Method for producing nicotinamide ribofuranoside salts, nicotinamide ribofuranoside salts themselves, and uses thereof

Abstract

The present invention relates to a method for preparing nicotinamide ribofuranoside salts, particularly pharmaceutically acceptable nicotinamide ribofuranoside salts. The present invention further relates to the nicotinamide ribofuranoside salts themselves, particularly carboxylic acid salts in crystalline form, and their use in dietary supplements and pharmaceutical compositions.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a method for preparing nicotinamide ribofuranoside salts, particularly pharma- ceutically acceptable nicotinamide ribofuranoside salts. The present invention further relates to the nicotinamide ribofuranoside salts themselves, particularly the carboxylate salts in crystalline form, and their use in dietary supplements and pharmaceutical compositions. [Background technology]

[0002] 2. Background of the Invention Nicotinamide riboside (nicotinamide-β-D-ribofuranoside; CAS number 1341-23-7) with the following chemical formula: [ka] is nicotinamide adenine dinucleotide (NAD + / NADH) and nicotinamide adenine dinucleotide phosphate (NADP + / NADPH). In addition, nicotinamide riboside is an equivalent of niacin (vitamin B3).

[0003] Nicotinamide riboside inhibits NAD synthesis in liver and skeletal muscle + It has been reported that acetylcholinesterase (ADH) increases NAD levels in the cerebral cortex and prevents weight gain in mice fed a high-fat diet. It has also been reported that ADH increases NAD levels in the cerebral cortex in a transgenic mouse model of Alzheimer's disease. + Increases levels of nicotinamide, and inhibits cognitive decline. For these reasons, nicotinamide riboside salts have been proposed for use in dietary supplements and pharmaceutical compositions. In fact, the chloride salt of nicotinamide-β-D-ribofuranoside is a commercially available dietary supplement.

[0004] However, the widespread application of these compounds as dietary supplements has been limited by preparation methods that have low yields, poor stereoselectivity, and / or use expensive and / or hazardous reagents, or result in pyridinium salts with pharma- ceutical unsuitable counterions. Many known synthetic methods are therefore unsuitable for large-scale, commercial synthesis.

[0005] WO2016 / 014927 discloses crystalline forms of nicotinamide riboside chloride that are described as having advantageous properties, such as ease of purification, compared to amorphous forms of nicotinamide riboside salts.

[0006] WO2017 / 218580 discloses synthetic methods for preparing nicotinamide riboside salts, including salts containing pharma- ceutically acceptable anions. The methods may include converting one pharma- ceutically acceptable counterion of a nicotinamide-β-D-ribofuranoside moiety to another pharma- ceutically acceptable counterion through ion exchange chromatography or a salt exchange reaction and precipitation. In certain embodiments, the methods described include converting a salt of nicotinamide riboside or an analog thereof, where the salt is not a chloride salt, to its corresponding chloride salt.

[0007] WO2015 / 186068 A1 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.

[0008] CN108774278 discloses the reaction of nicotinamide triacetyl ribofuranoside triflate with a base to deacetylate the furanoside. The deacetylated product is then treated with an acid to give the corresponding salt product.

[0009] However, for certain applications, alternative pharma- ceutically acceptable salts of nicotinamide riboside, as well as methods that allow for their preparation in an inexpensive, efficient and convenient manner, are desired.

[0010] Object of the invention Thus, there is a need in the art for pharma- ceutically acceptable nicotinamide ribofuranoside salts, preferably crystalline salts, and methods for producing pharma-ceutically acceptable nicotinamide ribofuranoside salts in high purity and yield at low cost and on an industrial scale. Summary of the Invention

[0011] Summary of the Invention This object has been achieved by a process which uses nicotinamide-β-D-ribofuranoside bromide or nicotinamide-β-D-ribofuranoside trifluoromethanesulfonate as starting materials for the preparation of nicotinamide-β-D-ribofuranoside salts other than its bromide and triflate salts via salt metathesis involving a counterion exchange reaction.

[0012] Nicotinamide-β-D-ribofuranoside nonafluorobutanesulfonate, nicotinamide-β-D-ribofuranoside fluorosulfonate or nicotinamide-β-D-ribofuranoside percolate are other suitable starting materials in the process according to the invention.

[0013] In yet another embodiment, nicotinamide-β-D-ribofuranoside chloride or iodide is used as a starting material in the process according to the invention.

[0014] In one embodiment, it is preferred to use nicotinamide-β-D-ribofuranoside bromide and nicotinamide-β-D-ribofuranoside trifluoromethanesulfonate, and especially nicotinamide-β-D-ribofuranoside iodide, as starting materials.

[0015] In a preferred embodiment, a nicotinamide-β-D-ribofuranoside salt is made available via the method according to the invention, where the salt may advantageously be provided in crystalline form.

[0016] According to a first aspect, the present invention relates to a method for preparing a nicotinamide-β-D-ribofuranoside salt, comprising the following steps (A): (A) subjecting nicotinamide-β-D-ribofuranoside bromide, nicotinamide-β-D-ribofuranoside chloride, nicotinamide-β-D-ribofuranoside iodide, nicotinamide-β-D-ribofuranoside trifluoromethanesulfonate, nicotinamide-β-D-ribofuranoside nonafluorobutanesulfonate, nicotinamide-β-D-ribofuranoside fluorosulfonate or nicotinamide-β-D-ribofuranoside percolate to salt metathesis involving counterion exchange to provide a nicotinamide-β-D-ribofuranoside salt.

[0017] The nicotinamide-β-D-ribofuranoside salts produced by the above process are not bromides, iodides, triflates, nonaflates, fluorosulfonates or percolates.

[0018] According to a second aspect, the present invention relates to a method for preparing nicotinamide-β-D-ribofuranoside salt, comprising the steps (A) and (B) of: (A) 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 subjecting the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside nonafluorobutanesulfonate, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside fluorosulfonate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside percolate to salt metathesis involving counterion exchange to provide a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt; (B) deacylation of the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt to provide a nicotinamide-β-D-ribofuranoside salt.

[0019] The nicotinamide-β-D-ribofuranoside salts produced by the above process are not bromides, iodides, triflates, nonaflates, fluorosulfonates or percolates.

[0020] According to a third aspect, the present invention provides 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, The present invention relates to a method for producing a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt from 3,5-tri-O-acyl-β-D-ribofuranoside nonafluorobutanesulfonate, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside fluorosulfonate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside percolate, comprising the following step (A): (A) 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 subjecting the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside nonafluorobutanesulfonate, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside fluorosulfonate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside percolate to salt metathesis involving counterion exchange to provide a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt.

[0021] The nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salts produced by the above process are not bromides, iodides, triflates, nonaflates, fluorosulfonates or percolates.

[0022] According to a fourth aspect, the present invention relates to crystalline nicotinamide-β-D-ribofuranoside D-, L- or DL-hydrogen malate; or crystalline nicotinamide-β-D-ribofuranoside D-, L- or DL-hydrogen tartrate; each characterized by an X-ray powder diffraction pattern.

[0023] The nicotinamide-β-D-ribofuranoside salts prepared by the process of the present invention are often obtained in amorphous form and must subsequently be crystallized, if desired and possible.

[0024] However, the dealt with D-, L- or DL-hydrogen malates and D-, L- or DL-hydrogen tartrates can surprisingly be directly obtained through salt metathesis in crystalline form with high purity and excellent yield.This is very advantageous, for example, from the viewpoint of application and further processing.Therefore, it is proposed to use these salts in or as dietary supplements.Furthermore, the above salts can be provided as starting materials for producing further nicotinamide-β-D-ribofuranoside salts or related compounds.

[0025] According to a fifth aspect, the present invention relates to a dietary supplement comprising a nicotinamide-β-D-ribofuranoside salt obtainable by a process as described in the first or second aspect, or comprising a nicotinamide-β-D-ribofuranoside salt as described in the fourth aspect.

[0026] According to a sixth aspect, the present invention relates to a pharmaceutical composition comprising a nicotinamide-β-D-ribofuranoside salt obtainable by a process as described in the first or second aspect, or comprising a nicotinamide-β-D-ribofuranoside salt as described in the fourth aspect.

[0027] According to a seventh aspect, the present invention relates to a method for carrying out a chemical synthesis, comprising the steps (A) of: (A) providing a nicotinamide-β-D-ribofuranoside salt obtained by a process as described in the first or second aspect, or providing a compound as described in the fourth aspect.

[0028] According to an eighth aspect, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: (A) Tetra-O-acyl-β-D-ribofuranose of the following chemical formula: [ka] wherein each R is alkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl, preferably C 1-10R is independently selected from alkylcarbonyl and benzoyl, and more preferably acetyl, and wherein R is optionally C 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) independently substituted with one or more substituents selected from in the presence of 0.9 to 1.5 molar equivalents of trimethylsilyl triflate or iodide per mole of tetra-O-acyl-β-D-ribofuranose, Nicotinamide of the following formula [ka] reacting with The present invention relates to a method for producing nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside triflate or iodide, comprising the steps of:

[0029] In a ninth aspect, the present invention relates to a compound selected from nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside nonafluorobutanesulfonate, nicotinamide-β-D-ribofuranoside nonafluorobutanesulfonate, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside percolate, and nicotinamide-β-D-ribofuranoside percolate, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside iodide, nicotinamide-β-D-ribofuranoside iodide, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside fluorosulfonate, and nicotinamide-β-D-ribofuranoside fluorosulfonate. [Brief description of the drawings]

[0030] BRIEF DESCRIPTION OF THE DRAWINGS The invention is further illustrated by the accompanying drawings, in which: [Figure 1] FIG. 1 shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside D-hydrogen malate; [Diagram 2] FIG. 2 shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside L-hydrogen maleate; [Diagram 3] FIG. 3 shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside DL-hydrogen maleate; [Figure 4] FIG. 4 shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside D-hydrogen tartrate monohydrate; [Diagram 5] FIG. 5 shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside L-hydrogen tartrate; [Figure 6] FIG. 6 shows the powder X-ray pattern of crystalline nicotinamide-β-D-ribofuranoside DL-hydrogen tartrate; [Figure 7] FIG. 7 shows the powder X-ray pattern of crystalline nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside L-hydrogen tartrate; [Figure 8] FIG. 8 shows the powder X-ray pattern of crystalline nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside D-hydrogen tartrate; [Figure 9] FIG. 9 shows the powder X-ray pattern of crystalline anhydrous nicotinamide-β-D-ribofuranoside D-hydrogen tartrate; {x-axis: position [°2θ] (copper (Cu)); y-axis: counts} DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Detailed Description of the Invention Various aspects of the invention will now be described in more detail with reference to the drawings.

[0032] First, second and third aspects: Method according to the invention According to a first aspect, the present invention provides a compound of the formula [ka] Anion X - =Br - , Cl - , I - , CF3SO3 - (triflate), n-C4F9SO3 - (Nonaflate), FSO3 - or ClO4 - via salt metathesis involving counterion exchange to anion Y - This relates to a method of replacing

[0033] Thus, in a first aspect, the present invention relates to a method for preparing a nicotinamide-β-D-ribofuranoside salt, comprising the steps (A) of: (A) subjecting nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate to salt metathesis involving counterion exchange to provide a nicotinamide-β-D-ribofuranoside salt.

[0034] In an alternative embodiment, according to the second aspect, there is provided a compound of formula: nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate [ka] , anion Y - Via Br - , Cl - , I - , CF3SO3 - , n-C4F9SO3 - , FSO3 - or ClO4 -The acyl group is then cleaved to provide the desired nicotinamide-β-D-ribofuranoside salt.

[0035] Thus, in a second aspect, the present invention relates to a method for preparing a nicotinamide-β-D-ribofuranoside salt, comprising the steps (A) and (B) of: (A) subjecting a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate to salt metathesis involving counterion exchange to provide a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt; and (B) deacylation of the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt to provide a nicotinamide-β-D-ribofuranoside salt.

[0036] If desired, the nicotinamide 2,3,5-tri-O-acyl-β-D-ribofuranoside salt obtained in step (A) may be used for a purpose other than that in step (B).

[0037] Thus, in a third aspect, the present invention relates to a method for preparing a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt, comprising the steps (A) of: (A) subjecting a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate to salt metathesis involving counterion exchange to provide a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt.

[0038] Nicotinamide-β-D-ribofuranosyl bromide [N1-(β-D-ribofuranosyl)-3-aminocarbonylpyridinium bromide] of the following formula as used in step (A) of the method described in the first aspect: [ka] is a well-known compound (CAS number 78687-39-5). For example, Lee et al. have disclosed a method for its chemical synthesis (Chem. Commun., 1999, 729-730). Further synthesis methods are disclosed in EP18173208.2, which is unpublished at the filing date of this application.

[0039] The above references also disclose the preparation of nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromides as precursors to nicotinamide-β-D-ribofuranoside bromide.

[0040] Nicotinamide-β-D-ribofuranosyl triflate [N1-(β-D-ribofuranosyl)-3-aminocarbonylpyridinium triflate] with the following chemical formula: [ka] is also a well-known compound (CAS number 445489-49-6).

[0041] 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 the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) in acetonitrile 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 (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).

[0042] Nicotinamide-β-D-ribofuranoside nonaflate and nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside nonaflate, respectively nicotinamide-β-D-ribofuranoside percolate and nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside percolate, 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 number 68734-62-3), respectively trimethylsilyl percolate (CAS number 18204-79-0) to provide nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside nonaflate, respectively percolate. The acyl group can then be cleaved by known methods to provide the nicotinamide-β-D-ribofuranoside nonaflate, respectively, percolate.

[0043] Nicotinamide-β-D-ribofuranoside chloride, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, nicotinamide-β-D-ribofuranoside iodide, 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 sulfonate are trimethylsilyl chloride (CAS number 75-77-4), trimethylsilyl iodide (CAS number 16029-98-4), trimethylsilyl fluorosulfonate (CAS number 16029-98-4), trimethylsilyl fluorosulfonate (CAS number 16029-98-4), trimethylsilyl iodide ... They can be prepared by reacting nicotinamide with tetra-O-acyl-β-D-ribofuranose in a solvent such as acetonitrile in the presence of 3167-56-4) to provide nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, iodide, or respective fluorosulfonate. The acyl group can then be cleaved by known methods to provide nicotinamide-β-D-ribofuranoside chloride, iodide, or respective fluorosulfonate.

[0044] As used in this disclosure, the term "salt metathesis" is used synonymously with terms such as "double replacement reaction," "double displacement reaction," or "double decomposition reaction." Salt metathesis, which exchanges counterions between two different salts, is a known technique.

[0045] Thus, step (A) defines a reaction in which a first salt, e.g., nicotinamide-β-D-ribofuranoside salt, NR + Br - (or Nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt AcONR + Br - ) Cat + and anion Y - and then subjected to salt metathesis with a suitable second salt containing NR + Br - (or AcONR + Br - ) in Br - Y - Through exchange with nicotinamide-β-D-ribofuranoside salt NR + Y - (or AcONR + Y - ) and Cat + Br - The reaction is summarized by the following equation:

[0046] NR + Br - (or AcONR + Br - )+Cat + Y - →NR + Y - (or AcONR + Y - )+Cat + Br -

[0047] The driving force for salt metathesis reactions such as those shown above is the formation of more stable salts as well as the removal of products from the chemical equilibrium of the reaction, e.g., the formed NR + Y - (AcONR + Y - ) or Cat + Br - Thus, in order to drive the reaction to the product, the educts must be selected in terms of favorable energy, respectively in terms of solubility in each other or in the solvent.

