- New crystalline salts of nicotinamide riboside as food additives
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NR+ is a highly effective vitamin B3 type supplement due to its unique ability to replenish NAD+ levels. While NR+ chloride is already on the market as a nutritional supplement, its synthesis is challenging, expensive, and low yielding, making it cumbersome for large-scale industrial production. Here we report the novel crystalline NR+ salts, D/L/DL-hydrogen tartrate and D/L/DL-hydrogen malate. Their high-yielding, one-pot manufacture does not require specific equipment and is suitable for multi-ton scale production. These new NR+ salts seem ideal for nutritional applications due to their bio-equivalence compared to the approved NR+ chloride. In addition, the crystal structures of all stereoisomers of NR+ hydrogen tartrate and NR+ hydrogen malate and a comparison to the known NR+ halogenides are presented.
- Haase, Robert,Hery-Barranco, Adrian,Pala, Laura,Parris, Jaclyn,Schabert, Günter,Spingler, Bernhard,Spitz, Urs
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- Preparation method β - nicotinamide ribose chloride
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The invention belongs to the technical field of organic synthetic medicines, and particularly relates to a method for preparing β - nicotinamide ribose chloride. The method comprises the following steps: mixing a tetraacetylribose solution and a hydrogen chloride saturated solution, carrying out chlorination reaction to obtain a chlorination reaction solution, and I intermediate containing the structure shown first in the chlorination reaction solution. The chlorination reaction solution, the nicotinamide and first organic solvent are mixed to carry out nuclear saccharification reaction to obtain II intermediate with the structure shown 2nd. The II intermediate of the structure shown in Formula second the ammonia methanol solution and second organic solvent were mixed to conduct deacetyl reaction to obtain the β - nicotinamide ribose chloride. Β - nicotinamide ribose chloride prepared according to the preparation method provided by the invention has high yield.
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Paragraph 0039; 0078; 0082-0098
(2021/11/10)
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- Synthesis method of beta-nicotinamide riboside chloride
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The invention discloses a synthesis method of beta-nicotinamide riboside chloride. According to the method, TMSCl is used as a chlorination reagent, boron trifluoride diethyl ether is used as a catalyst, and a glycosylation reaction of tetraacetylribose and nicotinamide is catalyzed. The reaction conditions are mild, and the product yield is high; the used reagents are low in cost, easy to obtainand suitable for industrial production; the reaction conditions are relatively safe and environmentally friendly, the reaction process is simple, and ion exchange reaction is not needed; a reaction product is relatively easy to purify and separate, and high quality of the product can be ensured; and the reagents used in the reaction process are lower in cost, and the production cost can be reduced.
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Paragraph 0017; 0024-0029
(2021/03/11)
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- NMN intermediate NR chloride synthesis method
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The invention provides an intermediate synthesis method, and particularly relates to an NMN intermediate NR chloride synthesis method which is characterized in that D-ribose is used as a raw material, a certain temperature is controlled, an NR-sulfonyl hydrazine intermediate is prepared through a reaction with sulfonyl hydrazine under an acidic condition, chlorosuccinimide is further used for oxidative denitrification, and the NR-sulfonyl hydrazine intermediate reacts with nicotinate or nicotinamide, the NMN intermediate NR chloride is synthesized so that the cheaper source is provided for the starting material for synthesizing the NR chloride, the tedious step for synthesizing the NR chloride and the yield reduction caused by the low-efficiency ribose protection and deprotection step are avoided, the atom economy is high, and the industrial production is convenient.
