Efficient and scalable synthesis of nicotinoyl riboside and reduced nicotinoyl riboside, modified derivatives thereof, phosphorylated analogs thereof, adenosine dinucleotide conjugates thereof, and novel crystalline forms thereof

Abstract

The present disclosure provides a method for preparing a nicotinoyl riboside compound or derivative having formula (I): wherein X″, Z 1 , Z 2 ,n,R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 It is described herein, its reduced analog, its modified derivative, its phosphorylated analog, and its adenosine dinucleotide conjugate, or its salt, its solvate, or its prodrug; and its novel crystalline form. #imgabs0#

Description

Technical Field

[0001] The present disclosure relates to synthetic methods for preparing nicotinoyl riboside and reduced nicotinoyl riboside, modified derivatives thereof, phosphorylated analogs thereof, and adenosine dinucleotide conjugates thereof, as well as nicotinamide riboside (particularly nicotinamide riboside chloride), crystalline forms of derivatives thereof, nicotinic acid riboside, crystalline forms of derivatives thereof, and nicotinamide mononucleotide, and crystalline forms of derivatives thereof, comprising processing of reagents (by solvent-based processes), liquid-assisted mixing, milling, grinding, solvent-assisted milling, and / or extrusion. Background Art

[0002] Dietary vitamin B3 (which encompasses nicotinamide ("Nam" or "NM"), niacin ("NA"), and nicotinamide riboside ("NR")) is a coenzyme of nicotinamide adenine dinucleotide ("NAD + ”), its phosphorylated parent (“NADP + ” or “NAD(P) + ”), and their respective reduced forms (“NADH” and “NADPH”, respectively). Once converted into NAD(P) + Along with NAD(P)H, the vitamin B3 metabolite is used as a co-substrate in multiple intracellular protein modification processes that control many essential signaling events (e.g., adenosine diphosphate ribosylation and deacetylation) and as a cofactor in over 400 redox enzymatic reactions, thereby controlling metabolism. This is demonstrated by a range of metabolic endpoints, including deacylation of key regulatory metabolic enzymes, leading to restored mitochondrial activity and oxygen consumption. Critically, mitochondrial dysfunction and cellular damage are associated with depletion of the NAD(P)(H)-cofactor pool when it is present at suboptimal intracellular concentrations. Vitamin B3 deficiency is mediated through NAD(P) + Depletion produced significant impairment of cellular activity, and additional NAD(P) production through NA, Nam, NR, and nicotinamide mononucleotide ("NMN") supplementation was + The beneficial effects on bioavailability were mainly observed in cells and tissues where metabolism and mitochondrial function were impaired.

[0003] Despite extensive optimization of solution-based methods for nucleotide preparation over the years, the synthesis of nicotinoyl riboside, monophosphorylation of the active hydroxyl group, and subsequent conjugation remain difficult and problematic due to low yields, product stability, and isolation from polar solvents. Current methods also suffer from atomic and energetic inefficiencies, for example, due to the use of large excesses of solvent and the need for temperature-controlled reaction conditions.

[0004] Reported syntheses of nicotinamide riboside (NR) have become more scalable but use corrosive and expensive reagents, and lengthy deprotection steps, and therefore still exhibit batch-to-batch quality variations, presenting difficulties in maintaining good standards.

[0005] The nucleosides and nucleotide of partial protection have been found to have a wide range of applications, to realize the bioavailability of the improvement of nucleosides and nucleotide parents.This partial protection also comprises the hydroxyl modification that ester group, carboxylate group and acetyl group are carried out, except introducing hydrolyzable phosphoramidate or with the mixed anhydride modification of the phosphate monoester of Pu Luoti De (Protides) and cyclosal ear (CycloSal) derivative form.Although the protection of previous type has become more scalable, the modification at phosphorus center is still difficult to realize on a large scale, particularly for pH change highly responsive and being easy to the nucleosides entity by thermal degradation.

[0006] It has been consistently shown that reduced nicotinamide riboside ("NRH") plays a role in increasing intracellular NAD + Although the physiological and potential therapeutic effects have not been examined due to the lack of sufficient amounts of material for extensive studies, it is expected that the phosphorylated forms of NRH and reduced nicotinic acid riboside ("NARH") or its derivatives may also have similar effects on increasing NAD levels. + ability.

[0007] Reported syntheses of reduced nicotinamide riboside (NRH) are becoming more widely available, but are still performed on a small scale using corrosive and expensive reagents, and lengthy deprotection steps, and therefore still exhibit batch-to-batch quality variations, making it difficult to maintain good standards. In this specification, reduced nicotinamide riboside (NRH) generally refers to a "reduced pyridine" nucleus, more specifically, a 1,4-dihydropyridine compound.

[0008] Overall, the preparation of 5'-nucleotides remains time-consuming, atom-inefficient, and costly due to the numerous protection and deprotection steps required. The required chlorodialkylphosphates, tetraalkylpyrophosphates, chlorophosphites, or phosphoramidites used in these preparations are also expensive starting materials due to their chemical functionalization and chemical instability, and the associated synthetic difficulties that ensue. Phosphorylation reaction conditions are difficult to control and often utilize unapproved or toxic organic solvents, limiting the market for the resulting compounds.

[0009] A known alternative to the protection / deprotection process is the use of phosphorus oxychloride (P(O)Cl 3 ) (i.e., Yoshikawa conditions), but this method still suffers from the following drawbacks. Although not limited by theory, in this method, polar trialkyl phosphate solvents such as P(O)(OMe) 3 are used in large excesses, which are believed to increase the reaction rate while limiting the undesirable reactivity of P(O)Cl as a chlorinating agent. Therefore, it is believed that the use of excess P(O)Cl 3 / P(O)(OR) 3 is a better combination for the chemoselective 5 '-O-phosphorylation of unprotected nucleosides. However, the use of trialkyl phosphate solvents such as P(O)(OMe) 3 hinders their implementation in the preparation of materials for final human use because these solvents are highly toxic (known carcinogens, non-GRAS approved) and are difficult to remove from the final polar product. See M. Yoshikawa et al., Studies of Phosphorylation. III. Selective Phosphorylation of Unprotected Nucleosides, 42 Bull. Chem. Soc. Japan 3505 (1969); Jaemoon Lee et al., A chemical synthesis of nicotinamide adenine dinucleotide (NAD+), Chem. Commun. 729 (1999); each of which is incorporated herein by reference in its entirety.

[0010] Nicotinamide adenine dinucleotide (NAD + ) remains an expensive cofactor, and its commercial availability is limited only by its complex chemistry and highly reactive pyrophosphate bond, which makes it challenging to form on a large scale.

[0011] Nicotinyl ribosides such as nicotinamide riboside (NR) and nicotinic acid riboside (“NAR”), nicotinamide mononucleotide (NMN), and NAD + They are considered useful bioavailable precursors to the NAD(P)(H) pool for combating and treating a wide range of non-infectious diseases, particularly those associated with mitochondrial dysfunction and impaired cellular metabolism. Optimizing the large-scale synthesis of these vitamin B3 derivatives is therefore of great value in making these compounds more widely available to society in terms of nutritional and pharmaceutical entities.

[0012] Reduced nicotinoyl ribosides, such as reduced nicotinamide riboside (NRH), reduced nicotinic acid riboside (NARH), reduced nicotinamide mononucleotide ("NMNH"), reduced nicotinic acid mononucleotide ("NaMNH"), and reduced nicotinamide adenine dinucleotide ("NADH") are considered useful bioavailable precursors in the NAD(P)(H) pool for combating and treating a wide range of non-infectious diseases, particularly those associated with mitochondrial dysfunction and impaired cellular metabolism. Therefore, optimizing the large-scale synthesis of these vitamin B3 derivatives is of great value in making these compounds more widely available to society in terms of nutritional and pharmaceutical entities.

[0013] The crystalline form of useful molecules can have advantageous properties relative to the respective amorphous forms of such molecules. For example, crystalline forms are generally easier to handle and process, for example, when preparing a composition comprising a crystalline form. Crystalline forms typically have higher storage stability and are easier to purify. Pharmaceutically useful compounds using crystalline forms can also improve the performance characteristics of drug products comprising the compound. Obtaining crystalline forms is also useful for expanding the full range of materials available to formulation scientists for formulation optimization, for example, by providing products with different characteristics (for example, better processing or handling characteristics, improved dissolution profiles, or improved shelf life).

[0014] WO 2016 / 014927 A2 (incorporated herein by reference in its entirety) describes crystalline forms of nicotinamide riboside, including Form I of nicotinamide riboside chloride. Pharmaceutical compositions comprising crystalline Form I of nicotinamide riboside chloride, and methods of producing such pharmaceutical compositions are also disclosed.

[0015] WO 2016 / 144660A1 (incorporated herein by reference in its entirety) describes crystalline forms of nicotinamide riboside, including Form II of nicotinamide riboside chloride. Pharmaceutical compositions comprising crystalline Form II of nicotinamide riboside chloride and methods of producing such pharmaceutical compositions are also disclosed.

[0016] In view of the above, a need exists for a method that is atom efficient in terms of reagent and solvent equivalence, does not require polar non-GRAS ("generally recognized as safe") solvents, is versatile with respect to limitations associated with solubility and reagent mixing, is time- and energy-efficient, and provides an efficient, practical, and scalable method for preparing nicotinoyl riboside, reduced nicotinoyl riboside, modified derivatives thereof, phosphorylated analogs thereof, and adenosine dinucleotide conjugates thereof.

[0017] In view of the above, there exists a need for novel crystalline forms of nicotinoyl riboside, reduced nicotinoyl riboside, modified derivatives thereof, phosphorylated analogs thereof, and adenosine dinucleotide conjugates thereof. Summary of the Invention

[0018] In embodiments, the present disclosure relates to a synthetic sequence that can efficiently produce nicotinoyl riboside, its derivatives, its phosphorylated analogs, and its adenosine dinucleotide conjugates, or salts thereof, solvates thereof, or prodrugs thereof, by a process enabled by processing reagents through liquid-assisted mixing, grinding, milling, and / or extrusion.

[0019] In another embodiment, the present disclosure relates to a synthetic sequence that can efficiently produce reduced nicotinoyl riboside, its derivatives, its phosphorylated analogs, and its adenosine dinucleotide conjugates, or salts thereof, solvates thereof, or prodrugs thereof, by a process achieved by processing reagents through liquid-assisted mixing, grinding, milling, and / or extrusion.

[0020] In yet another embodiment, the present disclosure relates to a scalable method for preparing nicotinamide riboside (NR) and nicotinic acid riboside (NAR) and derivatives thereof, or salts thereof, solvates thereof, or prodrugs thereof by liquid-assisted mixing and / or extrusion.

[0021] In yet another embodiment, the present disclosure relates to a scalable method for preparing reduced nicotinamide riboside (NRH) and reduced nicotinic acid riboside (NARH) and derivatives thereof, or salts thereof, solvates thereof, or prodrugs thereof by liquid-assisted mixing, milling, and / or extrusion.

[0022] In yet another embodiment, the present disclosure relates to a scalable process for preparing nicotinamide riboside triacetate ("NRTA") and nicotinic acid riboside triacetate ("NARTA") and derivatives thereof, or salts thereof, solvates thereof, or prodrugs thereof by liquid-assisted mixing, milling, and / or extrusion.