[0048] A similar mechanism applies to the reactions of the chloride, iodide, triflate, nonaflate, fluorosulfonate and percolate.

[0049] If the salt metathesis reaction is carried out in a solvent, the same effects on the reaction will be explained in more detail in the sections on each solvent below.

[0050] The term "salt metathesis" as used herein does not mean that the anion of the β-nicotinamide riboside is exchanged with another anion by ion exchange using an ion exchanger. Thus, the method described in step (A) excludes anion exchange with an ion exchanger.

[0051] However, the method does not exclude that an ion exchanger may be used in any reaction step before step (A) or after step (A).

[0052] The 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 trifluoride used in step (B) of the method according to the second embodiment The nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside nonafluorobutanesulfonate, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside fluorosulfonate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside percolate are known or can be prepared by known methods.

[0053] The term "acyl" in reference to nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salts, i.e., bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate thereof, means that acyl is alkylcarbonyl, arylcarbonyl and heteroarylcarbonyl, preferably C 1-10 is independently selected from alkylcarbonyl and benzoyl, and more preferably is acetyl, and wherein R is optionally C 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 each of the groups is independently substituted with one or more substituents selected from:

[0054] In one embodiment, 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).

[0055] In another embodiment, the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt is not purified prior to deacylation in step (B).

[0056] The deacylation (deprotection) in step (B) can be carried out by a method known in the art, for example, by subjecting the salt obtained in step (A) to an acid such as hydrogen bromide, hydrogen chloride, hydrogen iodide or sulfuric acid, or a base such as ammonia.

[0057] Preferred embodiments according to the first, second and third aspects: Nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate used in step (A) as starting material According to the present invention, the nicotinamide-β-D-ribofuranoside salt or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt used in step (A) is the bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, the bromide and triflate being sufficiently compatible compounds and therefore have been used in the art as starting materials for many subsequent process steps.

[0058] Furthermore, at least the nicotinamide-β-D-ribofuranoside bromide, or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide or nicotinamide-β-D-ribofuranoside chloride or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride may be provided in a crystalline form which is preferred for its purity with a view to producing further crystalline nicotinamide-β-D-ribofuranoside salts.

[0059] In a preferred embodiment, nicotinamide-β-D-ribofuranoside bromide or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide is used as disclosed in EP18173208.2 (unpublished as of the filing date of this application), which reference is incorporated herein in its entirety.

[0060] Thus, in one embodiment of the first aspect, the method according to the invention comprises, before step (A), the following steps (X) and (Y) and (Z): (X) Tetra-O-acyl-β-D-ribofuranose of the following formula: [ka] is exposed to hydrogen bromide in acetic acid to give tri-O-acyl-D-ribofuranoside bromide (in the form of a mixture of β- and α-anomers) of the following formula: [ka] providing; (Y) Tri-O-acyl-D-ribofuranoside bromide is converted to nicotinamide of the following formula: [ka] This is reacted with nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide of the following formula: [ka] providing; and (Z) The nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside obtained in step (Y) is deacylated by removing the R group using hydrogen bromide in acetic acid to obtain a nicotinamide-β-D-ribofuranoside bromide compound of the following chemical formula: [ka] wherein the nicotinamide-β-D-ribofuranoside bromide obtained in step (Z) is used in step (A).

[0061] Essentially, in other embodiments, acids different from HBr in acetic acid or bases such as ammonia may be used in the deacylation step (Z).

[0062] The nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide obtained in step (Y) is typically obtained in a mixture with the α-anomer, for example, the molar ratio β:α may be about 85:15.

[0063] Thus, in one embodiment, if no purification is performed at the stage of a mixture of β- and α-anomers, in a subsequent step the educt is also provided as a mixture of β- and α-anomers. Purification can result in the pure β-anomer.

[0064] In another embodiment, nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide may be purified to obtain the pure β-anomer before cleavage of the acyl group is carried out.

[0065] According to another embodiment of the first aspect, the present invention relates to a method comprising, before step (A), the steps (X) and (Y) (X) Tetra-O-acyl-β-D-ribofuranose of the following formula: [ka] wherein each R is alkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl, preferably C 1-10 R is independently selected from alkylcarbonyl and benzoyl, and more preferably acetyl, and wherein R is optionally C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Thioalkyl, halogen, nitro, cyano, NH(C1-6 alkyl), N(C 1-6 alkyl)2, and SO2N(C 1-6 alkyl) independently substituted with one or more substituents selected from in the presence of trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, trimethylsilyl triflate, trimethylsilyl nonaflate, trimethylsilyl fluorosulfonate or trimethylsilyl percolate to produce nicotinamide of the following formula: [ka] and nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaflate, fluorosulfonate or percolate of the following chemical formula, respectively. [ka] providing; (Y) The nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaflate or percolate obtained in step (X) is deacylated by removing the R group to obtain a nicotinamide-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaflate, fluorosulfonate or percolate compound of the following chemical formula: [ka] wherein the nicotinamide-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaflate, fluorosulfonate or percolate formed in step (Y) is used in step (A).

[0066] In one embodiment of the second aspect, the method according to the invention comprises, before step (A), the following steps (X) and (Y): (X) Tetra-O-acyl-β-D-ribofuranose of the following formula: [ka] is exposed to hydrogen bromide in acetic acid to give tri-O-acyl-D-ribofuranoside bromide (in the form of a mixture of β- and α-anomers) of the formula [ka] providing; (Y) Tri-O-acyl-D-ribofuranoside bromide is converted to nicotinamide of the following formula: [ka] This is reacted with nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide of the following formula: [ka] wherein the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide obtained in step (Y) is used in step (A).

[0067] The product obtained in step (Y) can also be used in the process described in the third embodiment.

[0068] R is alkylcarbonyl, arylcarbonyl and heteroarylcarbonyl, preferably C 1-10 an acyl group independently selected from alkylcarbonyl and benzoyl, and more preferably acetyl, where R is optionally C 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 1-6and each of the groups is independently substituted with one or more substituents selected from:

[0069] The term "acyl," which is used synonymously with the term "acyl group" in nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, means that the acyl group may be independently selected from alkylcarbonyl, arylcarbonyl, or heteroarylcarbonyl.

[0070] The term "alkylcarbonyl" is used interchangeably with the term "alkanoyl."

[0071] In one embodiment, R is alkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl, preferably C 1-10 It is independently selected from alkylcarbonyl and benzoyl, and is preferably acetyl.

[0072] In one embodiment, the acyl can be substituted.

[0073] In one embodiment, the acyl may be independently substituted with one or more of the following substituents: 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.

[0074] In one embodiment, acyl is a C yl such as formyl, acetyl, propionyl, butyryl, valeryl, or cyclohexyl. 1-6 and alkanoyl, optionally substituted with one or more substituents as described above.

[0075] In another embodiment, acyl is benzoyl or naphthoyl, preferably benzoyl, optionally substituted with one or more substituents described above.

[0076] The tetra-O-acyl-β-D-ribofuranoses are known compounds or can be prepared by known methods.

[0077] In a preferred embodiment, commercially available tetra-O-acetyl-β-D-ribofuranose (CAS number 13035-61-5) of the formula: [ka] is used in step (X) to provide 2,3,5-tri-O-acyl-D-ribofuranoside bromide.

[0078] The nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide obtained in step (Y) is typically produced as a mixture of anomers, such as a mixture of β and α anomers, with a β:α ratio of about 5:1 to 6:1.

[0079] In one embodiment, the crude nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide may be used in step (A) of the process according to the second aspect, i.e. may be subjected to salt metathesis. The salt formed is subsequently deacylated according to step (B) to provide the desired nicotinamide-β-D-ribofuranoside salt.

[0080] In another embodiment, the crude nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide may be used in step (Z) to obtain nicotinamide-β-D-ribofuranoside bromide via deacylation. The nicotinamide-β-D-ribofuranoside bromide may then be used in step (A) of the process according to the first aspect to provide the desired nicotinamide-β-D-ribofuranoside salt via salt metathesis.

[0081] In yet another embodiment, it may be advantageous to purify and crystallize the crude nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide obtained in step (Y) prior to step (Z). Using purified and crystallized nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide in the deacylation (deprotection) step according to step (Z) may improve the propensity of the nicotinamide-β-D-ribofuranoside bromide to crystallize and thus be in substantially pure form.

[0082] Preferably, the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide obtained in step (Y) can be recrystallized from acetone to obtain the pure β-anomer.

[0083] Thus, in one embodiment, the method further comprises the step (Y1): (Y1) A step of purifying the product obtained in step (Y).

[0084] Preferably, the purification according to step (Y1) is a crystallization or recrystallization.

[0085] The yield over steps (X), (Y) and (Y1) is typically in the range of 40-50%.

[0086] In one embodiment, the purified nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide can be used in step (A) described in the second aspect, i.e. subjected to salt metathesis. The formed salt is subsequently deacylated by step (B) to provide the desired nicotinamide-β-D-ribofuranoside salt.

[0087] In another embodiment, the purified nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide is deacylated to obtain nicotinamide-β-D-ribofuranoside bromide which can be used in step (A) of the process according to the first aspect to provide the desired nicotinamide-β-D-ribofuranoside salt via salt metathesis.

[0088] When step (A) described in the first embodiment is carried out, the acyl group of the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide obtained in step (Y) or (Y1) must be cleaved, i.e. the protected hydroxyl group is deprotected.

[0089] Essentially any method known in the art can be used to remove the acyl group from the protected OH group. The cleavage can be advantageously carried out with hydrogen bromide in acetic acid.

[0090] The method can also be beneficially carried out on a larger scale.

[0091] Nicotinamide-β-D-ribofuranoside bromide often precipitates in crystalline form directly from the solution obtained in the deprotection step.

[0092] Crystalline nicotinamide-β-D-ribofuranoside bromide can be obtained with a purity of 97% or more, i.e., almost free of the α-anomer and containing only traces of nicotinamide, which is used to substitute for the bromide in the tri-O-acyl-β-D-ribofuranoside bromide, respectively, to neutralize the excess hydrogen bromide.

[0093] If necessary, the nicotinamide-β-D-ribofuranoside bromide may be further purified, preferably by recrystallization. A suitable solvent is, for example, methanol.

[0094] In a preferred embodiment, the method further comprises the step (Z1): (Z1) A step of purifying the product obtained in step (Z).

[0095] In a preferred embodiment, the purification according to step (Z1) comprises or is a crystallization or recrystallization.

[0096] The yield over steps (Z) and (Z1) is typically in the range of 60-70%.

[0097] Advantageously, other salts, preferably crystalline salts, whose anion is preferably a pharma- ceutically acceptable anion, can be prepared starting from the bromide or triflate thereof via salt metathesis according to the method of the invention.

[0098] Preferably, nicotinamide-β-D-ribofuranoside hydrogen malate and nicotinamide-β-D-ribofuranoside hydrogen tartrate may be synthesized as well as their 2,3,5-O-triacyl compounds, preferably in crystalline form.

[0099] In another embodiment of the second aspect, the present invention relates to a method comprising, prior to step (A), the step (X): (X) Tetra-O-acyl-β-D-ribofuranose of the following formula: [ka] wherein each R is alkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl, preferably C 1-10 R is independently selected from alkylcarbonyl and benzoyl, and more preferably acetyl, and wherein R is optionally C 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) independently substituted with one or more substituents selected from in the presence of trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, trimethylsilyl triflate, trimethylsilyl nonaflate, trimethylsilyl fluorosulfonate or trimethylsilyl percolate to produce nicotinamide of the following formula: [ka] and obtaining nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaflate, fluorosulfonate or percolate of the following chemical formula: [ka] wherein the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaflate, fluorosulfonate or percolate formed in step (X) is used in step (A).

[0100] Pharmaceutically acceptable ions Preferably, salt Cat + Y - The counterion Y of the salt obtained in step (A) via counterion exchange derived from - is a pharma-ceutically acceptable ion.

[0101] As used herein, the term "pharmacologically acceptable ion" includes ions selected from the group consisting of: Inorganic ions; or Carboxylate, where the carboxylic acid from which the carboxylate is derived is carboxyl, hydroxyl, thio, keto, amino, mono C 1-6 Alkyl, Hydroxy C 1-6 Alkylene and di(C 1-6 (alkyl)amino; C 1-12 Alkyl sulfonates; or Aryl sulfonates, where the aryl moiety is carboxyl, hydroxyl, amino, mono-C 1-6 Alkyl and di(C 1-6 Alkyl)amino, halogen, C 1-6 is optionally substituted with one or more substituents independently selected from the group consisting of alkyl; and wherein the pharma- ceutically acceptable salt is not a bromide or iodide or triflate or nonaflate or fluorosulfonate or percolate.

[0102] In a preferred embodiment, the above The inorganic ion is selected from the group consisting of chloride, hydrogen sulfate, sulfate, dihydrogen phosphate, monohydrogen phosphate, phosphate, nitrate, hydrogen carbonate and carbonate; The carboxylate is selected from the group consisting of formate, acetate, oxalate, malonate, succinate, fumarate, maliate, citrate, malate, tartrate, ascorbate, glucuronate, α-ketoglutarate, benzoate and salicylate; C 1-12 The alkylsulfonates are selected from the group consisting of mesylates and camsylates; The arylsulfonates are selected from the group consisting of besylates and tosylates.

[0103] In a preferred embodiment, the pharma- ceutically acceptable ion is malate.

[0104] In a particularly preferred embodiment, the pharma- ceutically acceptable ion is hydrogen malate.

[0105] The term "hydrogen malate" means monocarboxylate.

[0106] In more particularly preferred embodiments, the hydrogen malate is the D-, L- or DL-stereoisomer.

[0107] In a more preferred embodiment, the pharma- ceutical acceptable anion is tartrate.

[0108] In a particularly preferred embodiment, the pharma- ceutical acceptable anion is hydrogen tartrate.

[0109] The term "hydrogen tartrate" refers to monocarboxylate.

[0110] In further particularly preferred embodiments, the hydrogen tartrate ion is the D-, L- or DL-stereoisomer.

[0111] The preparation of the D-, L- or DL-stereoisomers of hydrogen malate or hydrogen tartrate is particularly preferred since the process according to the invention can provide these compounds in high yields and with a degree of crystallinity which is particularly advantageous in terms of handling and further processing of the salts.

[0112] Typically, the crystalline compound is already obtained directly in the salt metathesis reaction.

[0113] This is advantageous 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.

[0114] Nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate and a pharma- ceutically acceptable ion Y, which is subjected to salt metathesis. - About Cat + Nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, can be subjected to salt metathesis using essentially any salt having a pharma-ceutically acceptable anion.

[0115] Cation Cat used in reference to pharma- ceutically acceptable anions includes, but is not limited to, + is preferably derived from an ammonium or phosphonium salt.