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Paragraph 0053; 0059-0061; 0068-0069
(2021/05/29)
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- Novel synthesis method of nicotinamide ribose
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The invention discloses a novel synthesis method of nicotinamide ribose. According to the method, 2,3,4,5-tetrabenzoyloxy ribose is added into an alcoholic solution; acetyl chloride is dropwise added;chlorination reaction is performed; a chlorination product and nicotinamide are condensed; benzoyl is removed from a condensation product in sodium methoxide; stirring and purification are performedthrough an organic solvent; and crystallization is performed to obtain a finished product. The novel synthesis method has the advantages that the 2,3,4,5-tetrabenzoyloxy ribose is used as a starting material; ribose 2-benzoyl is selectively chloridized by the acetyl chloride; a product with beta-nicotinamide riboside as a main ingredient is generated; a catalyst is common and easy to obtain; the cost can be effectively reduced; the reaction design ingredients are simple; post treatment is simple; after deprotection, a protective agent and alpha impurities are removed by the organic solvent; and the high-purity finished product can be obtained through recrystallization.
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Paragraph 0022; 0052; 0054; 0055; 0057; 0058; 0060-0063
(2020/11/22)
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- METHODS OF SYNTHESIZING NICOTINAMIDE RIBOSIDE
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Provided herein are efficient and scalable methods for the synthesis of nicotinamide riboside from riboside triacetate. Also provided are compositions comprising nicotinamide riboside, and therapeutic methods employing nicotinamide riboside.
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Paragraph 0242; 0243; 0249-0251
(2020/05/29)
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- Efficient synthesis method of nicotinamide riboside (NR) chloride
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The invention discloses an efficient synthesis method of a nicotinamide riboside (NR) chloride. An acetyl-protected compound A on ribose ring hydroxyl is used as a raw material and oxidized directly to obtain a compound B, and acetyl is removed to obtain the NR chloride. The efficient synthesis method comprises the following synthesis steps: 1) adding the compound A to an autoclave, adding ammonium chloride, platinum carbon and ethanol, introducing oxygen, and carrying out stirring at room temperature until reaction ends; 2) recovering the platinum carbon by filtration, removing a solvent under reduced pressure, adding absolute ethyl alcohol, carrying out cooling to precipitate a white solid, and performing filtration and drying to obtain the compound B; and 3) adding the compound B in a three-neck bottle to be dissolved in ethanol, introducing ammonia, keep the temperature, cooling a reaction solution to precipitate a solid after the reaction, and performing filtration and drying to obtain the NR chloride. Oxidation is carried out after the ribose hydroxyl is protected by the acetyl, side reaction is reduced, so that the oxidation yield is greatly increased, meanwhile, the oxidation reaction is conducted with an oxygen pressurization manner, and the reaction efficiency is greatly improved.
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Paragraph 0024; 0026
(2020/06/04)
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- Synthesis method of beta-nicotinamide mononucleotide
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The invention discloses a synthesis method of beta-nicotinamide mononucleotide, and relates to the technical field of drug synthesis. The synthesis method mainly comprises the following steps of S1, mixing and reacting nicotinamide, hexamethyldisilazane and a catalyst I in a reaction kettle to obtain silanization-protected nicotinamide; S2, adding tetraacetyl ribose, a solvent, a catalyst II and methanol for reaction so as to generate nicotinamide triacetyl riboside; S3, adding methanol and n-propylamine to generate nicotinamide riboside; S4, adding trimethyl phosphate and phosphorus oxychloride to generate beta-nicotinamide mononucleotide; and S5, separating and purifying the beta-nicotinamide mononucleoside acid. According to the invention, a plurality of continuous steps are controlledto be carried out in one reaction container, and the steps of separating and purifying an intermediate are avoided, so that the method has the advantages of high yield and high production efficiency.
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Paragraph 0027; 0029; 0031
(2020/09/20)
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- Organic acid salt of nicotinamide ribose and composition and method of making same
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The invention belongs to the technical field of medicines, and discloses an organic acid salt of nicotinamide ribose, the organic acid is selected from malic acid, malic acid, royal jelly acid and thelike, and the molar ratio of nicotinamide ribose to the organic acid is 1: 2 or 1: 1. The invention also discloses a composition compounded by the organic acid salt of nicotinamide ribose and a carrier, wherein the carrier is selected from nicotinic acid, glutamic acid, royal jelly acid, nervonic acid, microcrystalline cellulose or apple vinegar powder. According to the invention, organic acids with stronger acidity are adopted, and the organic acids and nicotinamide ribose form tight ion pairs, so that certain hydrophobicity is obtained and the stability of nicotinamide ribose is improved; the carrier can prevent water from permeating, and the stability of the organic acid salt to water is improved.