[0023] In yet another embodiment, the present disclosure relates to a scalable process for preparing reduced nicotinamide riboside triacetate ("NRH-TA") and reduced nicotinic acid riboside triacetate ("NARH-TA") and derivatives thereof, or salts thereof, solvates thereof, or prodrugs thereof by biphasic liquid-assisted mixing, milling, and / or extrusion.

[0024] In yet another embodiment, the present disclosure relates to batch and semi-continuous processes capable of producing nicotinamide riboside (NR) and nicotinic acid riboside (NAR) and triacetate derivatives thereof, or salts thereof, solvates thereof, or prodrugs thereof, whereby the use of solvents is kept to a minimum, and whereby conversion and reaction times are optimized by using containment conditions, continuous liquid-liquid extraction and / or mechanochemistry, and optimized purification sequences.

[0025] In yet another embodiment, the present disclosure relates to batch and semi-continuous processes capable of producing reduced nicotinamide riboside (NRH) and reduced nicotinic acid riboside (NARH) and triacetate derivatives thereof, or salts thereof, solvates thereof, or prodrugs thereof, wherein the use of solvents is kept to a minimum and thereby conversion and reaction times are optimized by using containment conditions, continuous liquid-liquid extraction and / or mechanochemistry, and optimized purification sequences.

[0026] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide riboside (NR), including but not limited to Form I of nicotinamide riboside chloride ("NR-Cl"), and methods of making the same.

[0027] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide riboside (NR), including but not limited to "NR methoxide Form II" of nicotinamide riboside chloride (NR-Cl), and methods for their preparation.

[0028] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinic acid riboside (NAR), including but not limited to "Form I" of nicotinic acid riboside (NAR), and methods of making the same.

[0029] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide riboside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-nicotinamide, "NR triacetate" or "NRTA"), including but not limited to "Form I" of nicotinamide riboside triacetate (NRTA) chloride, and methods for their preparation.

[0030] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinoside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-nicotinic acid, "NAR triacetate" or "NARTA"), including but not limited to "Form I" of nicotinoside triacetate (NARTA), and methods of making the same.

[0031] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide mononucleotide ("NMN") (including but not limited to "Form III" of nicotinamide mononucleotide (NMN)) and methods for their preparation. In yet another embodiment, the present disclosure relates to amorphous solid forms of nicotinamide mononucleotide (NMN) and methods for their preparation.

[0032] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide mononucleotide (NMN), including but not limited to "Form IV" of nicotinamide mononucleotide (NMN), and methods of making the same.

[0033] In yet another embodiment, the present disclosure relates to a crystalline form of a compound or derivative having formula (IV), or a salt thereof, a solvate thereof, or a prodrug thereof, and methods of preparing the same.

[0034] In yet another embodiment, the present disclosure relates to a crystalline form of a compound or derivative having formula (IV-H), or a salt, solvate, or prodrug thereof, and methods for their preparation.

[0035] In yet another embodiment, the present disclosure relates to a crystalline form of a compound or derivative having formula (V), or a salt thereof, a solvate thereof, or a prodrug thereof, and methods of preparing the same.

[0036] In yet another embodiment, the present disclosure relates to a crystalline form of a compound or derivative having formula (VI), or a salt, solvate, or prodrug thereof, and a method for preparing the same.

[0037] According to one embodiment, the present disclosure provides a novel method for preparing the following substances in commercial quantities: a compound or derivative having formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof, such as nicotinoyl riboside and its derivatives, and including but not limited to NR-Cl (nicotinamide riboside chloride salt form) and triacetylated form of NAR (nicotinoic acid riboside) (having formula (I) (wherein R 6 、R 7 and R 8 are each acetyl) compounds or derivatives thereof, and fully deprotected forms thereof (having formula (I) (wherein R 6 、R 7 and R 8 Each of the compounds or derivatives is hydrogen). According to this embodiment, the present disclosure provides a novel method whereby mechanical force and / or sealing conditions are used to minimize the amount of solvent and reagents, reduce reaction time, increase overall conversion, and facilitate product purification in a multi-step synthetic sequence, thereby minimizing the formation of by-products and thereby primarily producing by-products that can be easily removed by filtration or evaporation. The prototype product nicotinoyl riboside compound includes a compound or derivative having formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof;

[0038]

[0039] Optionally, wherein X as a counterion - is non-existent, or when X - When X exists, -selected from the group consisting of fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methylsulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;

[0040] Optionally, when X - When absent, the optional counterion is an inner salt;

[0041] Z 1 and Z 2 are independently NH or oxygen;

[0042] n is 0 or 1;

[0043] R 1 Selected from the group consisting of: hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-SO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0044] When R 1 It is hydrogen, Z 2 When is oxygen, and n is 0, the compound or derivative of formula (I) may optionally be in the form of a conjugated species of a carboxylate anion of the compound or derivative of formula (I), further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0045] R A Selected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0046] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0047] Each R Cindependently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-SO2(C1-C6)alkyl、-SO2NR B 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0048] R 2 、R 3 、R 4 and R 5 are each independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0049] R 6 selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 esters, vitamin B2 esters, vitamin B6 esters, choline esters, biotin esters, vitamin A esters, resveratrol esters, glutathione esters, glutathione disulfide esters, aryl (C1-C4)alkyl, heterocyclic (C1-C4)alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0050] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR CC(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0051] R 7 and R 8 independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)RC 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0052] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0053] According to such embodiments, suitable starting materials for the disclosed methods for preparing compounds or derivatives of formula (I), or salts, solvates, or prodrugs thereof, include compounds or derivatives of formula (1), or salts thereof:

[0054]

[0055] where Z 1 and Z 2 independently nitrogen or oxygen;

[0056] m is 1 or 2;

[0057] n is 0 or 1;

[0058] Each R 1 independently selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -ORC 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0059] When each R 1 It is hydrogen, Z 2 When m is oxygen, m is 1, and n is 0, the compound or derivative of formula (1) may optionally be in the form of a carboxylate anion conjugate base species of the compound or derivative of formula (1), further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0060] R A Selected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0061] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0062] Each R Cindependently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0063] R 2 、R 3 、R 4 and R 5 are each independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0064] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0065] According to such embodiments, suitable starting materials for the disclosed methods for preparing compounds or derivatives of formula (I), or salts, solvates, or prodrugs thereof, include compounds or derivatives of formula (2), or salts thereof:

[0066]

[0067] wherein X′ is selected from the group consisting of fluorine, chlorine, bromine, iodine, HCO 2 , acetoxy, propionyloxy, butyryloxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoyloxy, HOCO 2 , citratoyloxy, carbamoyloxy, glucosyloxy, lactoyloxy, succinyloxy, sulfonyloxy, trifluoromethanesulfonyloxy, trichloromethanesulfonyloxy, tribromomethanesulfonyloxy, and trifluoroacetoxy;

[0068] R 6 selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 esters, vitamin B2 esters, vitamin B6 esters, choline esters, biotin esters, vitamin A esters, resveratrol esters, glutathione esters, glutathione disulfide esters, aryl (C1-C4)alkyl, heterocyclic (C1-C4)alkyl, -N(R A )-CO2R C 、-N(R A )-CO2RB 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0069] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2RB wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0070] R A Selected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0071] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0072] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0073] R 7 and R 8independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0074] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0075] According to such embodiments, suitable starting materials for the disclosed methods for preparing compounds or derivatives of formula (2), or salts, solvates, or prodrugs thereof, include compounds or derivatives of formula (2a), or salts thereof:

[0076]

[0077] where R 6 selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 esters, vitamin B2 esters, vitamin B6 esters, choline esters, biotin esters, vitamin A esters, resveratrol esters, glutathione esters, glutathione disulfide esters, aryl (C1-C4)alkyl, heterocyclic (C1-C4)alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0078] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0079] R ASelected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0080] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0081] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0082] R 7 and R 8 independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C1-C4)alkyl, and substituted heterocycle(C1-C4)alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0083] R 14 is methyl or phenyl;

[0084] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0085] Generally, as described, appropriate synthetic methods are used that involve batch or continuous processing of reagents by liquid-assisted mixing, milling, grinding, and / or extrusion.

[0086] According to alternative embodiments, suitable starting materials for the disclosed methods of preparing compounds or derivatives of formula (I), or salts, solvates, or prodrugs thereof, include compounds or derivatives of formula (1a), or salts thereof:

[0087]

[0088] where Z 1 and Z 2 are independently NH or oxygen;

[0089] n is 0 or 1;

[0090] R 1 Selected from the group consisting of: hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NRC C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0091] When R 1 It is hydrogen, Z 2 When is oxygen, and n is 0, the compound or derivative of formula (1a) may optionally be in the form of a carboxylate anion conjugate base species of the compound or derivative of formula (1a), further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0092] R A Selected from the group consisting of: -H, -(C1-C8)alkyl, -(CH2)3-NH-(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0093] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0094] Each R Cindependently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0095] R 2 、R 3 、R 4 and R 5 Each is hydrogen;

[0096] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0097] According to yet another alternative embodiment, suitable starting materials for the disclosed methods of preparing compounds or derivatives of Formula I, or salts, solvates, or prodrugs thereof, include compounds or derivatives of Formula (1b), or salts thereof:

[0098]

[0099] where Z1 and Z 2 independently nitrogen or oxygen;

[0100] m is 1 or 2;

[0101] n is 0 or 1;

[0102] Each R 1 independently selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NRC 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0103] When each R 1 It is hydrogen, Z 2 When m is oxygen, m is 1, and n is 0, the compound or derivative of formula (1b) may optionally be in the form of a carboxylate anion conjugate base species of the compound or derivative of formula (1b), further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0104] R A Selected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0105] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0106] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0107] R 2 、R 3 、R 4 and R 5 Each is hydrogen;

[0108] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0109] In an embodiment, the method for preparing a compound or derivative of formula (2), or a salt thereof, may comprise the following steps:

[0110] (a) provides a compound or derivative having the formula (2a), or a salt thereof, wherein R 14 is methyl, then X' of the compound or derivative or salt thereof having the formula (2) is not acetoxy, and wherein when R of the compound or derivative or salt thereof having the formula (2a) is 14 is phenyl, then X' of the compound or derivative of formula (2), or its salt, is not acetoxy; (b) treating the compound or derivative of formula (2a), or its salt, with at least a stoichiometric amount of a Bronsted acid or nucleophilic substitution reagent in the presence of at least a molar equivalent of a polar organic solvent co-reagent; (c) processing the compound or derivative of formula (2a), or its salt, the Bronsted acid or nucleophilic substitution reagent, and the polar organic solvent co-reagent to produce the compound or derivative of formula (2), or its salt; and (d) isolating the compound or derivative of formula (2), or its salt.

[0111] Processing can be carried out under batch processing conditions or by continuous processing. Continuous processing can include one or more stirring methods selected from the group consisting of: liquid-assisted mixing, grinding, and extrusion under sealed conditions. The process described herein allows the preparation of compounds or derivatives of formula (2), or salts thereof, under virtually solvent-free conditions.

[0112] The polar organic solvent co-agent and the separating solvent used in the above process for preparing the compound or derivative of formula (2), or a salt thereof, may be a polar organic solvent selected from the group consisting of, for example, the residual solvents of Class 2 listed in Table 2, or optionally (for non-human use) the polar organic solvents listed in the United States Pharmacopeia and the National Formulary. <467> (US Pharmacopeial Convention 2006) (USP 30 <467> ) which is incorporated herein by reference in its entirety.

[0113] In another embodiment, the nucleophilic substituent of step (b) of the above method for preparing the compound or derivative of formula (2), or a salt thereof, is generated in situ by reacting an acid chloride with an alcohol in stoichiometric equivalents.