[0116] Preferably, in one embodiment, the cation of the salt is [NR 1 R 2 R 3 R 4 ] + where R 1 , R 2 , R 3 and R 4 , H, C 1-12 It is independently selected from alkyl and aryl and is optionally substituted.

[0117] In one embodiment, the cation of the salt is NH4 + It is.

[0118] In a preferred embodiment, the cation of the salt is derived from a primary ammonium salt, i.e., the cation of the salt is [NR 1 H3] + where R 1 is C 1-12 It is selected from alkyl and aryl and is optionally substituted.

[0119] In another preferred embodiment, the cation of the salt is derived from a secondary ammonium salt, i.e., the cation of the salt is [NR 1 R 2 H2] + where R 1 and R 2 is C1-12 It is independently selected from alkyl and aryl and is optionally substituted.

[0120] In a further preferred embodiment, [NR 1 R 2 R 3 R 4 ] + R in 1 , R 2 , R 3 and R 4 One of the is H. Therefore, the cation of the salt comes from the tertiary ammonium salt, i.e., the cation of the salt is [NR 1 R 2 R 3 H] + where R 1 , R 2 and R 3 is C 1-12 It is independently selected from alkyl and aryl and is optionally substituted.

[0121] In yet another embodiment, the cation is a quaternary ammonium salt. Thus, the cation of the salt is [NR 1 R 2 R 3 R 4 ] + where R 1 , R 2 , R 3 and R 4 is C 1-12 It is independently selected from alkyl and aryl and is optionally substituted.

[0122] In a preferred embodiment, [NR 1 R 2 R 3 R 4 ] + is [N(C2H5)4] + or [N(C4H9)4] + It is.

[0123] In a further preferred embodiment, R 1 , R 2 , R 3 or R 4One of them is benzyl.

[0124] In another embodiment, the cation of the salt is derived from an N-heteroaromatic system or an N-alkylated heteroaromatic system, such as pyridine or n-methylpyridine.

[0125] In another embodiment, the cation of the salt is [PR 1 R 2 R 3 R 4 ] + where R 1 , R 2 , R 3 and R 4 , H, C 1-12 It is independently selected from alkyl and aryl and is optionally substituted.

[0126] In a further preferred embodiment, [PR 1 R 2 R 3 R 4 ] + R in 1 , R 2 , R 3 and R 4 One of them is H.

[0127] It is also contemplated that lithium or sodium salts containing pharma- ceutically acceptable anions can be used in the salt metathesis reactions according to the present invention.

[0128] Suitable salts are commercially available or can be prepared by known methods, for example by reacting triethylamine or tributylamine or tetraethylammonium hydroxide or tetrabutylammonium hydroxide or benzyltrimethylammonium hydroxide with an acid such as sulfuric acid or a carboxylic acid such as malic acid or tartaric acid in a molar ratio capable of preparing a monovalent or divalent anion.

[0129] solvent The salt metathesis can be carried out without a solvent, i.e. by salt metathesis of a solid nicotinamide-β-D-ribofuranoside salt or a solid nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt with, for example, a liquid salt.

[0130] In a preferred embodiment, the salt metathesis in step (A) is carried out in the presence of a solvent.

[0131] The following non-limiting embodiments I, II, III or IV for carrying out the above-described salt metathesis reaction are preferred:

[0132] Embodiment I: The solvent is NR + Br - (or AcONR + Br - ) and Cat + Y - Both are soluble in the above solvent, but the NR obtained in step (A) + Y - (or AcONR + Y - ) does not dissolve in the above solvents and precipitates, while Cat + Br - is selected to be soluble. NR + Y - (or AcONR + Y - ) can then be isolated by filtration.

[0133] Embodiment II: The solvent is NR + Br - (or AcONR + Br - ) and Cat + Y - Both are soluble in the above solvent, but the NR obtained in step (A) + Y - (or AcONR + Y - ) is dissolved in the above solvent, while Cat + Br - is chosen so that it does not dissolve but precipitates. NR + Y- (or AcONR + Y - ) can then be isolated from the supernatant by known techniques, for example.

[0134] Embodiment III: The solvent is the NR obtained in step (A). + Br - and N.R. + Y - (or AcONR + Br - and AcONR + Y - ) is insoluble in the above solvents, whereas Cat + Br - and Cat + Y - Both are selected to be soluble. + Y - (or AcONR + Y - ) can then be isolated, for example, by filtration.

[0135] Embodiment IV: The solvent is the NR obtained in step (A). + Br - and N.R. + Y - (or AcONR + Br - and AcONR + Y - ) dissolves in the above solvents, while Cat + Y - and Cat + Br - is chosen so that it is not soluble. + Y - (or AcONR + Y - ) can then be isolated from the supernatant by known techniques, for example.

[0136] NR + Br - and AcONR + Br - Instead of NR + Cl -and AcONR + Cl - , N.R. + I - and AcONR + I - , N.R. + CF3SO3 - and AcONR + CF3SO3 - or NR + n-C4F9SO3 - and AcONR + n-C4F9SO3 - , N.R. + FSO3 - and AcONR + FSO3 - or NR + ClO4 - and AcONR + ClO4 - can also be used in embodiments I to IV.

[0137] Thus, by appropriate selection of the solvents used in the salt metathesis described in step (A), i.e., by defining a solubility chart, the outcome of the salt metathesis reaction can be predicted. A person skilled in the art can be expected to define such a solubility chart by routine experimentation.

[0138] In embodiment I, Cat + Y - Good results are provided when is an ammonium or phosphonium salt as described above, preferably an ammonium salt.

[0139] In a further preferred embodiment, embodiment I is characterized in that alcohol is used as the solvent or the solvent comprises alcohol, and Cat + Y - Good results are provided when is preferably an ammonium or phosphonium salt as described above, preferably an ammonium salt.

[0140] Preferably, the alcohol used in the salt metathesis is selected from the group consisting of methanol, ethanol, propanol or butanol, or a mixture of two or more thereof, optionally including water.

[0141] The inventors of the present invention have unexpectedly discovered that the nicotinamide-β-D-ribofuranoside and nicotinamide-triacyl-O-β-D-ribofuranoside salts formed provide an unusually high solubility differential compared to the nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, respectively, used in salt metathesis in certain alcohols, as is the method selected under the reaction conditions in embodiment I.

[0142] Preferably, in step (A), a saturated solution of nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate in one or more alcohols as described above, optionally containing water, and a suitable ammonium or phosphonium salt are combined with each other, whereby step (A) is carried out, i.e. the nicotinamide-β-D-ribofuranoside salt or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt produced by counterion exchange precipitates and can be isolated by filtration.

[0143] The term "saturated solution" refers to, in a preferred embodiment, NR + Br - (or AcONR + Br - ) and Cat + Y -This means that a concentrated solution of the compound is prepared such that the solubility limit at 23°C is not exceeded.

[0144] In another preferred embodiment, the term "saturated solution" refers to NR + Br - , N.R. + Cl - , N.R. + I - , N.R. + CF3SO3 - , N.R. + n-C4F9SO3 - , N.R. + FSO3 - , or N.R. + ClO4 - (or AcONR + Br - , AcONR + Cl - , AcONR + I - , AcONR + CF3SO3 - , AcONR + n-C4F9SO3 - , AcONR + FSO3 - or AcONR + ClO4 - ) and Cat + Y - This means that a concentrated solution of the compound is prepared such that the solubility limit at 23°C is not exceeded.

[0145] Preferably, the salt metathesis reaction according to step (A) is carried out at ambient temperature, ie in the range of 5-60°C, preferably 10-40°C.

[0146] It will be apparent that the salt metathesis reaction described in step (A) is not limited to the ammonium or phosphonium salts and alcohols described above.

[0147] In a preferred embodiment, the present invention relates to a method for preparing nicotinamide-β-D-ribofuranoside salts or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salts, wherein step (A) as described in the first and second aspects comprises at least the following steps (A1) and (A2): (A1) NH3 or NR 1 H2 or NR 1 R 2 H or NR 1 R 2 R 3 or [NR 1 R 2 R 3 R 4 ]OH with an acid preferably containing a pharma- ceutically acceptable anion to provide the respective ammonium salt, wherein R 1 , R 2 , R 3 and R 4 is C 1-12 It is independently selected from alkyl and aryl and is optionally substituted. (A2) reacting nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, with the ammonium salt from step (A1) to carry out salt metathesis involving counterion exchange to provide a nicotinamide-β-D-ribofuranoside salt or a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt, where acyl has the meaning given above.

[0148] In a preferred embodiment, NR 1 R 2 R 3 or [NR 1 R 2 R 3 R 4 ]OH is used in step (A1).

[0149] Similarly, in another embodiment, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: (A1)PH3 or PR 1 H2 or PR 1 R 2 H or PR 1 R 2 R 3 or [PR 1 R 2 R 3 R 4 ]OH with an acid to provide the respective phosphonium salt, wherein R 1 , R 2 , R 3 and R 4 is C 1-12 It is independently selected from alkyl and aryl and is optionally substituted. (A2) reacting nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, with the phosphonium salt from step (A0) in a salt metathesis involving counterion exchange to provide a nicotinamide-β-D-ribofuranoside salt or a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt, where acyl has the meaning given above. The present invention relates to a method for producing a nicotinamide-β-D-ribofuranoside salt or a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt.

[0150] In a preferred embodiment, PR 1 R 2 R 3 or [PR 1 R 2 R 3 R 4 ]OH is used in step (A1).

[0151] Further precipitation If necessary, the product obtained in step (A) or step (B) may be purified by known methods to obtain the pure β-anomer.

[0152] In one embodiment, the product may be recrystallized.

[0153] In another embodiment, the product may be dissolved in a suitable solvent and then precipitated by the addition of a solvent in which the product is insoluble.

[0154] Thus, the method described in the first, second or third aspect further comprises the step (C) of: (C) purifying the salt obtained in step (A) or (B), preferably by crystallization.

[0155] In one embodiment, the process according to the invention can start in step (A) from the pure β-anomer, i.e. pure nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, or pure nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate.

[0156] The term "pure" means that nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, or nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate may contain up to 5% of the α-anomer.

[0157] In one embodiment, the salt is provided in isolated form, and optionally purified, prior to use in step (A).

[0158] In another embodiment, the process may start in step (A) with the β-anomer containing 5% or more of the α-anomer, i.e., crude nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, or crude nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate.

[0159] In one embodiment, the salts are provided in dissolved form, i.e. non-purified, produced in their respective synthesis prior to their use in step (A).

[0160] In summary, the process according to the invention makes it possible to advantageously prepare nicotinamide-β-D-ribofuranoside salts by various routes starting from either the pure β-anomer or the β-anomer, including the α-anomer, preferably by routes (P1) to (P5).

[0161] Pathway (P1) comprises the following steps (α), (β), (γ) and (δ): (α) cleaving the acyl group of nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate, containing up to 5% of the α-anomer, to provide nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate; (β) isolating and optionally purifying the nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate; (γ) subjecting nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate to salt metathesis to provide a nicotinamide-β-D-ribofuranoside salt; (δ) isolating and optionally purifying the nicotinamide-β-D-ribofuranoside salt.

[0162] Pathway (P2) comprises the following steps (α), (β), (γ) and (δ): (α) subjecting a nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate containing up to 5% of the α-anomer to salt metathesis to provide a nicotinamide-2,3,5-O-triacyl β-D-ribofuranoside salt; (β) isolating and optionally purifying nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside; (γ) cleaving the acyl group of the nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside salt to provide a nicotinamide-β-D-ribofuranoside salt; (δ) isolating and optionally purifying the nicotinamide-β-D-ribofuranoside salt.

[0163] Pathway (P3) includes the following steps (α) and (β): (α) cleaving the acyl group of a nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate containing up to 5% of the α-anomer to provide a nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, and subjecting the formed nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate to salt metathesis without prior isolation to provide a nicotinamide-β-D-ribofuranoside salt; (β) isolating and optionally purifying the nicotinamide-β-D-ribofuranoside salt.

[0164] Pathway (P4) includes the following steps (α), (β), (γ) and (δ): (α) subjecting a nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate containing at least 5% of the α-anomer to salt metathesis to provide a nicotinamide-2,3,5-O-triacyl β-D-ribofuranoside salt; (β) isolating and optionally purifying nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside; (γ) cleaving the acyl group of nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside salt to provide nicotinamide-β-D-ribofuranoside salt; (δ) isolating and optionally purifying the nicotinamide-β-D-ribofuranoside salt.

[0165] The step (P5) includes the following steps (α) and (β): (α) cleaving the acyl group of a nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate containing 5% or more of the α-anomer to provide a nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, and subjecting the formed nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate to salt metathesis without prior isolation to provide a nicotinamide-β-D-ribofuranoside salt; (β) isolating and optionally purifying the nicotinamide-β-D-ribofuranoside salt.

[0166] The term "without prior isolation" as used in pathways (P3) and (P5) denotes that the salt metathesis is carried out in situ.

[0167] Preferably, salts with pharma- ceutically acceptable anions are also formed in situ, ie, in the reaction mixture resulting from the acyl group cleavage step.

[0168] In one embodiment, various routes are illustratively shown in the following scheme starting from nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside bromide and preparing its L-hydrogen tartrate:

[0169] Scheme 1: Routes P1 to P5 for the preparation of nicotinamide-β-D-ribofuranoside L-hydrogen tartrate starting from nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside bromide [ka]

[0170] In another embodiment, various pathways P1 to P5 are exemplarily shown in Scheme 2 for the preparation of L-hydrogen tartrate starting from nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside triflate (pathways P2 and P3 are not shown): [ka]

[0171] As already mentioned above, in one embodiment, the cleavage of the acyl group of the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salts can be carried out under acidic conditions using sulfuric acid, hydrochloric acid or hydrobromic or hydroiodic acid. The resulting acidic mixture can be neutralized, if necessary, with ammonia or an amine such as triethylamine or tributylamine before isolating the respective nicotinamide-β-D-ribofuranoside salt.

[0172] In another embodiment, cleavage of the acyl group in the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salts can be carried out under basic conditions using ammonia or triethylamine or tributylamine before isolating the respective nicotinamide-β-D-ribofuranoside salts.

[0173] Fourth Aspect: Crystalline nicotinamide-β-D-ribofuranoside hydrogen malate, nicotinamide-β-D-ribofuranoside hydrogen tartrate, nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside malate, and nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside tartrate According to a fourth aspect, the present invention relates to crystalline nicotinamide-β-D-ribofuranoside malate, nicotinamide-β-D-ribofuranoside tartrate, nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside malate, and nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside tartrate.

[0174] In preferred embodiments, the present invention relates to crystalline nicotinamide-β-D-ribofuranoside hydrogen malate, nicotinamide-β-D-ribofuranoside hydrogen tartrate, nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside hydrogen malate, and nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside hydrogen tartrate.

