Method for preparing nicotinamide ribofuranoside salt by salt metathesis, its crystalline form as tosylate salt and its co-crystallized form as chloride:iodide salt

Abstract

The present invention relates to a method for producing nicotinamide ribofuranoside salts, in particular crystalline nicotinamide ribofuranoside salts, via salt metathesis comprising subjecting nicotinamide ribofuranoside hydrogen malate or nicotinamide ribofuranoside hydrogen tartrate to salt metathesis to provide a nicotinamide ribofuranoside salt.In another method, an acylated nicotinamide ribofuranoside hydrogen malate or acylated nicotinamide ribofuranoside hydrogen tartrate is subjected to salt metathesis followed by deacylation to provide a nicotinamide ribofuranoside salt.

Description

[Technical Field]

[0001] The present invention relates to a method for producing a nicotinamide-β-D-ribofuranoside salt, such as nicotinamide-β-D-ribofuranoside chloride, from nicotinamide-β-D-ribofuranoside hydrogen malate, nicotinamide-β-D-ribofuranoside hydrogen tartrate, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen malate, or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen tartrate. The method of the present invention enables the production of nicotinamide-β-D-ribofuranoside salt in high yield, high purity, and high stereoselectivity using a simple method. The method also allows for the preparation of co-crystallized nicotinamide-β-D-ribofuranoside (chloride, iodide). [Background technology]

[0002] Nicotinamide riboside (NR or NR + , Nicotinamide-β-D-ribofuranoside; CAS No. 1341-23-7) [ka] is nicotinamide adenine dinucleotide (NAD + / NADH) and nicotinamide adenine dinucleotide phosphate (NADP + Nicotinamide riboside is a precursor to niacin (vitamin B3).

[0003] Nicotinamide riboside regulates hepatic and skeletal NAD +It has been reported that ATP increases NAD levels and prevents weight gain in mice fed a high-fat diet. It has also been shown to reduce NAD levels in the cerebral cortex in transgenic mice models of Alzheimer's disease. + For these reasons, nicotinamide riboside salts have been proposed for use in dietary supplements and pharmaceutical compositions.

[0004] NR + The synthesis and handling of salts is difficult compared to other nucleosides due to the relatively unstable glycosidic bond. + Only the bromide and chloride salts of have been described in crystalline salt form. The crystalline bromide salt is toxic and therefore unsuitable for use as a food additive, but is available and used as a starting material in chemical synthesis. On the other hand, the crystalline chloride salt is conveniently used in dietary supplements and as a pharmaceutically active ingredient.

[0005] NR + Current methods for producing salts often result in low yields, posing a significant challenge for large-scale production. Furthermore, these methods often suffer from poor stereoselectivity, making NR + This results in the formation of a mixture of the α and β anomers of NR. This is highly undesirable for certain uses, as only the β form is biologically active. + Further drawbacks of known methods for preparing salts include the use of expensive reagents, which makes the method uneconomical for commercial production. In addition, frequently used ion exchangers have low exchange capacities and therefore NR + It is not desirable for mass production of salts. Also, the use of large amounts of solvents is + This promotes undesired hydrolysis of the salt. Thus, known methods in the prior art for preparing NR salts, such as NR chloride, have drawbacks, especially when applied to large-scale commercial production.

[0006] WO 2017 / 218580 discloses a synthetic method for preparing nicotinamide riboside salts, which involves replacing the pharmaceutically acceptable counterion of the nicotinamide riboside salt with another pharmaceutically acceptable counterion, such as chloride anion, via ion exchange chromatography or salt exchange reaction and precipitation to provide a desired salt of NR and a pharmaceutically acceptable counterion, such as NR chloride salt. WO 2015 / 186068 discloses the reaction of nicotinamide-β-D-ribofuranoside triflate with sodium methylate in an ion exchange reaction to provide crystalline nicotinamide-β-D-riboside chloride. Furthermore, CN108774278 discloses the deacetylation of nicotinamide triacetyl ribofuranoside triflate with a base, followed by treatment of the deacetylated product with an acid to yield the corresponding salt product.

[0007] Object of the invention In view of the above, there is a need in the art for a method for producing nicotinamide ribofuranoside salts, particularly pharmaceutically acceptable salts of nicotinamide ribofuranoside such as the chloride salt, in high yield, high purity and high stereoselectivity on a commercial scale in a simple and cost-effective manner. Summary of the Invention

[0008] Surprisingly, it has been discovered that this object can be achieved by using nicotinamide-β-D-ribofuranoside hydrogen malate or nicotinamide-β-D-ribofuranoside hydrogen tartrate as a starting material, preferably in crystalline form, and subjecting the hydrogen malate salt or hydrogen tartrate salt to salt metathesis involving counterion exchange with a selected anion, e.g., chloride anion, to provide the desired nicotinamide-β-D-ribofuranoside salt, e.g., nicotinamide-β-D-ribofuranoside chloride salt.

[0009] This method is simple and cost-effective, and provides desirable nicotinamide-β-D-ribofuranoside salts, such as nicotinamide-β-D-ribofuranoside chloride salts, in high yield, purity, and stereoselectivity. Furthermore, the desirable nicotinamide-β-D-ribofuranoside salts are advantageously obtained in crystalline form, which are particularly useful in nutritional and pharmaceutical applications.

[0010] In another method, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen malate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen tartrate is subjected to salt metathesis to cleave the acyl group to provide the desired nicotinamide-β-D-ribofuranoside salt.

[0011] According to a first aspect, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: (A) subjecting nicotinamide-β-D-ribofuranoside hydrogen malate or nicotinamide-β-D-ribofuranoside hydrogen tartrate to salt metathesis involving counterion exchange to provide a nicotinamide-β-D-ribofuranoside salt; The present invention relates to a method for producing nicotinamide-β-D-ribofuranoside salt, comprising:

[0012] According to a second aspect, the present invention provides a method for producing a soluble polymer comprising the following steps (A) and (B): (A) subjecting nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen malate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen tartrate to salt metathesis involving counterion exchange to provide a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt; (B) deacylating the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt to provide a nicotinamide-β-D-ribofuranoside salt; wherein steps (A) and (B) are carried out simultaneously, or step (B) is carried out subsequent to step (A).

[0013] Preferred embodiments are defined in the appended claims. [Brief explanation of the drawings]

[0014] The present invention is further illustrated by the accompanying drawings in which: [Figure 1] Powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside D-hydrogen maleate; [Figure 2] Powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside L-hydrogen maleate; [Figure 3] Powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside DL-hydrogen maleate; [Figure 4] Shown is the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside D-hydrogen tartrate monohydrate; [Figure 5] Powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside L-hydrogen tartrate; [Figure 6] Powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside DL-hydrogen tartrate; [Figure 7] Powder X-ray pattern of crystalline nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside L-hydrogen tartrate; [Figure 8] Powder X-ray pattern of crystalline nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside D-hydrogen tartrate; [Figure 9] Powder X-ray pattern of crystalline anhydrous nicotinamide-β-D-ribofuranoside D-hydrogen tartrate; [Figure 10]Shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside tosylate; and [Figure 11] Figure 1 shows the powder X-ray pattern of co-crystallized nicotinamide-β-D-ribofuranoside (chloride, iodide), where the chloride and iodide are present in a 2:1 molar ratio. {X-axis: position [°2θ] (copper (Cu); Y-axis: counts), respectively}.

[0015] Detailed Description of the Invention Various aspects of the present invention will now be described in more detail with reference to the accompanying figures.

[0016] First and second aspects: method according to the invention According to a first aspect, the present invention provides a method for the conversion of an anion Y to a hydroxyl group via salt metathesis involving counterion exchange. - Therefore, the following equation [ka] Anion X in the compound - = Hydrogen maleate or hydrogen tartrate replaced, NR + Y - Preferably, the anion Y - is chloride. However, the method is not so limited.

[0017] Therefore, in a first aspect, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: (A) subjecting nicotinamide-β-D-ribofuranoside hydrogen malate or nicotinamide-β-D-ribofuranoside hydrogen tartrate to salt metathesis involving counterion exchange to provide a nicotinamide-β-D-ribofuranoside salt; The present invention relates to a method for producing nicotinamide-β-D-ribofuranoside salt, comprising:

[0018] According to a second aspect, a compound of the formula [ka] Nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen maleate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen tartrate is subjected to salt metathesis to form an anion Y - Via X - Depending on the reaction conditions, in one embodiment, steps (A) and (B) may proceed simultaneously, i.e., the acyl group is exchanged with the desired nicotinamide-β-D-ribofuranoside salt NR + Y - In another embodiment, step (B) is carried out subsequent to step (A). Preferably, the anion Y - is chloride. However, the method is not so limited.

