WO2017218580A1

WO2017218580A1 - Synthetic methods for the preparation of nicotinamide riboside and related compounds

Info

Publication number: WO2017218580A1
Application number: PCT/US2017/037315
Authority: WO
Inventors: Krzysztof Z. FELCZAK
Original assignee: Rejuvenation Therapeutics Corporation
Priority date: 2016-06-14
Filing date: 2017-06-13
Publication date: 2017-12-21
Also published as: TW201802105A

Abstract

The present application is directed to methods of making a pharmaceutically acceptable salt of nicotinamide riboside and related compounds by alkylating nicotinamide with a 1-chloro-D-ribofuranose derivative. The present invention relates to a method of making a compound of Formula (I): (a) reacting a compound of Formula (II) with a compound of Formula (III) to form a compound of Formula (IV).

Description

SYNTHETIC METHODS FOR THE PREPARATION OF NICOTINAMIDE RIBOSIDE AND RELATED COMPOUNDS

Cross -Reference to Related Applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 62/350,100, filed June 14, 2016, which is incorporated herein by reference in its entirety.

Technical Field

[0002] The present invention relates to cost-effective, scalable synthetic methods for the preparation of nicotinamide riboside and related compounds.

Background

[0003] Pyridine nucleosides are precursors of nicotinamide adenine dinucleotide (NAD⁺) and NADH, which are important regulators of energy production, redox reactions, and metabolism. Nicotinamide riboside is a nucleoside adduct of vitamin B3 (niacin) with the structure shown below.

[0004] As a metabolic precursor to NAD, nicotinamide riboside has been shown to enhance oxidative metabolism and protect against high-fat diet induced obesity in mice. These findings have prompted significant interest in nicotinamide riboside and its derivatives as dietary supplements, and nicotinamide riboside has the potential to produce beneficial effects for metabolic and age-related disorders. Bieganowski, P., and C. Brenner,

"Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans," Cell 2004, 117(4), 495- 501; Sauve, A. A., "NAD⁺ and Vitamin B₃: From Metabolism to Therapies," . Pharmacol. Exp. Ther. 2008, 324(3), 883-893; Yang, H. et al, "Nutrient- sensitive mitochondrial NAD+ levels dictate cell survival," Cell 2007, 130(6), 1095-1107. Recent reports have shown that nicotinamide riboside delays senescence in muscle, neural, and melanocyte stem cells, with implications for increasing lifespan and treating muscular dystrophy. Zhang, H. et ah, "NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice," Science 10.1126/science.aaf2693 (2016). Because nicotinamide riboside and related compounds are natural metabolic mediators, their use may be accompanied by a lower risk of side effects than synthetic supplements.

[0005] Wide use of these compounds as dietary supplements has been limited by production methods that are low yielding, poorly stereoselective, and/or employ expensive or hazardous reagents, or produce pyridinium salts comprising pharmaceutically unsuitable counterions. For these reasons, known synthetic methods are not amenable to large-scale, commercial synthesis.

[0006] By way of example, PCT Intl. Pat. Publ. No. WO2007/061798 (Examples 1 and 2; see also U.S. Patent No. 8,106,184) describes preparation of nicotinamide riboside by reaction of l,2,3,5-tetra-0-acetyl-P-D-ribofuranose ("ribose tetraacetate," structure A below) with ethyl nicotinate in CH₂CI₂ at reflux to generate compound B, which is de-acetylated and amidated in methanolic ammonia to provide nicotinamide riboside (NR).

[0007] However, the synthesis employs a molar equivalent of the expensive, hazardous, and air-sensitive reagent, trimethylsilyl trifluoromethanesulfonate (TMSOTf) to mediate the coupling step. Second, the coupled product is prepared as the corresponding trifluoromethanesulfonate (triflate; OTf) salt, which is unsuitable for use as a nutritional supplement due to toxicity associated with the triflate counterion. Conversion of the triflate salt to a pharmaceutically acceptable salt form would require an additional triflate-chloride ion exchange step, which would likewise be impractical for large-scale efforts. As nicotinamide riboside is chemically labile, exposure to further chemical manipulation also would increase the risk of decomposition. Similar procedures are described in PCT Publ. No. WO2015/014722 (pages 18-19), by coupling bis-silylated nicotinamide (prepared from nicotinamide and TMSC1 in hexamethyldisilazane (HMDS)) with ribose tetraacetate in the presence of five equivalents of TMSOTf. Conversion to the pharmaceutically acceptable chloride salt requires several additional steps (oxidation, reduction, and salt formation; see Figure 3 of WO2015/014722). Additional TMSOTf-mediated couplings between a nicotinamide derivative and a protected ribose have been reported. Franchetti, P. et al, Bioorg. Med. Chem. Lett. 2004, 14, 4655-4658; Tanimori, S. et al, Bioorg. Med. Chem. Lett. 2002, 12, 1135-1137; and Yang, T. et al, J. Med. Chem. 2007, 50, 6458-6461.

[0008] Mikhailopulo reported the synthesis of a pharmaceutically acceptable bromide salt of nicotinamide riboside from l-bromo-2,3,5-tri-0-acetyl-a-D-ribofuranose in

sulpholane, liquid sulfur dioxide, or nitromethane solvents, without the addition of an acid catalyst such as TMSOTf. Mikhailopulo, M. et al, Synthesis 1981, 388. Although reaction in liquid sulfur dioxide provided triacetylated nicotinamide riboside in almost quantitative yield, this solvent is unsuitable for industrial scale. The reaction in nitromethane provided only a 50% yield of protected nicotinamide riboside, contaminated with the corresponding a- anomer and nicotinamide starting material. Honda reports good yields and selectivity for coupling pyridine derivatives with protected chloro and bromo sugars in refluxing

nitromethane in the presence of an acid scavenger such as CdC(¾, which helped curb various side reactions. Honda et al, Chem. Pharm. Bull. 1987, 35(9), 3975-3978.

[0009] Previous reports have described a pharmaceutically acceptable chloride salt of nicotinamide riboside {see, e.g., WO2016/014927), and synthesis of this compound by reaction of l-chloro-2,3,5-tri-0-acetyl-a-D-ribofuranose (2a) with ethyl nicotinate to generate nicotinamide 2b) in acetonitrile as shown below.

[0010] However, these reactions generally provided low yields, poor stereoselectivity, and/or procedures or reagents that are not amenable to commercial scale synthesis of a nutritional supplement. See, e.g., Haynes, L.J. et al, J. Chem. Soc. 1957, 3727; Fischer et al, Berichte 1910, 43, 1750; Viscontini et al, Helv. Chim. Acta 1955, 38, 909; Hughes et al, J. Chem. Soc. 1957, 3733; Freyne et al, Carbohydrate Res. 1980, 72, 235 (noting rapid anomerization of l-chloro-2,3,5-tribenzoyl ribose in acetonitrile); Woenckhaus et al, Justus Leibigs Ann. Chem. 1970, 736, 126 (producing chloride salt of a β-anomer from 1-chloro sugar after 18 days in dioxane); WO08/093290 (pages 60-61); W098/16186. For example, Haynes describes the synthesis of an intermediate peracetyl nicotinamide riboside in acetonitrile in 62% yield but indicate the product is contaminated with the corresponding a- anomer. As discussed by Jarman (J. Chem. Soc. C(2) 1969, 199-203), the Haynes reaction is performed under extremely dilute conditions (2.5 g nicotinamide in 400 mL acetonitrile) due to the low solubility of nicotinamide (approx. 1% w/v). Elevated reaction temperatures allowed for a higher concentration of nicotinamide, but led to increased decomposition of 1- chloro-2,3,5-tri-0-acetyl-a-D-ribofuranose and complex mixtures (Jarman, and references cited therein). Jarman overcomes nicotinamide' s poor solubility by warming a solution of nicotinamide in acetonitrile at approximately a concentration of about 0.17 M, cooling the solution, and adding a l-chloro-3,5-dibenzoyl ribose derivative, noting that the coupling reaction more rapidly than precipitation of nicotinamide from the solution, resulting in a 91% yield of predominantly β-anomer.

[0011] In summary, previously disclosed methods have disadvantages that preclude their use for commercial or industrial scale synthesis of nicotinamide riboside and related compounds. There is a need for a robust, scalable, cost-effective synthesis that generates the target compounds in a form suitable for use as a dietary supplement. The methods described herein overcome the disadvantages of the previously disclosed methods by providing a short, high yielding synthesis that uses safe, reasonably priced reagents with good solubility in suitable reaction media, and that produce the target compounds with high stereoselectivity and overall purity. The methods described herein employ low polarity or non-polar solvents for coupling halo-sugar derivatives with nicotinamide and related pyridine compounds.