[0175] In a particularly preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen malate is nicotinamide-β-D-ribofuranoside D-hydrogen malate and may be characterized by an X-ray powder diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 1 below:

[0176] [Table 1]

[0177] In a more particularly preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen malate is nicotinamide-β-D-ribofuranoside L-hydrogen malate and may be characterized by a powder X-ray diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 2 below:

[0178] [Table 2]

[0179] In a more particularly preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen malate is nicotinamide-β-D-ribofuranoside DL-hydrogen malate and may be characterized by an X-ray powder diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 3 below:

[0180] [Table 3]

[0181] In a more particularly preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen tartrate is nicotinamide-β-D-ribofuranoside D-hydrogen tartrate monohydrate, which can be characterized by a powder X-ray diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 4 below:

[0182] [Table 4]

[0183] In a further particularly preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen tartrate is a nicotinamide-β-L-ribofuranoside L-hydrogen tartrate that can be characterized by a powder X-ray diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 5 below:

[0184] [Table 5]

[0185] In a further particularly preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen tartrate is nicotinamide-β-D-ribofuranoside DL-hydrogen tartrate which can be characterized by a powder X-ray diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 6 below:

[0186] [Table 6]

[0187] In a further particularly preferred embodiment, the crystalline nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside hydrogen tartrate 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 ±0.2° 2θ substantially as provided in Table 7 below:

[0188] [Table 7]

[0189] In a further particularly preferred embodiment, the crystalline nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside hydrogen tartrate is nicotinamide-2,3,5-triacetyl-O-β-D-ribofuranoside D-hydrogen tartrate that can be characterized by a powder X-ray diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 8 below:

[0190] [Table 8]

[0191] In a more particularly preferred embodiment, the crystalline nicotinamide-β-D-ribofuranoside hydrogen tartrate is anhydrous nicotinamide-β-D-ribofuranoside D-hydrogen tartrate that can be characterized by a powder X-ray diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 9 below:

[0192] [Table 9]

[0193] Thus, in a particularly preferred embodiment, the present invention relates to a crystalline nicotinamide-β-D-ribofuranoside salt selected from the group consisting of:

[0194] Nicotinamide-β-D-ribofuranoside D-hydrogen malate characterized by the powder X-ray diffraction pattern defined in Figure 1;

[0195] Nicotinamide-β-D-ribofuranoside L-hydrogen malate characterized by a powder X-ray diffraction pattern as defined in Figure 2;

[0196] Nicotinamide-β-D-ribofuranoside DL-hydrogen malate characterized by the powder X-ray diffraction pattern defined in Figure 3;

[0197] Nicotinamide-β-D-ribofuranoside D-hydrogen tartrate monohydrate characterized by a powder X-ray diffraction pattern as defined in Figure 4;

[0198] Nicotinamide-β-D-ribofuranoside L-hydrogen tartrate characterized by a powder X-ray diffraction pattern as defined in Figure 5;

[0199] Nicotinamide-β-D-ribofuranoside DL-hydrogen tartrate characterized by the powder X-ray diffraction pattern defined in Figure 6;

[0200] Nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside L-hydrogen tartrate characterized by a powder X-ray diffraction pattern as defined in Figure 7;

[0201] Nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside D-hydrogen tartrate characterized by a powder X-ray diffraction pattern as defined in FIG. 8;

[0202] Anhydrous nicotinamide-β-D-ribofuranoside D-hydrogen tartrate characterized by the powder X-ray diffraction pattern defined in FIG.

[0203] Another embodiment of the fourth aspect relates to a nicotinamide-β-D-ribofuranoside salt obtainable by the process according to any one of the embodiments of the first or second aspect.

[0204] Fifth aspect: Nutritional supplements According to a fifth aspect, the present invention relates to a dietary supplement comprising a nicotinamide-β-D-ribofuranoside salt obtainable by the process described in the first or second aspect or comprising a nicotinamide-β-D-ribofuranoside salt as described in the fourth aspect.

[0205] Suitable methods for producing such dietary supplements containing nicotinamide-β-D-ribofuranoside salts are known in the art or may be prepared analogously to such known methods.

[0206] Sixth Aspect: Pharmaceutical Composition According to a sixth aspect, the present invention relates to a pharmaceutical composition comprising a nicotinamide-β-D-ribofuranoside salt obtainable by the process described in the first or second aspect, or comprising a nicotinamide-β-D-ribofuranoside salt as described in the fourth aspect.

[0207] The pharmaceutical composition includes a nicotinamide riboside kinase pathway or NAD +It may be used in the prevention or treatment of diseases or conditions involving other pathways of biosynthesis, which pathways are known to those of skill in the art.

[0208] Seventh aspect: Use of the compound described in the fourth aspect as a starting material for chemical synthesis The crystalline compounds described in the fourth aspect, due to their purity and ready availability, may serve as starting materials for the preparation of other nicotinamide-β-D-ribofuranoside salts, such as the commercially available chlorides, or related compounds, i.e. they may be used as starting materials in chemical syntheses.

[0209] According to a seventh aspect, the present invention relates to a method for carrying out a chemical synthesis, comprising the steps (A) of: (A) providing a nicotinamide-β-D-ribofuranoside salt obtained by a process as described in the first, second or third aspect, or providing a compound as described in the fourth aspect.

[0210] Eighth embodiment: Preparation of nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside triflate or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, bromide, iodide, nonaflate, fluorosulfonate or percolate The inventors have further modified the method developed by Tanimori as disclosed in the third aspect, which was previously believed to require a huge excess of 7.3 equivalents of TMSOTf per equivalent of tetra-O-acyl-β-D-ribofuranose to form nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside triflate that is sufficiently pure for subsequent reaction.

[0211] The inventors of the present invention have unexpectedly discovered that the use of much less TMSOTf results in a product with higher purity compared to the product obtained with a huge molar excess of TMSOTf, which is particularly advantageous in economic terms.

[0212] Therefore, in the eighth aspect, the present invention provides a method for producing a pharmaceutical composition comprising the steps of: (A) reacting nicotinamide with tetra-O-acyl-β-D-ribofuranose in the presence of 0.9 to 1.5 molar equivalents of TMSOTf per mole of tetra-O-acyl-β-D-ribofuranose; The present invention relates to a method for producing nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside triflate, comprising the steps of:

[0213] Preferably, 1.0 to 1.5 molar equivalents, more preferably 1.0 to 1.3 molar equivalents, and even more preferably 1.0 to 1.2 molar equivalents of TMSOTf are used.

[0214] Preferably, acetonitrile is used as the solvent.

[0215] The reaction is preferably carried out at a temperature range of 10 to 40°C, more preferably 20 to 30°C.

[0216] Nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside triflate may be obtained after removal of the solvent as an amorphous foam.

[0217] The acyl group is then cleaved by known methods to provide nicotinamide-β-D-ribofuranoside triflate.

[0218] Both the acylated as well as the deacylated products can be used in the respective methods according to the invention described in the first, second and third aspects.

[0219] In one embodiment, the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside triflate is not isolated prior to salt metathesis or prior to deacylation.

[0220] The iodide can be prepared in a similar manner. Thus, in this embodiment, the present invention provides a method for preparing a compound comprising the steps of: (A) reacting nicotinamide with tetra-O-acyl-β-D-ribofuranose in the presence of 0.9 to 1.5 molar equivalents of TMSI per mole of tetra-O-acyl-β-D-ribofuranose; The present invention relates to a method for producing nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside iodide, comprising the steps of:

[0221] The reaction is preferably carried out at a temperature range of 10 to 50°C, more preferably 20 to 40°C.

[0222] This reaction can also be expanded to the preparation of its bromides, chlorides, nonaflates, fluorosulfonates and percolates. Thus, in one embodiment, this aspect also comprises the following step (A): (A) reacting nicotinamide with tetra-O-acyl-β-D-ribofuranose in the presence of 0.9 to 1.5 molar equivalents of TMSBr, TMSCl, TMSOSO2C4F9, TMSOSO2F or TMSOClO3 per mole of tetra-O-acyl-β-D-ribofuranose; The present invention relates to a method for producing nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, nonaflate, fluorosulfonate or percolate, comprising the steps of:

[0223] The synthesis of the iodide is particularly preferred due to the high yield and purity of the product formed, and the economic advantages.

[0224] Ninth embodiment: Nicotinamide-β-D-ribofuranoside iodide, nonafluorobutanesulfonate, fluorosulfonate, percolate, Nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside iodide, nonafluorobutanesulfonate, fluorosulfonate, percolate According to a ninth aspect, the present invention relates to:

[0225] Nicotinamide-β-D-ribofuranoside iodide, nonafluorobutanesulfonate, fluorosulfonate or percolate of the formula: [ka]

[0226] and nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside iodide, nonafluorobutanesulfonate, fluorosulfonate or percolate of the formula: [ka] wherein R is alkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl, preferably C 1-10 an acyl group independently selected from alkylcarbonyl and benzoyl, and more preferably acetyl, where R is optionally C 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 wherein preferably, R is acetyl.

[0227] In another aspect of the invention, the nicotinamide used in the synthesis according to the invention, such as steps (X) and (Y) described in the first and second aspects, is used in the form of a precursor, i.e. in the form of a nicotinic acid ester.

[0228] In one embodiment, the ester moiety is a C 1 , which may be branched, unbranched or cyclic. 1-10In another embodiment, the ester moiety is selected from alkoxy and is optionally substituted. In another embodiment, the ester moiety is phenoxy and is optionally substituted. In another embodiment, the ester moiety is benzyloxy and is optionally substituted. As used herein, the term "optionally substituted" is used in 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 See alkyl)2.

[0229] Each compound bearing a nicotinate moiety may then be subjected to salt metathesis as described above.

[0230] Finally, the nicotinic ester moiety of each compound is transferred to the nicotinamide moiety with ammonia.

[0231] In another embodiment, the present invention relates to a method for producing a second nicotinamide-β-D-ribofuranoside salt from a first nicotinamide-β-D-ribofuranoside salt, or a second nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt from a first nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt, comprising the steps (A1) and (A2): (A1) NH3 or NR 1 H2 or NR 1 R 2 H or NR 1 R 2 R 3 or [NR 1 R 2 R 3 R 4 ]OH with an acid to provide an ammonium salt, wherein R 1 , R 2 , R 3 and R 4 is C 1-12 It is independently selected from alkyl and aryl and is optionally substituted. (A2) reacting the first nicotinamide-β-D-ribofuranoside salt or the first nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt with the ammonium salt from step (A1) to perform salt metathesis including counterion exchange to provide a second nicotinamide-β-D-ribofuranoside salt or a second nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt.

[0232] In a preferred embodiment, NR 1 R 2 R 3 or [NR 1 R 2 R 3 R 4 ]OH is used in step (A1).

[0233] The acetyl moieties used in the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salts are described above.

[0234] Preferably, step (A2) is carried out in a solvent comprising an alcohol selected from the group consisting of methanol, ethanol, propanol or butanol or a mixture of two or more thereof, optionally comprising water; or the solvent is selected from the group consisting of methanol, ethanol, propanol or butanol or a mixture of two or more thereof, optionally comprising water.

[0235] In another embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: + or NR 1 H3 + or NR 1 R 2 H2 + or NR 1 R 2 R 3 H + or [NR 1 R 2 R 3 R 4 ] + wherein R1 , R 2 , R 3 and R 4 is C 1-12 It is independently selected from alkyl and aryl and is optionally substituted.

[0236] Preferably, the nicotinamide-β-D-ribofuranoside salt or the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt is subjected to salt metathesis.

[0237] The acetyl moieties used in the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salts are described above.

[0238] Preferably, the salt metathesis reaction is carried out in a solvent comprising an alcohol selected from the group consisting of methanol, ethanol, propanol or butanol or a mixture of two or more thereof, optionally comprising water; or the solvent is selected from the group consisting of methanol, ethanol, propanol or butanol or a mixture of two or more thereof, optionally comprising water.

[0239] The following examples further illustrate the invention. EXAMPLES

[0240] Working Example Example 1: Preparation of nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside bromide used as starting salt in step (A) of the process according to the second or third embodiment 274 g of β-D-ribofuranose 1,2,3,5-tetraacetate was dissolved in 274 ml of acetonitrile. 180 ml of hydrogen bromide in glacial acetic acid (concentration 33%) was added to the stirred solution while maintaining the temperature at 0°C-5°C. Stirring was continued for another 15 minutes. 41 g of nicotinamide was added while stirring for another 15 minutes. Next, a hot (70°C) solution of 96 g of nicotinamide in 700 ml of acetonitrile was added and then the mixture was cooled to about 0°C-5°C. Stirring was continued for 15 hours after which the suspension formed was filtered. The filtrate was subjected to distillation. The oily residue obtained was diluted with acetone to obtain crystals of the title product. The title product was filtered and dried to give 167 g (43% yield) of nearly colorless product; melting point: 133-134°C. 1 H-NMR (400 MHz, DMSO-d6): 2.09 (s, 6H), 2.13 (s, 3H) 4.45 (m, 2H, H5'), 4.69 (m, 1H, H4'), 5.43 (t, 1H, H3'), 5.62 (dd, 1H, H2'), 6.69 (d, 1H, H1'), 8.23 ​​(s, 1H, NH), 8.41 (dd, 1H, H5), 8.74 (s, 1H, NH), 9.13 (d, 1H, H4), 9.28 (d, 1H, H6), 9.49 (s, 1H, H2); 13 C-NMR (100 MHz, DMSO-d6): 20.3, 20.4, 20.5, 62.1 (C5'), 68.7 (C3'), 75.3 (C2'), 81.8 (C4'), 97.2 (C1'), 128.1 (C5), 133.9 (C3), 141.2 (C2), 143.1 (C6), 145.5 (C4), 162.7 (CONH2), 169.2, 169.4, 170.1

[0241] Example 2: Preparation of nicotinamide-β-D-ribofuranoside bromide used as starting salt in step (A) in the process according to the first aspect 167 g of the product obtained in Example 1 was dissolved in 870 ml of methanol. Then 135 ml of hydrogen bromide in acetic acid (concentration 33%) was added to the stirred solution while maintaining the temperature at 5°C-10°C. The resulting mixture was stirred at 20°C for 2 days, whereupon the product started to crystallize. The formed crystals were filtered, washed with isopropanol and dried. The title compound was obtained as a pale yellow crystalline powder in a yield of 77 g (63%). Melting point: 118-119°C. 1 H-NMR (400 MHz, D2O): 3.83 (dd, 1H, H5'), 3.98 (dd, 1H, H5'), 4.29 (t, 1H, H3'), 4.39-4.48 (m, 2H, H4', H2'), 6.18 (d, 1H, H1'), 8.22 (t, 1H, H5), 8.91 (d, 1H, H4), 9.20 (d, 1H, H6), 9.52 (s, 1H, H2); 13 C-NMR (100 MHz, D2O): 60.0 (C5'), 69.5 (C3'), 77.2 (C2'), 87.5 (C4'), 99.7 (C1'), 128.3 (C5), 133.7 (C3), 140.2 (C2), 142.5 (C6), 145.5 (C4), 165.6 (CONH2).

[0242] Example 3: Preparation of Nicotinamide-β-D-ribofuranoside L-hydrogen tartrate from Nicotinamide-β-D-ribofuranoside bromide using various ammonium L-hydrogen tartrate salts for salt metathesis Example 3a: Use of TEA·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. Thus, 15 ml of a 1.73 molar solution of TEA·L-hydrogen tartrate was prepared.