[0114] In an embodiment, a method of preparing a compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof, optionally at a specific anomeric ratio (α / β), may comprise the following steps:

[0115] (a) providing a compound or derivative of formula (2), or a salt thereof; (b) using a molar equivalent of a compound or derivative of formula (1), or a salt thereof (optionally wherein each R 1 (c) treating the compound or derivative of formula (2), or its salt, and the compound or derivative of formula (1), or its salt (optionally wherein each R 1 is a TMS group) to produce the compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof, optionally in a specific anomeric ratio (α / β); (d) removing by-products produced by the processing step under reduced pressure and temperature controlled conditions; (e) separating the unreacted compound or derivative of formula (2), or a salt thereof; optionally, (e1) adding acetone; optionally, (e2) separating the unreacted compound or derivative of formula (1), or a salt thereof; and (f) separating the compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof.

[0116] Processing can be carried out under batch processing conditions or by continuous processing. Continuously processing can include one or more stirring methods selected from the group consisting of: liquid-assisted mixing, milling, grinding and extrusion. The process described herein enables the preparation of compounds or derivatives of formula (I) or salts thereof, solvates thereof or prodrugs thereof, optionally in a specific anomeric ratio (α / β).

[0117] The polar organic solvent co-reagent and separating solvent used in the above process for preparing a compound or derivative of formula (I), optionally in a specific anomeric ratio (α / β), or a salt, solvate, or prodrug thereof, can be a polar organic solvent from the group consisting of, for example, the residual solvents of Class 2 listed in Table 2, or optionally (for non-human use) the polar organic solvents listed in the United States Pharmacopeia and the National Formulary. <467> (US Pharmacopeial Convention 2006) (USP 30 <467> ) which is incorporated herein by reference in its entirety.

[0118] In an alternative embodiment of the above method for preparing a compound or derivative of formula (I), or a salt, solvate, or prodrug thereof, the compound or derivative of formula (2), or a salt thereof, is further treated with a molar equivalent of a Lewis acid in step (b).

[0119] In yet another alternative embodiment of the above method for preparing a compound or derivative of formula (I), or a salt, solvate, or prodrug thereof, the compound or derivative of formula (I), or a salt, solvate, or prodrug thereof, is produced as a mixture of an α-anomer and a β-anomer at an anomeric ratio of α-anomer to β-anomer of from about 1.5:1 to about 1:4 on a weight percent basis.

[0120] In yet another alternative embodiment of the above method for preparing a compound or derivative of formula (I), or a salt, a solvate, or a prodrug thereof, the compound or derivative of formula (I), or a salt, a solvate, or a prodrug thereof, is produced as a β-anomer.

[0121] In yet another alternative embodiment of the above method for preparing a compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof, the α-anomer and the β-anomer of the compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof can be separated separately by a method which may further comprise the following steps:

[0122] (c1) adding acetone to: optionally the compound of formula (2) or a derivative thereof, or a salt thereof, optionally the compound of formula (1) or a derivative thereof, or a salt thereof (optionally wherein each R 1 is a TMS group), and the compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof, so as to precipitate the β-anomer of the compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof; (c2) filtering the following: optionally the compound or derivative of formula (2), or a salt thereof, optionally the compound or derivative of formula (1), or a salt thereof (optionally wherein each R 1 is a TMS group), and the compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof, so as to separate the β-anomer of the compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof; (c3) washing the β-anomer of the compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof with acetone; (c4) combining the acetone from these addition and washing steps; and (c5) removing the acetone under reduced pressure; wherein these steps (c1) to (c5) are performed sequentially after step (c).

[0123] In certain embodiments, the method of preparing a crystalline form of a compound or derivative of formula (I), or a salt, solvate, or prodrug thereof, optionally at a specific anomeric ratio (α / β), may comprise the following steps:

[0124] (a) adding a volume of methanol and water in a weight:weight ratio of 95:5 to the compound or derivative of formula (I) or its salt, solvate, or prodrug thereof, optionally at a specific anomeric ratio (α / β) at room temperature so as to dissolve approximately 15% of the compound or derivative of formula (I) or its salt, solvate, or prodrug thereof, optionally at a specific anomeric ratio (α / β) in the volume of methanol and water; (b) stirring the compound or derivative of formula (I) or its salt, solvate, or prodrug thereof, optionally at a specific anomeric ratio (α / β) at 50° C. until the compound or derivative of formula (I) or its salt, solvate, or prodrug thereof, optionally at a specific anomeric ratio (α / β), is significantly dissolved. in said volume of methanol and water; (c) cooling a solution of a compound or derivative of formula (I), or a salt, a solvate, or a prodrug thereof, optionally in a specific anomeric ratio (α / β), in said volume of methanol and water to -10°C with stirring to precipitate a crystalline form of the compound or derivative of formula (I), or a salt, a solvate, or a prodrug thereof, optionally in a specific anomeric ratio (α / β); (d) isolating the crystalline form of the compound or derivative of formula (I), or a salt, a solvate, or a prodrug thereof, optionally in a specific anomeric ratio (α / β); and (e) drying the crystalline form of the compound or derivative of formula (I), or a salt, a solvate, or a prodrug thereof, optionally in a specific anomeric ratio (α / β).

[0125] In yet another alternative embodiment of the above method for preparing a crystalline form of a compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof, the compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 is a crystalline form of nicotinamide riboside chloride having the formula (XII):

[0126]

[0127] In yet another alternative embodiment, the method of preparing a compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof, optionally at a specific anomeric ratio (α / β), may comprise the following steps:

[0128] (a) providing a compound or derivative of formula (1), or a salt thereof; optionally, (a1) treating the compound or derivative of formula (1), or a salt thereof, with an excess of one or more trimethylsilylating agents, and optionally, heating the compound or derivative of formula (1), or a salt thereof, and the one or more trimethylsilylating agents to reflux for about 12 hours to produce a compound or derivative of formula (1), or a salt thereof (wherein each R 1 is a trimethylsilyl ("TMS") group); optionally, (a2) cooling the mixture to room temperature; optionally, (a3) ​​isolating the compound or derivative of formula (1), or a salt thereof (wherein each R 1 is a TMS group); (b) treating the compound or derivative of formula (1), or a salt thereof (optionally wherein each R 1 is a TMS group); (c) processing the compound or derivative of formula (1), or a salt thereof (optionally wherein each R 1 is a TMS group), the compound or derivative of formula (2), or a salt thereof, and an organic solvent co-reagent to produce the compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof (optionally wherein each R 1 is a TMS group), optionally generated in a specific anomeric ratio (α / β); (d) adding water to: optionally the compound or derivative of formula (1), or a salt thereof (optionally wherein each R 1 is a TMS group), optionally the compound or derivative of formula (2), or a salt thereof, the organic solvent co-reagent, and the compound or derivative of formula (I) optionally in a specific anomeric ratio (α / β), or a salt thereof, a solvate thereof, or a prodrug thereof (optionally wherein R 1 is a TMS group); optionally, (d1) adding a saturated NaHCO3 solution to the following: optionally the compound or derivative of formula (1), or a salt thereof (optionally wherein each R 1 is a TMS group), optionally the compound or derivative of formula (2), or a salt thereof, the organic solvent co-reagent, the compound or derivative of formula (I) optionally in a specific anomeric ratio (α / β), or a salt thereof, a solvate thereof, or a prodrug thereof (optionally wherein each R 1is a TMS group), and water; (e) adjusting the pH of the aqueous phase; (f) separating the organic phase from the aqueous phase; (g) lyophilizing the aqueous phase to provide a compound or derivative of formula (I) optionally in a specific anomeric ratio (α / β), or a salt, solvate, or prodrug thereof; optionally, (g1) treating the compound or derivative of formula (I), or a salt, solvate, or prodrug thereof, with (3 < x < 100) molar equivalents of an alcohol and a reagent selected from the group consisting of: at least a sub-molar equivalent of a Bronsted inorganic base, (x ≤ 20) molar equivalents of a Bronsted inorganic acid, and (3 ≤ x < 20) molar equivalents of an acyl chloride; optionally, (g2) processing the compound or derivative of formula (I), or a salt, solvate, or prodrug thereof, with the alcohol and the reagent to produce a compound or derivative of formula (I), or a salt, solvate, or prodrug thereof (where R 6 、R 7 and R 8 are each hydrogen); and optionally, (g3) separating a compound or derivative of formula (I), or a salt, solvate, or prodrug thereof (where R 6 、R 7 and R 8 are each hydrogen).

[0129] Processing can be carried out under batch processing conditions or by continuous processing. Continuous processing can include one or more mixing methods selected from the group consisting of: liquid-assisted mixing, milling, grinding, and extrusion. The processes described herein enable the preparation of a compound or derivative of formula (I), or a salt, solvate, or prodrug thereof, optionally in a specific anomeric ratio (α / β).

[0130] The polar organic co-solvent used in the above methods for preparing a compound or derivative of formula (I), or a salt, solvate, or prodrug thereof, optionally in a specific anomeric ratio (α / β), can be a polar organic solvent from the following: for example, preferably Class 2 residual solvents listed in Table 2, or optionally (for non-human use) Class 3 residual solvents listed in Table 3 of the United States Pharmacopeia and The National Formulary 30<467> (U.S. Pharmacopeial Convention 2006) (USP 30 in <467>), the full text of which is incorporated herein by reference.

[0131] In yet another alternative embodiment, the above method for preparing a compound or derivative of formula (I), or a salt, a solvate, or a prodrug thereof (wherein the reagent in step (g1) is a Bronsted inorganic base) may further comprise the following steps:

[0132] (g2a) neutralizing the Bronsted inorganic base using a concentrated acid solution under controlled conditions; wherein step (g2a) is performed after step (g2).

[0133] In yet another alternative embodiment, the above method for preparing a compound or derivative of formula (I), or a salt, a solvate, or a prodrug thereof (wherein the reagent in step (g1) is a Bronsted inorganic acid) may further comprise the following steps:

[0134] (g2a) neutralizing the Bronsted inorganic acid using a concentrated alkaline solution under controlled conditions, wherein step (g2a) is performed after step (g2).

[0135] In an embodiment, a method of preparing a compound or derivative of formula (Ia), or a salt thereof, a solvate thereof, or a prodrug thereof, optionally at a specific anomeric ratio (α / β), may comprise the following steps:

[0136] (a) providing a compound or derivative of formula (2), or a salt thereof; (b) treating the compound or derivative of formula (2), or a salt thereof, with a molar equivalent of a compound or derivative of formula (1a), or a salt thereof; (c) processing the compound or derivative of formula (2), or a salt thereof, and the compound or derivative of formula (1a), or a salt thereof, to produce the compound or derivative of formula (1a), or a salt thereof, a solvate thereof, or a prodrug thereof, optionally in a specific anomeric ratio (α / β); (d) removing by-products produced by the processing steps under reduced pressure and temperature controlled conditions; (e) isolating unreacted compound or derivative of formula (2), or a salt thereof; optionally, (e1) adding acetone; optionally, (e2) isolating unreacted compound or derivative of formula (1a), or a salt thereof; and (f) isolating the compound or derivative of formula (1a), a salt thereof, a solvate thereof, or a prodrug thereof.