Summary of the Invention

[0012] The present invention is directed to a method of making a l-(3-substituted pyridyl)-P-ribose comprising reacting a 3-substituted pyridine with a 2,3,5-protected or 3,5- protected 1-a-chloro ribose at the 1-position of the ribose using a quarternization reaction. The present invention relates to a compound of Formula (I):

(I);

wherein R¹ is -C0₂H, -C0₂(C^alkyl), -C(0)NR^aR^b, Ci_₄alkyl, -NR^aR^b, Ci_₄haloalkyl, halo, - CN, -SO₃H, or -S0₂Ci-₄alkyl;

where R^a and R^b are each independently H or Ci_₄alkyl;

2 3

R" and R^J are each independently H, -OH, Ci_₄alkyl, or F; X^" is a pharmaceutically acceptable counterion selected from the group consisting of p- toluenesulfonate (tosylate), methanesulfonate (mesylate), acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, a-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, and carbonate;

comprising:

(a) reacting a compound of Formula (II :

wherein

R^2a and R^3a are each independently H, -OH, -OP, Ci_₄alkyl, or F; and

each P is independently a hydroxyl protecting group;

with a compound of Formula (III):

where R^la is -C0₂H, -C0₂(C^alkyl), -C(0)NR^cR^d, -C(OR^c)=NR^d, C^alkyl, -NR^cR^d,

Ci_₄haloalkyl, halo, -CN, -SO₃H, or -S0₂Ci_₄alkyl;

where R^c and R^d are each independently H, Ci_₄alkyl, or -Si(R^e)₃, wherein each R^e is independently Ci_6 alkyl;

to form a compound of Formula (I

where R^la, X^", P, R^2a, and R^3a are each as defined above.

[0013] Where the compound of Formula (IV) is not itself a compound of Formula (I), the method further comprises: (b) converting the compound of Formula (IV) to a compound of Formula (I).

[0014] The method generates nicotinamide riboside and avoids the typical use of an expensive, hazardous reagent such as TMSOTf, and generates a pharmaceutically acceptable salt form of the compound directly without the need for a separate counterion manipulation step such as ion exchange chromatography. [0015] The present disclosure also provides compounds of Formula (I) that are prepared according to any of the methods disclosed herein, pharmaceutical compositions comprising such compounds, and methods of administering to a subject such compounds.

[0016] The present disclosure is also directed to isolated forms of certain

intermediates in the synthetic methods, including the compounds of Formula (3a), (3b), (4a), (4b), and (5a). Also contemplated are compounds of Formula (IV), Formula (IV a), Formula (IVb), and Formula (IVc) as intermediates. Also contemplated are compounds of Formula (I) and Formula (la). In some embodiments, the compounds are not nicotinamide riboside, chloride or triflate salt, nicotinic acid, nicotinic acid riboside, methyl nicotinate, methyl nicotinate riboside, ethyl nicotinate, or ethyl nicotinate riboside.

[0017] Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

[0018] For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference.

Detailed Description of the Invention

[0019] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[0021] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation. [0022] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

[0023] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about." It is understood that, whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.

[0024] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0025] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0026] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to particular method steps, reagents, or conditions are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed. [0027] The nomenclature used herein to name the subject compounds is illustrated herein. This nomenclature has generally been derived using standard practice for nucleoside and sugar derivatives, and/or from the commercially available AutoNom software (MDL, San Leandro, Calif.), Version 14.0.

[0028] A "pharmaceutically acceptable salt" is a salt form that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.

[0029] The term "substituted" means that the specified group or moiety bears one or more substituents. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is

unsubstituted or substituted by one or more substituents. Where the term "substituted" is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system.

[0030] A "protecting group" as used herein refers to a group that blocks reaction at a particular site on the molecule. For example, a hydroxyl protecting group may be an ester (such as an acetate, benzoate, or pivaloate), an acyl group (such as an acetyl, benzoyl, or pivaloyl), a benzyl derivative (benzyl, p-methoxybenzyl, p-nitrobenzyl), a silyl derivative (trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl), or an acetonide derivative (e.g., isopropylidene protecting two adjacent hydroxyl groups). In some embodiments, the protecting group is an acetate or benzoate ester. In certain embodiments, the protecting group is a phosphate or a protected phosphate group.

[0031] The term "alkyl" refers to a saturated, branched or linear hydrocarbon chain. In some embodiments, each Ci_₄alkyl is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

[0032] The term "haloalkyl" refers to an alkyl substituted with one or more halo groups. Examples include -CF₃, -CHF₂, -CH₂F, and -CH₂CH₂C1.

[0033] The term "halo" refers to a bromo, chloro, iodo, or fluoro group.

[0034] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. It will be appreciated by those skilled in the art that compounds of the invention having an anomeric center may exist one or more anomeric forms. Such compounds may exist in or be isolated as a single anomeric form. Formulae depicted herein may encompass any anomeric or stereoisomeric form, or a mixture thereof. Anomerically pure forms may be prepared using methods known to one of ordinary skill in the art, including, for example, resolution of a mixture of anomers by recrystallization, by stereoselective synthesis, or by chromatographic separation.

(IVa)

[0035] In some embodiments, the present disclosure relates to a method of reducing a compound of Formula (I). In some embodiments, the present disclosure relates to a method of reducing a compound of Formula (I) to a 1,4-dihydropyridine derivative, further comprising isolating the beta anomer of the 1,4-dihydropyridine derivative of Formula (I) by fractional crystallization or silica chromatography. In some embodiments, the 1,4-dihydropyridine derivative of a compound of Formula (I) is a compound of Formula (la), wherein R 1 , R 2 , and R are as defined for Formula (I). In other embodiments, the present disclosure relates to a method of reducing a compound of Formula (IV). In some embodiments, the present disclosure relates to a method of reducing a compound of Formula (IV) to a 1,4- dihydropyridine derivative, further comprising isolating the beta anomer of the 1,4- dihydropyridine derivative of Formula (IV) by fractional crystallization or silica

chromatography. In some embodiments, the 1,4-dihydropyridine derivative of a compound of Formula (IV) is a compound of Formula (IVa), wherein R^la, R^2a, and R^3a are as defined for Formula (IV). In some embodiments, the reducing step is achieved by using a reducing agent or electrochemical means. In certain embodiments, the reducing agent is sodium dithionate. In some embodiments, the compounds of Formula (la) or Formula (IVa) are converted back to the compound of Formula (I) or the compound of Formula (IV) by oxidation. In certain embodiments, the oxidation is achieved by using activated charcoal or through

electrochemical means.

[0036] In some embodiments presented herein, products that are substantially pure anomerically may be prepared directly from the contemplated reactions. For example, direct stereoisomeric selectivity may also be achieved by decreasing acid concentration in reaction mixture and/or lowering reaction temperature, which may inhibit or reduce undesired anomerization. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.

[0037] In some embodiments, the product of the reacting step is produced as greater than 50%, or greater than about 60%, or greater than about 70%, or greater than about 80% beta anomer. In some embodiments, the product of the reacting step is produced as greater than about 90%, or greater than about 92%, or greater than about 94%, or greater than about 95%, or greater than about 96%, or greater than about 97%, or greater than about 98%, or greater than about 99% beta anomer. In some embodiments, these proportions of beta anomer are achieved without a separate isolation or purification step (e.g., chromatography) beyond standard reaction workup.

[0038] In some embodiments of Formula (I), R¹ is -C0₂H, -C0₂(Ci_₄alkyl), - C(0)NR^aR^b, Ci_₄alkyl, -NR^aR^b, Ci_₄haloalkyl, halo, -CN, -S0₃H, or -S0₂Ci_₄alkyl. In some embodiments, R¹ is -C0₂H, -C0₂(Ci_₄alkyl), or -C(0)NR^aR^b. In some embodiments, R¹ is - CONH₂. In some embodiments, R¹ is -C0₂H.

[0039] In some embodiments, R 2 and R 3 are each independently H, -OH, Ci_₄alkyl, or

F. In some embodiments, R 2 and R 3 are each independently H or -OH. In some

embodiments, R 2 and R 3 are each -OH. In some embodiments, R 2 and R 3 are each acyloxy and the 5' OH position is replaced with acyloxy. In some embodiments, the 5' OH is phosphorylated with a phosphate or a protected phosphate group.

[0040] In some embodiments, for certain compounds described herein, X^" is an anion selected from the group consisting of substituted or unsubstituted carboxylic acid, a substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or unsubstituted sulfate, a substituted or unsubstituted carbonate, and a substituted or unsubstituted carbamate. As such, suitable salt forms include, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, and a-glycerophosphate salts. Suitable inorganic salts may also be formed, including chloride, bromide, sulfate, nitrate, phosphate, bicarbonate, and carbonate salts. In some embodiments, X^" is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, a-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, and carbonate. In some embodiments, X^" is fumarate, maleate, N-acetyl-D-tyrosinate, camsylate or oxalate. In some embodiments, X^" is chloride or bromide. In other embodiments, X^" is chloride. When P at the 5' position of any compounds described herein is a phosphate group, X^" is absent.

[0041] In some embodiments, the described methods include converting one X^" to another X^" through ion exchange chromatography or salt exchange reaction and precipitation. In some embodiments, the described methods include converting a salt of nicotinamide riboside or analogs thereof, where the salt is not the chloride salt, to the corresponding chloride salt. In certain embodiments, salts of the nicotinamide riboside cation or analogs having rigid anions such as fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, and oxalate may form low solubility crystals. As a result, the corresponding beta and alpha anomers of these salts may be more readily separable by recrystallization, thereby facilitating purification and leading to a purer product. Following purification, salts having rigid anions may be further converted to other salts, such as the corresponding chloride salts. In some

embodiments, the described methods include purifying a salt of nicotinamide riboside or analogs, wherein the X^" is selected from the group consisting of fumarate, maleate, N-acetyl- D-tyrosinate, camsylate, and oxalate. In certain embodiments, the described methods include purifying a salt of nicotinamide riboside or analogs, wherein the X^" is selected from the group consisting of fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, and oxalate, and further converting the salt to the corresponding chloride salt.