[0243] 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 above prepared solution of triethylammonium L-hydrogen tartrate was added to the clear colorless solution. A white product started to precipitate.

[0244] The suspension was stirred for an additional hour at room temperature. The product was filtered, washed with methanol, and dried in vacuum at 35° C. 6.62 g (95%) of a white crystalline powder was obtained; melting point: 129-130° C.; IC: residual bromide 0.20%. The solid may be recrystallized from aqueous methanol, if desired. 1 H-NMR (400 MHz, D2O): 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, 2x CHOH, 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). 13 C-NMR (100 MHz, DO): 60.2 (C5'), 69.7 (C3'), 72.8 (2x CHOH, 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 (2x COO, H-tartrate). Impurities: 8.2, 46.6 (TEA). Solvent: 48.9 (methanol). XRD: Crystal (Figure 5)

[0245] Example 3b: Use of TBA·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 6.3 ml of tributylamine (26.0 mMol) was added. The pH of the slightly yellowish solution was approximately 4. In this way, 17.5 ml of a 1.53 molar solution of tributylammonium L-hydrogen tartrate was prepared.

[0246] 5.80 g of nicotinamide-β-D-ribofuranoside bromide was dissolved in 3.5 ml of water at room temperature with stirring. 10 ml of methanol was added. 11.1 ml of the above prepared tributylammonium L-hydrogen tartrate solution was added to the clear colorless solution. The white product immediately begins to crystallize.

[0247] The suspension was stirred for an additional hour at room temperature. The product was filtered, washed with methanol and dried in vacuum at 35° C. 6.37 g (91%) of a white crystalline powder was obtained; melting point: 128° C.; IC: residual bromide 0.62%.

[0248] Impurities (NMR): <1 mol% nicotinamide, 2.7 mol% TBA salt: 0.84 (t, 9H), 1.28 (m, 6H), 1.58 (m, 6H), 3.04 (q, 6H); Solvent: 3.7 mol% methanol: 3, 25 (s, 3H).

[0249] Example 3c: Use of Tetrabutylammonium 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 17.0 ml of a 40% solution of tetrabutylammonium hydroxide in water (26.0 mMol) was added. The pH of the slightly yellowish solution was approximately 4. In this way, 29 ml of a 0.9 molar solution of tetrabutylammonium L-hydrogen tartrate was prepared.

[0250] 5.80 g of nicotinamide-β-D-ribofuranoside bromide was dissolved in 3.5 ml of water with stirring at room temperature. 10 ml of methanol was added. 19.3 ml of the above prepared solution of tetrabutylammonium L-hydrogen tartrate was added to the clear colorless solution. A white product started to crystallize.

[0251] The suspension was stirred for an additional hour at room temperature. The product was filtered, washed with methanol, and dried in vacuum at 35° C. 5.60 g (80%) of a white crystalline powder was obtained; melting point: 129-130° C.; IC: residual bromide 0.13%.

[0252] Impurities (NMR): <1 mol% nicotinamide; 0.35 mol% TBA salt: 0.36 (t, 9H), 1,27 (m, 6H), 1,56 (m, 6H), 3.11 (q, 6H); Solvent: 2.4 mol% methanol: 3.26 (s, 3H).

[0253] Example 4: The crystalline nicotinamide-β-D-ribofuranoside salts in the table below were prepared analogously to Example 3a.

[0254] [Table 10]

[0255] Example 5: Preparation of Nicotinamide-β-D-ribofuranoside L-Hydrogen Malate from Nicotinamide-β-D-ribofuranoside Bromide Using Various Ammonium L-Hydrogen Malate Salts for Salt Metathesis Example 5a: Use of TEA·L-hydrogen malate 5.8 g of nicotinamide-β-D-ribofuranoside bromide was suspended in 10 ml of methanol with stirring. 10 ml of a 1.73 molar solution of triethylammonium L-hydrogen maleate 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 in vacuum at 35° C. 4.15 g (62%) of a white crystalline powder was obtained. Melting point: 116.5-117° C. IC: Residual bromide 0.10%. The product may be recrystallized from methanol if desired. 1 H-NMR (400 MHz, D2O): 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). 13 C-NMR (100 MHz, DO): 40.0 (CH2, 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 (CONH2), 176.3 (COO, H-malate), 179.0 (COO, H-malate). Solvent: 48.9 (methanol). XRD: Crystal (Figure 2)

[0256] Example 5b: Use of TBA·L-hydrogen maleate 3.50 g of L-malic acid (26.0 mMol) was dissolved in 10 ml of methanol with stirring. The colorless solution was cooled in an ice bath and 6.3 ml of tributylamine (26.0 mMol) was added. The pH of the slightly yellowish solution was approximately 5. Thus, 17.5 ml of a 1.53 molar solution of tributylammonium L-hydrogenmalate was prepared.

[0257] 5.80 g of nicotinamide-β-D-ribofuranoside bromide was suspended in 17.5 ml of methanol with stirring. 11.1 ml of the above prepared solution of tributylammonium L-hydrogen maleate was added. The suspension was heated until the solid was completely dissolved. After colling, a white solid crystallized. The suspension was stirred for 30 minutes and then filtered. The residue was washed with methanol and dried in vacuum at 35° C. 4.89 g (73%) of a white crystalline powder was obtained; melting point: 115.5° C.; IC: residual bromide 0.64%.

[0258] Impurities: <1 mol% nicotinamide; 0.2 mol% TBA salts; 2 mol% methanol.

[0259] Example 6: The crystalline nicotinamide-β-D-ribofuranoside salts in the table below were prepared analogously to Example 5a.

[0260] [Table 11]

[0261] Example 6d: Monohydrated Compound 6c by Recrystallization 2.0 g of nicotinamide-β-D-ribofuranoside D-hydrogen tartrate prepared in Example 6c 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 formed suspension was filtered. The residue was washed with methanol and dried in vacuum at 35° C. 1.54 g (77%) of a white crystalline powder of its monohydrate was obtained. Water content: 4.24% (determined by Karl Fischer method (K. Fischer)); Melting point: 115-116° C.; IC: Residual bromide: <0.01%. XRD: Crystalline (Figure 4)

[0262] Example 7: Preparation of Nicotinamide-β-D-ribofuranoside meso-hydrogen tartrate 0.57 g of nicotinamide-β-D-ribofuranoside bromide was suspended in 1 ml of methanol with stirring. 1 ml of a 1.69 molar solution of triethylammonium meso-hydrogen tartrate was added. The suspension was heated to boiling point and then cooled. The emulsion formed was added dropwise to 20 ml of ethanol. The suspension formed was filtered and the residue was dried in vacuum at room temperature. 0.44 g (62%) of a flaky hygroscopic powder was obtained. 1H-NMR (400 MHz, DO): 3.82 (dd, 1H, H5'), 3.97 (dd, 1H, H5'), 4.28 (t, 1H, H3'), 4.38-4.46 (m, 2H, H4', H2'), 4.35 (s, 1.5H, 2x CHOH, meso-H-tartrate), 6.17 (d, 1H, H1'), 8.21 (t, 1H, H5), 8.91 (d, 1H, H4), 9.20 (d, 1H, H6), 9.53 (s, 1H, H2). Impurity: 5 mol% nicotinamide: 7.65 (m, 1H), 8.33 (m, 1H), 8.68 (d, 1H), 8.90 (s, 1H); 10.2 mol% TEA salt: 1.20 (t, 9H), 3.12 (q, 6H). Solvent: 16 mol% methanol: 3.25 (s, 3H); 40 mol% ethanol: 1.09 (t, 3H), 3.56 (q, 2H). 13 C-NMR (100 MHz, DO): 60.2 (C5'), 69.7 (C3'), 73.7 (2x CHOH, meso-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), 175.7 (2x COO, H-tartrate). Impurities: 125.0, 138.6, 146.0, 149.8 (nicotinamide); 8.2, 46.6 (TEA). Solvent: 48.9 (methanol); 16.8, 57.4 (ethanol).

[0263] Example 8: Preparation of Nicotinamide-β-D-ribofuranoside D-glucuronate 5.10 g of glucuronic acid was suspended in 15 ml of methanol with stirring. The colorless suspension was cooled in an ice bath and 3.60 ml of triethylamine was added. 19.5 ml of a 1.35 molar solution of TEA·D-glucuronate was prepared.

[0264] 5.0 g of nicotinamide-β-D-ribofuranoside bromide was dissolved in 3.0 ml of water with stirring at room temperature. 10 ml of methanol was added. 11.1 ml of the above prepared triethylammonium D-glucuronate solution was added. This clear yellowish solution was slowly dripped into 455 ml of n-butanol, where a white suspension was formed.

[0265] The suspension was stirred for a further 5 hours at room temperature. The product was filtered, washed with isopropanol and dried in vacuum at 35°C. 6.64 g of the dried crude product was dissolved in 6.6 ml of water and diluted with 33 ml of methanol. The yellowish solution was added dropwise to 550 ml of butanol, whereupon a white suspension was formed. The suspension was filtered, the residue was washed with isopropanol and dried at 35°C. Melting point: 66-76°C; residual bromide 1.43% (IC). 1 H-NMR (400 MHz, D2O): NR: 3.82 (dd, 1H, H5'), 3.97 (dd, 1H, H5'), 4.28 (t, 1H, H3'), 4.38-4.45 (m, 2H, H4', H2'), 6.17 (d, 1H, H1'), 8.21 (t, 1H, H5), 8.91 (d, 1H, H4), 9.20 (d, 1H, H6), 9.53 (s, 1H, H2); GlcUA (anomeric mixture): 3.19 (m), 3.42 (m), 3.50 (m), 3.63 (m), 4.00 (t), 4.55 (d, β-anomer), 5.14 (d, α-anomer). Impurities: 2 mol% nicotinamide; 0.9 mol% TEA salt: 1.19 (t, 9H), 3.11 (q, 6H). Solvent: 23 mol% methanol: 3.26 (s, 3H); 5.7 mol% butanol: 0.80 (t, 1H, H4), 1.25 (m, 2H, H3), 1.43 (m, 2H, H2). 13C-NMR (100 MHz, DO): NR: 60.2 (C5'), 69.7 (C3'), 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); GlcUA: 71.3, 71.7, 71.8, 72.0, 72.5, 74.0, 75.5, 76.1, 92.1, 95.9, 175.7, 176.7. Solvent: 48.9 (methanol); 13.1, 18.4, 33.4, 61.5 (butanol).

[0266] Example 9: Nicotinamide-β-D-ribofuranoside L-ascorbate The crude product was prepared similarly to Example 8, but using ethanol for precipitation. 3.11 g of the crude product was dissolved in 1.9 ml of water. The orange clear solution was filtered and diluted with 16 ml of methanol. This solution was added dropwise to 238 ml of ethanol, which produced an orange suspension. The product was isolated by filtration and dried at 35° C. 1.13 g of a yellowish powder was obtained (yield 36.3%). IC: residual bromide 0.38%. 1H-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'), 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); ascorbate: 3.64 (m, 2H), 3.92 (m, 1H), 4.43 (m, 1H). Impurities: 16 mol% nicotinamide: 7.49 (t, 1H), 8.13 (d, 1H), 8.60 (d, 1H), 8.82 (s, 1H); no TEA salt. Solvent: 1.3 mol% methanol: 3.25 (s, 3H); 46 mol% ethanol: 1.08 (t, 3H), 3.55 (q, 2H). 13 C-NMR (100 MHz, D2O): 60.2 (C5'), 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), 165.8 (CONH2); Ascorbate: 62.5, 69.5, 78.2, 113.3, 174.6, 177.2. Impurities: Nicotinamide: 124.2, 129.3, 136.5, 147.6, 151.7. Solvent: 16.8, 57.4 (ethanol).

[0267] Example 10: Nicotinamide-β-D-ribofuranoside citrate 5.52 g of citric acid monohydrate was dissolved in 55 ml of DMSO with stirring. The colorless solution was cooled in an ice bath and 12 ml of triethylamine was added. 73 mL of a 0.36 molar solution of TEA·citrate was prepared.

[0268] 9.0 g of nicotinamide-β-D-ribofuranoside bromide was suspended in 18 ml of DMSO. 73 ml of the above-produced solution was added and heated to 55° C. The brown solution was added to 1125 ml of isopropanol, which produced a white suspension. The solid was isolated by filtration and dried at 35° C. 6.32 g (74%) of powder was obtained.

[0269] 3.22 g of the crude product was dissolved in a mixture of 16 ml of methanol and 2 ml of water. This solution was added dropwise to 220 ml of isopropanol, which produced a white suspension. The solid was isolated by filtration, washed with isopropanol, and dried in vacuum at 35° C. A white powder of 2.67 was obtained (82.9%). IC: Residual bromide 0.19% 1 H-NMR (400 MHz, DO): 2.61 (m, 4H, CH2, citrate), 3.82 (dd, 1H, H5'), 3.97 (dd, 1H, H5'), 4.28 (t, 1H, H3'), 4.38-4.46 (m, 2H, H4', H2'), 6.17 (d, 1H, H1'), 8.21 (t, 1H, H5), 8.90 (d, 1H, H4), 9.20 (d, 1H, H6), 9.52 (s, 1H, H2). Impurity: 6 mol% nicotinamide: 7.50 (dd, 1H), 8.15 (m, 1H), 8.61 (d, 1H), 8.82 (s, 1H); 1.5 mol% TEA salt: 1.19 (t, 9H), 3.11 (q, 6H). Solvent: 31 mol% methanol: 3.26 (s, 3H); 18 mol% isopropanol: 1.08 (d, 6H), 3.92 (m, 1H). 13C-NMR (100 MHz, D2O): 44.6 (CH2, citrate), 60.2 (C5'), 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 (CONH2), 176.9 (2x COO, citrate), 180.0 (COO, citrate). Impurities: nicotinamide: 124.3, 129.3, 136.7, 147.5, 151.6; TEA salt: 8.2, 46.6. Solvent: 48.9 (methanol); 23.7, 64.2 (Isopropanol).

[0270] Example 11: Preparation of Nicotinamide-β-D-riboside-2,3,5-triacetate L-hydrogen tartrate Example 11a: Nicotinamide-β-D-riboside-2,3,5-triacetate bromide via salt metathesis 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 molar solution of triethylammonium L-hydrogen tartrate was obtained.

[0271] 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 above-produced triethylammonium L-hydrogen tartrate solution was added. A white crystalline powder started to precipitate slowly. The residue obtained after filtration was dried in vacuum at 35° C. 6.00 g (65.2%) of a white crystalline powder was obtained. Melting point 128° C.; IC: residual bromide <0.1%. 1H-NMR (400 MHz, D2O): 2.08, 2.12, 2.15 (3x s, 3x 3H, COCH3), 4.43 (s, 2H, 2x CHOH, 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). 13 C-NMR (100 MHz, DO): 19.8, 19.9, 20.2 (3x COCH3), 62.6 (C5'), 69.4 (C3'), 72.8 (2x CHOH, 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 (3x CO), 176.3 (2x COO, H-tartrate). XRD: Crystalline (Figure 7)

[0272] Example 11b: Via ion exchange using an ion exchanger (for comparison) 145 g of Ambersep 900 hydroxide form was suspended in 110 ml of water. Then, 21 g of L-tartaric acid was added with stirring. The ion exchanger loaded with L-hydrogen tartrate was isolated by filtration and washed three times with water.