[0137] Processing can be carried out under batch processing conditions or by continuous processing. Continuously processing can include one or more stirring methods selected from the group consisting of: liquid-assisted mixing, milling, grinding and extrusion. The process described herein enables the preparation of compounds or derivatives of formula (Ia) or salts thereof, solvates thereof, or prodrugs thereof, optionally at a specific anomeric ratio (α / β).

[0138] The polar organic solvent co-reagent and the separating solvent used in the above process for preparing the compound or derivative of formula (Ia), or a salt, solvate or prodrug thereof, optionally at a specific anomeric ratio (α / β), can be a polar organic solvent from the group consisting of, for example, the residual solvents of Class 2 listed in Table 2, or optionally (for non-human use) the polar organic solvents listed in the United States Pharmacopeia and the National Formulary. <467> (US Pharmacopeial Convention 2006) (USP 30 <467> ) which is incorporated herein by reference in its entirety.

[0139] In another embodiment, the method of preparing a compound or derivative of formula (Ia), or a salt thereof, a solvate thereof, or a prodrug thereof, optionally at a specific anomeric ratio (α / β), may comprise the following steps:

[0140] (a) providing a compound or derivative of formula (2), or a salt thereof; (b) treating the compound or derivative of formula (2), or a salt thereof, with a molar equivalent of a compound or derivative of formula (1b), or a salt thereof; (c) processing the compound or derivative of formula (2), or a salt thereof, and the compound or derivative of formula (1b), or a salt thereof, to produce the compound or derivative of formula (Ia), or a salt thereof, a solvate thereof, or a prodrug thereof, optionally in a specific anomeric ratio (α / β); (d) removing by-products produced by the processing steps under reduced pressure and temperature controlled conditions; (e) isolating unreacted compound or derivative of formula (2), or a salt thereof; optionally, (e1) adding acetone; optionally, (e2) isolating unreacted compound or derivative of formula (1b), or a salt thereof; and (f) isolating the compound or derivative of formula (Ia), a salt thereof, a solvate thereof, or a prodrug thereof.

[0141] In yet another alternative embodiment, the above method for preparing a compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof may further comprise the following steps:

[0142] (a1) provides a compound or derivative having the formula (2a), or a salt thereof, wherein R 14 is methyl, then X' of the compound or derivative or salt thereof having the formula (2) is not acetoxy, and wherein when R of the compound or derivative or salt thereof having the formula (2a) is 14is phenyl, then X' of the compound or derivative of formula (2), or its salt is not benzoyloxy; (a2) treating the compound or derivative of formula (2a), or its salt with at least a stoichiometric equivalent of a Bronsted acid or a nucleophilic substitution reagent in the presence of at least a molar equivalent of a polar organic solvent co-reagent; (a3) ​​processing the compound or derivative of formula (2a), or its salt, the Bronsted acid or nucleophilic substitution reagent, and the polar organic solvent co-reagent to produce the compound or derivative of formula (2), or its salt; and (a4) isolating the compound or derivative of formula (2), or its salt; wherein these steps (a1) to (a4) are performed sequentially before step (a).

[0143] In yet another alternative embodiment, the nucleophilic substituent of step (a2) of the above process for preparing the compound or derivative of formula (2), or a salt thereof, is generated in situ by reacting an acid chloride with an alcohol in stoichiometric equivalents.

[0144] According to one embodiment, the present disclosure provides a method for preparing a compound or derivative of formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen). According to such an embodiment, the present disclosure provides a novel method whereby mechanical force is used to minimize the amount of solvent, reduce reaction time, increase overall conversion, and facilitate product purification in a multi-step synthetic sequence, thereby minimizing the formation of by-products and thereby producing primarily by-products that can be easily removed by filtration or evaporation. Prototype product analogs of nicotinoyl riboside compounds include compounds or derivatives of formula (IH), or salts thereof, solvates thereof, or prodrugs thereof (wherein R 6 、R 7 and R 8 each is hydrogen):

[0145]

[0146] Optionally, wherein X as a counterion - does not exist, or when X - When X exists, - selected from the group consisting of fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, succinate, sulfonate, triflate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;

[0147] Optionally, when X -When absent, the optional counterion is an inner salt;

[0148] Z 1 and Z 2 are independently NH or oxygen;

[0149] n is 0 or 1;

[0150] R 1 Selected from the group consisting of: hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0151] When R 1 It is hydrogen, Z 2 When is oxygen, and n is 0, the compound or derivative of formula (IH) may optionally be in the form of a carboxylate anion conjugate base species of the compound or derivative of formula (IH), further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0152] R A Selected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0153] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0154] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0155] R 2 、R 3 、R 4 and R 5 are each independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C2, -(C1-C6) perfluoroalkyl, and -(C1-C6) alkylene-OR C ;

[0156] Provided that the absolute configuration of C** is R or S, or a mixture of R and S.

[0157] In an embodiment, a method for preparing a compound or derivative of formula (I-H), or a salt, solvate, or prodrug thereof (where R 6 , R 7 and R 8 are each hydrogen):

[0158] (a) Providing a compound or derivative of formula (I), or a salt, solvate, or prodrug thereof (where R 6 , R 7 and R 8 are each -C(O)R', and where R' is methyl or -C1 alkyl); (b) Treating the compound or derivative of formula (I), or a salt, solvate, or prodrug thereof (where R 6 , R 7 and R 8 are each -C(O)R', and where R' is methyl or -C1 alkyl) with (3 < x < 20) molar equivalents of an alcohol (e.g., methanol or ethanol) and a reagent selected from the group consisting of: at least sub-molar equivalent of a Bronsted inorganic base, (x ≤ 20) molar equivalents of a Bronsted inorganic acid, and (3 ≤ x < 20) molar equivalents of an acyl chloride; (c) Processing the compound or derivative of formula (I), or a salt, solvate, or prodrug thereof (where R 6 , R 7 and R 8 are each -C(O)R', and where R' is methyl or -C1 alkyl), the alcohol, and the reagent to produce the compound or derivative of formula (I-H), or a salt, solvate, or prodrug thereof (where R 6 , R 7 and R 8 are each hydrogen); and (d) Isolating the compound or derivative of formula (I-H), or a salt, solvate, or prodrug thereof (where R 6 , R 7 and R 8 are each hydrogen).

[0159] Processing can be carried out under batch processing conditions or by continuous processing. Continuous processing can include one or more mixing methods selected from the group consisting of: liquid-assisted mixing, milling, grinding, and extrusion. The processes described herein enable the preparation of a compound or derivative of formula (I-H), or a salt, solvate, or prodrug thereof (where R6 、R 7 and R 8 each is hydrogen).

[0160] In the preparation of a compound or derivative of formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 The polar organic solvent co-reagent and separation solvent used in the above process wherein the polar organic solvent is hydrogen (the polar organic solvents) can be selected from the group consisting of, for example, the Class 2 residual solvents listed in Table 2, or optionally (for non-human use) the polar organic solvents listed in the United States Pharmacopeia and the National Formulary. <467> (US Pharmacopeial Convention 2006) (USP 30 <467> ) which is incorporated herein by reference in its entirety.

[0161] In the preparation of a compound or derivative of formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 In an alternative embodiment of the above method wherein each is hydrogen), when the reagent of step (b) is a Bronsted inorganic base, the method may further comprise the following steps:

[0162] (c1) neutralizing the Bronsted inorganic base using a concentrated acid solution under controlled conditions; wherein step (c1) is performed after step (c).

[0163] In the preparation of a compound or derivative of formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 In another alternative embodiment of the above method wherein the reagent of step (b) is a Bronsted inorganic acid, the method may further comprise the following steps:

[0164] (c1) neutralizing the Bronsted inorganic acid using a concentrated alkaline solution under controlled conditions; wherein step (c1) is performed after step (c).

[0165] In the preparation of a compound or derivative of formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8In yet another alternative embodiment of the above method wherein each is hydrogen), the method may further comprise the following steps:

[0166] (a1) providing a compound or derivative of formula (1), or a salt thereof (optionally wherein each R 1 is a TMS group): (a2) using a molar equivalent of a compound or derivative of formula (2), or a salt thereof (wherein R 6 、R 7 and R 8 Each is -C(O)R', and wherein R' is methyl or -C1 alkyl) treating a compound or derivative having formula (1), or a salt thereof (optionally wherein each R 1 is a TMS group); (a3) ​​processing the compound or derivative of formula (1), or a salt thereof (optionally wherein each R 1 is a TMS group), the compound or derivative of formula (2), or a salt thereof (wherein R 6 、R 7 and R 8 Each is -C(O)R', and wherein R' is methyl or -C1 alkyl), and the organic solvent co-reagent, so as to produce a compound or derivative of formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof (optionally wherein each R 1 is a TMS group); (a4) adding water to the following: optionally the compound or derivative of formula (1), or a salt thereof (optionally wherein each R 1 is a TMS group), optionally the compound or derivative of formula (2), or a salt thereof (wherein R 6 、R 7 and R 8 each being -C(O)R', and wherein R' is methyl or -C1 alkyl), the organic solvent co-reagent, and the compound or derivative thereof of formula (I), its salt, its solvate, or its prodrug; and (a5) isolating the compound or derivative thereof of formula (I), its salt, its solvate, or its prodrug (optionally wherein each R 1 is a TMS group); wherein these steps (a1) to (a5) are performed sequentially before step (a).

[0167] In yet another alternative embodiment of the above method for preparing a compound or derivative of formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof, the compound or derivative of formula (I) is further treated with a molar equivalent of a Lewis acid in step (a2), the compound or derivative of formula (I), or a salt thereof (optionally wherein each R 1 is a TMS group).

[0168] In a specific embodiment, a compound or derivative of formula (IH), or a salt, a solvate, or a prodrug thereof (wherein R 6 、R 7 and R 8 The method of obtaining a crystalline form of each of the compounds (each of which is hydrogen) may comprise the steps of:

[0169] (a) adding the compound or derivative of formula (IH), or a salt, a solvate, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen) is added with a certain volume of methanol and water in a weight: weight ratio of 95:5 so as to convert about 15% of the compound of formula (I) or derivative, or salt, solvate, or prodrug thereof (wherein R 6 、R 7 and R 8 (b) stirring the compound or derivative of formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen), until the compound or derivative of formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 (c) stirring the compound or derivative of formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen) in the volume of methanol and water is cooled to -10 ° C to precipitate the compound or derivative of formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 (d) isolating a compound or derivative of formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 and (e) drying the compound or derivative of formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 each being hydrogen).