[0019] Therefore, in a second aspect, the present invention provides a method for producing a pharmaceutical composition comprising the following steps (A) and (B): (A) subjecting nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen malate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen tartrate to salt metathesis involving counterion exchange to provide a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt; and (B) deacylating the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt to provide a nicotinamide-β-D-ribofuranoside salt; wherein steps (A) and (B) are carried out simultaneously, or step (B) is carried out subsequent to step (A).

[0020] The term "acyl" as used in connection with nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salts includes alkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl, preferably C 1-10means an acyl group independently selected from alkylcarbonyl and benzoyl, more preferably acetyl, said acyl group being 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Thioalkyl, halogen, nitro, cyano, NH(C 1-6 alkyl), N(C 1-6 alkyl)2 and SO2N(C 1-6 alkyl)2.

[0021] Preferably, the hydrogen malate is D-, L-, or DL-hydrogen malate. Further, preferably, the hydrogen tartrate is D-, L-, or DL-hydrogen tartrate. Advantageously, the D-, L-, or DL-hydrogen malate or D-, L-, or DL-hydrogen tartrate can be provided with high purity and high stereoselectivity for the β anomer.

[0022] Furthermore, the salt used in step (A) of the method according to the first aspect of the present invention, i.e., nicotinamide-β-D-ribofuranoside hydrogen malate or nicotinamide-β-D-ribofuranoside hydrogen tartrate, or both, may be a crystalline salt. Similarly, the salt used in step (A) of the method according to the second aspect of the present invention, i.e., nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen malate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen tartrate, or both, may be a crystalline salt. In the present invention, crystalline NR2, which is particularly highly pure and stereoselective with respect to the β anomer, is used. + The use of crystalline salts is preferred because it allows for the preparation of the salts.

[0023] As used herein, the term "salt metathesis" is used synonymously with terms such as "double replacement reaction," "double displacement reaction," or "metathesis reaction." Salt metathesis for exchanging counterions between two different salts is a known technique. It should be understood that the term "salt metathesis" does not mean that the anion of β-nicotinamide riboside is exchanged for another anion by ion exchange using an ion exchanger. Thus, the method according to the present invention defined in step (A) excludes anion exchange with an ion exchanger. However, the method does not exclude the use of an ion exchanger in any reaction step before or after step (A).

[0024] Step (A) defines the reaction, wherein the first salt, i.e., nicotinamide-β-D-ribofuranoside salt NR + X - or Nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt AcONR + X - is subjected to salt metathesis with a suitable compound to give the anion Y - The compound provides a cation Cat + and the anion Y - Contains Cat + Y - However, counterion exchange, i.e., Y - by NR + X - or AcONR + X - X in - Nicotinamide-β-D-ribofuranoside salt NR via exchange + Y - or Nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt AcONR + Y - and Cat + X - These reactions are summarized by the following equation: NR + X - + Cat + Y - → NR + Y - + Cat + X - AcONR + X - + Cat + Y - → AcONR + Y - + Cat + X - , The compound Cat + Y - may be a suitable salt or a suitable acid.

[0025] The driving force for salt metathesis reactions such as those described above is not only the formation of more stable salts, but also the reversibility of the formation of e.g. + Y - and Cat + X - or one of the formed AcONR + Y - and Cat + X - The removal of the product from the chemical equilibrium of the reaction may be by precipitation of one of the educts. Therefore, to promote the reaction to the product, the educts should be selected with favorable energies relative to each other and their solubility in the solvent.

[0026] In a preferred embodiment, nicotinamide-β-D-ribofuranoside hydrogen malate or hydrogen tartrate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen malate or hydrogen tartrate is reacted with an acid, e.g., an organic acid or an inorganic acid, to effect anion exchange. + is H +The acid is preferably a strong acid. As used herein, the term "strong acid" means that the acid is stronger than malic acid or tartaric acid. Preferably, the strong acid has a pK of 2 or less, more preferably 1 or less, or even more preferably 0 or less. a It has.

[0027] Preferably, the acid Cat + Y - =H + Y - is used in molar excess relative to the starting materials nicotinamide-β-D-ribofuranoside hydrogen maleate or hydrogen tartrate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen maleate or hydrogen tartrate. Preferably, more than 1.1 molar equivalents of acid H + Y - is used, more preferably at least 1.2 or at least 1.3 or at least 1.4 or at least 1.5 equivalents.

[0028] Cat + H + That is, acid H + Y - is used for counterion exchange, steps (A) and (B) in the process according to the second aspect typically proceed simultaneously, i.e., cleavage of the acyl group in the starting nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen malate or hydrogen tartrate and / or the formed nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt and formation of the desired nicotinamide-β-D-ribofuranoside salt can proceed simultaneously.

[0029] Cat + H + Not, i.e., acid H + Y - Not Salt Cat + Y -is used in the process according to the second aspect of the present invention, steps (A) and (B) usually proceed in successive steps, i.e., cleavage of the acyl group from the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt (step (B)) is carried out after the formation of the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt by metathesis (step (A)). Cleavage of the acyl group can be carried out according to methods known in the art, for example, by subjecting the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt obtained in step (A) to an acid such as hydrogen bromide, hydrogen chloride, hydrogen iodide or sulfuric acid, or to a base such as ammonia.

[0030] According to the second aspect of the present invention, the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt obtained in step (A) may be isolated and purified before being deacylated in step (B). Alternatively, the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt of step (A) may not be purified before being deacylated in step (B).

[0031] According to the present invention, the counter ions (Y - )teeth, inorganic ions; Carboxylate, including carboxyl, hydroxyl, thio, keto, amino, mono C 1-6 Alkyl, Hydroxy C 1-6 Alkylene and di(C 1-6 carboxylate optionally substituted with one or more substituents independently selected from the group consisting of (alkyl)amino; C 1-12 alkyl sulfonates; or Aryl sulfonates, wherein the aryl moiety is carboxyl, hydroxyl, amino, mono-C 1-6 Alkyl and di(C 1-6 alkyl)amino, halogen and C 1-6aryl sulfonates optionally substituted with one or more substituents independently selected from the group consisting of alkyl; and wherein said Y - is not hydrogen malate or hydrogen tartrate.

[0032] The inorganic ion may be selected from the group consisting of bromide, chloride, iodide, hydrogen sulfate, sulfate, dihydrogen phosphate, monohydrogen phosphate, phosphate; The carboxylate may be selected from the group consisting of formate, acetate, oxarate, malonate, succinate, fumarate, maleate, citrate, ascorbate, α-ketoglutarate, glucuronate, benzoate, and salicylate; C 1-12 The alkyl sulfonate may be selected from the group consisting of mesylate and camsylate; and The aryl sulfonate can be selected from the group consisting of besylate and tosylate.

[0033] Preferably, the counterion Y -is selected from chloride and bromide, preferably from hydrogen chloride or hydrogen bromide used to effect counterion exchange by salt metathesis. More preferably, the counterion is chloride, especially hydrogen chloride used to effect counterion exchange by salt metathesis.

[0034] The salt metathesis can be carried out without a solvent, i.e., via salt metathesis using, for example, a liquid salt or a liquid acid of a solid nicotinamide-β-D-ribofuranoside salt or a solid nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt. However, the salt metathesis in step (A) is preferably carried out in the presence of a solvent.

[0035] In the following, four preferred embodiments for carrying out the salt metathesis reaction defined above are described.

[0036] Embodiment I : The solvent is NR + X - (or AcONR + X - ) and Cat + Y - are both selected so as to be soluble in the solvent, however, the NR obtained in step (A) + Y - (or AcONR + Y - ) is insoluble in the solvent and precipitates, whereas Cat + X - In this case, NR + Y - (or AcONR + Y - ) can be isolated by filtration.

[0037] Embodiment II : The solvent is NR + X - (or AcONR + X - ) and Cat + Y- are both selected so as to be soluble in the solvent, however, the NR obtained in step (A) + Y - (or AcONR + Y - ) is soluble in the solvent, whereas Cat + X - is insoluble and precipitates. In this case, NR + Y - (or AcONR + Y - ) can be isolated from the supernatant by known techniques.

[0038] Embodiment III : The solvent is NR in step (A). + X - and NR + Y - (or AcONR + X - and AcONR + Y - ) are both insoluble in the solvent, whereas Cat + X - and Cat + Y - are chosen so that both are soluble. In this case, NR + Y - (or AcONR + Y - ) can be isolated, for example, by filtration. + Y - Particularly good results are obtained when is an acid as defined above and preferably the solvent is an alcohol.