[0273] 10.0 g of nicotinamide-2,3,5-tri-O-acetyl-β-D-riboside bromide was dissolved in 70 ml of water with stirring. 22 g of supported ion exchanger was added and stirred for 16 minutes. The ion exchanger was separated by filtration and washed twice with water. The filtrate was again subjected to 22 g of supported ion exchanger and washed and filtered, where the filtrate was recovered. This was repeated twice. The filtrate was concentrated. 14.08 g of colorless oil was obtained. This oil was subjected to aqueous methanol, where a white suspension was obtained. 9.09 g of white powder was obtained after filtration and drying.

[0274] 5.05 g of the amorphous product was dissolved in 25 ml of methanol where it started to crystallize after a few minutes. The crystals were isolated by filtration and dried in vacuum at 35° C. The weight was 3.92 g, melting point was 130° C. The XRD was identical to that of the product obtained in Example 11a.

[0275] Example 12: Preparation of Nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside Triflate Example 12a: According to the present invention 11.55 g (0.094 mol) of nicotinamide and 29.7 g (0.093 mol) of β-D-ribofuranose 1,2,3,5-tetraacetate were dissolved in 750 ml of acetonitrile dried over 3 Å molecular sieves with stirring at room temperature. 18.2 ml (0.097 mol) of trimethylsilyl triflate were added within 20 min. The yellow solution was stirred for 20 min. The solvent was subsequently removed in vacuum at 35° C. The foam formed was dissolved in 300 ml of dichloromethane and 4.5 g of activated charcoal were added. The suspension was filtered. The filtrate was concentrated. 49.5 g (100%) of a yellow foam was obtained. 1H-NMR (400 MHz, D2O): 2.02, 2.06, 2.09 (3x s, 3x 3H, COCH3), 4.45 (m, 2H, H5'), 4.82 (m, 1H, H4´), 5.38 (t, 1H, H3'), 5.49 (dd, 1H, H2'), 6.51 (d, 1H, H1'), 8.22 (t, 1H, H5), 8.92 (d, 1H, H4), 9.13 (d, 1H, H6), 9.37 (s, 1H, H2). Impurities: 3 mol% alpha-anomer, 4 mol% nicotinamide. 13 C-NMR (100 MHz, D2O): 19.8, 19.9, 20.2 (3x COCH3), 62.6 (C5'), 69.4 (C3'), 76.4 (C2'), 82.7 (C4'), 97.3 (C1'); 114.9 + 118.1 + 121.2 + 124.4 (q, CF3); 128.7 (C5), 134.2 (C3), 140.4 (C2), 143.1 (C6), 146.2 (C4), 165.5 (CONH2), 172.3, 172.4, 173.3 (3x CO).

[0276] Example 12b: For comparison The process was carried out as described by Tanimori using a high excess of trimethylsilyl triflate, where the product was isolated as described in Example 12a. The resulting foam contained an approximately 2:1:1 mixture of β-anomer:α-anomer:nicotinamide.

[0277] Example 13: Preparation of nicotinamide-β-D-riboside-2,3,5-triacetate L-hydrogen tartrate from nicotinamide-β-D-riboside-2,3,5-triacetate triflate prepared by Example 12 5.00 g of nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside triflate from Example 12 was dissolved in 50 ml of ethanol. 1.42 g of L-tartaric acid was added. Subsequently, 1.31 ml of triethylamine was added. The resulting emulsion was heated briefly to promote crystallization and cooled. The precipitate formed was isolated by filtration and dried in vacuum at 30° C. 5.07 g (101.4%) of a white crystalline powder was obtained (mp 127° C.). 1 H-NMR (400 MHz, D2O): 2.08, 2.12, 2.16 (3x s, 3x 3H, COCH3), 4.43 (s, 2H, 2x CHOH, H-tartrate), 4.52 (m, 2H, H5'), 4.88 (m, 1H, H4´), 5.44 (t, 1H, H3'), 5.56 (dd, 1H, H2'), 6.58 (d, 1H, H1'), 8.28 (t, 1H, H5), 8.99 (d, 1H, H4), 9.20 (d, 1H, H6), 9.43 (s, 1H, H2). Impurities: < 1 mol% Nicotinamide; 0.35 mol% TEA salt: 1.21 (t, 9H), 3.13 (q, 6H). Solvent: 2 mol% ethanol: 3.57 (q, 2H), 1.10 (t, 3H). 13 C-NMR (100 MHz, DO): 19.8, 19.9, 20.2 (3x COCH3), 62.6 (C5'), 69.4 (C3'), 72.8 (2x CHOH, H-tartrate), 76.3 (C2'), 82.6 (C4'), 97.3 (C1'), 128.6 (C5), 134.2 (C3), 140.4 (C2), 143.1 (C6), 146.3 (C4), 165.5 (CONH2), 172.3, 172.4, 173.3 (3x CO), 176.3 (2x COO, H-tartrate).

[0278] Example 14: Preparation of nicotinamide-β-D-riboside-2,3,5-triacetate D-hydrogen tartrate from nicotinamide-β-D-riboside-2,3,5-triacetate bromide Crystalline nicotinamide-2,3,5-O-triacetyl-β-D-riboside D-hydrogen tartrate was prepared according to Example 11a.

[0279] For comparison, a product was prepared by the method of Example 11b. The amorphous product subjected to crystallization was identical to the product obtained in Example 11a.

[0280] The XRD is shown in FIG.

[0281] Example 15: Deacylation of Nicotinamide-β-D-riboside-2,3,5-triacetate L-hydrogen tartrate (from Example 11) illustrating Route 2 Example 15a: Deacylation using sulfuric acid and neutralization using 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 obtain 10% methanolic sulfuric acid.

[0282] 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 the product and nicotinamide as an impurity were present as detected by thin layer chromatography.

[0283] Conversion to Nicotinamide-β-D-riboside 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 adding 0.8 ml of triethylamine, the product started to crystallize. The suspension was stirred for another hour and then stored in a refrigerator for 12 hours. The resulting crystals were filtered, washed with isopropanol, and dried in vacuum at 30°C. 1.01 g (44.2%) of a white crystalline powder was obtained with a melting point of 126-127°C. 1 H-NMR (400 MHz, 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, 2x CHOH, 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). 13 C-NMR (100 MHz, DO): 60.2 (C5'), 69.7 (C3'), 72.8 (2x CHOH, 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 (2x COO, H-tartrate). Impurities: 8.2, 46.6 (TEA salt). Solvent: 48.9 (methanol).

[0284] Example 15b: Deacylation using HBr in glacial acetic acid and neutralization using triethylamine Deacylation of Nicotinamide-β-D-riboside-2,3,5-triacetate L-hydrogen tartrate: 3.0 g of Nicotinamide-β-D-riboside-2,3,5-triacetate L-hydrogen tartrate was suspended in 15 ml of methanol with stirring. The suspension was cooled to 5° C. and 3.0 ml of HBr 33% in glacial acetic acid was added. A yellowish solution was formed after stirring at room temperature for 3 days. Thin layer chromatography revealed that the deacylation was complete.

[0285] Conversion of Nicotinamide-β-D-riboside L-Hydrogen Tartrate after Neutralization with Triethylamine: 1 ml of triethylamine was added in portions to the above solution. 1.5 ml of water was added, whereupon a yellow solution was formed. Subsequently, 0.85 g of L-tartaric acid was added. After addition of 0.8 ml of triethylamine, the product started to crystallize. The product suspension was stirred for another hour at room temperature. The formed crystals were filtered, washed with 7 ml of isopropanol and 5 ml of acetone, and dried in vacuum at 30°C. 0.82 g (36%) of a white crystalline powder with a melting point of 129-130°C was obtained. 1 H-NMR (400 MHz, DO): Similar to Example 15a. Impurities: 1 mol% nicotinamide; 0.1 mol% TEA salt. Solvent: 2.7 mol% methanol. 13 C-NMR (100 MHz, DO): Similar to Example 15a.

[0286] Example 16: Deacylation of Nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside Bromide (from Example 1) Illustrating Route 3 Example 16a: Deacylation using sulfuric acid and neutralization using triethylamine Preparation of diluted sulfuric acid in methanol: 20 ml of methanol was cooled to 0° C. 2.00 g of 96% sulfuric acid was added with stirring. 21 ml of 0.93 M methanolic sulfuric acid was obtained.

[0287] Deacylation of Nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside bromide: 5.00 g of Nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside bromide was suspended in 24.4 ml of methanol with stirring, whereby some of the educt was dissolved. 5.6 ml of the above methanolic sulfuric acid was added. The resulting colorless solution was stirred at room temperature. The solution was stirred for 3 days, whereby a suspension was formed.

[0288] Conversion of Nicotinamide-β-D-riboside L-Hydrogen Tartrate after Neutralization with Triethylamine: 1.36 ml of triethylamine was added to the above suspension. After adding 3.4 ml of water, a clear solution was produced. 1.63 g of L-tartaric acid was added, whereupon the product started to precipitate. After adding another 1.35 ml of triethylamine, more product precipitated. The suspension was filtered, the resulting solid was washed with methanol, and dried in vacuum at 30° C. 2.4 g (55%) of a crystalline white powder was obtained. Melting point 129.5° C. IC: Residual bromide 0.05%. 1 H-NMR (400 MHz, 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, 2x CHOH, Impurities: 2 mol% Nicotinamide: 7.83 (m, 1H), 8.54 (m, 1H), 8.76 (d, 1H), 9.00 (s, 1H); 0.7 mol% TEA salt: 1.19 (t, 9H), 3.11 (q, 6H). Solvent: 7 mol% methanol: 3.25 (s, 3H). 13C-NMR (100 MHz, DO): 60.2 (C5'), 69.7 (C3'), 72.8 (2x CHOH, 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 (2x COO, H-tartrate). Solvent: 48.9 (methanol).

[0289] Example 16b: Deacylation using HBr in glacial acetic acid and neutralization using triethylamine Deacylation of Nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside bromide: 5.00 g of Nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside bromide was dissolved in 30 ml of methanol at room temperature with stirring. After adding 3.75 ml of HBr 33% in glacial acetic acid, the yellow solution formed was stirred at room temperature for 3 days. A white suspension of Nicotinamide-β-D-ribofuranoside bromide was formed as controlled by thin layer chromatography.

[0290] Conversion of nicotinamide-β-D-ribofuranoside bromide to nicotinamide-β-D-ribofuranoside L-hydrogen tartrate after neutralization with triethylamine: 2.50 ml of triethylamine was added in portions to the above suspension. Subsequently, 2.5 ml of water was added. 1.63 g of L-tartaric acid was added to the yellowish solution formed. The product started to precipitate after further addition of 1.52 ml of triethylamine at pH 3.5-4. The crystalline product was filtered, washed with 10 ml of isopropanol and 10 ml of acetone, and dried in vacuum at 30°C. 2.93 g (66.9%) of white crystalline powder was obtained. Melting point 127.5-128.5°C. IC: Residual bromide 0.33%. 1H-NMR (400 MHz, DO): similar to Example 15a. Impurities: 1 mol% nicotinamide; 2.3 mol% TEA salt. Solvent: 7 mol% methanol. 13C-NMR (100 MHz, D2O): Similar to Example 15a.

[0291] Example 16c: Deacylation using triethylamine 5.00 g of nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside bromide were dissolved in 30 ml of methanol at room temperature with stirring. 1.52 ml of triethylamine (1 eq.) were added. The yellow solution was stirred for 24 h. A control by thin layer chromatography showed almost complete conversion, however also the formation of nicotinamide. 1.63 g of L-tartaric acid were added to the formed suspension. The product started to precipitate. The product suspension was stirred for 1 h at 0° C., the formed product was isolated by filtration, washed with 12 ml of isopropanol and 12 ml of acetone and dried in vacuum at 30° C. 1.86 g (42.4%) of a white powder was obtained. Melting point 127° C.; IC: residual bromide 0.26%. 1H-NMR (400 MHz, D2O): similar to Example 15a. Impurities: 6 mol% nicotinamide; 1.7 mol% TEA salt. Solvent: 18 mol% methanol, 0.5 mol% isopropanol. 13C-NMR (100 MHz, D2O): Similar to Example 15a.

[0292] Example 16d: Deacylation using triethylamine at 0-5°C

[0293] Example 16c was repeated with the difference that nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside bromide was subjected to triethylamine at 0° C. The yield increased to 85.8%.

[0294] Example 17: Preparation of nicotinamide-β-D-riboside-2,3,5-triacetate L-hydrogen tartrate by separation of its L-hydrogen tartrate salt from the mixture of β- and α-anomers formed by glycosylation of nicotinamide with 1-bromo-2,3,5-triacetyl-D-ribofuranoside illustrating route 4 To 100 ml of the crude mixture of anomers containing theoretically 54 mmol of nicotinamide-D-ribofuranoside-2,3,5-triacetate (obtained analogously to Example 1), 11.7 ml of triethylamine was added, in which the acids contained (HBr and acetic acid) were partially neutralized. 5.16 g of L-tartaric acid was added to the orange-yellow solution with stirring. As soon as the tartaric acid was completely dissolved, 4.8 ml of triethylamine was added.

[0295] The solution was concentrated by distilling off 42 mL, whereupon needles of triethylamine hydrobromide began to precipitate. 30 mL of isopropanol was added and the suspension was cooled to 0° C. with stirring. The suspension was filtered and the residue (triethylamine hydrobromide) was washed with 14 mL of isopropanol.

[0296] The filtrate was seeded with some crystals of the product. Then, 30 ml of tert-butyl-methyl ether were slowly added, whereupon the product started to precipitate. The product was stored in the refrigerator for 12 hours. After filtration, it was washed twice with 25 ml of isopropanol each time and the solid was dried in vacuum at 35°C. 13.86 g (48.5%) of nicotinamide-β-D-riboside-2,3,5-triacetate L-hydrogen tartrate was obtained in the form of white crystals. Melting point 123-124°C. IC: residual bromide 2.64%. 1H-NMR (400 MHz, D2O): 2.08, 2.12, 2.15 (3x s, 3x 3H, COCH3), 4.43 (s, 2H, 2x CHOH, H-tartrate), 4.52 (m, 2H, H5'), 4.88 (m, 1H, H4´), 5.44 (t, 1H, H3'), 5.56 (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: < 1 mol% Nicotinamide; 20 mol% TEA salt: 1.21 (t, 9H), 3.13 (q, 6H). Solvent: 2.2 mol% isopropanol: 1.09 (d, 6H), 3.93 (m, 1H). 13 C-NMR (100 MHz, D2O): 19.8, 19.9, 20.2 (3x COCH3), 62.6 (C5'), 69.4 (C3'), 72.8 (2x CHOH, 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 (3x CO), 176.3 (2x COO, H-Tartrate). Impurities: TEA salt: 8.2, 46.7.