[0170] According to one embodiment, the present disclosure provides a novel method for preparing compounds or derivatives of formula (II), or salts, solvates, or prodrugs thereof (e.g., phosphorylated analogs of nicotinoyl riboside) in commercial quantities. According to such an embodiment, the present disclosure provides a novel method whereby mechanical force is used to minimize the amount of solvent, reduce reaction time, increase overall conversion, and facilitate product purification in a multi-step synthetic sequence, thereby minimizing the formation of by-products and thereby producing primarily by-products that can be easily removed by filtration or evaporation. Phosphorylated analogs of the prototype product of the nicotinoyl riboside compound include compounds or derivatives of formula (II), or salts, solvates, or prodrugs thereof:

[0171]

[0172] Optionally, wherein X as a counterion - is non-existent, or when X - When X exists, - selected from the group consisting of fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methylsulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;

[0173] Optionally, when X - When absent, the optional counterion is an inner salt;

[0174] Y 1 and Y 2 Each is independently selected from the group consisting of hydrogen, sodium, potassium, lithium, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R Bwherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, and substituted amino are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0175] Or alternatively, Y 1 and Y 2 and -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0176] Optionally, wherein Y 3 is oxygen, sulfur, or absent;

[0177] Z 1 and Z 2 are each independently NH or oxygen;

[0178] Z 3 and Z 4 are each independently nitrogen or oxygen;

[0179] m is 1 or 2;

[0180] n is 0 or 1;

[0181] q is 1 or 2;

[0182] R 1 Selected from the group consisting of: hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R Bwherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0183] When R 1 It is hydrogen, Z 2 When is oxygen, and n is 0, the compound or derivative of formula (II) may optionally be in the form of a carboxylate anion conjugate base species of the compound or derivative of formula (II), further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0184] R ASelected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0185] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0186] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0187] R 2 、R 3 、R 4 and R 5 are each independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0188] R 7 and R 8independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0189] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2RC 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0190] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0191] In an embodiment, a compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 The method of using oxygen may include the following steps:

[0192] (a) providing a compound or derivative of formula (I), or a salt, a solvate, or a prodrug thereof (wherein R 6 is hydrogen); (b) treating the compound or derivative of formula (I), or a salt, a solvate, or a prodrug thereof (wherein R6 is hydrogen), optionally with (0 < x ≤ 20) molar equivalents of a Bronsted base and a reagent selected from the group consisting of: a phosphorylating reagent, a phosphorylating reagent, and a thiophosphorylating reagent; (c) processing the compound or derivative of formula (I), or its salt, its solvate, or its prodrug (where R 6 is hydrogen), the reagent, and optionally, the Bronsted base, to produce the compound or derivative of formula (II), or its salt, its solvate, or its prodrug; (d) optionally adding to ice water the compound or derivative of formula (I), or its salt, its solvate, or its prodrug (where R 6 is hydrogen), optionally the reagent, optionally the Bronsted base, and the compound or derivative of formula (II), or its salt, its solvate, or its prodrug (where Y 3 is oxygen); and (e) isolating the compound or derivative of formula (II), its salt, its solvate, or its prodrug.

[0193] In an alternative embodiment of the above method for preparing a compound or derivative of formula (II), or its salt, its solvate, or its prodrug, the method may further comprise the following steps:

[0194] (e1) Treating the compound or derivative of formula (II), or its salt, its solvate, or its prodrug, with one or more deprotecting reagents in a polar organic co-reagent to remove any protecting groups of R 7 、R 8 、Y 1 、and / or Y 2 ; wherein step (e1) is carried out after step (e).

[0195] In yet another alternative embodiment of the above method for preparing a compound or derivative of formula (II), or its salt, its solvate, or its prodrug (where the reagent in step (b) is a phosphitylating reagent), the method may further comprise the following steps:

[0196] (c1) Adding an oxidizing agent to: optionally the compound or derivative of formula (I), or its salt, its solvate, or its prodrug (where R 6 is hydrogen), optionally the phosphitylating reagent, optionally the Bronsted base, and the compound or derivative of formula (II), or its salt, its solvate, or its prodrug; (c2) optionally processing the compound or derivative of formula (I), or its salt, its solvate, or its prodrug (where R 6is hydrogen), optionally the phosphitylation agent, optionally the Bronsted base, and the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof, to produce a compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is sulfur or oxygen); wherein these steps (c1) and (c2) are performed sequentially after step (c).

[0197] Processing can be carried out under batch processing conditions or by continuous processing. Continuous processing may include one or more stirring methods selected from the group consisting of: liquid-assisted grinding and extrusion. The process described herein enables the preparation of compounds or derivatives of formula (II), or salts thereof, solvates thereof, or prodrugs thereof (wherein Y 3 is oxygen).

[0198] In the preparation of a compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 The polar organic solvent co-reagent and separation solvent used in the above method of oxygen) can be a polar organic solvent from the group consisting of, for example, the Class 2 residual solvents listed in Table 2, or optionally (for non-human use) the polar organic solvents listed in the United States Pharmacopeia and National Formulary. <467> (US Pharmacopeial Convention 2006) (USP 30 <467> ) which is incorporated herein by reference in its entirety.

[0199] In a specific embodiment, a compound or derivative of formula (II), or a salt, a solvate, or a prodrug thereof (wherein Y 3 The method of obtaining a crystalline form of oxygen may comprise the following steps:

[0200] (a) adding the compound of formula (II) or derivative, or salt, solvate, or prodrug thereof (wherein Y 3 is oxygen); (b) stirring the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is oxygen), and the volume of methanol and water, so that the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3(c) filtering the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is oxygen) in the volume of methanol and water to remove any undissolved solids; (d) to the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is oxygen) to the solution of the volume of methanol and water, adding a certain volume of acetone, wherein the volume of acetone is about 2 to about 5 times the combined volume of methanol and water; (e) cooling the compound or derivative of formula (II), or its salt, solvate, or prodrug thereof (wherein Y 3 is oxygen), the volume of acetone, and the volume of methanol and water to precipitate the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 (f) isolating the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is oxygen) crystalline form; and (g) drying the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is a crystalline form of oxygen).

[0201] In a specific embodiment, a compound or derivative of formula (II), or a salt, a solvate, or a prodrug thereof (wherein Y 3 An alternative method for obtaining a crystalline form of (a) oxygen) may comprise the following steps:

[0202] (a) adding the compound of formula (II) or derivative, or salt, solvate, or prodrug thereof (wherein Y 3 is oxygen); (b) stirring the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is oxygen), and the volume of methanol and water, so that the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 (c) filtering the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is oxygen) in the volume of methanol and water to remove any undissolved solids; (d) cooling the compound or derivative of formula (II), or a salt, a solvate, or a prodrug thereof (wherein Y 3is oxygen), and the volume of methanol and water to produce an oil layer at the bottom of the volume of methanol and water; (e) decanting the volume of methanol and water from the oil layer at the bottom of the volume of methanol and water; and (f) drying the oil layer at room temperature to allow the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 Is oxygen) in the form of crystals.

[0203] In a specific embodiment, a compound or derivative of formula (II), or a salt, a solvate, or a prodrug thereof (wherein Y 3 Another alternative method of producing a crystalline form of (is oxygen) may comprise the following steps:

[0204] (a) adding a compound or derivative of formula (II), or a salt, a solvate, or a prodrug thereof (wherein Y 3 Is oxygen), wherein the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is oxygen) is added in an amount of about 200 mg per ml of the volume of ethanol and water; (b) stirring the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is oxygen), and the volume of ethanol and water, so that the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 (c) filtering the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is oxygen) in the volume of ethanol and water to remove any undissolved solids; (d) the compound or derivative of formula (II), or a salt, solvate, or prodrug thereof (wherein Y 3 is oxygen) in the volume of ethanol and water and cooled to -10 ° C for about 48 hours to produce the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 (e) from the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is oxygen) in a crystalline form, the volume of ethanol and water is decanted to isolate the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 Is oxygen) crystalline form; and (f) drying the compound or derivative of formula (II), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 is a crystalline form of oxygen).

[0205] According to one embodiment, the present disclosure provides a novel method for preparing compounds or derivatives of formula (III), or salts, solvates, or prodrugs thereof (such as adenosine dinucleotide conjugates of nicotinoyl riboside) in commercial quantities. According to this embodiment, the present disclosure provides a novel method whereby mechanical force is used to minimize the amount of solvent, reduce reaction time, increase overall conversion, and facilitate product purification, thereby minimizing the formation of by-products. Prototype product nicotinoyl riboside compounds include compounds or derivatives of formula (III), or salts, solvates, or prodrugs thereof:

[0206]

[0207] Optionally, wherein X as a counterion - is non-existent, or when X - When X exists, - selected from the group consisting of fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methylsulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;

[0208] Optionally, when X - When absent, the optional counterion is an inner salt;

[0209] Each Y 1 independently selected from the group consisting of hydrogen, sodium, potassium, lithium, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R Bwherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, and substituted amino are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0210] Each W 1 independently selected from the group consisting of hydrogen, sodium, potassium, lithium, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R Bwherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, and substituted amino are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0211] Or alternatively, Y 1 and W 1 and -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0212] Optionally, wherein Y 3 is oxygen, sulfur, or absent;

[0213] Optionally, wherein W 3 is oxygen, sulfur, or absent;

[0214] Z 1 and Z 2 are each independently NH or oxygen;

[0215] Z 3 and Z 5 are each independently nitrogen or oxygen;

[0216] m is 1 or 2;

[0217] n is 0 or 1;

[0218] q is 1 or 2;

[0219] R 1 Selected from the group consisting of: hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R Bwherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0220] When R 1 It is hydrogen, Z 2 When is oxygen, and n is 0, the compound or derivative of formula (III) may optionally be in the form of a carboxylate anion conjugate base species of the compound or derivative of formula (III), further optionally associated with a positively charged counterion selected from the group consisting of calcium cations, magnesium cations, potassium cations, sodium cations, zinc cations, and ammonium cations;

[0221] R ASelected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0222] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0223] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0224] R 2 、R 3 、R 4 and R 5 are each independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0225] R 7 and R 8independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0226] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2RC 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0227] R 9 and R 10independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0228] R 11is selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C1-C4)alkyl, and substituted heterocycle(C1-C4)alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0229] R 12is selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C1-C4)alkyl, and substituted heterocycle(C1-C4)alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0230] Each R 13independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0231] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0232] According to such embodiments, suitable starting materials for the disclosed methods for preparing compounds or derivatives of formula (III), or salts, solvates, or prodrugs thereof, include compounds or derivatives of formula (3), or salts thereof:

[0233]

[0234] Where W 1 and W 2 Each is independently selected from the group consisting of hydrogen, sodium, potassium, lithium, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, and substituted amino are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0235] Or alternatively, W 1 and W2 and -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0236] Optionally, wherein W 3 is oxygen, sulfur, or absent;

[0237] Z 5 and Z 6 are each independently nitrogen or oxygen;

[0238] t is 1 or 2;

[0239] u is 1 or 2;

[0240] R 9 and R 10independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0241] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2RC 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0242] R ASelected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0243] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0244] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0245] R 11 is selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C1-C4)alkyl, and substituted heterocycle(C1-C4)alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0246] R 12is selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C1-C4)alkyl, and substituted heterocycle(C1-C4)alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0247] Each R 13independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0248] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0249] In an embodiment, the method for preparing a compound or derivative of formula (III), or a salt thereof, a solvate thereof, or a prodrug thereof may comprise the following steps:

[0250] (a) Provide a compound or derivative having formula (II), or a salt, solvate, or prodrug thereof; (b) Treat the compound or derivative having formula (II), or a salt, solvate, or prodrug thereof, with a compound or derivative having formula (3), or a salt thereof, and a reagent in the presence of a water or organic solvent cosolvent in an amount up to 10 molar equivalents, the reagent being selected from the group consisting of: (1 < x ≤ 10) molar equivalents of a carbodiimide reagent, (0 < x ≤ 10) molar equivalents of an amine, and (0 < x ≤ 10) molar equivalents of a Bronsted acid; (c) Process the compound or derivative having formula (II), or a salt, solvate, or prodrug thereof, the compound or derivative having formula (3), or a salt thereof, the reagent, and the water or organic solvent cosolvent to produce the compound or derivative having formula (III), or a salt, solvate, or prodrug thereof; (d) Optionally add to ice water the compound or derivative having formula (II), or a salt, solvate, or prodrug thereof, optionally the compound or derivative having formula (3), or a salt thereof, optionally the reagent, the water or organic solvent cosolvent, and the compound or derivative having formula (III), or a salt, solvate, or prodrug thereof; and (e) Isolate the compound or derivative having formula (III), its salt, solvate, or prodrug.