[0042] In some embodiments, the compound of Formula (I) is nicotinamide riboside, chloride salt. In other embodiments, the compound of Formula (I) is nicotinic acid riboside. In other embodiments, the compound of Formula (I) is picolinic acid riboside or isonicotinic acid riboside.

[0043] In some embodiments of Formula (II), each P is independently acetyl, benzoyl, p-chlorobenzoyl, p-nitrobenzoyl, tolyl, propionyl, butyryl, pivaloyl, decanoyi, aeetylglycyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, trimethylsilyl, triisopropylsilyl, t- butyldimethylsilyl, or t-butyldiphenylsilyl, or the two P groups in R^2a and R^3a, taken together, form an isopropylidene. In some embodiments, each P is acetyl or benzoyl. In one aspect, the present disclosure relates to a prodrug of a compound of Formula (I). In some

embodiments, the prodrug is a compound of Formula (IVb) having at least one labile protecting group P. In some embodiments, the labile protecting group P is an acyl group chosen such that P is labile to one or more enzymes present in mammalian tissues, including esterases, amidases, lipases and/or proteases. In certain embodiments, the labile protecting group P is an acyl group selected from the group consisting of acetyl, butyryl, decanoyi, and aeetylglycyl. [0044] In certain embodiments of Formula (II), P at the 5' position is a phosphate or protected phosphate. In certain embodiments of Formula (II), when P is phosphate at the 5' position, X^" is absent. In some embodiments, R^2a and R^3a are each OP, wherein each P of R^2a and R^3a is independently an acyl group, and P is protected phosphate at the 5' position. In other embodiments, R^2a and R^3a are each independently OH or OP and P is phosphate or protected phosphate at the 5' position.

[0045] In some embodiments, R^2a and R^3a in Formula (II) are each independently H, - OH, -OP, Ci_₄alkyl, or F. In other embodiments, R^2a and R^3a are each independently H, -OH, or -OP. In other embodiments, R^2a and R^3a are each independently H or -OH.

[0046] In some embodiments, the compound of Formula (II) is a 3,5-diprotected-l-a- chlororibose. In other embodiments, the compound of Formula (II), is a 2,3,5-triprotected-l- a-chlororibose. In other embodiments, the compound of Formula (II) is the compound of Formula (2a).

[0047] In some embodiments of Formula (III), R^la is -C0₂H, -C0₂(Ci_₄alkyl), -C(0)NR^cR^d, -C(OR^c)=NR^d, C alkyl, -NR^cR^d, Ci_₄haloalkyl, halo, -CN, -S0₃H, or -S0₂Ci_ ₄alkyl.

[0048] In some embodiments of Formula (III), R^c and R^d are each independently H, Ci_₄alkyl, or -Si(R^e)₃. In some embodiments of Formula (III), R^c and R^d are each

independently H, Ci_₄alkyl, or -Si(CH₃)₃. In some embodiments, R^c and R^d are each H or -Si(CH₃)₃. In other embodiments, R^c and R^d are each independently H or -Si(R^e)₃. In certain embodiments, R^c and R^dare each independently H or -Si(CH₃)₂C(CH₃)₃. In some embodiments, where R^c and R^d are each independently -Si(R^e)₃, the silyl group(s) may improve the solubility of the compound of Formula (III) in the reaction solvent. In other embodiments, the silyl group(s) may activate the compound of Formula (III) in the reacting step with the compound of Formula (II).

[0049] One of ordinary skill in the art will recognize that the following drawn structures depict tautomers of the same com ound:

[0050] Thus, when R^la is C(0)NR^cR^d, and R^c and R^d are each -Si(CH₃)₃, it is understood that such structure also encompasses a compound where R^la is - C(OSi(CH₃)₃)=N(Si(CH₃)₃). In some embodiments, the compound of Formula (III) may exist as a mixture of tautomers, where R^la is -C(0)N(Si(CH₃)₃)₂ and -C(OSi(CH₃)₃)=N(Si(CH₃)₃). In certain embodiments, the compound of formula (III) may exist in a single tautomeric form. In some embodiments, the single tautomeric form is the compound of Formula (III), where R^la is -C(0)N(Si(CH₃)₃)₂. In other embodiments, the single tautomeric form is the compound of Formula (III), where R^la is

-C(OSi(CH₃)₃)=N(Si(CH₃)₃).

[0051] One of ordinary skill in the art would further recognize the same relationship generally extends to tautomers of the compound of Formula (III), wherein R^la is - C(0)N(Si(R^e)₃)₂ and -C(OSi(R^e)₃)=N(Si(R^e)₃), and wherein each R^e is independently Ci_₆ alkyl. In some embodiments, the compound of Formula (III) may exist as a mixture of tautomers, where R^la is -C(0)N(Si(R^e)₃)₂ and -C(OSi(R^e)₃)=N(Si(R^e)₃). In certain embodiments, the compound of formula (III) may exist in a single tautomeric form. In some embodiments, the single tautomeric form is the compound of Formula (III), where R^la is - C(0)N(Si(R^e)₃)₂. In other embodiments, the single tautomeric form is the compound of Formula (III), where R^la is

-C(OSi(R^e)₃)=N(Si(R^e)₃). In some embodiments, the two silyl protecting groups are linked through -Si(R^e)₂-(CH₂)_n-(R^e)₂Si-, wherein n is 2, 3 or 4 and wherein R^e is methyl or ethyl. In certain embodiments, the linked silyl protecting groups impart additional stability to the compound of Formula (III).

[0052] Similarly, compounds of Formula (IV) that include this substituent group encompass both drawn forms of the silylated amide group. In some embodiments, the compound of Formula (IV) may exist as a mixture of tautomers, where R^la is -

C(0)N(Si(R^e)₃)₂ and -C(OSi(R^e)₃)=N(Si(R^e)₃), wherein each R^e is independently Ci_₆ alkyl.

In certain embodiments, the compound of formula (IV) may exist in a single tautomeric form.

In some embodiments, the single tautomeric form is the compound of Formula (IV), where

R^la is -C(0)N(Si(R^e)₃)₂. In other embodiments, the single tautomeric form is the compound of Formula (III), where R^la is -C(OSi(R^e)₃)=N(Si(R^e)₃).In some embodiments, the compound of Formula (IV) may exist as a mixture of tautomers, where R^la is -C(0)N(Si(CH₃)₃)₂ and -

C(OSi(CH₃)₃)=N(Si(CH₃)₃). In certain embodiments, the compound of formula (IV) may exist in a single tautomeric form. In some embodiments, the single tautomeric form is the compound of Formula (IV), where R^la is -C(0)N(Si(CH₃)₃)₂. In other embodiments, the single tautomeric form is the compound of Formula (III), where R ^a is - C(OSi(CH₃)3)=N(Si(CH₃)3).

[0053] In some embodiments, the compound of Formula (III) is the compound of Formula (3 a) or Formula (3b), or is a compound of Formula (3 a), or is a compound of Formula (3b).

[0054] In some embodiments of Formula (IV), R¹, X^", P, R^2a, and R^3a are each independently as described above. In some embodiments of Formula (IV), R^la is -C0₂H, -C0₂(Ci-₄alkyl), -C(0)NR^aR^b, Ci_₄alkyl, -NR^aR^b, Ci_₄haloalkyl, halo, -CN, -S0₃H, or -S0₂Ci_ ₄alkyl; or is -C0₂H, -C0₂(Ci_₄alkyl), or -C(0)NR^aR^b; or is -CONH₂; or is -C0₂H. In some embodiments, R^la is -C0₂H, -C0₂(C^alkyl), -C(0)NR^cR^d, or -C(OR^c)=NR^d, where R^c and R^d are each independently H or -Si(R^e)₃, wherein each R^e is independently Ci_₆ alkyl. In some embodiments, R^la is -C(OR^c)=NR^d' where R^c and R^d are each independently -Si(R^e) , wherein each R^e is independently Ci_₆ alkyl. In some embodiments, R^la is - C(OSi(CH₃)₃)=N(Si(CH₃)₃). In some embodiments, X^" in Formula (IV) is an anion selected from the group consisting of substituted or unsubstituted carboxylic acid, a substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or

un substituted sulfate, a substituted or unsubstituted carbonate, and a substituted or

unsubstituted carbamate: or is a tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, or a-glycerophosphate anion; or is a chloride, bromide, sulfate, nitrate, phosphate, bicarbonate, or carbonate anion; or is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, a- glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl- D-tyrosinate, camsylate, oxalate, bicarbonate, and carbonate; or is chloride or bromide; or is chloride. In other embodiments of Formula (IV), each P is independently acetyl, benzoyl, pivaloyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, trimethylsilyl, t-butyldimethylsilyl, or t- butyldiphenylsilyl, or the two P groups in R^2a and R^3a, taken together, form an

isopropylidene; or each P is acetyl or benzoyl. In certain embodiments, R^2a and R^3a in

Formula (IV) are each independently H, -OH, -OP, Ci^alkyl, or F; or are each independently H, -OH, or -OP; or are each independently H or -OH. In some embodiments, the compound of Formula (IV) is the com ound of Formula (4a) or (4b) or (5a).

4a 4b

[0055] In some embodiments of compounds of Formula (3b) and (4b), R is H or Ci_ ₄alkyl. In some embodiments, R is methyl or ethyl.

