677，636cm -1。
实施例7
以谷氨酸为载体的烟酰胺核糖苹果酸盐的制备
在氮气保护下，将0.01mol实施例4的烟酰胺核糖苹果酸盐加入0.01mol谷氨酸中，低温研磨10min左右，至物料大约200目，得到6.65g NR苹果酸谷氨酸盐的混合物。
IR(KBr)ν max3415，2937，1692，1593，1404，1092，1028，670cm -1。
实施例8
以王浆酸为载体的烟酰胺核糖苹果酸盐的制备
在氮气保护下，将0.01mol实施例4的烟酰胺核糖苹果酸盐加入0.01mol王浆酸中，低温研磨10min左右，至物料大约200目，得到7.05g NR苹果酸王浆酸盐的混合物。
IR(KBr)ν max3437，2934，1698，1651，1401，1095，684cm -1。
实施例9
以神经酸为载体的烟酰胺核糖苹果酸盐的制备
在氮气保护下，将0.01mol实施例4的烟酰胺核糖苹果酸盐加入0.01mol神经酸中，低温 研磨10min左右，至物料大约200目，得到8.85g NR苹果酸神经酸盐的混合物。
IR(KBr)ν max3415，2924，1695，1465，1418，1290，1098，728，674cm -1。
实施例10
以微晶纤维素为载体的烟酰胺核糖苹果酸盐的制备
在氮气保护下，将1g实施例4的烟酰胺核糖苹果酸盐加入1g微晶纤维素中，低温研磨10min左右，至物料大约200目，得到2g NR苹果酸盐微晶纤维素的混合物。
IR(KBr)ν max3425，2930，1688，1644，1513，1395，1095，1018，667cm -1。
实施例11
以微晶纤维素为载体的烟酰胺核糖苹果酸盐的制备
在氮气保护下，将1g实施例3的烟酰胺核糖苹果酸盐加入1g微晶纤维素中，低温研磨10min左右，至物料大约200目，得到2g NR苹果酸盐微晶纤维素的混合物。
IR(KBr)ν max3365，2906，1695，1591，1396，1099，675cm -1。
实施例12
以微晶纤维素为载体的烟酰胺核糖柠檬酸盐的制备
在氮气保护下，将1g实施例2的烟酰胺核糖柠檬酸盐加入1g微晶纤维素中，低温研磨10min左右，至物料大约200目，得到2g NR柠檬酸盐微晶纤维素的混合物。
IR(KBr)ν max 3437,2927,2378,1740,1698,1641,,1513,1398,1111，897,671cm -1。
实施例13
以微晶纤维素为载体的烟酰胺核糖柠檬酸盐的制备
在氮气保护下，将1g实施例1的烟酰胺核糖柠檬酸盐加入1g微晶纤维素中，低温研磨10min左右，至物料大约200目，得到2g NR柠檬酸盐微晶纤维素的混合物。
IR(KBr)ν max 3415,2921,2368,1698,1625,1513,1401,1098,894,670,619cm -1。
实施例14
以苹果醋粉为载体的烟酰胺核糖苹果酸盐的制备
在氮气保护下，将1g实施例4的烟酰胺核糖苹果酸盐加入1g苹果醋粉(10％)中，低温研磨10min左右，至物料大约200目，得到2g NR苹果酸盐苹果醋粉的混合物。
IR(KBr)ν max3406，2930，1692，1584，1408，1092，1028，674cm -1。
对比例
烟酰胺核糖氯盐的制备
在氮气保下，温度为-10～-5℃，将烟酰胺核糖(0.0220mol，1eq)溶于50mL甲醇,然后滴 加17％的氯化氢甲醇溶液10g，搅拌溶清，加入1g活性碳搅拌1h,过滤,滤液加入150mL无水甲基叔丁基醚搅拌30min,氮气保护下过滤、无水乙醚漂洗，-5℃以下干燥得8g产物。
按照实施例10的方法制成以微晶纤维素为载体的烟酰胺核糖氯盐。
表征数据：
HNMR(400MHz,MeOD)：9.72(s,1H),9.44-9.46(d,1H),9.05-9.07(d,1H),8.29-8.33(t,1H),6.22-6.23(d,1H),4.45-4.47(t,1H),4.41-4.43(q,1H),4.31-4.33(t,1H),3.99-4.03(d,1H)，3.84-3.88(d,1H)。
IR(KBr)ν max3336，2935，1687，1616，1400，1100，675cm -1。
稳定性测试
一、样品准备
1、将实施例1～4、实施例10～13和对比例的产物分装入13个瓶中，每瓶50mg，充入氮气，密封，先测试一瓶(初始样品)，另外12瓶，分两组保存，每组6瓶，按照测试次序标出1～6。然后分别在2～8℃和-20℃保存，每月定期测试一个样品。