[0297] Example 18: Deacylation of an anomeric mixture of nicotinamide-α / β-D-riboside-2,3,5-triacetate bromide illustrating route 5 100 ml of crude solution (see Example 1), containing theoretically about 54 mmol of anomers of nicotinamide-D-ribofuranoside-2,3,5-triacetate bromide, was completely concentrated using a rotary evaporator at a temperature ranging from 35 to 40 ° C. The yellow viscous oil obtained was diluted with 44 ml of methanol. Subsequently, 10 ml of HBr 33% in glacial acetic acid were added. The yellowish clear solution was stirred at room temperature. After 1 day, nicotinamide-β-D-riboside bromide precipitated. After 5 days, complete deacylation was achieved, controlled by thin layer chromatography.

[0298] Isolation of Nicotinamide-β-D-riboside as L-Hydrogen Tartrate: To neutralize HBr and acetic acid, 7.5 ml of triethylamine was added to the above suspension. After adding 4 ml of water, a clear solution was obtained. 8.6 g of tartaric acid was added to this yellowish solution and filtered to remove the insoluble precipitate. Subsequently, 5.4 ml of triethylamine was added, whereupon the desired product started to precipitate. After filtering and washing with ethanol and methanol, the obtained solid was dried in vacuum at 30°C. 7.27 g (33.3%) of a white crystalline powder was obtained. Melting point 128.5-129.5°C; IC: residual bromide 0.16%. 1 H-NMR (400 MHz, DO): similar to Example 15a. Impurities: 3 mol% nicotinamide; 1.2 mol% TEA salt. Solvent: 7 mol% methanol. 13 C-NMR (100 MHz, DO): Similar to Example 15a.

[0299] Example 19: Deacylation of Nicotinamide-β-D-riboside-2,3,5-triacetate triflate illustrating Route 5 Example 19a: Deacylation using sulfuric acid and neutralization using triethylamine

[0300] Preparation of diluted sulfuric acid in methanol: 27 g of methanol was cooled to 0° C. 3.00 g of 96% sulfuric acid was added with stirring. 30 g of 10% methanolic sulfuric acid was obtained.

[0301] Deacylation of nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside triflate: 3.00 g of nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside triflate was dissolved in 15 ml of methanol with stirring. 5.86 g of the above methanolic sulfuric acid was added. The resulting colorless solution was stirred at room temperature. The solution was stirred for 3 days. Thin layer chromatographic control revealed complete deacylation and some nicotinamide impurities.

[0302] Conversion of Nicotinamide-β-D-riboside L-hydrogen tartrate after neutralization with triethylamine: 1.1 ml of triethylamine was added to the above solution. 3.3 ml of a 1.7 molar methanolic solution of triethylammonium L-hydrogen tartrate was added, whereupon the product immediately started to precipitate. Subsequently, 0.40 g of L-tartaric acid was added. The product suspension was stored in a refrigerator for 12 hours. After filtration, the solid obtained was washed with methanol and ethanol and dried in vacuum at 30°C. 1.23 g (53.8%) of a white crystalline powder was obtained. Melting point 127-128°C. 1 H-NMR (400 MHz, D2O): 3.82 (dd, 1H, H5'), 3.96 (dd, 1H, H5'), 4.27 (t, 1H, H3'), 4.37-4.45 (m, 2H, H4', H2'), 4.41 (s, 2H, 2x CHOH, Impurities: 2 mol% Nicotinamide: 7.83 (m, 1H), 8.54 (m, 1H), 8.76 (d, 1H), 9.00 (s, 1H); 2.9 mol% TEA salt: 1.19 (t, 9H), 3.11 (q, 6H). Solvent: 16 mol% methanol: 3.25 (s, 3H), 2 mol% ethanol. 13 C-NMR (100 MHz, DO): 60.2 (C5'), 69.7 (C3'), 72.8 (2x CHOH, 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 (2x COO, H-tartrate). Impurities: 8.2, 46.6 (TEA salt). Solvent: 48.9 (methanol).

[0303] Example 19b: Deacylation using HBr in glacial acetic acid and neutralization using triethylamine 8.00 g nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside triflate was dissolved in 32 ml of methanol with stirring. The solution was cooled to 0-5°C. After adding 5.2 ml of HBr 33% in glacial acetic acid, the solution was kept stirring at room temperature. The product was deacylated after 2 days by thin layer chromatography control.

[0304] The solution was divided into two portions.

[0305] Isolation of the intermediate bromide formed: Half of the solution (20.5 ml) was seeded with nicotinamide-β-D-ribofuranoside bromide and stirred at room temperature. After about 30 minutes a suspension was formed. This suspension was filtered and the residue was washed with methanol and ethanol and then dried in vacuum at 30° C. 0.62 g (24.5%) of a white crystalline powder was obtained. 1 H-NMR (400 MHz, D2O): 3.83 (dd, 1H, H5'), 3.98 (dd, 1H, H5'), 4.29 (t, 1H, H3'), 4.39-4.48 (m, 2H, H4', H2'), 6.18 (d, 1H, H1'), 8.22 (t, 1H, H5), 8.92 (d, 1H, H4), 9.20 (d, 1H, H6), 9.52 (s, 1H, H2). 13 C-NMR (100 MHz, D2O): 60.2 (C5'), 69.7 (C3'), 77.4 (C2'), 87.7 (C4'), 99.9 (C1'), 128.5 (C5), 134.0 (C3), 140.4 (C2), 142.7 (C6), 145.7 (C4), 165.8 (CONH2).

[0306] Conversion of Nicotinamide-β-D-riboside L-hydrogen tartrate after neutralization with triethylamine: 1.8 ml of triethylamine was added to the remaining half of the solution, where the HBr and acetic acid were partially neutralized. 4.4 ml of a 1.7 molar methanolic solution of triethylammonium L-hydrogen tartrate was added to the yellowish solution, where the product started to precipitate. After filtration and washing with methanol and ethanol, and drying in vacuum at 30°C, 1.62 g (53.2%) of a white crystalline powder was obtained. Melting point 127-128°C. 1 H-NMR (400 MHz, DO): similar to Example 19a. Impurities: 1 mol% nicotinamide; 3.7 mol% TEA salt. Solvent: 12.5 mol% methanol. 13 C-NMR (100 MHz, DO): Similar to Example 19a.

[0307] Example 19c: Deacylation using triethylamine Deacylation of nicotinamide-D-riboside-2,3,5-triacetate triflate: 3.00 g of triflate was dissolved in 18 ml of methanol with stirring. 0.8 ml of triethylamine (1 equiv.) was added to the solution cooled to 0 °C. After stirring at 0-5 °C for 4 days, thin layer control showed complete conversion.

[0308] Conversion to Nicotinamide-β-D-riboside L-Hydrogen Tartrate: The brown-orange solution obtained in the above step was allowed to warm to room temperature. Subsequently, 0.86 g of L-tartaric acid was added. The product started to precipitate. The product suspension was cooled to 0° C. and stirred. After storage in the refrigerator for 12 hours, the suspension was filtered and the solid obtained was washed with 5 ml of isopropanol and dried in vacuum at 30° C. 1.44 g (63.0%) of a tan crystalline powder was obtained. Melting point 127° C. 1 H-NMR (400 MHz, DO): similar to Example 19a. Impurities: 2 mol% nicotinamide; 1.9 mol% TEA salt. Solvent: 13.3 mol% methanol, 4 mol% isopropanol. 13 C-NMR (100 MHz, DO): Similar to Example 19a.

[0309] Since in the above sequence one equivalent of triethylamine is required for deacylation, it can be concluded that triethylamine is unexpectedly catalytically active.

[0310] Example 19d: Deacylation using HBr in glacial acetic acid, neutralization using tributylamine Deacylation of nicotinamide-2,3,5-tri-O-acetyl-D-ribofuranoside triflate: 2.00 g of triflate was dissolved in 8 ml of methanol with stirring. The solution was cooled to 0-5°C. After adding 1.3 ml of HBr 33% in glacial acetic acid, the yellow-greenish solution was stirred at room temperature. After 2 days, no educt could be detected in the solution by thin-layer chromatography.

[0311] Conversion to Nicotinamide-β-D-ribofuranoside L-hydrogen malate after neutralization with tributylamine: 1.3 ml of tributylamine was added to the above solution. After adding 0.6 ml of water, any precipitated material was completely dissolved. 0.51 g of L-malic acid was added to the tan solution. After adding another 0.9 ml of tributylamine, the product started to crystallize. The formed product was filtered, washed with methanol, and dried in vacuum at 30° C. 0.48 g (33%) of Nicotinamide-β-D-ribofuranoside L-hydrogen malate was obtained. Melting point 115.5-116.5° C. 1 H-NMR (400 MHz, D2O): 2.55 (dd, 1H, CH2, H-malate), 2.73 (dd, 1H, CH2, H-malate), 3.83 (dd, 1H, H5'), 3.98 (dd, 1H, H5'), 4.28 (t, 1H, H3'), 4.29 (dd, 1H, CHOH, H-malate), 4.39-4.46 (m, 2H, H4', H2'), 6.18 (d, 1H, H1'), 8.21 (t, 1H, H5), 8.91 (d, 1H, H4), 9.20 (d, 1H, H6), 9.53 (s, 1H, H2). Impurities: < 1 mol% nicotinamide; 0.35 mol% TBA salt: 0.85 (t, 9H), 1.29 (m, 6H), 1.59 (m, 6H), 3.05 (q, 6H). Solvent: 2.3 mol% methanol: 3.27 (s, 3H). 13 C-NMR (100 MHz, DO): 40.0 (CH2, malate), 60.2 (C5'), 68.5 (CHOH, H-malate), 69.8 (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), 165.8 (CONH2), 176.3 (COO, H-malate), 179.0 (COO, H-malate).

[0312] Example 20: Preparation of Nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside Iodide 6.00 g (0.049 mol) of nicotinamide and 14.9 g (0.047 mol) of β-D-ribofuranose 1,2,3,5-tetraacetate were suspended in 190 ml of acetonitrile dried over 3 Å molecular sieves with stirring at room temperature. The suspension was warmed to 35° C., during which most of the solid dissolved. 6.9 ml (0.048 mol) of trimethylsilyl iodide were added within 20 min, and the yellow suspension was stirred at 35° C. for another 2 h. The internal temperature was subsequently maintained at 40° C. and 45° C. for 1 h each. The solvent was removed in vacuum at 35° C. The foam formed was dissolved in 100 ml of dichloromethane, and 1.2 g of activated charcoal was added. The suspension was filtered. The filtrate was concentrated. 22 g (93%) of a thick yellow foam was obtained. 1 H-NMR (400 MHz, D2O): 2.05, 2.07, 2.12 (3x s, 3x 3H, COCH3), 4.46 (m, 2H, H5'), 4.84 (m, 1H, H4´), 5.41 (t, 1H, H3'), 5.53 (dd, 1H, H2'), 6.58 (d, 1H, H1'), 8.28 (t, 1H, H5), 8.94 (d, 1H, H4), 9.18 (d, 1H, H6), 9.38 (s, 1H, H2). Impurities: 15 mol% alpha-anomer, 3 mol% nicotinamide. 13 C-NMR (100 MHz, D2O): 20.0, 20.1, 20.4 (3x COCH3), 62.6 (C5'), 69.3 (C3'), 76.1 (C2'), 82.5 (C4'), 97.2 (C1'), 128.8 (C5), 134.1 (C3), 140.4 (C2), 143.1 (C6), 146.2 (C4), 165.1 (CONH2), 172.0, 172.1, 173.0 (3x CO).

[0313] Example 21: Deacylation of Nicotinamide-β-D-riboside-2,3,5-triacetate iodide illustrating Route 5 Deacylation using sulfuric acid and neutralization using triethylamine

[0314] Preparation of dilute sulfuric acid in methanol: 10 ml of methanol was cooled to 0° C. 1.20 ml of 96% sulfuric acid was added with stirring. Methanolic sulfuric acid was used for the deacetylation below.

[0315] Deacylation of nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside iodide: 11.0 g of nicotinamide-2,3,5-tri-O-acetyl-β-D-ribofuranoside iodide was dissolved in 33 ml of methanol with stirring. The above prepared methanolic sulfuric acid was added. The resulting orange-brown solution was stirred at room temperature for 1 day. A thin layer chromatographic control revealed complete deacylation and some impurities. 3.5 ml of triethylamine was added.

[0316] The solution was divided into two portions.

[0317] Conversion to nicotinamide-β-D-riboside L-hydrogen tartrate after neutralization with triethylamine: To half of the above solution, 1.65 g of L-tartaric acid was added, followed by another 1.6 ml of triethylamine. The product started to precipitate almost immediately. The product suspension was stirred for 1 h at ambient temperature, 2 h in an ice bath, and stored in a refrigerator for 12 h. After filtration, the solid obtained was washed with methanol and dried in vacuum at 30 °C. 2.10 g (48%) of an almost white crystalline powder of nicotinamide-β-D-ribofuranoside L-hydrogen tartrate was obtained. Melting point 125.5-126 °C. 1 H-NMR (400 MHz, DO): similar to Example 19a. Impurities: 1 mol% nicotinamide; 3.8 mol% TEA salt. Solvent: 18.2 mol% methanol. 13 C-NMR (100 MHz, DO): Similar to Example 19a.