[0056] In some embodiments, where the compound of Formula (IV) is not itself a compound of Formula (I), the method further comprises: (b) converting the compound of Formula (IV) to a compound of Formula (I). In some embodiments, the converting step comprises one or more of: (1) converting -OP groups to hydroxyl groups; (2) hydrolyzing an R¹ -C0₂Ci_₄alkyl group to an R¹ -C0₂H group; (3) converting an R¹ -C(0)N(Si(CH₃)₃)₂ group to an R¹ -C(0)NH₂ group; (4) converting an R¹ -C(OSi(R^e)₃)=N(Si(R^e)₃) group to an R¹ -C(0)NH₂ group; and (5) producing a -CONR^aR^b group via amide coupling or N- alkylation. Methods for accomplishing these transformations are known to one of ordinary skill in the art. In some embodiments, the converting step is accomplished by treatment of the compound of Formula (IV) with ammonia in a Ci_₄alkyl-OH solvent, such as methanol or ethanol.

[0057] In some embodiments, the reacting of the compound of Formula (II) with the compound of Formula (III) is performed in a low polarity or non-polar solvent. Exemplary solvents include dichloromethane, chloroform, ethyl acetate, 1,2-dichloroethane, 1,4-dioxane, toluene, 1,2-dimethoxyethane, nitromethane, and acetonitrile, and mixtures thereof. In some embodiments, the solvent is dichloromethane or chloroform. In some embodiments, the reacting of the compound of Formula (II) with a compound of Formula (III) is performed where the starting concentration of the compound of Formula (III) is greater than about 0.03 M, or greater about 0.05 M, or greater than about 0.1 M, or greater than about 0.2 M, or greater than about 0.5 M, or about 0.05 to about 0.2 M. In some embodiments, the compound of Formula (III) is soluble in the reaction solvent at the recited concentration. [0058] In some embodiments, the reacting of the compound of Formula (II) with a compound of Formula (III) is performed at a temperature in the range of about -15 °C to about 80 °C, or about 0 °C to about 30 °C, or about 20 °C to about 30 °C, or at reflux temperature of the solvent used, or at about room temperature (e.g., approximately 25 °C).

[0059] In some embodiments, the reacting of the compound of Formula (II) with a compound of Formula (III) is performed in the presence of an acid scavenger. In some embodiments, the acid scavenger is CdC0₃, CaC0₃, K₂C0₃, Na₂C0₃, or molecular sieves (4A), or a mixture thereof. In some embodiments, the acid scavenger is CdC0₃. In other embodiments, the acid scavenger is CaC0₃, K₂C0₃, Na₂C0₃, or molecular sieves (4A), or a mixture thereof. In some embodiments, the acid scavenger is molecular sieves (4A).

[0060] In some embodiments, the reacting of the compound of Formula (II) with a compound of Formula (III) is performed under physical agitation. In some embodiments, the physical agitation comprises polishing, shearing, scratching, cutting, kneading, extruding and/or grinding. In some embodiments, the physical agitation is provided by a ball mill grinder. In some embodiments, the physical agitation is provided by a planetary ball mill grinder. In certain embodiments, the physical agitation is performed in the absence of solvent. In other embodiments, the physical agitation is performed in the presence of a minimal amount of solvent.

[0061] In some embodiments, the reacting of the compound of Formula (II) with a compound of Formula (III) is performed under microwave irradiation.

[0062] The present invention is also directed to methods of preparing a compound of Formula (I), comprising reacting a 3,5-diprotected-l-a-chlororibose, or a 2,3,5-triprotected-l- a-chlororibose, or l-chloro-2,3,5-tri-0-acetyl-a-D-ribofuranose, with nicotinamide, a derivative of nicotinamide, or a nicotinic acid Ci_₄alkyl ester to form a compound of Formula (4a) or Formula (4b). The present invention is also directed to methods of preparing a compound of Formula (I), comprising reacting a 3,5-diprotected-l-a-chlororibose, or a 2,3,5- triprotected-l-a-chlororibose, or l-chloro-2,3,5-tri-0-acetyl-a-D-ribofuranose, with nicotinamide or a derivative of nicotinamide to form a compound of Formula (5a). In one aspect is a method of making nicotinamide riboside, chloride salt, comprising reacting nicotinamide or the compound of Formula (3a) with l-chloro-2,3,5-tri-0-acetyl-a-D- ribofuranose to form the compound of Formula (4a). In one aspect is a method of making nicotinamide riboside, ch loride salt, comprising reacting nicotinamide or the compound of Formula (3a) with l-chloro-2,3,5-tri-0-acetyl-a-D-ribofuranose to form the compound of Formula (5a). [0063] In one aspect, the present disclosure relates to a method of making nicotinamide riboside, chloride salt (Formula (1)), comprising reacting a compound of Formula (4a) with ammonia in a Ci_₄alkyl-OH solvent, as shown in Scheme 1, to form the compound of Formula (1). In one aspect, the present disclosure relates to a method of making nicotinamide riboside, chloride salt (Formula (1)), comprising reacting a compound of Formula (5a) with ammonia in a Ci_₄alkyl-OH solvent, as shown in Scheme 2, to form the compound of Formula (1). In certain embodiments, bases such as sodium methoxide or sodium ethoxide are used in place of ammonia. In one aspect, the method of making a compound of Formula (1) comprises reacting a compound of Formula (3 a) with a compound of Formula (2a) to provide a compound of Formula (4a). In one aspect, the method of making a compound of Formula (1) comprises reacting a compound of Formula (3 a) with a compound of Formula (2a) to provide a compound of Formula (5 a).

[0064] In another aspect, the present disclosure also relates to a method of making a compound of Formula (1) comprising reacting a compound of Formula (4b) with ammonia. In another aspect, the present disclosure also relates to a method of preparing a nicotinic acid riboside internal salt, comprising reacting a compound of Formula (4b) with a base that hydrolyzes all of the ester linkages in the compound of Formula (4b). In certain

embodiments, the base is sodium hydroxide in methanol. In other embodiments, the method further comprises reacting a compound of Formula (3b) with a compound of Formula (2a) to provide a compound of Formula (4b). In certain embodiments, R is H or C_1-4 alkyl for the compounds of Formula (3b) and (4b).

Scheme 2

[0065] In other embodiments, the method comprises preparing a compound of Formula (2a) (l-chloro-2,3,5-tri-0-acetyl-a-D-ribofuranose) from l,2,3,5-tetra-0-acetyl-P-D- ribofuranose.

[0066] In some aspects, the present disclosure is directed to a method of making a compound of Formula (I) or Formula (1), comprising reacting nicotinamide with (Ν,Ο- bistrimethylsilyl)acetamide, or with (N,0-bistrimethylsilyl)trifluoroacetamide, to form the compound of Formula (3a). In other embodiments, the present disclosure is directed to a method of making the compound of Formula (3 a) by reacting nicotinamide with (Ν,Ο- bistrimethylsilyl)acetamide, or with (N,0-bistrimethylsilyl)trifluoroacetamide. In some embodiments, the silylating agent is (N,0-bistrimethylsilyl)acetamide. In some

embodiments, the reaction is performed using heat, or using microwave irradiation. In some embodiments, the product compound of Formula (3a) is not isolated but is used directly in the next reaction step.

[0067] The presently disclosed methods are advantageous over those described previously for several distinct reasons. Starting materials of Formula (3a) and (3b) are soluble in a variety of organic solvents. Suitable solvents include dichloromethane, chloroform, ethyl acetate, 1,2-dichloroethane, 1,4-dioxane, toluene, 1,2-dimethoxyethane, nitromethane, and acetonitrile, and mixtures thereof. In some embodiments, the solvent is dichloromethane or chloroform. Reactions with these starting materials may be run at a high concentration of reagents of Formulae (3a), (3b), and/or (2a) (e.g., greater than about 0.03 M, or about 0.05 M, or about 0.1 M, or about 0.2 M, or about 0.5 M), leading to increased reaction rates and higher stereoselectivity. It is known that l-chloro-2,3,5-tri-0-acetyl-a-D- ribofuranose (Formula (2a)) can anomerize in a polar solvent like acetonitrile, which may affect stereoselectivity of coupling reaction and cause formation of undesired levels of a- nicotinamide riboside. See Hubbard, A. J. et ah, Nucleic Acids Res. 1984, 12(17), 6827-6837. The enhanced solubility of intermediates of Formula (3a) and (3b) allow coupling reactions to be performed in non-polar solvents such as chloroform and dichloromethane, in which anomerization of the 1-chloro ribose derivative is limited, and therefore stereoselectivity of the coupling is improved. In some embodiments, the reacting step is performed in a reaction solvent is selected such thai the rate of anomerization of the 1-chloro sugar derivative is slower than the rate of coupling of the sugar with the pyridine analog.