[0039] Embodiment IV : The solvent is NR in step (A). + X - and NR + Y - (or AcONR + X - and AcONR + Y - ) is soluble in the solvent, whereas Cat + Y- and Cat + X - is chosen so that it is insoluble in NR + Y - (or AcONR + Y - ), for example, can then be isolated from the supernatant by known techniques.

[0040] Preferably, the solvent used in step (A) of the process according to the invention is an alcohol selected from the group consisting of methanol, ethanol, propanol (e.g. n-propanol, iso-propanol) or butanol (e.g. n-butanol, iso-butanol, sec-butanol, tert-butanol) or a mixture of two or more thereof, said alcohol or mixture of alcohols optionally comprising water.

[0041] Consequently, by appropriate selection of the solvent used in the salt metathesis reaction defined in step (A), the desired salt can be obtained and isolated.

[0042] Preferably, in step (A), a suspension of nicotinamide-β-D-ribofuranoside hydrogen malate or nicotinamide-β-D-ribofuranoside hydrogen tartrate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen malate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen tartrate in one or more alcohols as defined above, optionally containing water, and a suitable acid are combined with each other to carry out step (A), i.e., a nicotinamide-β-D-ribofuranoside salt or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt (which may already be deacylated to give the nicotinamide-β-D-ribofuranoside salt) is formed by counterion exchange and typically precipitates so that it can be isolated, for example, by filtration.

[0043] The isolated nicotinamide-β-D-ribofuranoside salt or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt is generally obtained in crystalline form, with high purity and high stereoselectivity for the β anomer. Thus, the crystalline compound is obtained directly from the salt metathesis reaction without the need for ion exchangers or complex purification and / or crystallization procedures. This is a significant advantage of the method according to the present invention compared to, for example, counterion exchange via an ion exchanger, where the compound is typically obtained in amorphous form and must be crystallized in a subsequent step to obtain the desired purity and stereoisomer. Nevertheless, it is contemplated that the product obtained by the method of the present invention may be further purified, if necessary, by a crystallization step.

[0044] Preferably, the salt metathesis reaction according to step (A) is carried out at ambient temperature, ie in the range of from 5 to 60°C, preferably at a temperature of from 10 to 40°C.

[0045] NR + D-, L- or DL-hydrogen maleate or NR + D-, L-, or DL-hydrogen tartrate or AcONR + D-, L-, or DL-hydrogen maleate or AcONR + The preparation of D-, L-, or DL-hydrogen tartrate is described in more detail herein below.

[0046] Preparation of nicotinamide-β-D-ribofuranoside hydrogen malate or hydrogen tartrate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen malate or hydrogen tartrate The salt of nicotinamide-β-D-ribofuranoside hydrogen maleate or the salt of hydrogen tartrate, or the salt of nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside hydrogen maleate or the salt of hydrogen tartrate used as a starting material in step (A) is produced by salt metathesis involving counterion exchange of nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or perchlorate, or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or perchlorate with hydrogen maleate or hydrogen tartrate.

[0047] Nicotinamide-β-D-ribofuranoside bromide is a well-known compound (CAS No. 78687-39-5). For example, Lee et al. disclose its chemical synthesis method (Chem. Commun., 1999, 729-730). The reference also discloses the preparation of nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide as a precursor of nicotinamide-β-D-ribofuranoside bromide.

[0048] Nicotinamide-β-D-ribofuranoside triflate is also a well-known compound (CAS No. 445489-49-6). Nicotinamide-β-D-ribofuranoside triflate and nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside triflate can be prepared, for example, by reacting nicotinamide with tetra-O-acyl-β-D-ribofuranose in acetonitrile in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) to provide nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside triflate. The acyl group can then be cleaved according to known methods to provide nicotinamide-β-D-ribofuranoside triflate (see, e.g., Makarova et al., "Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives," Beilstein J Org Chem 2019, 15:401-430; Tanimori et al., "An Efficient Chemical Synthesis of Nicotinamide Riboside (NAR) and Analogues," Bioorganic & Medicinal Chemistry Letters 12 (2002) 1135-1137).

[0049] Nicotinamide-β-D-ribofuranoside nonaflate and nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside nonaflate, nicotinamide-β-D-ribofuranoside perchlorate and nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside perchlorate, respectively, can be prepared by reacting nicotinamide with tetra-O-acyl-β-D-ribofuranose in a solvent such as acetonitrile in the presence of trimethylsilyl nonafluorobutanesulfonate (CAS No. 68734-62-3), respectively trimethylsilyl perchlorate (CAS No. 18204-79-0), to provide nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside nonaflate, respectively perchlorate. The acyl group can then be cleaved according to known methods to provide the nicotinamide-β-D-ribofuranoside nonaflate, respectively perchlorate.

[0050] Nicotinamide-β-D-ribofuranoside chloride and nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, nicotinamide-β-D-ribofuranoside iodide and nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside iodide, nicotinamide-β-D-ribofuranoside fluorosulfonate and nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside fluorosulfonate are prepared by the reaction of trimethylsilyl chloride with 2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, 2,3,5-tri-O-acyl-β-D-ribofuranoside iodide, and 2,3,5-tri-O-acyl-β-D-ribofuranoside fluorosulfonate, respectively. Nicotinamides can be prepared by reacting nicotinamide with tetra-O-acyl-β-D-ribofuranose in a solvent such as acetonitrile in the presence of methylsilyl iodide (CAS No. 75-77-4), trimethylsilyl iodide (CAS No. 16029-98-4), or trimethylsilyl fluorosulfonate (CAS No. 3167-56-4), respectively, to provide nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, iodide, and fluorosulfonate. The acyl group can then be cleaved according to known methods to provide nicotinamide-β-D-ribofuranoside chloride, iodide, and fluorosulfonate, respectively.

[0051] Nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside iodide, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside trifluoromethanesulfonate, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside nona Fluorobutanesulfonate, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside fluorosulfonate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside perchlorate are either known or can be prepared according to known methods for producing the respective hydrogen maleates and hydrogen tartrates used in step (A) of the process according to the second embodiment as described above.

[0052] To obtain the hydrogen malate or hydrogen tartrate used in step (A) of the process according to the invention, nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or perchlorate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or perchlorate can be reacted with a salt of hydrogen malate or hydrogen tartrate in a salt metathesis reaction.

[0053] The ammonium salts, trialkylammonium salts, etc. are particularly useful, for example, triethylammonium salts or tributylammonium salts.

[0054] As used herein, the term "hydrogen malate" refers to a monocarboxylate. Preferably, the hydrogen malate is a D-, L-, or DL-stereoisomer. As used herein, "hydrogen tartrate" refers to a monocarboxylate. Preferably, the hydrogen tartrate ion is a D-, L-, or DL-stereoisomer.

[0055] The preparation of the NR or AcONR D-, L- or DL-stereoisomers of hydrogen malate or hydrogen tartrate is advantageous because the process according to the invention makes it possible to advantageously provide these compounds in high yield and in crystalline form, which is particularly advantageous in view of the handling and further processing of the salts.

[0056] Typically, crystalline compounds are obtained directly from salt metathesis reactions without the need to use ion exchangers or complex purification and / or crystallization methods. For example, nicotinamide-β-D-ribofuranoside bromide (NR + Br - ), the following crystalline nicotinamide-β-D-ribofuranoside hydrogen maleate and nicotinamide-β-D-ribofuranoside hydrogen tartrate are obtained via salt metathesis in very high purity: [Table 1]

[0057] In a preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen malate used in step (A) of the method according to the first aspect is nicotinamide-β-D-ribofuranoside D-hydrogen malate, which can be characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 1 below at ±0.2° 2θ or as provided in Figure 1: [Table 2]

[0058] In a further preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen malate used in step (A) of the method according to the first aspect is nicotinamide-β-D-ribofuranoside L-hydrogen malate, which can be characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 2 below at ±0.2° 2θ or as provided in Figure 2: [Table 3]

[0059] In a further preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen malate used in step (A) of the method according to the first aspect is nicotinamide-β-D-ribofuranoside DL-hydrogen malate, which can be characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 3 below at ±0.2° 2θ or as provided in Figure 3: [Table 4]

[0060] In a further particularly preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen tartrate used in step (A) of the method according to the first aspect is nicotinamide-β-D-ribofuranoside D-hydrogen tartrate monohydrate. This compound can be characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 4 below at ±0.2° 2θ or as provided in Figure 4: [Table 5]

[0061] In a further preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen tartrate used in step (A) of the method according to the first aspect is nicotinamide-β-D-ribofuranoside L-hydrogen tartrate, which can be characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 5 below at ±0.2° 2θ or as provided in Figure 5: [Table 6]