[0251] In an alternative embodiment of the above method for preparing a compound or derivative having formula (III), or a salt, solvate, or prodrug thereof, the method may further comprise the following steps:

[0252] (e1) Treat the compound or derivative having formula (III), or a salt, solvate, or prodrug thereof, with one or more deprotection reagents in a polar organic solvent cosolvent to remove any protecting groups of R 7 , R 8 , R 9 , R 10 , Y 1 , and / or W 1 ; wherein step (e1) is carried out after step (e).

[0253] In another alternative embodiment of the above method for preparing a compound or derivative having formula (III), or a salt, solvate, or prodrug thereof, in step (b) the compound or derivative having formula (II), or a salt, solvate, or prodrug thereof, the compound or derivative having formula (3), or a salt thereof, the reagent, and the water or organic solvent cosolvent may be further treated with at least a catalytic amount of a divalent metal salt.

[0254] Processing can be carried out under batch processing conditions or by continuous processing. Continuously processing can include one or more stirring methods selected from the group consisting of: continuous grinding and extrusion. The process described herein achieves the preparation of compounds or derivatives of formula (III) or salts thereof, solvates thereof, or prodrugs thereof under almost solvent-free conditions.

[0255] The polar organic solvent co-agent used in the above process for preparing the compound or derivative of formula (III), or a salt, solvate or prodrug thereof, can be a polar organic solvent from the group consisting of, for example, the Class 2 residual solvents listed in Table 2, or optionally (for non-human use) the polar organic solvents listed in the United States Pharmacopeia and the National Formulary. <467> (US Pharmacopeial Convention 2006) (USP 30 <467> ) which is incorporated herein by reference in its entirety.

[0256] According to one embodiment, the present disclosure provides a novel method for preparing the following substances in commercial quantities: a compound or derivative of formula (IV), or a salt thereof, a solvate thereof, or a prodrug thereof, such as a reduced nicotinoyl riboside and its derivatives, and including but not limited to triacetylated forms of NRH (reduced nicotinamide riboside) and NARH (reduced nicotinic acid riboside) (having formula (IV) (wherein R 6 、R 7 and R 8 Each is an acetyl group) compound or derivative), and its fully deprotected form (having formula (IV-H) (wherein R 6 、R 7 and R 8 Each of the compounds or derivatives is hydrogen). According to this embodiment, the present disclosure provides a novel method whereby mechanical force and / or sealing conditions, as well as extraction conditions, minimize the amount of solvent and reagents, reduce reaction time, increase overall conversion, and facilitate product purification in a multi-step synthetic sequence, thereby minimizing the formation of by-products and thereby primarily producing by-products that can be easily removed by filtration or evaporation. The prototype product reduced nicotinoyl riboside compound includes a compound or derivative having formula (IV), or a salt thereof, a solvate thereof, or a prodrug thereof:

[0257]

[0258] where Z 1 and Z 2 are independently NH or oxygen;

[0259] n is 0 or 1;

[0260] R 1 Selected from the group consisting of: hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0261] When R 1It is hydrogen, Z 2 When is oxygen, and n is 0, the compound or derivative of formula (IV) may optionally be in the form of a carboxylate anion conjugate base species of the compound or derivative of formula (IV), further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0262] R A Selected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0263] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0264] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR BC(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0265] R 2 and R 3 are each independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0266] R 4 Selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0267] wherein C* has an absolute configuration of R or S, or a mixture of R and S;

[0268] R 5 Selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0269] R 6 selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 esters, vitamin B2 esters, vitamin B6 esters, choline esters, biotin esters, vitamin A esters, resveratrol esters, glutathione esters, glutathione disulfide esters, aryl (C1-C4)alkyl, heterocyclic (C1-C4)alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0270] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-ORC ;

[0271] R 7 and R 8 independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0272] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0273] Generally, as described, appropriate synthetic methods are used, including batch and semi-continuous processing of reagents by liquid-assisted mixing, grinding, milling, and / or extrusion.

[0274] In an embodiment, a method for preparing a compound or derivative having formula (IV), or a salt, solvate, or prodrug thereof, may include the following steps:

[0275] (a) Providing a compound or derivative having formula (I), or a salt, solvate, or prodrug thereof; (b) Treating the compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, with a concentrated aqueous solution of a reducing agent reagent in the presence of (5 < x < 50) molar equivalents of an organic solvent co-reagent; (c) Processing the compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, the concentrated aqueous solution of the reducing agent reagent, and the organic solvent co-reagent to produce the compound or derivative having formula (IV), or a salt, solvate, or prodrug thereof; (d) Optionally adding to water the compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, optionally the concentrated aqueous solution of the reducing agent reagent, the organic solvent co-reagent, and the compound or derivative having formula (IV), or a salt, solvate, or prodrug thereof; (e) Optionally extracting with an organic solvent the compound or derivative having formula (I), or a salt, solvate, or prodrug thereof, optionally the concentrated aqueous solution of the reducing agent reagent, the organic solvent co-reagent, the compound or derivative having formula (IV), or a salt, solvate, or prodrug thereof, and water; and (f) Separating the compound or derivative having formula (IV), its salt, solvate, or prodrug.

[0276] Processing may be carried out under batch processing conditions or by continuous processing. Continuous processing may include one or more agitation methods selected from the group consisting of: liquid-assisted mixing, grinding, milling, and extrusion. The processes described herein enable the preparation of a compound or derivative having formula (IV), or a salt, solvate, or prodrug thereof, under substantially solvent-free conditions.

[0277] The organic solvent co-reagent and separation solvent used in the above method for preparing a compound or derivative having formula (IV), or a salt, solvate, or prodrug thereof, may be polar organic solvents selected from the following: for example, preferably Class 2 residual solvents listed in Table 2, or optionally (for non-human use) Class 3 residual solvents listed in Table 3 of the United States Pharmacopeia and The National Formulary 30 <467> (U.S. Pharmacopeial Convention 2006) (USP 30 in <467>), the entire text of which is incorporated herein by reference.

[0278] According to one embodiment, the present disclosure provides a method for preparing a compound or derivative having formula (IV-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen). According to this embodiment, the present disclosure provides a novel method whereby mechanical force is used to minimize the amount of solvent and reagents, reduce reaction time, increase overall conversion, and facilitate product purification in a multi-step or single-step synthesis sequence, thereby minimizing the formation of by-products and thereby producing primarily by-products that can be easily removed by filtration or evaporation. The prototype product reduced nicotinoyl riboside compound includes a compound or derivative having formula (IV-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 each is hydrogen):

[0279]

[0280] where Z 1 and Z 2 are independently NH or oxygen;

[0281] n is 0 or 1;

[0282] R 1 Selected from the group consisting of: hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NRC )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0283] When R 1 It is hydrogen, Z 2 When is oxygen, and n is 0, the compound or derivative of formula (IV-H) may optionally be in the form of a carboxylate anion conjugate base species of the compound or derivative of formula (IV-H), further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0284] R A Selected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0285] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0286] Each RC independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0287] R 2 and R 3 are each independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NRC 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0288] R 4 Selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0289] wherein C* has an absolute configuration of R or S, or a mixture of R and S;

[0290] R 5Selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0291] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0292] In an embodiment, a compound or derivative of formula (IV-H), or a salt, a solvate, a prodrug thereof (wherein R 6 、R 7 and R 8 are each hydrogen) may comprise the steps of:

[0293] (a) providing a compound or derivative of formula (IV), or a salt, a solvate, or a prodrug thereof; (b) treating the compound or derivative of formula (IV), or a salt, a solvate, or a prodrug thereof with a molar (x≤10) equivalent of an alcohol (e.g., methanol or ethanol) and a catalytic amount of a Bronsted inorganic base; (c) processing the compound or derivative of formula (IV), or a salt, a solvate, or a prodrug thereof, the alcohol, and the Bronsted inorganic base to produce the compound or derivative of formula (IV-H), or a salt, a solvate, or a prodrug thereof (wherein R 6 、R 7 and R 8are each hydrogen); and (d) isolating a compound or derivative of formula (IV-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 each is hydrogen).

[0294] Processing can be carried out under batch processing conditions or by continuous processing. Continuous processing may include one or more stirring methods selected from the group consisting of: liquid-assisted mixing, milling, grinding, and extrusion. The process described herein allows for the preparation of a compound or derivative of formula (IV-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 each is hydrogen).

[0295] Preparation of a compound or derivative of formula (IV-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 The organic solvent co-reagent and separation solvent used in the above process wherein the solvents are each hydrogen) can be an alcohol (e.g., methanol or ethanol), or any polar protic organic solvent from the group consisting of, for example, the Class 2 residual solvents listed in Table 2, or optionally (for non-human use) the solvents listed in the United States Pharmacopeia and National Formulary. <467> (US Pharmacopeial Convention 2006) (USP 30 <467> ) which is incorporated herein by reference in its entirety.

[0296] In an alternative embodiment, a compound or derivative of formula (IV-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 The above method wherein each is hydrogen may further comprise the following steps:

[0297] (a1) To provide a compound or derivative of formula (I), or a salt, solvate, or prodrug thereof: (a2) treating the compound or derivative of formula (I), or a salt, solvate, or prodrug thereof, with an aqueous concentrated base of a reducing agent reagent in the presence of (5 < x < 50) molar equivalents of a polar organic co-reagent; (a3) processing the compound or derivative of formula (I), or a salt, solvate, or prodrug thereof, the aqueous concentrated solution of the reducing agent reagent, and the polar organic co-reagent to produce a compound or derivative of formula (IV), or a salt, solvate, or prodrug thereof, while continuously extracting the compound or derivative of formula (IV), or a salt, solvate, or prodrug thereof, in situ into an organic solvent; (a4) isolating the compound or derivative of formula (IV), or a salt, solvate, or prodrug thereof; wherein steps (a1) to (a4) are carried out sequentially before step (a).