[0068] In addition, intermediate compounds of Formula (4a) and (4b) may be deprotected and converted into the target nicotinamide riboside, chloride salt, in a single step, for example, by reaction of compounds of Formula (4a) or (4b) in methanolic ammonia, optionally at a reduced temperature such as between about -30 and about 10 °C. Intermediate compounds of Formula (5a) may be deprotected and converted into the target nicotinamide riboside, chloride salt, in a single step, for example, by reaction of compounds of Formula (5a) in methanolic ammonia, optionally at a reduced temperature such as between about -30 and about 10 °C. Thus, the disclosed method efficiently enables the preparation of nicotinamide riboside, chloride salt. The methods described herein conveniently use inexpensive reagents that are either commercially available or are prepared readily from commercial reagents. For example, the compound of Formula (3a) is prepared quantitatively from nicotinamide by silylation, and used without purification for coupling with the chloro- ribose of Formula (2a). The compound of Formula (2a), l-chloro-2,3,5-tri-0-acetyl-a-D- ribofuranose, is conveniently prepared using known procedures from commercially available l,2,3,5-tetra-0-acetyl-P-D-ribofuranose. Reactions may be done in a single pot with more than one sequential reaction step.

[0069] In another aspect, the present disclosure also relates to the methods for the preparation of compounds derived from nicotinamide riboside. In some aspects, the method of making a compound of Formula (I) (e.g., nicotinamide riboside chloride salt) further comprises converting the compound of Formula (I) to a compound selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide

(NAD⁺), reduced nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide phosphate (NADP⁺), reduced nicotinamide adenine dinucleotide phosphate (NADPH), or a mixture of any of the foregoing. Methods for accomplishing these transformations are known to one of ordinary skill in the art.

[0070] In one aspect, the present disclosure also relates to a compound of Formula (I) obtainable or obtained by the methods described herein. In another aspect, the present disclosure relates to a compound of Formula (I):

wherein R¹ is -C0₂H, -C0₂(C^alkyl), -C(0)NR^aR^b, -C(OR^c)=NR^d, C^alkyl, -NR^aR^b, Ci_₄haloalkyl, halo, -CN, -SO₃H, or -S0₂Ci_₄alkyl;

where R^a and R^b are each independently H or Ci_₄alkyl;

R 2" and R 3^J are each independently H, -OH, Ci_₄alkyl, or F;

X^" is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, a-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, and carbonate;

and wherein the compound is not nicotinamide riboside, chloride or triflate salt, nicotinic acid riboside, methyl nicotinate riboside, or ethyl nicotinate riboside.

[0071] In one aspect, the present disclosure also relates to a reduced 1,4- dihydropyridine derivative of a compound of Formula (I), obtainable by or obtained by methods described herein. In another aspect, the present disclosure relates to a compound of Formula (la):

wherein R¹ is -C0₂H, -C0₂(C^alkyl), -C(0)NR^aR^b, -C(OR^a)=NR^b, C^alkyl, -NR^aR^b, Ci_₄haloalkyl, halo, -CN, -SO₃H, or -S0₂Ci_₄alkyl;

where R^a and R^b are each independently H or Ci_₄alkyl

R 2" and R 3^J are each independently H, -OH, Ci_₄alkyl, or F. [0072] In one embodiment, the compound of Formula (la) is a compound having the structure:

[0073] In one aspect, the o a compound of Formula (IV):

Ci_₄haloalkyl, halo, -CN, -S0₃H, or -S0₂Ci_₄alkyl;

where R^c and R^d are each independently H, Ci_₄alkyl, or-Si(R^e)₃, wherein each R^e is independently Ci_₆ alkyl;

R^2a and R^3a are each independently H, -OH, -OP, Ci_₄alkyl, or F;

each P is independently a hydroxyl protecting group; and

X^" is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, a-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, and carbonate, provided that when P is a phosphate group, X^" is absent;

[0074] In one aspect, the present disclosure relates to a reduced 1,4-dihydropyridine derivative of a compound of Formula (IV), obtainable by or obtained by methods described herein. In one aspect, the present disclosure relates to a compound of Formula (IVa):

wherein R^la is -C0₂H, -C0₂(C^alkyl), -C(0)NR^cR^d, -C(OR^c)=NR^d, Ci_₄alkyl, -NR^cR^d, Ci_₄haloalkyl, halo, -CN, -S0₃H, or -S0₂Ci_₄alkyl;

wherein R^c and R^d are each independently H, Ci_₄alkyl, or-Si(R^e)₃, wherein each R^e is independently Ci alkyl;

R^2a and R^3a are each independently H, -OH, -OP, Ci_₄alkyl, or F; and

each P is independently a hydroxyl protecting group.

[0075] In some embodiments of Formula (IVa), each P is independently a hydroxyl protecting group, wherein at least one P is an acyl group selected from the group consisting of acetyl, butyryl, decanoyl, and acetylglycyl.

[0076] In certain embodiments of Formula (IV) or Formula (IVa), P at the 5' position is a phosphate or protected phosphate. In some embodiments, R^2a and R^3a are each OP, wherein each P of R^2a and R^3a is independently an acyl group, and P is protected phosphate at the 5' position. In other embodiments, R^2a and R^3a are each independently OH or OP and P is phosphate or protected phosphate at the 5' position. In certain embodiments of Formula (IV), when P is phosphate at the 5' position, X^" is absent.

[0077] In some embodiments of Formula (IVa), R^2a and R^3a are each -OH and wherein P is a phosphate or a protected phosphate group. In one embodiment, the compound of Formula (IVa) is a compound having the structure:

[0078] In one aspect, the present disclosure relates to a compound of Formula (IVb):

wherein R^c and R^d are each independently H, Ci_₄alkyl, or-Si(R^e)₃, wherein each R^e is independently Ci_₆ alkyl;

R^2a and R^3a are each independently H, -OH, -OP, Ci_₄alkyl, or F; each P is independently a hydroxyl protecting group, wherein at least one P is an acyl group selected from the group consisting of acetyl, butyryl, decanoyl, and acetylglycyl; and

X^" is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, a-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, and carbonate; and wherein the compound is not nicotinamide riboside, chloride or triflate salt, nicotinic acid riboside, methyl nicotinate riboside, or ethyl nicotinate riboside.

[0079] In one aspect, the present disclosure relates to a compound of Formula (IVc):

wherein R^c and R^d are each independently H, Ci_₄alkyl, or-Si(R^e)₃, wherein each R^e is independently Ci_6 alkyl;

R^2a and R^3a are each independently -OH or -OP;

each P is independently a hydroxyl protecting group;

P' is a phosphate or a protected phosphate group; and

X^" is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, a-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, and carbonate, provided that when P' is a phosphate group, X^" is absent;

[0080] In another aspect, the present disclosure relates to a compound of Formula (3a), (4a), (4b), or (5a), or a pharmaceutically acceptable salt thereof.

[0081] The present disclosure also relates to pharmaceutical compositions comprising at least one compound of Formula (I) prepared by the methods of making described herein. The pharmaceutical compositions may contain an effective amount of the compound of Formula (I) prepared as described herein. Such compositions are generally formulated for oral, topical, parenteral, or enteral administration, or for inhalation. Such compositions may comprise suitable pharmaceutical carriers, diluents, and/or excipients, such as binders, disintegrants, fillers, lubricants, glidants, compression aids, colors, sweeteners, preservatives, dispersing agents, disintegration aids, encapsulating materials, coatings or films, or flavorings. In one aspect, the present disclosure relates to a composition comprising a compound of Formula (I) obtainable by or obtained by the methods described herein, and a pharmaceutically acceptable excipient. In another aspect, the present disclosure relates to a composition comprising a compound derived from nicotinamide riboside selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide

(NAD⁺), reduced nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide phosphate (NADP⁺), reduced nicotinamide adenine dinucleotide phosphate

(NADPH), or a mixture of any of the foregoing, obtainable by or obtained by the methods described herein, and a pharmaceutically acceptable excipient. Pharmaceutical compositions may be formulations for immediate or sustained release.

[0082] In one aspect, the present disclosure relates to a method of administering a compound of Formula (I) obtainable by or obtained by the method described herein, comprising administering the compound to a subject. In one aspect, the present disclosure also relates to a method for treatment of a disease or disorder that would benefit from increased NAD levels, comprising administering a compound of Formula (I) obtained by any of the methods described herein or a pharmaceutical composition comprising at least one compound of Formula (I), wherein the at least one compound of Formula (I) is obtained by any of the methods described herein, to a subject in need thereof. In another aspect, the present disclosure relates to a method for treatment of a disease or disorder that would benefit from increased NAD levels, comprising administering a pharmaceutical composition comprising a compound selected from the group consisting of nicotinamide mononucleotide

(NMN), nicotinamide adenine dinucleotide (NAD⁺), reduced nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide phosphate (NADP⁺), reduced nicotinamide adenine dinucleotide phosphate (NADPH), or a mixture of any of the foregoing, obtainable by or obtained by the methods described herein, to a subject in need thereof. In certain embodiments, the disease or disorder is a metabolic- or age-related disorder. In some embodiments, the disease or disorder is insulin resistance, a metabolic syndrome, diabetes, or obesity. In other embodiments, the disease or disorder is a mitochondrial disease or disorder.

In certain embodiments, the mitochondrial disease or disorder is a neuromuscular disorder, a disorder of neuronal instability, a neurodegenerative disorder, or a mitochondrial myopathy. In yet further embodiments, the mitochondrial disease or disorder is Friedrich's Ataxia, muscular dystrophy, multiple sclerosis, seizure disorders, migraine, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, ischemia, renal tubular acidosis, age- related neurodegeneration and cognitive decline, chemotherapy fatigue, age-related or chemotherapy-induced menopause or irregularities of menstrual cycling or ovulation, mitochondrial myopathies, mitochondrial damage (e.g., calcium accumulation, excitotoxicity, nitric oxide exposure, drug induced toxic damage or hypoxia), or mitochondrial deregulation.