[0062] In a further preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen tartrate used in step (A) of the method according to the first aspect is nicotinamide-β-D-ribofuranoside DL-hydrogen tartrate, which can be characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 6 below at ±0.2° 2θ or as provided in Figure 6: [Table 7]

[0063] In a further preferred embodiment, the crystalline nicotinamide-2,3,5-triacetyl-O-β-D-ribofuranoside hydrogen tartrate used in step (A) of the method according to the second aspect is nicotinamide-2,3,5-triacetyl-O-β-D-ribofuranoside L-hydrogen tartrate, which can be characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 7 below at ±0.2° 2θ or as provided in Figure 7: [Table 8]

[0064] In a further preferred embodiment, the crystalline nicotinamide-2,3,5-triacetyl-O-β-D-ribofuranoside hydrogen tartrate used in step (A) of the method according to the second aspect is nicotinamide-2,3,5-triacetyl-O-β-D-ribofuranoside D-hydrogen tartrate, which can be characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 8 below at ±0.2° 2θ or as provided in Figure 8: [Table 9]

[0065] In a further preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen tartrate used in step (A) of the method according to the first aspect is anhydrous nicotinamide-β-D-ribofuranoside D-hydrogen tartrate. This compound can be characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 9 below at ±0.2° 2θ or as provided in Figure 9: [Table 10]

[0066] In a further preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside salt obtained in the process according to the present invention is crystalline nicotinamide-β-D-ribofuranoside tosylate, which can be characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 10 below at ±0.2° 2θ or as provided in Figure 10: [Table 11]

[0067] Salt metathesis of nicotinamide-β-D-ribofuranoside salts and nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salts, respectively, using acids for counterion exchange The inventors of the present invention have found that the above reaction scheme NR + X - + Cat + Y - → NR + Y - + Cat + X - AcONR + X - + Cat + Y - → AcONR + Y - + Cat + X - , Cat + H + And H + Y - is a stronger acid than malic acid or tartaric acid, NR + X - To prepare the salt, use nicotinamide-β-D-ribofuranoside salt NR + X - , and nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt AcONR, respectively. + X - It further discloses that the above formula can be generalized to further salts of

[0068] Therefore, in another aspect, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: (A) Nicotinamide-β-D-ribofuranoside salt NR + X is acid H + Y - Nicotinamide-β-D-ribofuranoside salt NR + Y - and H + X - providing said H + Y - pK a <H+ X - pK a That is, Nicotinamide-β-D-ribofuranoside salt NR + X - Nicotinamide-β-D-ribofuranoside salt NR + Y - The present invention relates to a method for producing the same.

[0069] In a subsequent step, nicotinamide-β-D-ribofuranoside salt NR + Y - can be isolated according to known methods.

[0070] The reaction according to step (A) is + Y - In the solvent used, NR + It may be further supported if it is less soluble than X.

[0071] The reaction also uses nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt AcONR as a starting material. + X - wherein the deacylation is carried out simultaneously.

[0072] Therefore, according to a further aspect, the present invention provides a method for producing a medicament for the preparation of ... (A) Nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt AcONR + X - Acid H + Y - Nicotinamide-β-D-ribofuranoside salt NR + Y - and H + X - providing said H + Y - pK a <H + X - pK a That is, Nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt AcONR, + X - Nicotinamide-β-D-ribofuranoside salt NR + Y - The present invention relates to a method for producing the same.

[0073] In a subsequent step, nicotinamide-β-D-ribofuranoside salt NR + Y - can be isolated according to known methods.

[0074] AcONR + The acyl in X has the definition as defined above, i.e., acyl is selected from alkylcarbonyl, arylcarbonyl and heteroarylcarbonyl, preferably C 1-10 Independently selected from alkylcarbonyl and benzoyl, more preferably acetyl, said acyl being 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Thioalkyl, halogen, nitro, cyano, NH(C 1-6 alkyl), N(C 1-6 alkyl)2 and SO2N(C 1-6 and optionally substituted independently with one or more substituents selected from alkyl).

[0075] As disclosed above, preferably, the reaction is carried out in an alcohol selected from the group consisting of methanol, ethanol, propanol (e.g., n-propanol, iso-propanol), or butanol (e.g., n-butanol, iso-butanol, sec-butanol, tert-butanol), or a mixture of two or more thereof, said alcohol or mixture of alcohols optionally containing water.

[0076] Preferably, in step (A), a suspension of nicotinamide-β-D-ribofuranoside salt or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt in one or more alcohols, optionally containing water, as defined above, and a suitable acid are combined with each other to carry out step (A), i.e., nicotinamide-β-D-ribofuranoside salt is formed by counterion exchange and typically precipitates so that it can be isolated, for example, by filtration.

[0077] Preferably, acid H + Y - is the starting material nicotinamide-β-D-ribofuranoside salt NR + X or Nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt AcONR + X - Preferably, more than 1.1 molar equivalents of acid H + Y - is used, more preferably at least 1.2 or 1.3 or 1.4 or 1.5 equivalents.

[0078] Exemplarily mentioned is the preparation of nicotinamide-β-D-ribofuranoside tosylate starting from nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside triflate, with the addition of p-toluenesulfonic acid (pK a =-2.8), the same procedure is applied to the trifluoromethanesulfonic acid (pK a =0.23) is formed.

[0079] Further mentioned by way of example is the preparation of nicotinamide-β-D-ribofuranoside chloride or nicotinamide-β-D-ribofuranoside bromide starting from nicotinamide-β-D-ribofuranoside tosylate, with the aid of hydrochloric acid (pK a =-6) or hydrobromic acid (pK a =-8.9), the same procedure is applied to the p-toluenesulfonic acid (pK a =-2.8) is formed.

[0080] Salt metathesis of nicotinamide-β-D-ribofuranoside hydrogen maleate or hydrogen tartrate, respectively, with more than one counterion for counterion exchange In certain embodiments of the first or second aspect, the present invention discloses a method, wherein more than one counterion is used in the counterion exchange according to step (A).

[0081] Preferably, in one embodiment of the first aspect, more than one counterion is used in the counterion exchange according to step (A).

[0082] In one embodiment, two counterions are used.

[0083] In particularly preferred embodiments, the counterion is selected from chloride and iodide.

[0084] The present inventors have surprisingly discovered that chloride and iodide co-crystallize in the resulting crystalline nicotinamide-β-D-ribofuranoside salt.

[0085] As used in this disclosure, the term "co-crystallization" means that more than one counterion is incorporated into the crystal lattice of the formed nicotinamide-β-D-ribofuranoside salt.

[0086] Even more surprisingly, the present inventors have discovered that, depending on the ratio of chloride to iodide used in the counterion exchange reaction according to step (A), different chloride to iodide ratios can be designed for the resulting co-crystallized nicotinamide-β-D-ribofuranoside salt.

[0087] In particular, the present invention discloses co-crystallized nicotinamide-β-D-ribofuranoside (chloride / iodide) salts, wherein the molar ratios of chloride to iodide are 5:1, 3:1, 2:1, 1.5:1 and 1:1.

[0088] As referred to herein, the term "chloride to iodide ratio" means, for example, that a chloride to iodide ratio of 2:1 means that every third chloride in the crystal lattice of nicotinamide-β-D-ribofuranoside chloride is replaced by an iodide. Thus, the ratio is a numerical ratio, relative to the molar ratio.

[0089] Exemplarily characterized is co-crystallized nicotinamide-β-D-ribofuranoside (chloride / iodide), wherein the chloride and iodide are present in a 2:1 ratio, exemplarily characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 11 below, ±0.2° 2θ, or as provided in Figure 11: [Table 12]

[0090] As a result, the present invention also relates to crystalline forms of co-crystallized nicotinamide-β-D-ribofuranoside salts, the anions of which comprise or consist of chloride and iodide.

[0091] In embodiments, the molar ratio of chloride to iodide is 5:1, 3:1, 2:1, 1.5:1, and 1: 1. The X-ray diffraction patterns of each crystal are very similar, differing only in the intensities of the individual peaks.

[0092] In one embodiment, the invention relates to co-crystallized nicotinamide-β-D-ribofuranoside (chloride, iodide) characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 11 at ±0.2 degrees 2θ, or as provided in Figure 11.

[0093] Co-crystallized nicotinamide-β-D-ribofuranoside (chloride, iodide) can be used in pharmaceutical compositions and dietary supplements.

[0094] As a result, the present invention also relates to dietary supplements or pharmaceutical compositions comprising co-crystallized nicotinamide-β-D-ribofuranoside (chloride, iodide).