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Paragraph 0105-0110
(2020/08/07)
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- Crystal form 1A and crystal form 1B of beta-nicotinamide ribose chloride and preparation method of crystal form 1A and crystal form 1B
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The invention discloses a crystal form 1A and a crystal form 1B of beta-nicotinamide ribose chloride and preparation methods of the crystal form 1A and the crystal form 1B. In an X-ray powder diffraction pattern, the crystal form 1A has diffraction peaks with 2 theta of 13.0+/-0.2 degrees, 14.0+/-0.2 degrees, 23.8+/-0.2 degrees, 24.5+/-0.2 degrees and 25.4+/-0.2 degrees. In an X-ray powder diffraction pattern, the crystal form 1B has diffraction peaks with 2 theta of 5.0+/-0.2 degrees, 15.6+/-0.2 degrees, 21.6+/-0.2 degrees and 26.4+/-0.2 degrees. These two crystal forms of nicotinamide ribosehave more advantageous properties including substance morphology, stability (e.g., low content of solvent residue, low hygroscopicity, storage stability, polymorph transformation stability), solubility, chemical purity, and the like. The change of the properties is more beneficial to industrial production of high-purity nicotinamide ribose, and a wide space is provided for development of dosage forms of nicotinamide ribose.
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Paragraph 0056; 0061-0074; 0078
(2020/11/02)
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- PROCESS FOR THE PREPARATION OF NICOTINAMIDE RIBOSIDE CHLORIDE DERIVATIVES
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It relates to a process for the preparation of nicotinamide riboside chloride of formula (I) wherein R1-R4 are as defined herein, comprising the following steps: a) reacting a riboside precursor wherein the hydroxyl groups at positions 1, 2, 3 and 5 of the ribose are protected with hydroxyl protective groups; with nicotinamide in the presence of a Lewis acid selected from SnCI4 and TiCI4 in an appropriate solvent, to give the corresponding protected nicotinamide riboside chloride compound, wherein the hydroxyl groups at positions 2, 3 and 5 are protected with hydroxyl protective groups; and b) removing the protective groups of the compound obtained in step a) to give a compound of formula (I). It also relates to a process for the preparation of the protected nicotinamide riboside chloride compound.
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Page/Page column 16
(2019/07/13)
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- (THIO)NICOTINAMIDE RIBOFURANOSIDE SALTS AND COMPOSITIONS, METHODS OF MAKING, AND USES THEREOF
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The present invention relates to crystalline (thio)nicotinamide ribofuranoside salts, methods of making such crystalline salts, a pharmaceutical composition comprising same, and use of said crystalline salts as nutritional (dietary) supplements. Furthermore, the present invention relates to a composition comprising amorphous (thio)nicotinamide ribofuranoside salts and its use as nutritional (dietary) supplement.
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Paragraph 00175
(2019/12/04)
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- CRYSTALLINE FORMS OF NICOTINAMIDE RIBOSIDE CHLORIDE
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Provided herein are crystalline forms of nicotinamide riboside chloride and methods of making the same. Also provided are compositions comprising the crystalline form of nicotinamide riboside chloride, and therapeutic methods employing the crystalline form of nicotinamide riboside chloride.