[0318] Conversion to Nicotinamide-β-D-riboside L-hydrogenmalate after neutralization with triethylamine: 1.45 g of L-malic acid was added to the remaining half of the above solution, followed by another 1.1 ml of triethylamine. The solution was seeded. The product started to precipitate after a few minutes. The product suspension was stirred for 1 h at ambient temperature, 2 h in an ice bath, and then stored in a refrigerator for 12 h. After filtration, the solid obtained was washed with methanol and ethanol, and dried in vacuum at 30 °C. 1.37 g (32.7%) of Nicotinamide-β-D-ribofuranoside L-hydrogenmalate was obtained as an almost white crystalline solid. Melting point 114-115 °C. 1 H-NMR (400 MHz, DO): similar to Example 19d. Impurities: 0.5 mol% nicotinamide; 0.5 mol% TEA salt. Solvent: 2.4 mol% methanol, 0.4 mol% ethanol. 13 C-NMR (100 MHz, DO): Similar to Example 19d. The present invention includes the following aspects: <Aspect 1> A method for producing nicotinamide-β-D-ribofuranoside salt, comprising the steps of: (A) subjecting a nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate to salt metathesis involving counterion exchange to provide said nicotinamide-β-D-ribofuranoside salt; A method for producing nicotinamide-β-D-ribofuranoside salt, comprising: <Aspect 2> A method for producing nicotinamide-β-D-ribofuranoside salt, comprising the steps of (A) and (B): (A) subjecting a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate 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 the nicotinamide-β-D-ribofuranoside salt; A method for producing nicotinamide-β-D-ribofuranoside salt, comprising: <Aspect 3> Prior to step (A), the following steps (X), (Y) and (Z) are performed: (X) Tetra-O-acyl-β-D-ribofuranose of the following formula: [ka] wherein each R is alkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl, preferably C 1-10 R is independently selected from alkylcarbonyl and benzoyl, and more preferably acetyl, and wherein R is optionally C 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 S.O. 2 N(C 1-6 Alkyl) 2 and is exposed to hydrogen bromide in acetic acid to produce tri-O-acyl-D-ribofuranoside bromide of the following formula:

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[0023] 3. The method of any one of the preceding aspects, further comprising a pathway selected from the group consisting of: Aspect 14 The method of embodiment 13, wherein the salt metathesis in pathways (P3) and (P5) is carried out in situ. Aspect 15 15. The method of embodiment 13 or 14, wherein the salt containing the pharma- ceutically acceptable anion used in counterion exchange is formed in situ. Aspect 16 1. A crystalline nicotinamide-β-D-ribofuranoside salt or a crystalline nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside salt, crystalline nicotinamide-β-D-ribofuranoside D-hydrogen malate characterized by a powder X-ray diffraction pattern as set forth in FIG. 1; crystalline nicotinamide-β-D-ribofuranoside L-hydrogen malate characterized by a powder X-ray diffraction pattern as set forth in FIG. 2; Crystalline nicotinamide-β-D-ribofuranoside DL-hydrogen malate characterized by a powder X-ray diffraction pattern as defined in FIG. crystalline nicotinamide-β-D-ribofuranoside D-hydrogen tartrate monohydrate characterized by a powder X-ray diffraction pattern as defined in FIG. 4; crystalline nicotinamide-β-D-ribofuranoside L-hydrogen tartrate characterized by a powder X-ray diffraction pattern as defined in FIG. 5; crystalline nicotinamide-β-D-ribofuranoside DL-hydrogen tartrate characterized by a powder X-ray diffraction pattern as set forth in FIG. 6; crystalline nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside L-hydrogen tartrate characterized by an X-ray powder diffraction pattern as set forth in FIG. 7; crystalline nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside D-hydrogen tartrate characterized by an X-ray powder diffraction pattern as set forth in FIG. 8; and crystalline anhydrous nicotinamide-β-D-ribofuranoside D-hydrogen tartrate, characterized by an X-ray powder diffraction pattern as set forth in FIG. 9; crystalline nicotinamide-β-D-ribofuranoside salt or crystalline nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside salt selected from the group consisting of: Aspect 17 17. A dietary supplement comprising a nicotinamide-β-D-ribofuranoside salt obtainable by a method according to any one of aspects 1 to 15, or comprising a nicotinamide-β-D-ribofuranoside salt according to aspect 16. Aspect 18 17. A pharmaceutical composition comprising a nicotinamide-β-D-ribofuranoside salt obtainable by a method according to any one of aspects 1 to 15, or comprising a nicotinamide-β-D-ribofuranoside salt according to aspect 16. Aspect 19 The following step (A): (A) providing a nicotinamide-β-D-ribofuranoside salt obtained by a method according to any one of embodiments 1 to 15, or providing a compound according to embodiment 16; 23. A method for performing chemical synthesis comprising: Aspect 20 A method for producing nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside triflate or iodide, comprising the steps of: (A) Tetra-O-acyl-β-D-ribofuranose of the following chemical formula:

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Claims

1. A method for producing nicotinamide-β-D-ribofuranoside salt, comprising the steps of: (A) subjecting a nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate to salt metathesis involving counterion exchange to provide said nicotinamide-β-D-ribofuranoside salt; and The counter ion is a cation [NR 1 R 2 R 3 R 4 ] + or cations containing [PR 1 R 2 R 3 R 4 ] + wherein R is derived from a phosphonium salt comprising 1 , R 2 , R 3 and R 4 H, C 1-12 independently selected from alkyl and aryl; A method for producing nicotinamide-β-D-ribofuranoside salts.

2. A method for producing nicotinamide-β-D-ribofuranoside salt, comprising the steps of (A) and (B): (A) subjecting a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate 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 the nicotinamide-β-D-ribofuranoside salt; and The counter ion is a cation [NR 1 R 2 R 3 R 4 ] + or cations containing [PR 1 R 2 R 3 R 4 ] + wherein R is derived from a phosphonium salt comprising 1 , R 2 , R 3 and R 4 H, C 1-12 independently selected from alkyl and aryl; A method for producing nicotinamide-β-D-ribofuranoside salts.

3. Prior to step (A), the following steps (X), (Y) and (Z) are performed: (X) Tetra-O-acyl-β-D-ribofuranose of the following chemical formula: 【Chemistry 1】 wherein each R is independently selected from alkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl, and wherein R is optionally C 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 S.O. 2 N (C 1-6 Alkyl) 2 and is exposed to hydrogen bromide in acetic acid to produce tri-O-acyl-D-ribofuranoside bromide of the following formula: 【Chemistry 2】 providing (Y) The tri-O-acyl-D-ribofuranoside bromide is converted into nicotinamide having the following chemical formula: 【Chemistry 3】 to produce nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide of the following formula: 【Chemistry 4】 providing (Z) The nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide obtained in step (Y) is deacylated by removing the R group to obtain a nicotinamide-β-D-ribofuranoside bromide compound of the following chemical formula: 【Chemistry 5】 wherein the nicotinamide-β-D-ribofuranoside bromide formed in step (Z) is used in step (A); The method of claim 1 , comprising:

4. Prior to step (A), the following steps (X) and (Y) are performed: (X) Tetra-O-acyl-β-D-ribofuranose of the following chemical formula: 【Chemistry 6】 wherein each R is independently selected from alkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl, and wherein R is optionally C 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 S.O. 2 N (C 1-6 Alkyl) 2 and is exposed to hydrogen bromide in acetic acid to produce tri-O-acyl-D-ribofuranoside bromide of the following formula: 【Chemistry 7】 providing (Y) The tri-O-acyl-D-ribofuranoside bromide is converted into nicotinamide having the following chemical formula: 【Chemistry 8】 React with Nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide of the following chemical formula: 【Chemistry 9】 wherein the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide formed in step (Y) is used in step (A); The method of claim 2 , comprising:

5. Prior to step (A), the following steps (X) and (Y) are performed: (X) Tetra-O-acyl-β-D-ribofuranose of the following chemical formula: 【Chemistry 10】 wherein each R is independently selected from alkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl, and wherein R is optionally C 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 S.O. 2 N (C 1-6 Alkyl) 2 and in the presence of trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, trimethylsilyl triflate, trimethylsilyl nonaflate, trimethylsilyl fluorosulfonate or trimethylsilyl percolate to produce nicotinamide of the following formula: 【Chemistry 11】 to provide a nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaflate, fluorosulfonate, or percolate of the formula: 【Chemistry 12】 (Y) The nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaflate, fluorosulfonate or percolate obtained in step (X) is deacylated by removing the R group to obtain a nicotinamide-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaflate, fluorosulfonate or percolate compound represented by the following chemical formula: 【Chemistry 13】 wherein the nicotinamide-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaflate, fluorosulfonate or percolate formed in step (Y) is used in step (A), The method of claim 1 , comprising:

6. Prior to step (A), the following step (X): (X) Tetra-O-acyl-β-D-ribofuranose of the following chemical formula: 【Chemistry 14】 wherein each R is independently selected from alkylcarbonyl, arylcarbonyl, and heteroarylcarbonyl, and wherein R is optionally C 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 S.O. 2 N (C 1-6 Alkyl) 2 and in the presence of trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, trimethylsilyl triflate, trimethylsilyl nonaflate, trimethylsilyl fluorosulfonate or trimethylsilyl percolate to produce nicotinamide of the following formula: 【Chemistry 15】 to obtain nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, bromide, iodide, triflate, nonaflate, fluorosulfonate or percolate of the following chemical formula: 【Chemistry 16】 wherein the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate formed in step (X) is used in step (A); The method of claim 2 , comprising:

7. 7. The method according to any one of claims 1 to 6, wherein the counter ion of the salt obtained in step (A) via counter ion exchange is a pharma- ceutically acceptable ion.

8. The pharma- ceutically acceptable ion is Inorganic ions; Carboxylates, including carboxyl, hydroxyl, thio, keto, amino, mono C 1-6 Alkyl, Hydroxy C 1-6 Alkylene and di(C 1-6 and optionally substituted with one or more substituents independently selected from the group consisting of: C 1-12 Alkyl sulfonates; or Aryl sulfonates, wherein the aryl moiety is carboxyl, hydroxyl, amino, monoC 1-6 Alkyl and di(C 1-6 alkyl)amino, halogen, and C 1-6 is optionally substituted with one or more substituents independently selected from the group consisting of alkyl; and wherein said pharma- ceutically acceptable salt is not a bromide, triflate, nonaflate or percolate. The method of claim 7, wherein the compound is selected from the group consisting of:

9. the inorganic ion is selected from the group consisting of chloride, hydrogen sulfate, sulfate, dihydrogen phosphate, monohydrogen phosphate, phosphate; the carboxylate is selected from the group consisting of formate, acetate, oxalate, malonate, succinate, fumarate, maliate, citrate, malate, tartrate, ascorbate, α-ketoglutarate, glucuronate, benzoate, and salicylate; Said C 1-12 The alkylsulfonate is selected from the group consisting of mesylate and camsylate; the aryl sulfonate is selected from the group consisting of besylate and tosylate; The method according to claim 8.

10. the pharma- ceutically acceptable ion is malate, or The pharma- ceutically acceptable ion is tartrate; 10. The method according to any one of claims 7 to 9.

11. said salt metathesis being carried out in an alcohol selected from the group consisting of methanol, ethanol, propanol or butanol, or a mixture of two or more thereof, said alcohol or said mixture optionally containing water; or The salt metathesis is carried out in a solvent comprising methanol, ethanol, propanol or butanol, or a mixture of two or more thereof, wherein the solvent optionally contains water; 11. The method according to any one of claims 1 to 10.

12. The following route (P1) to (P5): (P1) A pathway comprising the following steps (α), (β), (γ) and (δ): (α) cleaving the acyl groups of nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate, containing up to 5% of the α-anomer, to provide said nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate; (β) isolating and optionally purifying the nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate; (γ) subjecting the nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate to salt metathesis to provide a nicotinamide-β-D-ribofuranoside salt; (δ) isolating and optionally purifying the nicotinamide-β-D-ribofuranoside salt; (P2) A pathway comprising the following steps (α), (β), (γ) and (δ): (α) subjecting a nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate containing up to 5% of the α-anomer to salt metathesis to provide a nicotinamide-2,3,5-O-triacyl β-D-ribofuranoside salt; (β) isolating and optionally purifying the nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside salt; (γ) cleaving the acyl group of the nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside salt to provide a nicotinamide-β-D-ribofuranoside salt; (δ) isolating and optionally purifying the nicotinamide-β-D-ribofuranoside salt; (P3) A pathway comprising the following steps (α) and (β): (α) cleaving the acyl group of a nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate containing up to 5% of the α-anomer to provide said nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, and subjecting the formed nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate to salt metathesis without prior isolation to provide a nicotinamide-β-D-ribofuranoside salt; (β) isolating and optionally purifying the nicotinamide-β-D-ribofuranoside salt; (P4) A pathway comprising the following steps (α), (β), (γ) and (δ): (α) subjecting a nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate, or percolate containing 5% or more of the α-anomer to salt metathesis to provide a nicotinamide-2,3,5-O-triacyl β-D-ribofuranoside salt; (β) isolating and optionally purifying the nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside salt; (γ) cleaving the acyl group of the nicotinamide-2,3,5-O-triacetyl-β-D-ribofuranoside salt to provide a nicotinamide-β-D-ribofuranoside salt; (δ) isolating and optionally purifying the nicotinamide-β-D-ribofuranoside salt; and (P5) A pathway comprising the following steps (α) and (β): (α) cleaving the acyl group of a nicotinamide-2,3,5-O-triacyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate containing 5% or more of the α-anomer to provide a nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, and subjecting the formed nicotinamide-β-D-ribofuranoside bromide or chloride or iodide or triflate or nonaflate or fluorosulfonate or percolate to salt metathesis without prior isolation to provide a nicotinamide-β-D-ribofuranoside salt; (β) isolating and optionally purifying the nicotinamide-β-D-ribofuranoside salt; The method of any one of claims 1 to 11, further comprising a pathway selected from the group consisting of:

13. The method according to claim 12, wherein the salt metathesis in pathways (P3) and (P5) is carried out in situ.

14. 14. The method of claim 12 or 13, wherein the salt containing the pharma- ceutically acceptable anion used in the counterion exchange is formed in situ.

15. 1. A method for producing a dietary supplement comprising a nicotinamide-β-D-ribofuranoside salt, comprising: A method for producing the nicotinamide-β-D-ribofuranoside salt according to any one of claims 1 to 14, method.

16. 1. A method for preparing a pharmaceutical composition comprising a nicotinamide-β-D-ribofuranoside salt, comprising: The method for producing the nicotinamide-β-D-ribofuranoside salt according to any one of claims 1 to 14, method.

17. The following step (A): (A) providing a nicotinamide-β-D-ribofuranoside salt obtained by the method according to any one of claims 1 to 14 23. A method for performing chemical synthesis comprising:

18. The following steps (A1) and (A2): (A1) NH 3 Or N.R. 1 H 2 Or N.R. 1 R 2 H or NR 1 R 2 R 3 or [NR 1 R 2 R 3 R 4 ]OH is reacted with an acid to provide the ammonium salt, wherein R 1 , R 2 , R 3 and R 4 is C 1-12 is independently selected from alkyl and aryl and is optionally substituted. (A2) reacting nicotinamide-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate, or nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside bromide, chloride, iodide, triflate, nonaflate, fluorosulfonate or percolate with the ammonium salt from step (A1) to perform salt metathesis including counterion exchange to provide the nicotinamide-β-D-ribofuranoside salt or the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt; 15. The method according to claim 1 , wherein step (A) comprises:

19. N.R. 1 R 2 R 3 or [NR 1 R 2 R 3 R 4 20. The method according to claim 18, wherein ]OH is used in step (A1).

20. 20. The method of any one of claims 1 to 14 and claims 18 and 19, wherein the nicotinamide-β-D-ribofuranoside salt or the nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt is an iodide.

21. The following steps (A1) and (A2): (A1) NH 3 Or N.R. 1 H 2 Or N.R. 1 R 2 H or NR 1 R 2 R 3 or [NR 1 R 2 R 3 R 4 ]OH is reacted with an acid to provide an ammonium salt, where R 1 , R 2 , R 3 and R 4 is C 1-12 is independently selected from alkyl and aryl and is optionally substituted. (A2) reacting the first nicotinamide-β-D-ribofuranoside salt or the first nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt with the ammonium salt from step (A1) to perform salt metathesis including counterion exchange to provide a second nicotinamide-β-D-ribofuranoside salt or a second nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt; A method for producing a second nicotinamide-β-D-ribofuranoside salt from a first nicotinamide-β-D-ribofuranoside salt, or a method for producing a second nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt from a first nicotinamide-2,3,5-tri-O-acyl-β-D-ribofuranoside salt, comprising:

22. N.R. 1 R 2 R 3 or [NR 1 R 2 R 3 R 4 22. The method according to claim 21 , wherein ]OH is used in step (A1).

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