[0095] The following examples further illustrate the present invention. [Example]

[0096] Preparation of starting materials Example 1: Preparation of nicotinamide-β-D-ribofuranoside L-hydrogen tartrate and nicotinamide-β-D-ribofuranoside DL-hydrogen tartrate from nicotinamide-β-D-ribofuranoside bromide Example 1a: Nicotinamide-β-D-ribofuranoside L-hydrogen tartrate 3.90 g of L-tartaric acid (26.0 mmol) was dissolved in 10 ml of methanol with stirring. The colorless solution was cooled in an ice bath, and 3.64 ml of triethylamine (26.1 mmol) was added. The pH of the slightly yellowish solution was approximately 4-4.5. In this way, 15 ml of a 1.73 M TEA·L-hydrogen tartrate (TEA = triethylamine) solution was prepared.

[0097] 5.8 g of nicotinamide-β-D-ribofuranoside bromide (NR·Br) was dissolved in 3.5 ml of water at room temperature with stirring. 10 ml of methanol was added. 10 ml of the triethylammonium L-hydrogen tartrate solution prepared above was added to the clear, colorless solution. A white product began to precipitate.

[0098] The suspension was stirred for an additional hour at room temperature. The product was filtered, washed with methanol, and dried under vacuum at 35°C. 6.62 g (95%) of a white crystalline powder was obtained; mp: 129-130°C; IC: residual bromide 0.20%. The solid may be recrystallized from aqueous methanol, if necessary.

[0099] 1 H-NMR (400 MHz, DO): 3.82 (dd, 1H, H5'), 3.97 (dd, 1H, H5'), 4.28 (t, 1H, H3'), 4.38-4.45 (m, 2H, H4', H2'), 4.41 (s, 2H, 2xCHOH, H-tartrate), 6.17 (d, 1H, H1'), 8.20 (t, 1H, H5), 8.90 (d, 1H, H4), 9.19 (d, 1H, H6), 9.52 (s, 1H, H2). Impurities: <1 mol% nicotinamide; 1.2 mol% TEA salt: 1.19 (t, 9H), 3.11 (q, 6H). Solvent: 7.3 mol% methanol: 3.25 (s, 3H).

[0100] 13 C-NMR (100 MHz, DO): 60.2 (C5'), 69.7 (C3'), 72.8 (2xCHOH, H-tartrate), 77.4 (C2'), 87.6 (C4'), 99.9 (C1'), 128.4 (C5), 133.9 (C3), 140.4 (C2), 142.6 (C6), 145.6 (C4), 165.8 (CONH2), 176.3 (2xCOO, H-tartrate). Impurities: 8.2, 46.6 (TEA). Solvent: 48.9 (methanol).

[0101] XRD: crystalline (see Figure 5)

[0102] Example 1b: Nicotinamide-β-D-ribofuranoside DL-hydrogen tartrate The crystalline nicotinamide-β-D-ribofuranoside salts in the table below were prepared similarly to the method described above: [Table 13]

[0103] Example 2: Preparation of nicotinamide-β-D-ribofuranoside L-hydrogenmalate, D-hydrogenmalate, nicotinamide-β-D-ribofuranoside DL-hydrogenmalate, and D-hydrogentartrate from nicotinamide-β-D-ribofuranoside bromide Example 2a: Nicotinamide-β-D-ribofuranoside L-hydrogen maleate 5.8 g of nicotinamide-β-D-ribofuranoside bromide was suspended in 10 ml of methanol with stirring. 10 ml of 1.73 M triethylammonium L-hydrogen maleate solution was added. The suspension was heated until the solid was completely dissolved. After cooling, a white solid precipitated. The suspension was stirred for 30 minutes and then filtered. The residue was washed with methanol and dried under vacuum at 35°C. 4.15 g (62%) of a white crystalline powder was obtained. Mp: 116.5-117°C. IC: Residual bromide 0.10%. The product may be recrystallized from methanol, if necessary.

[0104] 1 H-NMR (400 MHz, DO): 2.53 (dd, 1H, CH2, H-malate), 2.72 (dd, 1H, CH2, H-malate), 3.81 (dd, 1H, H5'), 3.97 (dd, 1H, H5'), 4.28 (t, 1H, H3'), 4.29 (dd, 1H, CHOH, H-malate), 4.38-4.45 (m, 2H, H4', H2'), 6.17 (d, 1H, H1'), 8.20 (t, 1H, H5), 8.90 (d, 1H, H4), 9.19 (d, 1H, H6), 9.52 (s, 1H, H2). Impurities: <1 mol% nicotinamide; 0.7 mol% TEA salt: 1.19 (t, 9H), 3.11 (q, 6H). Solvent: 6.3 mol% methanol: 3.25 (s, 3H).

[0105] 13C-NMR (100 MHz, DO): 40.0 (CH, H-malate), 60.2 (C5'), 68.5 (CHOH, H-malate), 69.7 (C3'), 77.4 (C2'), 87.7 (C4'), 99.9 (C1'), 128.4 (C5), 133.9 (C3), 140.4 (C2), 142.6 (C6), 145.6 (C4), 165.7 (CONH), 176.3 (COO, H-malate), 179.0 (COO, H-malate). Solvent: 48.9 (methanol).

[0106] XRD: crystalline (see Figure 2)

[0107] Example 2b: Nicotinamide-β-D-ribofuranoside D-hydrogen malate, Example 2c: Nicotinamide-β-D-ribofuranoside DL-hydrogen malate, and Example 2d: Nicotinamide-β-D-ribofuranoside D-hydrogen tartrate The crystalline nicotinamide-β-D-ribofuranoside salts in the table below were prepared similarly to the method described above: [Table 14]

[0108] Example 3: Preparation of nicotinamide-β-D-ribofuranoside D-hydrogen tartrate monohydrate by recrystallization of nicotinamide-β-D-ribofuranoside D-hydrogen tartrate from water 2.0 g of nicotinamide-β-D-ribofuranoside D-hydrogen tartrate (referred to herein as anhydrous), having the XRD of Figure 9, was dissolved in 9 ml of water. 70 ml of methanol was added to the colorless solution while stirring. After approximately 1 minute, white crystals precipitated. After 1 hour, the resulting suspension was filtered. The residue was washed with methanol and dried under vacuum at 35°C. 1.54 g (77%) of the monohydrate was obtained as a white crystalline powder. Water content: 4.24% (determined by Karl Fischer method (K. Fischer)); Mp.: 115-116°C; IC: Residual bromide: <0.01%. XRD: Crystalline (see Figure 4).

[0109] Example 4: Preparation of nicotinamide-β-D-ribofuranoside-2,3,5-triacetate L-hydrogen tartrate and nicotinamide-β-D-ribofuranoside-2,3,5-triacetate D-hydrogen tartrate via salt metathesis from nicotinamide-β-D-ribofuranoside-2,3,5-triacetate bromide Example 4a: Nicotinamide-β-D-ribofuranoside-2,3,5-triacetate L-hydrogen tartrate 3.90 g of L-tartaric acid was dissolved in 10 ml of methanol with stirring. The solution was cooled to 0-5°C. 3.64 ml of triethylamine was added. The pH value was 4.1. 15 ml of a 1.73 M triethylammonium L-hydrogen tartrate solution was obtained.

[0110] 8.0 g of nicotinamide-2,3,5-tri-O-acetyl-β-D-riboside bromide was suspended in 10 ml of methanol with stirring. 10 ml of the triethylammonium L-hydrogen tartrate solution prepared above was added. A white crystalline powder began to slowly precipitate. The residue obtained after filtration was dried under vacuum at 35°C. 6.00 g (65.2%) of a white crystalline powder was obtained. Mp. 128°C; IC: residual bromide <0.1%.

[0111] 1H-NMR (400 MHz, DO): 2.08, 2.12, 2.15 (3xs, 3x3H, COCH), 4.43 (s, 2H, 2xCHOH, H-tartrate), 4.52 (m, 2H, H5'), 4.88 (m, 1H, H4'), 5.44 (t, 1H, H3'), 5.55 (dd, 1H, H2'), 6.58 (d, 1H, H1'), 8.27 (t, 1H, H5), 8.99 (d, 1H, H4), 9.20 (d, 1H, H6), 9.43 (s, 1H, H2). Impurities: <0.1 mol% nicotinamide; 0.6 mol% TEA salt: 1.21 (t, 9H), 3.13 (q, 6H). Solvent: 2 mol% methanol: 3.27 (s, 3H).