[0083] In one aspect, the present disclosure relates to a method of administering a compound of the Formula (la), the reduced 1,4-dihydropyridine derivative of a compound of Formula (I). Such compounds could be used in place of the oxidized (pyridine) form for treatment of any and all of the diseases or disorders described herein. In other embodiments, the disease or disorder is a hypoxic condition such as acute stroke-associated hypoxia that leads to the formation of toxic, oxygen-derived free radicals and peroxides. In certain embodiments, the condition is exposure to agents such as oxygenated fatty acids that promote the formation of toxic, oxygen-derived free radicals in the body.

[0084] Compounds of Formula (I) prepared as described herein may be administered in an effective amount using any standard administration technique, at a dose of about 50 mg/day to about 20,000 mg/day, or about 50 to about 2500 mg/day, or about 100 to about 1000 mg/day.

Examples

[0085] The following examples are offered to illustrate but not to limit the invention. One of skill in the art will recognize that the following procedures may be modified using methods known to one of ordinary skill in the art.

Example 1. Preparation of l-chloro-2,3 5-tri-0-acetyl-q-D-ribofuranose (Formula (2a)).

[0086] A solution of l,2,3,5-tetra-0-acetyl-P-D-ribofuranose (500 mg) in

dichloromethane (50 mL) is cooled to 0 °C. Dry HCl_(g) is bubbled through the solution gently for 30 min. The solvent is quickly removed by distillation under vacuum at low temperature. The crude product is re-dissolved in anhydrous toluene and concentrated under vacuum (5x). The residue is dissolved in an appropriate solvent such as dichloromethane, chloroform, acetonitrile, 1,2-dichloroethane, ethyl acetate, or nitromethane, or a mixture thereof, and used directly in the coupling with a compound of Formula (la) or (lb) without further purification.

Example 2. Preparation of trimethylsilyl N-( rimethylsilyl)nicotinimidate (Formula (3a)).

[0087] Nicotinamide (400 mg, 3.28 mmol) is carefully dried under vacuum at 40 °C for 12 h, and suspended in 1,1,1,3,3,3-hexamethyldisilazane (54 mL). To the stirred suspension is added TMSC1 (0.83 mL, 6.56 mmol) and the resulting mixture is heated at reflux for 5 h. Evaporation of the solvent gives the crude silylated compound of Formula (3a), which is dissolved in an appropriate solvent such as dichloromethane, chloroform, acetonitrile, 1,2-dichloroethane, ethyl acetate, or nitromethane, or a mixture thereof.

Example 3. Preparation of a compound of Formula (4a).

[0088] To a solution of a compound of Formula (2a) (which may be prepared as described in Example 1 from l,2,3,5-tetra-0-acetyl- 5-D-ribofuranose, 1.65 g, 3.28 mmol) in dry 1,2-dichloroethane (60 mL) is added dropwise a solution of Ν,Ο-bis-TMS-nicotinamide (3a) and the reaction mixture is stirred at 0 °C until TLC indicates no remaining starting material. The mixture is filtered, the filter cake is washed with chloroform, and the combined filtrate and washings are concentrated in vacuo. The residue is dissolved in chloroform and quickly treated with dry ether. The resulting solid is filtered and washed with dry ether to give compound of Formula (4a) as a hygroscopic white powder.

Example 4. Preparation of nicotinamide riboside chloride salt of Formula (1 j.

[0089] The crude compound (4a) is quickly dissolved in dry methanol saturated with dry ammonia and stirred at -20 °C until the reaction is complete. The solvents are removed under vacuum, and the crude product is partitioned between methanol and hexane. The hexane layer is discarded and product is precipitated from the methanol layer by the addition of dry ethyl acetate. The collected product is washed with ethyl acetate and dried to give highly hygroscopic powder, which is stored as needed under suitable anhydrous conditions. Example 5. Preparation of a compound of Formula (4b).

[0090] To a solution of compound of Formula (2a) (which may be prepared as described in Example 1 from l,2,3,5-tetra-0-acetyl- ^D-ribofuranose, 1.65 g, 3.28 mmol) in dry 1,2-dichloroethane (60 mL) is added dropwise a solution of ethyl nicotinate (3b) and the reaction mixture is stirred at 0 °C until TLC indicates the reaction was complete. The mixture is filtered, the filter cake is washed with chloroform, and the combined filtrate and washings are concentrated under vacuum. The resulting residue is dissolved in chloroform and treated quickly with dry ether. The resulting solid is filtered and washed with dry ether to give Formula 3b as a hygroscopic white powder.

Example 6. Preparation of nicotinamide riboside chloride salt of Formula (1).

[0091] The crude compound of Formula (4b) is dissolved in 1.0 mL of 4 N

NH₃/MeOH at 0 °C, and stirred at 4 °C for 16 hours. The mixture is concentrated and co- evaporated several times with MeOH to remove residual ammonia. The residue is suspended in ethyl acetate, filtered, and washed with dry ethyl acetate. The resulting solid is dissolved in methanol, and the resulting solution is extracted with hexane. The methanol layer is then separated and concentrated, and the product is then precipitated by treatment with dry ethyl acetate or dry ether.

[0092] A solution of l,2,3,5-tetra-0-acetyl-/?-D-ribofuranose (1.74 g, 5.47 mmol) dissolved in 60 ml of anhydrous dichloromethane was cooled to 0°C. Dry HCl(g) (from a gas cylinder at -2.5 psi) was bubbled through the solution for 1 h until the reaction was complete as determined by TLC. The solvent was removed under vacuum at <15°C. The crude product was re-dissolved in 10 mL of anhydrous toluene and concentrated under an inert atmosphere (3x) to provide the compound of Formula (2a) as a clear oil without further purification. [0093] 1H NMR (499 MHz, Chloroform-d) δ 6.01 (s, 1H), 5.68 - 5.59 (m, 1H), 5.55 (d, J = 4.6 Hz, 1H), 4.59 - 4.47 (m, 1H), 4.47 - 4.39 (m, 1H), 4.18 (dd, J = 12.4, 5.6 Hz, 1H), 2.19 - 2.02 (m, 12H); MS: mass calculated for CnHi₅C10₇: 294.05; found (m/z): positive: 259.1 (M-C1)⁺.

Example 8. Preparation of trimethylsilyl-N-(trimethylsilyl)nicotinimidate (Formula (3a)).

[0094] Nicotinamide (0.800 g, 6.55 mmol) was pulverized, dried under vacuum at 40°C for 16 h, and suspended in anhydrous acetonitrile (20 mL). To the suspension of nicotinamide, bis(trimethylsilyl)acetamide (1.67 g, 8.20 mmol) was added and the resulting reaction mixture was stirred at reflux for 16 h under an inert atmosphere. After the complete consumption of the starting material as indicated by HPLC, the reaction product was concentrated in vacuo and isolated as a crude oil without further purification.

[0095] 1H NMR (499 MHz, Chloroform-d) δ 9.02 (dd, J = 17.4, 2.3 Hz, 1H), 8.72 (ddd, J = 14.8, 4.8, 1.7 Hz, 1H), 8.15 (ddt, J = 18.0, 7.9, 2.0 Hz, 1H), 7.41 - 7.34 (m, 1H), 0.35 (s, 6H), 0.22 (s, 7H), 0.05 (s, 3H). HPLC: Inject 1 mg/ml crude reaction mixture dissolved in methanol, product II retention time -6.45 minutes, <5% nicotinamide (I) detectable.

Example 9. Preparation of 5\3\2'-tri-Q-acetyl-l— β-D-ribofuranosylnicotinamide chloride (Formula (5a)).

[0096] To a 0°C solution of a compound of Formula (3 a) (prepared in Example 8, 1.75 g, 6.56 mmol, calculated based on 100% yield) in anhydrous chloroform (9 mL), calcium carbonate (5.00 g, 50.3 mmol) was added. A compound of formula (2a) (prepared in Example 7, 1.61 g, 5.46 mmol, calculated based on 100% yield) was dissolved in anhydrous chloroform (40 mL) and the solution was added dropwise over 30 minutes to the reaction mixture. The reaction mixture was stirred for 40 h at 0°C under an inert atmosphere. [0097] The reaction mixture was filtered to remove solids and the filtrate concentrated under vacuum. The resulting residue was dissolved in minimal amounts of anhydrous chloroform, and precipitated out by the addition of anhydrous diethyl ether. The precipitates were collected by vacuum filtration and washed multiple times with anhydrous diethyl ether. The solids were retrieved off the funnel by dissolving in anhydrous methanol and the resulting filtrate was evaporated to provide a compound of Formula (5a) as an orange solid (850 mg, 27.7% yield).

[0098] 1H-NMR: 2:0.33 mixture of nicotinamide: product (no TMS group) based on the aromatic peaks for nicotinamide at 7.89 and the acetate peaks at 2.15.

[0099] TLC: n-butanol/water/acetic acid (5:3:2) gives R_f = 0.8. HPLC: peaks at 4.31 minutes (nicotinamide) and 5.45 minutes (the product).