2、将实施例6～9、实施例14的产物分装入7个瓶中，每瓶50mg，充入氮气，密封，先测试一瓶(初始样品)，另外6瓶，按照测试次序标出1～6，然后分在2～8℃保存，每月定期测试一个样品。
二、测试样品溶液配制
每次取一瓶样品，用5mL或10mL的容量瓶，配制成5mL或10mL溶液，过滤膜，准备HPLC测试样品纯度。
三、HPLC测试
流动相：等度洗脱5％水(0.1％甲酸)+95％甲醇(0.1％甲酸)
波长：254nm
温湿度：23.0℃，54％RH
样品溶解：甲醇溶解
色谱柱：ODS-2，4.6*250mm，5μm，压力恒定在12-13Mpa
流量：1.0mL/min
进样量：5μL
运行时间：≥15min
四、分解率＝(初始样品纯度-6号样品纯度)/初始样品纯度×100％
表1(-20℃)
时间(月) 实施例1 实施例2 实施例3 实施例4 对比例
0 98.930 98.471 98.573 98.818 98.525
1 98.828 98.317 98.691 98.547 98.284
2 98.450 98.079 98.310 98.629 98.087
3 98.190 98.168 98.288 98.316 97.701
4 98.252 97.933 98.076 98.207 97.449
5 97.978 97.806 97.912 98.081 97.575
6 97.814 97.788 97.645 98.100 97.210
分解率 1.13％ 0.69％ 0.94％ 0.73％ 1.33％
表2(2～8℃)
时间(月) 实施例1 实施例2 实施例3 实施例4 对比例
0 98.930 98.471 98.573 98.818 98.525
1 98.198 98.492 98.482 98.424 98.171
2 98.409 98.240 98.185 98.360 98.206
3 98.171 98.097 98.270 98.298 97.540
4 97.957 97.626 97.946 98.239 97.612
5 97.823 97.704 97.592 97.707 97.384
6 97.670 97.498 97.337 97.816 97.109
分解率 1.27％ 0.99％ 1.25％ 1.01％ 1.44％
由表1、表2可知，温度越低，烟酰胺核糖的盐稳定性越好；烟酰胺核糖的苹果酸盐和柠檬酸盐(无论摩尔比是1：1还是1：2)均优于烟酰胺核糖氯盐(对比例)，这是因为苹果酸、柠檬酸能与NR形成致密离子对，具有一定的疏水性，从而提升了稳定性。
比较实施例1与实施例2，实施例3与实施例4，发现NR与有机酸以摩尔比1：2存在比NR与有机酸以摩尔比1：1更加稳定。当NR与有机酸以摩尔比1：1存在时，根据电子效应，优先以离子对形式存在；当NR与有机酸以摩尔比1：2投料时，根据HNMR发现，一分子的NR与两分子的有机酸稳定存在，首先一分子的有机酸与NR形成离子对，然后另一分子的有机酸与NR中呈碱性的酰胺由于酸碱作用形成氢键，进行酸碱配对，有助于改善盐的稳定性。另外，两分子的酸可以提供更强的酸性环境，而酸性越强，NR的稳定性越好，比如NMN(烟酰胺单核苷酸)的酸性比NR强，稳定性比NR高很多。再者，NR与有机酸以摩尔比1：2存在时，NR的含量降低，分子之间游离羟基和酰胺官能团的影响减弱，稳定 性上升。
表3(2～8℃)
时间(月) 实施例6 实施例7 实施例8 实施例9 实施例14
0 58.585 97.487 91.719 97.812 97.086
1 58.918 96.170 90.593 96.397 95.776
2 58.755 96.818 92.279 97.108 96.931
3 59.925 96.836 91.762 96.870 96.510
4 57.507 96.504 90.745 96.607 96.208
5 58.363 96.701 90.329 95.914 96.350
6 57.150 95.257 90.140 95.128 95.601
分解率 2.45％ 2.29％ 1.72％ 2.74％ 1.53％
烟酰胺核糖的有机酸盐与另一种有机酸或苹果醋粉复配后，虽然稳定性有所下降，但是仍然是可以接受的，因此，加入有机酸、苹果醋粉作为载体没有显著影响NR有机酸盐的稳定性。有机酸或苹果醋粉与烟酰胺核糖复配成复合营养添加剂，各组分可以互补、协调，产生叠加的效果，有潜在的应用价值。
表4(-20℃)
时间(月) 实施例10 实施例11 实施例12 实施例13 对比例
0 98.759 98.550 98.316 98.694 97.917