[0112] 13 C-NMR (100MHz, D2O): 19.8, 19.9, 20.2 (3xCOCH3), 62.6 (C5'), 69.4 (C3'), 72.8 (2xCHOH, H-Tartrate), 76.3 (C2'), 82.6 (C4'), 97.3 (C1 '), 128.6(C5), 134.2(C3), 140.4(C2), 143.1(C6), 146.2(C4), 165.5(CONH2), 172.3, 172.4, 173.3(3xCO), 176.3(2xCOO, H-Tartrate).

[0113] XRD: crystalline (see Figure 7).

[0114] Example 4b: Nicotinamide-β-D-ribofuranoside-2,3,5-triacetate D-hydrogen tartrate The product was prepared similarly to Example 4a using D-tartaric acid, and the XRD is shown in Figure 8.

[0115] Example 5: Deacylation of Nicotinamide-β-D-ribofuranoside-2,3,5-triacetate L-Hydrogen Tartrate with Sulfuric Acid and Neutralization with Triethylamine Preparation of dilute sulfuric acid in methanol 27 g of methanol was cooled to 0° C. 3.00 g of sulfuric acid was added with stirring to give 10% methanolic acid.

[0116] Deacylation of Nicotinamide-β-D-riboside-2,3,5-triacetate L-Hydrogen Tartrate 3.00 g of nicotinamide-β-D-riboside-2,3,5-triacetate L-hydrogen tartrate was suspended in 15 ml of methanol with stirring. After adding 11.7 g of the above methanolic sulfuric acid, a yellowish solution was produced. After stirring at room temperature for 5 days, only nicotinamide was present as a product and impurity, as detected by thin layer chromatography.

[0117] Conversion of nicotinamide-β-D-riboside to L-hydrogen tartrate after neutralization with triethylamine 1.1 ml of triethylamine was added to the above solution to adjust the pH to about 3.5. 0.85 g of L-tartaric acid was added. After the addition of 0.8 ml of triethylamine, the product began to crystallize. The suspension was stirred for another hour and then stored in a refrigerator for 12 hours. The formed crystals were filtered off, washed with isopropanol, and dried under vacuum at 30°C. 1.01 g (44.2%) of a white crystalline powder was obtained, having a melting point of 126-127°C.

[0118] 1 H-NMR (400MHz, D2O): 3.82 (dd, 1H, H5'), 3.96 (dd, 1H, H5'), 4.27 (t, 1H, H3'), 4.37-4.45 (m, 2H, H4', H2'), 4.42 (s, 2H, 2xCHOH, H-tartrate), 6.17 (d, 1H, H1'), 8.20 (t, 1H, H5), 8.90 (d, 1H, H4), 9.19 (d, 1H, H6), 9.52 (s, 1H, H2). Impurities: 3 mol% nicotinamide: 7.85 (m, 1H), 8.56 (m, 1H), 8.77 (d, 1H), 9.00 (s, 1H); 3.4 mol% TEA salt: 1.18 (t, 9H), 3.11 (q, 6H). Solvent: 11.3 mol% methanol: 3.25 (s, 3H).

[0119] 13C-NMR (100 MHz, DO): 60.2 (C5'), 69.7 (C3'), 72.8 (2xCHOH, H-tartrate), 77.4 (C2'), 87.6 (C4'), 99.9 (C1'), 128.4 (C5), 133.9 (C3), 140.4 (C2), 142.6 (C6), 145.6 (C4), 165.8 (CONH2), 176.3 (2xCOO, H-tartrate). Impurities: 8.2, 46.6 (TEA salt). Solvent: 48.9 (methanol).

[0120] Preparation of nicotinamide riboside bromide, chloride, and p-tosylate salts from nicotinamide riboside hydrogen maleate and hydrogen tartrate crystalline salts Example 6: Preparation of nicotinamide-β-D-riboside bromide Example 6a: Preparation of nicotinamide-β-D-riboside bromide using nicotinamide-β-D-riboside L-hydrogen maleate as the starting material and hydrogen bromide in glacial acetic acid for ion exchange via salt metathesis 5 g (12.88 mmol) of nicotinamide-β-D-ribofuranoside L-hydrogen maleate was suspended in 20 ml of methanol at room temperature. 4.74 g (19.3 mmol, 1.5 equiv.) of a solution of hydrogen bromide in glacial acetic acid (33.3%) was added dropwise to the white suspension within 1 hour. A clear solution formed during the acid addition, and the product began to precipitate after the acid addition was complete. The resulting suspension was stirred at room temperature for 1 hour, followed by another hour of stirring while cooling with ice water. The resulting white solid in the form of crystals was filtered off and then washed with 14 ml of isopropanol and 14 ml of acetone. 3.68 g (85.3%) of crystalline nicotinamide-β-D-ribofuranoside bromide was obtained, having a melting point of 117°C. The melting point and IR data were consistent with those of the respective reference examples synthesized by known methods.

[0121] 1H-NMR (400 MHz, DO): 3.87 (dd, 1H, H5'), 4.01 (dd, 1H, H5'), 4.34 (m, 1H, H3'), 4.44 (q, 1H, H4'), 4.52 (t, 1H, H2'), 6.23 (d, 1H, H1'), 8.27 (t, 1H, H5), 8.96 (dt, 1H, H4), 9.24 (d, 1H, H6), 9.56 (s, 1H, H2). Impurities: <1 mol% nicotinamide; <0.5 mol% malic acid. Solvent: 2.3 mol% methanol.

[0122] 13 C-NMR (100MHz, D2O): 60.3 (C5'), 69.8 (C3'), 77.4 (C2'), 87.7 (C4'), 100.0 (C1 '), 128.5 (C5), 134.0 (C3), 140.4 (C2), 142.7 (C6), 145.7 (C4), 165.8 (CONH2).

[0123] Example 6b: Preparation of nicotinamide-β-D-riboside bromide using nicotinamide-β-D-riboside L-hydrogen maleate as the starting material and aqueous hydrobromic acid for ion exchange via salt metathesis 5 g (12.88 mmol) of nicotinamide-β-D-ribofuranoside L-hydrogen maleate was suspended in 20 ml of methanol at room temperature. 3.25 g (19.3 mmol, 1.5 equiv.) of aqueous hydrobromic acid (48% concentration) was added dropwise to the white suspension within 20 minutes. During the acid addition, a clear solution formed, and the product began to precipitate after the acid addition was complete. The resulting suspension was stirred at room temperature for 10 minutes, and then stirred for an additional 2 hours while cooling with ice water. The resulting white solid in the form of crystals was filtered off and then washed with 14 ml of isopropanol and 14 ml of acetone. 3.58 g (83%) of crystalline nicotinamide-β-D-ribofuranoside bromide was obtained in the form of white crystals with a melting point of 117°C. The melting point and NMR data were consistent with those of Example 6a.

[0124] Example 7: Preparation of nicotinamide-β-D-riboside chloride using nicotinamide-β-D-riboside L-hydrogen malate as the starting material and hydrogen chloride for ion exchange via salt metathesis 5 g (12.88 mmol) of nicotinamide-β-D-ribofuranoside L-hydrogen maleate was suspended in 20 ml of methanol. 3.20 ml (19.4 mmol, 1.5 equiv.) of a solution of hydrogen chloride (6.7 mole / kg) in ethanol was added within 1 hour. During the acid addition, a clear solution formed, and the product began to precipitate after the acid addition was complete. The resulting suspension was stirred at room temperature for 1 hour, followed by another hour of stirring while cooling with ice water. The resulting white solid in the form of crystals was filtered off and then washed with 14 ml of isopropanol and 14 ml of acetone. 2.88 g (76.9%) of crystalline nicotinamide-β-D-ribofuranoside chloride was obtained, having a melting point of 113°C. The XRD analysis was consistent with that of a reference sample synthesized by known methods.

[0125] Example 8: Preparation of nicotinamide-β-D-riboside tosylate using nicotinamide-β-D-riboside L-hydrogen maleate as the starting material and p-toluenesulfonic acid for ion exchange via salt metathesis 50 g (128.8 mmol) of nicotinamide-β-D-ribofuranoside L-hydrogen maleate was suspended in 250 ml of methanol. 36.8 g (193 mmol, 1.5 equiv.) of p-toluenesulfonic acid (as monohydrate) was added. A clear solution was obtained. The solvent was partially evaporated under vacuum at 40°C, whereupon the product began to precipitate. 500 ml of ethanol was added to the residue. The resulting suspension was stirred at room temperature for 1 hour. The resulting white solid in the form of crystals was filtered off and then washed with 140 ml of isopropanol and 140 ml of acetone. 49.8 g (90.7%) of crystalline nicotinamide-β-D-ribofuranoside tosylate was obtained, having a melting point of 124°C.