[0100] HPLC Conditions: column: Agilent SB-C18 Poroshell 120, 4.6 x 150 mm, 2.7 μηι, solvent A: 25 mM ammonium acetate in water, solvent B: acetonitrile, flow rate: 9 ml/min, gradient: 5% solvent B for 0.5 minutes, to 95% solvent B over 6 minutes, 95% solvent B for 2.5 minutes, to 5% solvent B over 1 minute.

Example 10. Preparation of nicotinamide riboside chloride salt (Formula (I)).

[0101] To a 0°C solution of crude compound (4a) (prepared in Example 9, 850 mg, 2.04 mmol) in anhydrous methanol (10.1 mL), saturated ammonia in anhydrous methanol (7 M, 13.1 mL) was added. The reaction mixture was stirred for 3 h at 0°C under an inert atmosphere and monitored by TLC. The solvent was removed immediately in vacuo and the isolated residue co-evaporated one additional time with anhydrous methanol (10 mL). The crude residue was dissolved in minimal amounts of anhydrous methanol and extracted with hexane. The product was precipitated out of the methanol layer by the addition of anhydrous ethyl acetate. The solids were collected by filtration and were washed with anhydrous ethyl acetate to provide a compound of formula (I) as an orange solid (0.229 g, 38.6% yield).

[0102] 1H-NMR: a 60:40 mixture of β :α isomers based on the chemical shift (6.30 ppm vs. 6.60 ppm) of the proton on the anomeric carbon.

[0103] MS: mass calculated for CiiHi₅N₂0₅ ⁺: 255.10; found (m/z): positive: 255.3 (M)⁺. TLC: n-butanol/water/acetic acid (5:3:2) gives R_f = 0.36.

[0104] HPLC: peaks at 1.99, 2.54, 2.84, 3.78, and 4.12 minutes. HPLC Conditions: column: Agilent SB-C18 Poroshell 120, 4.6 x 150 mm, 2.7 μιη, solvent A: 25 mM ammonium acetate in water, solvent B: acetonitrile, flow rate: 9 ml/min, gradient: 5% solvent B for 0.5 minutes, to 95% solvent B over 6 minutes, 95% solvent B for 2.5 minutes, to 5% solvent B over 1 minute.

Example 11. Preparation of l-((2R,3R,4S,5R)-4-(benzoyloxy)-5-((benzoyloxy)methyl)-3- hvdroxytetrahvdrofuran-2-yl)-3-((Z)-2,2,6,6-tetramethyl-5-oxa-3-aza-2,6-disilahept-3-en-4- vDpyridin-l-ium chloride.

[0105] The title compound is prepared in an analogous procedure to Example 9, substituting the compound of formula (2a) with ((2R,3S,4R,5R)-3-(benzoyloxy)-5-chloro-4- hydroxytetrahydrofuran-2-yl)methyl benzoate.

Claims

1. A method of making a compou :

(I);

wherein R¹ is -C0₂H, -C0₂(C^alkyl), or -C(0)NR^aR^b;

where R^a and R^b are each independently H or Ci_₄alkyl;

R 2" and R 3^J are each independently H, -OH, Ci_₄alkyl, or F;

X^" is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, a-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, and carbonate;

comprising:

(a) reacting a compound of Formula (II):

wherein

R^2a and R^3a are each independently H, -OH, -OP, Ci_₄alkyl, or F; and

each P is independently a hydroxyl protecting group;

with a compound of Formula (III):

where R^la is -C0₂H, -C0₂(C^alkyl), -C(0)NR^cR^d, or -C(OR^c)=NR^d;

where R^c and R^d are each independently H or -Si(R^e)₃, wherein each R^e is independently Ci_₆ alkyl; to form a compound of Formula (IV):

where R^la, X^", P, R^2a, and R^3a are each as defined above.

2. The method of claim 1, wherein the reacting of the compound of Formula (II) with the compound of Formula (III) is performed in a reaction solvent.

3. The method of claim 2, wherein the reaction solvent is a low polarity or non-polar reaction solvent, or is selected from the group consisting of dichloromethane, chloroform, ethyl acetate, 1,2-dichloroethane, 1,4-dioxane, toluene, 1,2-dimethoxyethane, nitromethane, and acetonitrile, and mixtures thereof, or is dichloromethane or chloroform.

4. The method of claim 2 or claim 3, wherein the reacting of the compound of Formula (II) with a compound of Formula (III) is performed where the starting concentration of the compound of Formula (III) in the reaction solvent is greater than about 0.03 M, or greater about 0.05 M, or greater than about 0.1 M, or greater than about 0.2 M, or greater than about 0.5 M, or about 0.05 to about 0.2 M.

5. The method of claim 4, wherein the compound of Formula (III) is soluble in the reaction solvent at the recited concentration.

6. The method of any one of claims 1-5, wherein the reacting step is performed at a temperature in the range of about -15 °C to about 80 °C, or about 0 °C to about 30 °C, or about 20 °C to about 30 °C, or at about room temperature (e.g., approximately 25 °C).

7. The method of any one of claims 2-5, wherein the reacting step is performed at reflux temperature of the solvent used.

8. The method of any one of claims 1-7, wherein the reacting step is performed in the presence of an acid scavenger.

9. The method of claim 8, wherein the acid scavenger is CdC0₃, CaC0₃, K₂C0₃, Na₂C0₃, or molecular sieves (4A).

10. The method of any one of claims 1-9, wherein R 2 and R 3 in Formula (I) are each independently H, -OH, Ci_₄alkyl, or F; or R 2" and R 3^J are each independently H or -OH; or R 2 and R are each -OH.

11. The method of any one of claims 1-10, wherein X^" in Formula (I) is an anion selected from the group consisting of substituted or unsubstituted carboxylic acid, a substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or unsubstituted sulfate, a substituted or unsubstituted carbonate, and a substituted or unsubstituted carbamate; or X^" in Formula (I) is a tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, or a-glycerophosphate anion; or X^" in Formula (I) is a chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, or carbonate anion; or X^" in Formula (I) is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, a-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, bicarbonate, and carbonate; or X^" in Formula (I) is chloride or bromide; or X^" in Formula (I) is chloride.

12. The method of claim 1, wherein the compound of Formula (I) is nicotinic acid riboside.

13. The method of claim 1, wherein the compound of Formula (I) is nicotinamide riboside, chloride salt.

14. The method of any one of claims 1-13, wherein for compounds of Formula (II), each P is independently acetyl, benzoyl, p-chlorobenzoyl, p-nitrobenzoyl, tolyl, propionyl, butyryl, pivaloyl, decanoyl, acetylglycyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, or t-butyldiphenylsilyl, or the two P groups in R ^a and R ^a, taken together, form an isopropylidene; or each P is acetyl or benzoyl.

15. The method of any one of claims 1-14, wherein R^2a and R^3a in Formula (II) are each independently H, -OH, -OP, Ci^alkyl, or F; or are each independently H, -OH, or -OP; or are each independently H or -OH.

16. The method of claim 1, wherein the compound of Formula (II) is the compound of Formula (2a):

17. The method of any one of claims 1-16, wherein the compound of Formula (III) is the compound of Formula (3 a):

18. The method of claim 1, wherein for compounds of Formula (IV), R¹ is -CON¾.

19. The method of claim 1, wherein X^" in Formula (IV) is an anion selected from the group consisting of substituted or unsubstituted carboxylic acid, a substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or unsubstituted sulfate, a substituted or unsubstituted carbonate, and a substituted or unsubstituted carbamate; or is a tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, or a-glycerophosphate anion; or is a chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, or carbonate anion; or is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, α-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, bicarbonate, and carbonate; or is chloride or bromide; or is chloride, provided that when P is phosphate, X^~ is absent.

20. The method of claim 1, wherein for compounds of Formula (IV), each P is independently acetyl, benzoyl, p-chlorobenzoyl, p-nitrobenzoyl, tolyl, propionyl, butyryl, pivaloyl, decanoyl, acetylglycyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, trimethylsilyl, triisopropylsilyl, t- butyldimethylsilyl, or t-butyldiphenylsilyl, or the two P groups in R^2a and R^3a, taken together, form an isopropylidene; or each P is acetyl or benzoyl.

21. The method of claim 1, wherein R^2a and R^3a in Formula (IV) are each independently H, - OH, -OP, Ci_₄alkyl, or F; or are each independently H, -OH, or -OP; or are each independently H or -OH.

22. The method of claim 1, wherein the compound of Formula (IV) is the compound of Formula (4a).

23. The method of claim 1, further comprising: (b) converting the compound of Formula (IV) to a compound of Formula (I).

24. The method of claim 23, wherein the converting step comprises one or more of: (1) converting -OP groups to hydroxyl groups; (2) hydrolyzing an R¹ -C0₂Ci_₄alkyl group to an R¹ C0₂H group; (3) converting an R¹ -C(0)N(Si(CH₃)₃)₂ group to an R¹ -C(0)NH₂ group; and (4) producing a -CONR^aR^b group via amide coupling or N-alkylation.

25. The method of claim 23, wherein the converting step is accomplished by treatment of the compound of Formula (IV) with ammonia in a Ci_₄alkyl-OH solvent, or in methanol or ethanol.

26. The method of any one of claims 1-25, wherein the method further comprises converting the compound of Formula (I) to a compound selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD⁺), reduced nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide phosphate (NADP⁺), reduced nicotinamide adenine dinucleotide phosphate (NADPH), or a mixture of any of the foregoing.

27. The method of any one of claims 1-26, wherein the reacting of the compound of Formula (II) with the compound of Formula (III) is performed in a planetary bail mill grinder.