1 98.632 98.180 98.440 98.633 97.874
2 98.714 98.442 98.259 98.441 97.656
3 98.557 98.395 98.213 98.527 97.326
4 98.324 98.308 98.007 98.372 97.470
5 98.491 98.273 98.110 98.393 97.319
6 98.425 98.112 98.041 98.238 97.277
分解率 0.34％ 0.45％ 0.28％ 0.46％ 0.65％
表5(2～8℃)
时间(月) 实施例10 实施例11 实施例12 实施例13 对比例
0 98.759 98.550 98.316 98.694 97.917
1 98.691 98.339 98.282 98.625 97.776
2 98.506 98.031 98.326 98.458 98.015
3 98.239 98.274 98.028 98.083 97.693
4 98.317 97.932 97.805 98.121 97.542
5 98.342 97.786 97.734 97.833 97.380
6 98.251 97.875 97.782 98.017 97.154
分解率 0.51％ 0.68％ 0.54％ 0.69％ 0.78％
将烟酰胺核糖的有机酸与微晶纤维素复配后，以微晶纤维素为载体的NR有机酸盐的稳定性更高(实施例10～13相比实施例1～4)，这是因为微晶纤维素具有疏水性和耐热性，可以防止水分渗入。尽管都加入了微晶纤维素，但是NR与有机酸以摩尔比1：2存在(实施例10、12)比NR与有机酸以摩尔比1：1(实施例11、13)更加稳定；NR的苹果酸盐或柠檬酸盐与微晶纤维素复配后稳定性也好于相应的NR氯盐复配微晶纤维素(对比例)，这进一步佐证了之前的结论。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何属于本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求的保护范围为准。

Claims (10)

  1. 烟酰胺核糖的有机酸盐，其特征在于，所述有机酸选自苹果酸、鞣酸、二十碳五烯酸、二十二碳六烯酸、咖啡酸、反式肉桂酸、反式-4-羟基-肉桂酸、柠檬酸一钠、柠檬酸二钠、柠檬酸、绿原酸、葡萄糖酸、阿魏酸、王浆酸、神经酸、菊苣酸、迷迭香酸、鼠尾草酸、烟酸、己二酸、月桂酸、水杨酸、甘草酸一钾、叶酸、硫酸软骨素、酒石酸氢钾、谷氨酸、天门冬氨酸。
  2. 根据权利要求1所述的烟酰胺核糖的有机酸盐，其特征在于，所述烟酰胺核糖与有机酸的摩尔比为1：2。
  3. 根据权利要求1所述的烟酰胺核糖的有机酸盐，其特征在于，所述烟酰胺核糖与有机酸的摩尔比为1：1。
  4. 根据权利要求1～3任意一项所述的烟酰胺核糖的有机酸盐，其特征在于，所述有机酸为柠檬酸、苹果酸、王浆酸。
  5. 权利要求1～3任意一项所述的烟酰胺核糖的有机酸盐的制备方法，其特征在于，在氮气保护下，将烟酰胺核糖溶于甲醇，加入有机酸，搅拌后加入甲基叔丁基醚或乙酸乙酯，继续搅拌，经过滤、洗涤、干燥得到产物。
  6. 烟酰胺核糖的有机酸盐的组合物，其特征在于，包括烟酰胺核糖的有机酸盐和载体，所述载体为苹果酸、鞣酸、二十碳五烯酸、二十二碳六烯酸、咖啡酸、反式肉桂酸、反式-4-羟基-肉桂酸、乳酸、柠檬酸一钠、柠檬酸二钠、柠檬酸、绿原酸、葡萄糖酸、阿魏酸、王浆酸、神经酸、菊苣酸、迷迭香酸、鼠尾草酸、烟酸、己二酸、月桂酸、甘草酸一钾、叶酸、硫酸软骨素、酒石酸氢钾、水杨酸、甘氨酸、谷氨酸、丙氨酸、精氨酸、亮氨酸、异亮氨酸、缬氨酸、胱氨酸、半胱氨酸、甲硫氨酸、苏氨酸、丝氨酸、苯丙氨酸、酪氨酸、色氨酸、脯氨酸、羟脯氨酸、天门冬氨酸；所述有机酸盐如权利要求1～3任意一项所述。
  7. 根据权利要求6所述的烟酰胺核糖的有机酸盐的组合物，其特征在于，所述载体为烟酸、谷氨酸、王浆酸、神经酸，所述有机酸盐为烟酰胺核糖的苹果酸盐。
  8. 烟酰胺核糖的有机酸盐的组合物，其特征在于，包括烟酰胺核糖的有机酸盐和载体，所述载体为微晶纤维素或苹果醋粉；所述有机酸盐如权利要求1～3任意一项所述。
  9. 根据权利要求8所述的烟酰胺核糖的有机酸盐的组合物，其特征在于，所述有机酸盐为烟酰胺核糖的苹果酸盐或柠檬酸盐。
  10. 权利要求6～9任意一项所述的组合物的制备方法，其特征在于，在氮气保护下，将烟酰胺核糖的有机酸盐与载体研磨混合即得。
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