[0126] 1 H-NMR (400 MHz, DO): 3.81 (dd, 1H, H5'), 3.96 (dd, 1H, H5'), 4.27 (m, 1H, H3'), 4.40 (m, 2H, H4', H2'), 6.13 (d, 1H, H1'), 8.12 (t, 1H, H5), 8.80 (dt, 1H, H4), 9.13 (d, 1H, H6), 9.46 (s, 1H, H2); tosylate: 2.26 (s, 3H, CH3), 7.21 (d, 2H), 7.52 (d, 2H). Impurities: <1 mol% nicotinamide; malic acid not visible! Solvent: 1 mol% methanol, 0.3 mol% ethanol.

[0127] 13 C-NMR (100 MHz, DO): 60.2 (C5'), 69.8 (C3'), 77.4 (C2'), 87.7 (C4'), 99.9 (C1'), 128.3 (C5), 133.7 (C3), 139.5 (C2), 142.3 (C6), 145.5 (C4), 165.5 (CONH2); tosylate: 20.5 (CH3), 125.3 (2C), 129.4 (2C), 140.2, 142.5.

[0128] XRD: crystalline (Figure 10)

[0129] DSC: Peak from 129 to 132°C

[0130] Solubility in methanol While 1 g of NR·Br requires 50 ml of methanol for dissolution and 1 g of NR·Cl requires 40 ml of methanol for dissolution, 1 g of NR·p-tosylate requires only 15 ml of methanol. The greater solubility of NR·p-tosylate compared to NR·Cl may be advantageous for applications where solubility is required.

[0131] Example 9: Preparation of nicotinamide-β-D-riboside bromide Example 9a: Preparation of nicotinamide-β-D-riboside bromide using nicotinamide-β-D-riboside L-hydrogen tartrate as the starting material and hydrogen bromide in glacial acetic acid for ion exchange 5 g (12.37 mmol) of nicotinamide-β-D-ribofuranoside L-hydrogen tartrate was suspended in 25 ml of methanol at room temperature. 4.55 g (18.6 mmol, 1.5 equiv.) of a solution of hydrogen bromide in glacial acetic acid (33.3 wt %) was added dropwise to the white suspension within 1 hour. The suspension was stirred at room temperature for 3 hours, then stirred for another hour while cooling with ice water. The resulting white solid in the form of crystals was filtered off and then washed with 14 ml of isopropanol and 14 ml of acetone. 3.20 g (77.2%) of crystalline nicotinamide-β-D-ribofuranoside bromide was obtained, having a melting point of 118°C. This product was identical to the product from Example 6.

[0132] Example 9b. Preparation of nicotinamide-β-D-riboside bromide using nicotinamide-β-D-riboside L-hydrogen tartrate as the starting material and aqueous hydrobromic acid for ion exchange via salt metathesis The reaction was carried out similarly to Example 6b. Yield 79.4%. Melting point 117-118°C. The product was identical to the product from Example 9a.

[0133] Example 10: Preparation of nicotinamide-β-D-riboside chloride using nicotinamide-β-D-riboside L-hydrogen tartrate as starting material and hydrochloric acid for ion exchange via salt metathesis 5 g (12.37 mmol) of nicotinamide-β-D-ribofuranoside L-hydrogen tartrate was suspended in 20 ml of methanol. 1.75 ml (18.5 mmol, 1.5 equiv.) of hydrochloric acid (32.5%) was added within 1 hour. During the acid addition, a clear solution formed, and the product began to precipitate after the acid addition was complete. The resulting suspension was stirred at room temperature for 1 hour, and then stirred for another hour while cooling with ice water. The resulting white solid in the form of crystals was filtered off and then washed with 14 ml of isopropanol and 14 ml of acetone. 1.91 g (53.1%) of crystalline nicotinamide-β-D-ribofuranoside chloride was obtained, having a melting point of 114°C. This product was identical to the product from Example 7.

[0134] Example 11: Preparation of nicotinamide-β-D-riboside tosylate using nicotinamide-β-D-riboside L-hydrogen tartrate as the starting material 5 g (12.37 mmol) of nicotinamide-β-D-ribofuranoside L-hydrogen tartrate was suspended in 20 ml of methanol. 3.54 g (18.6 mmol, 1.5 equiv.) of p-toluenesulfonic acid (as monohydrate) was added. A clear solution was obtained. The solvent was evaporated, and 5 ml of methanol was added to the oily residue. After the addition of 20 ml of isopropanol, the product began to precipitate. The resulting suspension was stirred at room temperature for 1 hour. The resulting white solid in the form of crystals was filtered off and then washed with 15 ml of isopropanol and 15 ml of acetone. 4.33 g (82.2%) of crystalline nicotinamide-β-D-ribofuranoside tosylate was obtained, having a melting point of 120°C. The XRD analysis was consistent with that of the product from Example 8.

[0135] Example 12: Preparation of nicotinamide riboside tosylate Example 12a: Preparation of nicotinamide riboside tosylate from the triflate salt of triacetylnicotinamide riboside in methanol 4 g (7.54 mmol) of nicotinamide-β-D-riboside-2,3,5-triacetate triflate was dissolved in 6 ml of methanol at room temperature. 1.74 g (9.05 mmol; 1.2 equiv.) of p-toluenesulfonic acid (as monohydrate) was added. The yellow solution was stirred overnight at room temperature, and the product began to precipitate. The solid was filtered off and washed twice with isopropanol. Yield: 1.22 g (38%), melting point: 126 °C.

[0136] 1 H-NMR (400 MHz, DO): 3.80 (dd, 1H, H5'), 3.94 (dd, 1H, H5'), 4.26 (m, 1H, H3'), 4.38 (m, 2H, H4', H2'), 6.12 (d, 1H, H1'), 8.08 (t, 1H, H5), 8.78 (dt, 1H, H4), 9.11 (d, 1H, H6), 9.42 (s, 1H, H2); tosylate: 2.23 (s, 3H, CH3), 7.17 (d, 2H), 7.49 (d, 2H). Impurity: <1 mol% nicotinamide. Solvent: 0.5 mol% methanol, 0.1 mol% isopropanol.

[0137] 13 C-NMR (100 MHz, DO): 60.2 (C5'), 69.8 (C3'), 77.5 (C2'), 87.7 (C4'), 99.9 (C1'), 128.3 (C5), 133.8 (C3), 139.5 (C2), 142.2 (C6), 145.4 (C4), 165.4 (CONH2); tosylate: 20.5 (CH3), 125.3 (2C), 129.4 (2C), 140.1, 142.5.

[0138] Example 12b: Preparation of nicotinamide riboside tosylate from the triflate salt of triacetylnicotinamide riboside in ethanol 4 g (7.54 mmol) of nicotinamide-β-D-riboside-2,3-5-triacetate triflate was dissolved in 12 ml of ethanol at room temperature. 2.90 g (15.1 mmol; 2 equiv.) of p-toluenesulfonic acid (as monohydrate) was added. The yellow solution was stirred overnight at room temperature, whereupon the product began to precipitate. The solid was filtered off and washed twice with isopropanol. Yield 2.03 g (63%), melting point: 102 °C.

[0139] 1 H-NMR (400 MHz, DO): 3.78 (dd, 1H, H5'), 3.93 (dd, 1H, H5'), 4.24 (m, 1H, H3'), 4.36 (m, 2H, H4', H2'), 6.10 (d, 1H, H1'), 8.06 (t, 1H, H5), 8.73 (dt, 1H, H4), 9.08 (d, 1H, H6), 9.40 (s, 1H, H2); tosylate: 2.21 (s, 3H, CH3), 7.14 (d, 2H), 7.47 (d, 2H). Impurities: 4 mol% nicotinamide and impurities in the sugar region. Solvent: 2.7 mol% ethanol, 8.5 mol% isopropanol, 4.4 mol% acetone.

[0140] 13 C-NMR (100 MHz, DO): 60.2 (C5'), 69.8 (C3'), 77.5 (C2'), 87.7 (C4'), 99.9 (C1'), 128.3 (C5), 133.6 (C3), 139.5 (C2), 142.2 (C6), 145.4 (C4), 165.3 (CONH2); tosylate: 20.5 (CH3), 125.3 (2C), 129.4 (2C), 140.1, 142.4.