28. A method of making a compound of Formula (I), comprising reacting l-chloro-2,3,5-tri- O-acetyl-a-D-ribofuranose with nicotinamide, a derivative of nicotinamide, or a nicotinic acid C_1-4alkyl ester to form a compound of Formula (4a) or Formula (4b).

29. A method of making nicotinamide riboside, chloride salt, comprising reacting nicotinamide or compound (3a) with l-chloro-2,3,5-tri-0-acetyl-a-D-ribofuranose to form the compound of Formula (4a).

30. A method of making nicotinamide riboside, chloride salt (Formula (1)), comprising reacting a compound of Formula (4a) with ammonia in a C_1-4alkyI-OH solvent to form the compound of Formula (1).

31. A method of making a compound of Formula (1) comprising reacting a compound of Formula (3a) with a compound of Formula (2a) to provide a compound of Formula. (4a).

32. A method of making a compound of Formula (1) comprising reacting a compound of Formula (4b) with ammonia.

33. The method of claim 32, further comprising reacting a compound of Formula (3b) with a compound of Formula (2a) to provide a compound of Formula (4b).

34. The method of claims 32 and 33, wherein for compounds of Formula (3b) and (4b), R is H or Cj-₄alkyl.

35. The method of any one of claims 29-34, wherein the reacting step is performed at a high concentration of reagents of Formulae (3a), (3b), and/or (2a) (e.g., greater than about 0.03 M, or about 0.05 M, or about 0.1 M, or about 0.2 M, or about 0.5 M for one or more reagent).

36. The method of any one of claims 29-35, wherein the reacting step is performed in a reaction solvent in which the rate of anomerization of the 1-chloro sugar derivative is slower than the rate of coupling of the sugar with the pyridine analog.

37. The method of any one of claims 1-36, wherein the product of the reacting step is produced as greater than 50%, or greater than about 60%, or greater than about 70%, or greater than about 80%, or as greater than about 90%, or greater than about 92%, or greater than about 94%, or greater than about 95%, or greater than about 96%, or greater than about 97%, or greater than about 98%, or greater than about 99% beta anomer.

38. The method of any one of claims 1-37, further comprising reducing the compound of Formula (I) to a compound of Formula (la).

39. The method of claim 38, further comprising isolating the beta anomer of the compound of Formula (la).

40. The method of claim 39, further comprising converting the compound of Formula (la) back to a compound of Formula (I) by oxidation.

41. The method of any one of claims 1-37, further comprising reducing the compound of Formula (IV) to a compound of Formula (IVa).

42. The method of claim 41 , further comprising isolating the beta anomer of the compound of Formula (IVa).

43. The method of claim 42, further comprising converting the compound of Formula (IVa) back to a compound of Formula (IV) by oxidation.

44. The method of claim any one of claims 38-43, wherein the reducing step is achieved by reduction with sodium dithionate or through electrochemical means.

45. The method of claim any one of claims 38-44, wherein the con verting step is achie ved by- oxidation with activated charcoal or through electrochemical means.

46. A method of preparing a l-(3-substituted pyridyi)-P-ribose comprising reacting a first starting material 3-substituted pyridine with a second starting material 2,3,5-protected or 3,5- protected 1-ot-chloro ribose.

47. The method of claim 46, wherein the reacting step is: (a) performed at a concentration of one or more of the starting materials that is greater than about 0.03 M, or about 0.05 M, or about 0.1 M, or about 0.2 M, or about 0.5 M; and/or (b) performed in the presence of an acid scavenger.

48. A method of making a compound of Formula (I) or Formula (1), comprising reacting nicotinamide with (N,0-bistrirnethylsilyl)acetamide, or with (Ν,Ο- bistrimethylsilyl)trifluoroacetamide, to form the compound of Formula (3a).

49. A compound of Formula (I) obtainable by or obtained by the method of any one of claims 1-48.

50. A compound of Formula (I):

wherein R¹ is -C0₂H, -C0₂(C_walkyl), -C(0)NR^aR^b, Ci_₄alkyl, -NR^aR^b, Ci_₄haloalkyl, halo, -SO₃H, or -S0₂Ci_₄alkyl;

where R^a and R^b are each independently H or Ci_₄alkyl; FT 2 and R 3^J are each independently H, -OH, Ci_₄alkyl, or F;

X^" is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, α-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, and carbonate;

51. A compound of Formula (la):

wherein R¹ is -C0₂H, -C0₂(C^alkyl), -C(0)NR^aR^b, -C(OR^a)=NR^b Ci_₄alkyl, -NR^aR^b, Ci_₄haloalkyl, halo, -CN, -S0₃H, or -S0₂Ci_₄alkyl;

wherein R^a and R^b are each independently H or Ci_₄alkyl; and

R 2" and R 3^J are each independently H, -OH, Ci_₄alkyl, or F.

52. A compound of Formula (IV)

wherein R^la is -C0₂H, -C0₂(C^alkyl), -C(0)NR^cR^d, -C(OR^c)=NR^d, Ci_₄alkyl, -NR^cR^d,

Ci_₄haloalkyl, halo, -CN, -S0₃H, or -S0₂Ci_₄alkyl;

wherein R^c and R^d are each independently H, Ci_₄alkyl, or -Si(R^e)₃, wherein each R^e is independently Ci_₆ alkyl;

R^2a and R^3a are each independently H, -OH, -OP, Ci_₄alkyl, or F;

each P is independently a hydroxyl protecting group; and

X^" is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, α-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, and carbonate, provided that when P is phosphate, X^" is absent;

53. A compound of Formula (IV

wherein R^la is -C0₂H, -C0₂(C_walkyl), -C(0)NR^cR^d, -C(OR^c)=NR^d, Ci_₄alkyl, -NR^cR^d,

Ci_₄haloalkyl, halo, -CN, -SO₃H, or -S0₂Ci_₄alkyl;

wherein R^c and R^d are each independently H, Ci_₄alkyl, or-Si(R^e)₃, wherein each R^e is

independently Ci_₆ alkyl;

R^2a and R^3a are each independently H, -OH, -OP, Ci_₄alkyl, or F; and

each P is independently a hydroxyl protecting group.

54. The compound of claim 53, wherein each P is independently a hydroxyl protecting group, wherein at least one P is an acyl group selected from the group consisting of acetyl, butyryl, decanoyl, and acetylglycyl.

55. The compound of claim 53, wherein R^2a and R^3a are each -OH and wherein P is a phosphate or a protected phosphate group.

56. A compound of Formula (IV

(IVb); wherein R^la is -C0₂H, -C0₂(C_walkyl), -C(0)NR^cR^d, -C(OR^c)=NR^d, Ci_₄alkyl, -NR^cR^d, Ci_₄haloalkyl, halo, -CN, -SO₃H, or -S0₂Ci_₄alkyl;

independently Ci_₆ alkyl;

R^2a and R^3a are each independently H, -OH, -OP, Ci_₄alkyl, or F;

each P is independently a hydroxyl protecting group, wherein at least one P is an acyl group selected from the group consisting of acetyl, butyryl, decanoyl, and acetylglycyl; and

X^" is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, α-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, and carbonate, provided that when P is a phosphate group, X^" is a non-entity;

57. A compound of Formula (IV

Ci_₄haloalkyl, halo, -CN, -S0₃H, or -S0₂Ci_₄alkyl;

independently Ci_6 alkyl;

R^2a and R^3a are each independently -OH or -OP;

each P is independently a hydroxyl protecting group;

P' is a phosphate or a protected phosphate group; and

X^" is a pharmaceutically acceptable counterion selected from the group consisting of tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, α-glycerophosphate, chloride, bromide, sulfate, nitrate, phosphate, fumarate, maleate, N-acetyl-D-tyrosinate, camsylate, oxalate, bicarbonate, and carbonate, provided that when P' is a phosphate group, X^" is a non-entity;

58. A compound of Formula (4a), or a pharmaceutically acceptable salt thereof.

59. A pharmaceutical composition comprising a compound of Formula (I) obtained by the method of any one of claims 1-48, and a pharmaceutically acceptable excipient.

60. A pharmaceutical composition comprising a compound selected from the group consisting of nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAD⁺), reduced nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide phosphate (NADP⁺), reduced nicotinamide adenine dinucleotide phosphate (NADPH), or a mixture of any of the foregoing, wherein the compound is obtained by the method of claim 26, and a pharmaceutically acceptable excipient.

61. A method of administering a compound of Formula (I) obtained by the method of any one of claims 1-48, comprising administering the compound to a subject.

62. A method for treatment of a mitochondrial or metabolic disorder, comprising

administering a pharmaceutical composition according to claim 59 or 60 to a subject in need thereof.

63. The method of claim 62, wherein the disorder is a metabolic disorder selected from the group consisting of insulin resistance, a metabolic syndrome, diabetes, or obesity.

64. The method of claim 62, wherein the disorder is a mitochondrial disorder selected from the group consisting of Friedrich's Ataxia, muscular dystrophy, multiple sclerosis, seizure disorders, migraine, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, ischemia, renal tubular acidosis, age-related neurodegeneration and cognitive decline, chemotherapy fatigue, age-related or chemotherapy-induced menopause or irregularities of menstrual cycling or ovulation, mitochondrial myopathies, mitochondrial damage, or mitochondrial deregulation.