[0298] According to one embodiment, the present disclosure provides a novel method for preparing a compound or derivative of formula (V), or a salt, solvate, or prodrug thereof (such as a phosphorylated analogue of a reduced nicotinyl nucleoside) in commercial quantities. According to such an embodiment, the present disclosure provides a novel method whereby mechanical force is used to minimize the amount of solvent, reduce the reaction time, increase the overall conversion rate, and facilitate product purification in a multi-step synthesis sequence, thereby minimizing the formation of by-products and thereby mainly producing by-products that can be easily removed by filtration or evaporation. Prototype products of phosphorylated analogues of reduced nicotinyl nucleoside compounds include a compound or derivative of formula (V), or a salt, solvate, or prodrug thereof:

[0299]

[0300] Y 1 and Y 2 each independently selected from the group consisting of hydrogen, sodium, potassium, lithium, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、以及-C**H-(R A )-CO2R Bwherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, and substituted amino are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0301] Or alternatively, Y 1 and Y 2 and -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0302] Optionally, wherein Y 3 is oxygen, sulfur, or absent;

[0303] Z 1 and Z 2 are each independently NH or oxygen;

[0304] Z 3 and Z 4 are each independently nitrogen or oxygen;

[0305] m is 1 or 2;

[0306] n is 0 or 1;

[0307] q is 1 or 2;

[0308] R 1 Selected from the group consisting of: hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R Bwherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0309] When R 1 It is hydrogen, Z 2 When is oxygen, and n is 0, the compound of formula (V) or derivative may optionally be in the form of a carboxylate anion conjugate base species of the compound of formula (V) or derivative, further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0310] R ASelected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0311] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0312] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0313] R 2 and R 3 are each independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0314] R 4 Selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)RC 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0315] wherein C* has an absolute configuration of R or S, or a mixture of R and S;

[0316] R 5 Selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0317] R 7 and R 8independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0318] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2RC 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0319] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0320] According to such embodiments, suitable starting materials for the disclosed methods of preparing compounds or derivatives of formula (V), or salts, solvates, or prodrugs thereof, include compounds or derivatives of formula (IVb), or salts, solvates, or prodrugs thereof:

[0321]

[0322] where Z 1 and Z 2are independently NH or oxygen;

[0323] n is 0 or 1;

[0324] R 1 Selected from the group consisting of: hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0325] When R 1 It is hydrogen, Z 2 When is oxygen, and n is 0, the compound or derivative of formula (IVb) may optionally be in the form of a carboxylate anion conjugate base species of the compound or derivative of formula (IVb), further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0326] R A Selected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0327] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0328] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)RB 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0329] R 2 and R 3 are each independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0330] R 4 Selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0331] wherein C* has an absolute configuration of R or S, or a mixture of R and S;

[0332] R 5 Selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0333] R 7 and R 8 independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0334] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0335] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0336] In an embodiment, a method for preparing a compound or derivative of formula (V), or a salt, solvate, or prodrug thereof (where Y 3 is oxygen) may comprise the following steps:

[0337] (a) Providing a compound or derivative of formula (IVb), or a salt, solvate, or prodrug thereof (where R 6 is hydrogen); (b) Treating the compound or derivative of formula (IVb), or a salt, solvate, or prodrug thereof (where R 6 is hydrogen), optionally with (0 < x ≤ 20) molar equivalents of a Bronsted base and a reagent selected from the group consisting of: a phosphitylation reagent, a phosphorylation reagent, and a thiophosphorylation reagent; (c) Processing the compound or derivative of formula (IVb), or a salt, solvate, or prodrug thereof (where R 6 is hydrogen), the reagent, and optionally, the Bronsted base, to produce the compound or derivative of formula (V), or a salt, solvate, or prodrug thereof; (d) Optionally adding to ice water the compound or derivative of formula (IVb) (where R 6 is hydrogen), or a salt, solvate, or prodrug thereof, optionally the phosphorylation reagent, optionally the Bronsted base, and the compound or derivative of formula (V), or a salt, solvate, or prodrug thereof; and (e) Isolating the compound or derivative of formula (V), its salt, solvate, or prodrug.

[0338] ​​​​​​​​​​​​​​​​​​6 is hydrogen), optionally the phosphitylation agent, optionally the Bronsted base, and the compound or derivative of formula (V), or a salt, solvate, or prodrug thereof; (c2) processing the oxidant reagent, optionally the compound or derivative of formula (IVb), or a salt, solvate, or prodrug thereof (wherein R 6 is hydrogen), optionally the phosphitylation agent, optionally the Bronsted base, and the compound or derivative of formula (V), or a salt, a solvate, or a prodrug thereof, to produce a compound or derivative of formula (V), or a salt, a solvate, or a prodrug thereof (wherein Y 3 is sulfur or oxygen); wherein these steps (c1) and (c2) are performed sequentially after step (c).

[0342] Processing can be carried out under batch processing conditions or by continuous processing. Continuous processing may include one or more stirring methods selected from the group consisting of: liquid-assisted grinding and extrusion. The methods described herein allow for the preparation of compounds or derivatives of formula (V), or salts thereof, solvates thereof, or prodrugs thereof (wherein Y 3 is oxygen).

[0343] In the preparation of a compound or derivative of formula (V), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein Y 3 The polar organic solvent co-reagent and separation solvent used in the above method of oxygen) can be a polar organic solvent from the group consisting of, for example, the Class 2 residual solvents listed in Table 2, or optionally (for non-human use) the polar organic solvents listed in the United States Pharmacopeia and National Formulary. <467> (US Pharmacopeial Convention 2006) (USP 30 <467> ) which is incorporated herein by reference in its entirety.

[0344] According to one embodiment, the present disclosure provides a novel method for preparing compounds or derivatives of formula (VI), or salts, solvates, or prodrugs thereof (such as adenosine dinucleotide conjugates of reduced nicotinoyl riboside) in commercial quantities. According to this embodiment, the present disclosure provides a novel method whereby mechanical force is used to minimize the amount of solvent, reduce reaction time, increase overall conversion, and facilitate product purification, thereby minimizing the formation of by-products. Prototype product reduced nicotinoyl riboside compounds include compounds or derivatives of formula (VI), or salts, solvates, or prodrugs thereof:

[0345]

[0346] Each of the Y 1 independently selected from the group consisting of hydrogen, sodium, potassium, lithium, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, and substituted amino are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0347] Each W 1independently selected from the group consisting of hydrogen, sodium, potassium, lithium, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, and substituted amino are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0348] Or alternatively, Y 1 and W 1and -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0349] Optionally, wherein Y 3 is oxygen, sulfur, or absent;

[0350] Optionally, wherein W 3 is oxygen, sulfur, or absent;

[0351] Z 1 and Z 2 are each independently NH or oxygen;

[0352] Z 3 and Z 5 are each independently nitrogen or oxygen;

[0353] m is 1 or 2;

[0354] n is 0 or 1;

[0355] q is 1 or 2;

[0356] R1 Selected from the group consisting of: hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0357] When R 1 It is hydrogen, Z 2When is oxygen, and n is 0, the compound or derivative of formula (VI) may optionally be in the form of a carboxylate anion conjugate base species of the compound or derivative of formula (VI), further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0358] R A Selected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0359] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0360] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NRB C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0361] R 2 and R 3 are each independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0362] R 4 Selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NRC 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0363] wherein C* has an absolute configuration of R or S, or a mixture of R and S;

[0364] R 5 Selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NRC 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0365] R 7 and R 8 independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0366] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0367] R 9 and R 10independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0368] R 11is selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C1-C4)alkyl, and substituted heterocycle(C1-C4)alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0369] R 12is selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C1-C4)alkyl, and substituted heterocycle(C1-C4)alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0370] Each R 13independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0371] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0372] According to such embodiments, suitable starting materials for the disclosed methods for preparing compounds or derivatives of formula (VI), or salts, solvates, or prodrugs thereof, include compounds or derivatives of formula (3), or salts thereof:

[0373]

[0374] Where W 1 and W 2 Each is independently selected from the group consisting of hydrogen, sodium, potassium, lithium, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted amino, thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, and substituted amino are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0375] Or alternatively, W 1 and W2 and -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0376] Optionally, wherein W 3 is oxygen, sulfur, or absent;

[0377] Z 5 and Z 6 are each independently nitrogen or oxygen;

[0378] t is 1 or 2;

[0379] u is 1 or 2;

[0380] R 9 and R 10independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0381] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2RC 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0382] R ASelected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0383] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0384] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0385] R 11 is selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C1-C4)alkyl, and substituted heterocycle(C1-C4)alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0386] R 12is selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the substituted (C1-C8)alkyl, substituted (C1-C8)cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl(C1-C4)alkyl, and substituted heterocycle(C1-C4)alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0387] Each R 13independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0388] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0389] In an embodiment, the method for preparing a compound or derivative of formula (VI), or a salt thereof, a solvate thereof, or a prodrug thereof may comprise the following steps:

[0390] (a) Provide a compound or derivative of formula (V), or a salt, solvate, or prodrug thereof; (b) Treat the compound or derivative of formula (V), or a salt, solvate, or prodrug thereof, with a compound or derivative of formula (3), or a salt thereof, and a reagent selected from the group consisting of: (1 < x ≤ 10) molar equivalents of a carbodiimide reagent, (0 < x ≤ 10) molar equivalents of an amine, and (0 < x ≤ 10) molar equivalents of a Bronsted acid, in the presence of water or an organic solvent cosolvent in an amount up to 10 molar equivalents; optionally, (c) Process the compound or derivative of formula (V), or a salt, solvate, or prodrug thereof, the compound or derivative of formula (3), or a salt thereof, the reagent, and the water or organic solvent cosolvent to produce the compound or derivative of formula (VI), or a salt, solvate, or prodrug thereof; (d) Optionally add to ice water the compound or derivative of formula (V), or a salt, solvate, or prodrug thereof, optionally the compound or derivative of formula (3), or a salt thereof, optionally the reagent, the water or organic solvent cosolvent, and the compound or derivative of formula (VI), or a salt, solvate, or prodrug thereof; and (e) Isolate the compound or derivative of formula (VI), its salt, solvate, or prodrug.

[0391] In an alternative embodiment of the above method for preparing a compound or derivative of formula (VI), or a salt, solvate, or prodrug thereof, the method may further comprise the following steps:

[0392] (e1) Treat the compound or derivative of formula (VI), or a salt, solvate, or prodrug thereof, with one or more deprotecting reagents in a polar organic solvent cosolvent to remove any protecting groups of R 7 , R 8 , R 9 , R 10 , Y 1 , and / or W 1 ; wherein step (e1) is carried out after step (e).

[0393] In yet another alternative embodiment of the above method for preparing a compound or derivative of formula (VI), or a salt, solvate, or prodrug thereof, in step (b), the compound or derivative of formula (V), or a salt, solvate, or prodrug thereof, the compound or derivative of formula (3), or a salt thereof, the reagent, and the water or organic solvent cosolvent may be further treated with at least a catalytic amount of a divalent metal salt.

[0394] Processing can be carried out under batch processing conditions or by continuous processing. Continuously processing can include one or more stirring methods selected from the group consisting of: continuous grinding and extrusion. The process described herein enables the preparation of compounds or derivatives of formula (VI) or salts thereof, solvates thereof, or prodrugs thereof under virtually solvent-free conditions.

[0395] The polar organic solvent co-agent used in the above process for preparing the compound or derivative of formula (VI), or a salt, solvate or prodrug thereof, can be a polar organic solvent from the group consisting of, for example, the Class 2 residual solvents listed in Table 2, or optionally (for non-human use) the polar organic solvents listed in the United States Pharmacopeia and the National Formulary. <467> (US Pharmacopeial Convention 2006) (USP 30 <467> ) which is incorporated herein by reference in its entirety.

[0396] In an embodiment, the present disclosure provides a novel crystalline NR methanolate salt Form II of nicotinamide riboside chloride according to Formula (VII):

[0397]

[0398] In another embodiment, the crystalline NR methoxide Form II may be characterized by a powder X-ray diffraction pattern having peaks at 23.7°, 24.5°, and 25.4° 2θ ± 0.2° 2θ. In yet another embodiment, the crystalline NR methoxide Form II may be characterized by a powder X-ray diffraction pattern having peaks at 12.9°, 23.7°, 24.5°, and 25.4° 2θ ± 0.2° 2θ. In yet another embodiment, the crystalline NR methoxide Form II may be characterized by a powder X-ray diffraction pattern having peaks at 12.9°, 13.9°, 14.8°, 23.7°, 24.5°, and 25.4° 2θ ± 0.2° 2θ. In yet another embodiment, the crystalline NR methoxide Form II may be characterized by a powder X-ray diffraction pattern having peaks at 12.9°, 13.9°, 14.8°, 23.7°, 24.5°, and 25.4° 2θ ± 0.2° 2θ. Figure 16 In yet another embodiment, the crystalline NR methoxide salt Form II can be characterized by a powder X-ray diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 7.