[0141] Example 13a: Preparation of co-crystallized nicotinamide-β-D-ribofuranoside (chloride, iodide), the chloride and iodide present in a 1.5:1 ratio 5 g (12.88 mmol) of nicotinamide-β-D-ribofuranoside L-hydrogen maleate was dissolved in 7.8 ml (7.2 mmol) of 0.92 N HCl in a 250 ml round-bottom flask at room temperature with 1.9 ml (14.4 mmol) of HI (57% in water) (1.1 equivalents) and ethanol (0.56 equivalents). Addition of 10 ml of methanol and 26 ml of ethanol produced a light yellow emulsion, which redissolved almost completely with the addition of 3 ml of methanol. Very slow crystallization began (the crystallization rate can be accelerated by adding seed crystals). The suspension was further diluted with 60 ml of ethanol and stored overnight in the refrigerator. The pale yellow suspension was filtered, and the resulting solid was washed three times with ethanol. The solid was dried under vacuum at 25°C. Yield: 2.32 g of a yellow microcrystalline powder; melting point: 104°C.

[0142] 1 H-NMR (400 MHz, DO): 3.87 (dd, 1H, H5'), 4.01 (dd, 1H, H5'), 4.34 (m, 1H, H3'), 4.43 (q, 1H, H4'), 4.51 (t, 1H, H2'), 6.23 (d, 1H, H1'), 8.27 (t, 1H, H5), 8.95 (dt, 1H, H4), 9.25 (d, 1H, H6), 9.55 (s, 1H, H2). Impurities: <0.5 mol% nicotinamide; <0.2 mol% malic acid. Solvent: 0.7 mol% ethanol.

[0143] 13 C-NMR (100MHz, D2O): 60.3 (C5'), 69.8 (C3'), 77.4 (C2'), 87.7 (C4'), 100.0 (C1 ), 128.5(C5), 134.0(C3), 140.4(C2), 142.7(C6), 145.7(C4), 165.8(CONH2).

[0144] The following table shows the results when nicotinamide-β-D-ribofuranoside L-hydrogen malate used as starting material is subjected to a mixture of HCl (32.5% by weight in water, 1N HCl in ethanol, respectively) and HI (57% by weight in water) according to step (A) of the process as defined in the first aspect of the present invention: [Table 15]

[0145] The table shows that the iodide content in the crystals correlates with the iodide content in the solution used for counterion exchange, however the general trend is that less iodide is incorporated into the crystal lattice than is present in the solution compared to the chloride content.

[0146] The table below shows the melting points measured at a heating rate of 1°C / min: [Table 16]

[0147] The table below shows the solubility in mL solvent per g of co-crystallized nicotinamide-β-D-ribofuranoside (chloride / iodide) compared to nicotinamide-β-D-ribofuranoside L-hydrogen maleate and nicotinamide-β-D-ribofuranoside chloride in methanol: [Table 17]

[0148] The solubility of the co-crystallized salt is significantly better than that of the pure chloride. The solubility increases with increasing iodide content. Consequently, co-crystallized nicotinamide-β-D-ribofuranoside (chloride / iodide) should allow for tailor-made solubility determined by the chloride / iodide ratio. This is advantageous from an application point of view.

[0149] Example 14: Preparation of nicotinamide-β-D-ribofuranoside bromide from nicotinamide-β-D-ribofuranoside tosylate 1.5 g (3.52 mmole) of nicotinamide-β-D-ribofuranoside tosylate prepared according to Example 12a was suspended in 7.5 ml of methanol in a 50 ml round-bottom flask. 1.25 ml (7.14 mmole) of HBr (33% in glacial acetic acid) was added at room temperature. The suspension began to dissolve. The remaining solid dissolved upon slight warming. The product began to precipitate. The suspension was stirred at room temperature for 1 hour. The white suspension was filtered, and the resulting solid was washed with 2 ml of methanol, followed by 5 ml of a 1:1 mixture of methanol and ethanol, and finally 5 ml of ethanol. The solid was dried under vacuum at 25°C. Yield: 0.77 g (65.3%) of a white crystalline solid; melting point 120.5°C.

[0150] 1 H-NMR (400 MHz, DO): 3.87 (dd, 1H, H5'), 4.01 (dd, 1H, H5'), 4.33 (m, 1H, H3'), 4.44 (q, 1H, H4'), 4.50 (t, 1H, H2'), 6.23 (d, 1H, H1'), 8.26 (t, 1H, H5), 8.95 (dt, 1H, H4), 9.24 (d, 1H, H6), 9.56 (s, 1H, H2). Impurities: <0.1 mol% nicotinamide; <0.1 mol% residual tosylate. Solvent: 0.7 mol% methanol.

[0151] 13 C-NMR (100MHz, D2O): 60.3 (C5'), 69.8 (C3'), 77.4 (C2'), 87.7 (C4'), 100.0 (C1 '), 128.5 (C5), 134.0 (C3), 140.4 (C2), 142.7 (C6), 145.7 (C4), 165.8 (CONH2).

[0152] Example 15: Preparation of nicotinamide-β-D-ribofuranoside chloride from nicotinamide-β-D-ribofuranoside tosylate 1.5 g (3.52 mmole) of nicotinamide-β-D-ribofuranoside tosylate prepared according to Example 12a was suspended in 6 ml of methanol in a 50 ml round-bottom flask. The suspension was heated to 60°C, at which point the solid completely dissolved. 1.00 ml (10.6 mmole) of HCl 32.5% was added. Upon seeding, the product began to precipitate. The suspension was stirred at room temperature for 3 hours. The white suspension was filtered, and the resulting solid was washed three times with 2 ml of ethanol each. The solid was dried under vacuum at 25°C. Yield: 0.57 g (55.8%) of a white crystalline solid; melting point: 119°C.

[0153] 1 H-NMR (400 MHz, DO): 3.84 (dd, 1H, H5'), 4.00 (dd, 1H, H5'), 4.30 (m, 1H, H3'), 4.42 (q, 1H, H4'), 4.46 (t, 1H, H2'), 6.20 (d, 1H, H1'), 8.22 (t, 1H, H5), 8.92 (dt, 1H, H4), 9.21 (d, 1H, H6), 9.54 (s, 1H, H2). Impurities: <0.1 mol% nicotinamide; 0.9 mol% residual tosylate. Solvent: 0.6 mol% methanol.

[0154] 13 C-NMR (100MHz, D2O): 60.3 (C5'), 69.8 (C3'), 77.4 (C2'), 87.7 (C4'), 100.0 (C1 '), 128.5 (C5), 134.0 (C3), 140.4 (C2), 142.7 (C6), 145.7 (C4), 165.8 (CONH2).

Claims

1. A method for producing nicotinamide-β-D-ribofuranoside salt NR + Y −, comprising the following steps (A): (A) subjecting nicotinamide-β-D-ribofuranoside hydrogen malate or nicotinamide-β-D-ribofuranoside hydrogen tartrate to salt metathesis, including counterion exchange, to provide a nicotinamide-β-D-ribofuranoside salt; the nicotinamide-β-D-ribofuranoside hydrogen malate or nicotinamide-β-D-ribofuranoside hydrogen tartrate reacts with an acid H + Y − , the acid having a pK a of 2 or less; and wherein the salt metathesis is carried out in (i) an alcohol selected from methanol, ethanol, propanol, or butanol, or a mixture of two or more thereof, wherein the alcohol or the mixture may contain water, or (ii) a solvent comprising methanol, ethanol, propanol, or butanol, or a mixture of two or more thereof, wherein the solvent or the alcohol may contain water.

2. 2. The method of claim 1, wherein the hydrogen malate is D-, L-, or DL-hydrogen malate, or the hydrogen tartrate is D-, L-, or DL-hydrogen tartrate.

3. 3. The method of claim 1, wherein the nicotinamide-β-D-ribofuranoside hydrogen maleate or nicotinamide-β-D-ribofuranoside hydrogen tartrate is in the form of a crystalline salt.

4. A method described in any one of claims 1 to 3, wherein the acid is selected from hydrobromic acid, hydrochloric acid and p-toluenesulfonic acid, and the counterion is selected from chloride, bromide and tosylate.

5. The following step (X) is carried out before the step (A): (X) A salt of nicotinamide-β-D-ribofuranoside and a counter ion, wherein the counter ion is Cl － ,Br － , I － , C.F. ３ SO ３ － , n-C ４ F ９ SO ３ － , FSO ３ － and ClO ４ － wherein the nicotinamide-β-D-ribofuranoside hydrogen malate or nicotinamide-β-D-ribofuranoside hydrogen tartrate is selected from the group consisting of: The method according to any one of claims 1 to 4, comprising:

6. In the counterion exchange described in step (A), more than one counterion is used, or more than one acid H is used in step (A). ＋ Y － The method according to any one of claims 1 to 5, wherein

7. The method of claim 6 wherein two counterions are used.

8. 8. The method of claim 6 or 7, wherein the counterion is selected from chloride and iodide.

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