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Page/Page column 29; 30
(2019/07/13)
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- Preparation and purification method for heterocyclic compounds
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The invention relates to synthesis of heterocyclic compounds and in particular relates to a preparation and purification method for nicotinamide nucleoside onium salts. The method comprises the following steps: dissolving a compound B and an ammonium salt into a solvent 1 in the presence of a catalyst, introducing air to react in a closed manner at a suitable temperature, removing the catalyst by filtration after the reaction is ended, and concentrating reaction liquid so as to obtain a crude product; dissolving the crude product in a solvent 2, separating out a crystal, and performing filtering and drying, thereby obtaining the nicotinamide nucleoside onium salts shown as a formula (I). The preparation and purification method disclosed by the invention is simple in process operation, high in reaction speed, high in product purity, recyclable in catalyst, low in cost and environmentally friendly, is suitable for commercialized production, and has excellent application prospects.
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Paragraph 0048-0060; 0064-0067
(2019/10/08)
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- EFFICIENT AND SCALABLE SYNTHESES OF NICOTINOYL RIBOSIDES AND REDUCED NICOTINOYL RIBOSIDES, MODIFIED DERIVATIVES THEREOF, PHOSPHORYLATED ANALOGS THEREOF, ADENYLYL DINUCLEOTIDE CONJUGATES THEREOF, AND NOVEL CRYSTALLINE FORMS THEREOF
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The present disclosure provides methods of making nicotinoyl riboside compounds or derivatives of formula (I): wherein X?, Z1, Z2, n, R1, R2, R3, R4, R5, R6, R7, and R8 are described herein, reduced analogs thereof, modified derivatives thereof, phosphorylated analogs thereof, and adenylyl dinucleotide conjugates thereof, or salts, solvates, or prodrugs thereof; and novel crystalline forms thereof.
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Paragraph 2716-2718; 2723-2726; 2804-2807
(2018/05/26)
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- Method for preparing niacinamide nucleoside salt
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The invention relates to a method for preparing niacinamide nucleoside salt. The method comprises the following steps: replacing ions by niacinamide nucleoside trifluoromethane sulfonate prepared by deacetylation of triacetyl niacinamide nucleoside trifluoromethane in an organic solvent with acids, crystallizing to separate out a crude product, and pulping, thereby obtaining the corresponding niacinamide nucleoside salt. The ion replacement process in the invention overcomes the defects of chemical methods and extraction methods, and is suitable for industrial production.
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Paragraph 0026; 0028; 0029; 0030; 0032; 0034
(2018/12/02)
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- SYNTHETIC METHODS FOR THE PREPARATION OF NICOTINAMIDE RIBOSIDE AND RELATED COMPOUNDS
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The present application is directed to methods of making a pharmaceutically acceptable salt of nicotinamide riboside and related compounds by alkylating nicotinamide with a 1-chloro-D-ribofuranose derivative. The present invention relates to a method of making a compound of Formula (I): (a) reacting a compound of Formula (II) with a compound of Formula (III) to form a compound of Formula (IV).
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- PREPARATION AND USE OF CRYSTALLINE BETA-D-NICOTINAMIDE RIBOSIDE
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Provided herein are crystalline beta-D-nicotinamide riboside chloride compositions and methods of preparation and use thereof. Also provided are related pharmaceutical compositions and methods of use thereof. The crystalline beta-D-nicotinamide riboside chloride compositions may be used to treat a disease or disorder that would benefit from increased NAD levels including a mitochondrial disease or disorder, insulin resistance, a metabolic syndrome, diabetes, obesity, or for increasing insulin sensitivity in a subject.
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Page/Page column 73; 74; 75
(2015/12/24)
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- METHODS OF PREPARING NICOTINAMIDE RIBOSIDE AND DERIVATIVES THEREOF
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The invention relates to methods of preparing nicotinamide riboside and derivatives thereof. In an aspect, the invention relates to a method of preparing a compound of formula (I), wherein n is 0 or 1; m is 0 or 1; Y is O or S; R1 is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted primary or secondary amino, and substituted or unsubstituted azido; R2- R5, which may be the same or different, are each independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted aryl; and X- is an anion, selected from an anion of a substituted or unsubstituted carboxylic acid, a halide, a substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or unsubstituted sulfate, a substituted or unsubstituted carbonate, and a substituted or unsubstituted carbamate.
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