[0399] In yet another embodiment, crystalline NR methoxide Form II can be characterized by an IR spectrum with peaks at 565.1, 611.3, 638.3, and 680.8 cm -1 ±0.2cm -1In yet another embodiment, the crystalline NR methoxide salt Form II may be characterized by an IR spectrum with peaks at 565.1, 611.3, 638.3, 680.8, 981.6, 1004.8, 1026.0, 1060.7, 1078.0, and 1097.3 cm -1 ±0.2cm -1 In yet another embodiment, the crystalline NR methoxide salt Form II may be characterized by an IR spectrum with peaks at 565.1, 611.3, 680.8, 981.6, 1004.8, 1026.0, 1060.7, 1078.0, 1097.3, 1400.1, 1621.9, 1648.9, and 1700.9 cm -1 ±0.2cm -1 In yet another embodiment, the crystalline NR methoxide salt Form II may be characterized by an IR spectrum substantially as follows: Figure 22 In yet another embodiment, crystalline NR methoxide Form II may be characterized by an IR spectrum having peaks ± 0.2 cm substantially as provided in Table 8. -1 .

[0400] In yet another embodiment, crystalline NR methoxide Form II may be characterized by a DSC thermogram substantially as follows Figure 30 In yet another embodiment, the crystalline NR methoxide Form II may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event with an onset temperature of 125° C.±2° C. In yet another embodiment, the crystalline NR methoxide Form II may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event with a peak temperature of 132° C.±2° C. In yet another embodiment, the crystalline NR methoxide Form II may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event with an onset temperature of 125° C.±2° C. and a peak temperature of 132° C.±2° C.

[0401] In an embodiment, crystalline NR methoxide Form II can be prepared by a method that can include the following steps:

[0402] (a) adding a volume of methanol and water in a weight:weight ratio of 95:5 to the compound or derivative of formula (VII), or its salt or solvate thereof at room temperature so as to dissolve approximately 15% of the compound or derivative of formula (VII), or its salt or solvate thereof in the volume of methanol and water; (b) stirring the compound or derivative of formula (VII), or its salt or solvate thereof at 50°C until all of the compound or derivative of formula (VII), or its salt or solvate thereof is significantly dissolved in the volume of methanol and water; (c) cooling the solution of the compound or derivative of formula (VII), or its salt or solvate thereof in the volume of methanol and water to -10°C with stirring to precipitate the crystalline NR methanol salt Form II; (d) isolating the crystalline NR methanol salt Form II; and (e) drying the crystalline NR methanol salt Form II.

[0403] In an alternative embodiment of the above method for preparing crystalline NR methoxide Form II, the method may further comprise the following steps:

[0404] (a) providing a compound or derivative of formula (Ia), optionally in a specific anomeric ratio (α / β), or a salt or solvate thereof:

[0405]

[0406] Optionally, wherein X as a counterion - is non-existent, or when X - When X exists, - selected from the group consisting of fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methylsulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;

[0407] Z 2 It is NH;

[0408] n is 0;

[0409] R 1 It is hydrogen;

[0410] R 2 、R 3 、R 4 and R 5 Each is hydrogen;

[0411] R 6 、R 7 and R8 each is -C(O)R';

[0412] R' is a methyl group; ;

[0414] (a2) treating the compound or derivative of formula (Ia), or its salt or solvate thereof, with a molar equivalent of an alcohol and at least a submolar equivalent of a Bronsted inorganic base; (a3) ​​processing the compound or derivative of formula (Ia), or its salt or solvate thereof, the alcohol, and the Bronsted inorganic base to produce the compound or derivative of formula (VII), or its salt or solvate thereof; (a4) neutralizing the Bronsted inorganic base using a concentrated acid solution; and (a5) isolating the compound or derivative of formula (VII), or its salt or solvate thereof; wherein these steps (a1) to (a5) are performed sequentially before step (a).

[0415] Processing can be performed under batch processing conditions or by continuous processing. Continuous processing can include one or more agitation methods selected from the group consisting of: liquid-assisted mixing, milling, and extrusion.

[0416] In another alternative embodiment of the above method for preparing crystalline NR methoxide Form II, the method may further comprise the following steps:

[0417] (a1) providing a compound or derivative of formula (Ia), optionally in a specific anomeric ratio (α / β), or a salt or solvate thereof:

[0418]

[0419] Optionally, wherein X as a counterion - is non-existent, or when X - When X exists, - selected from the group consisting of fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methylsulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;

[0420] Z 2 It is NH;

[0421] n is 0;

[0422] R 1 It is hydrogen;

[0423] R 2 、R3 , R 4 and R 5 are each hydrogen;

[0424] R 6 , R 7 and R 8 are each -C(O)R';

[0425] R' is methyl; ;

[0427] (a2) Treat the compound or derivative of formula (Ia), or its salt or solvate, with (3 < x < 100) molar equivalents of an alcohol and (x ≤ 20) molar equivalents of a Bronsted inorganic acid; (a3) Process the compound or derivative of formula (Ia), or its salt or solvate, the alcohol, and the Bronsted inorganic acid under sealed conditions to produce the compound or derivative of formula (VII), or its salt or solvate, or its salt or solvate; and (a4) Isolate the precipitated compound or derivative of formula (VII), or its salt or solvate; wherein steps (a1) to (a4) are carried out sequentially before step (a).

[0428] The processing can be carried out under batch processing conditions or by continuous processing. Continuous processing can include one or more stirring methods selected from the group consisting of: liquid-assisted mixing, milling, and extrusion.

[0429] In yet another alternative embodiment of the above method for preparing crystalline NR methanolate form II, the method can further comprise the following steps:

[0430] (a3a) Neutralize the Bronsted inorganic acid with a concentrated base solution under controlled conditions; wherein step (a3a) is carried out after step (a3).

[0431] In yet another alternative embodiment of the above method for preparing crystalline NR methanolate form II, the method can further comprise the following steps:

[0432] (a1) Provide a compound or derivative of formula (Ia), or its salt or solvate, optionally in a specific anomeric ratio (α / β):

[0433]

[0434] Optionally, wherein X as a counterion - is absent, or when X - is present, X -Selected from the group consisting of: fluoride ion, chloride ion, bromide ion, iodide ion, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methyl sulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;

[0435] Z 2 is NH;

[0436] n is 0;

[0437] R 1 is hydrogen;

[0438] R 2 、R 3 、R 4 and R 5 are each hydrogen;

[0439] R 6 、R 7 and R 8 are each -C(O)R';

[0440] R' is methyl; ;

[0442] (a2) Treating the compound or derivative of formula (Ia), or its salt or solvate, with (3 < x < 100) molar equivalents of an alcohol and (3 ≤ x < 20) molar equivalents of an acyl chloride; (a3) Processing the compound or derivative of formula (Ia), or its salt or solvate, the alcohol, and the acyl chloride under sealed conditions to produce the compound or derivative of formula (VII), or its salt or solvate; and (a4) Separating the precipitated compound or derivative of formula (VII), or its salt or solvate; wherein steps (a1) to (a4) are carried out sequentially before step (a).

[0443] The processing can be carried out under batch processing conditions or by continuous processing. Continuous processing can include one or more stirring methods selected from the group consisting of: liquid-assisted mixing, milling, and extrusion.

[0444] In yet another alternative embodiment of the above method for preparing crystalline NR methoxide form II, the method can further comprise the following steps:

[0445] (a3a) adding a concentrated base solution to the following under controlled conditions: optionally the compound or derivative of formula (Ia), or a salt or solvate thereof, the alcohol, the acid chloride, and the compound or derivative of formula (VII), or a salt or solvate thereof; wherein step (a3a) is performed after step (a3).

[0446] In an embodiment, the present disclosure provides a novel crystalline Form I of nicotinic acid riboside (NAR) according to formula (VIII):

[0447]

[0448] In another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks at 19.2°, 21.6°, and 26.4° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks at 15.7°, 19.2°, 21.6°, 26.4°, and 28.9° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks at 12.8°, 13.2°, 15.7°, 19.2°, 20.5°, 21.6°, 26.4°, 28.3°, and 28.9° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern substantially as Figure 17 In yet another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 4.

[0449] In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum with peaks at 534.2, 680.8, 754.0, and 773.3 cm -1 ±0.2cm -1 In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum with peaks at 534.2, 680.8, 754.0, 773.3, 1087.7, 1114.7, and 1359.6 cm -1 ±0.2cm -1 In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum having peaks at 534.2, 680.8, 754.0, 773.3, 1087.7, 1114.7, 1359.6, 1579.4, 1612.2, 1639.2 cm -1 ±0.2cm -1 In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum substantially as follows: Figure 23In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum having peaks ±0.2 cm substantially as provided in Table 5. -1 .

[0450] In yet another embodiment, the above crystalline Form I may be characterized by a DSC thermogram substantially as follows Figure 32 In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the onset temperature is 156° C.±2° C. In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the peak temperature is 164° C.±2° C. In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the onset temperature is 156° C.±2° C. and the peak temperature is 164° C.±2° C.

[0451] In an embodiment, crystalline NAR Form I can be prepared by a method comprising the steps of:

[0452] (a) dissolving the compound or derivative of formula (VIII), or its salt or solvate thereof, in a certain volume of methanol; (b) adding a certain volume of acetone equal to the volume of the methanol to the compound or derivative of formula (VIII), or its salt or solvate thereof in the volume of methanol; (c) precipitating the crystalline Form I; and (d) isolating the crystalline Form I.

[0453] In an alternative embodiment of the above method for preparing crystalline NAR Form I, the method may further comprise the following steps:

[0454] (a1) providing a compound or derivative having the formula (1a), or a salt thereof:

[0455]

[0456] where Z 2 It is oxygen;

[0457] n is 0;

[0458] R 1 It is hydrogen;

[0459] wherein the compound or derivative of formula (1a) may optionally be in the form of a carboxylate anion conjugate base species of the compound or derivative of formula (1a), further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0460] R 2 、R 3 、R 4 and R 5 Each is hydrogen;

[0461] (a2) treating the compound or derivative of formula (1a), or a salt thereof, with an excess of one or more trimethylsilylating agents to produce a compound or derivative of formula (1a), or a salt thereof (wherein R 1 is a TMS group); (a3) ​​removing one or more trimethylsilylating agents; (a4) treating the compound or derivative of formula (1a), or its salt (wherein R 1 is a TMS group):

[0462]

[0463] wherein X′ is selected from the group consisting of fluorine, chlorine, bromine, iodine, HCO 2 , acetoxy, propionyloxy, butyryloxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoyloxy, HOCO 2 , citratoyloxy, carbamoyloxy, glucosyloxy, lactoyloxy, succinyloxy, sulfonyloxy, trifluoromethanesulfonyloxy, tribromomethanesulfonyloxy, tribromomethanesulfonyloxy, and trifluoroacetoxy;

[0464] R 6 、R 7 and R 8 each is -C(O)R';

[0465] R' is a methyl group;

[0466] (a5) processing the compound or derivative of formula (1a), or a salt thereof (wherein R 1 is a TMS group), the compound or derivative of formula (2), or a salt thereof, the TMSOTf, and the organic solvent co-reagent, so as to produce the compound or derivative of formula (Ia), or a salt thereof, or a solvate thereof (wherein R 1 is a TMS group); (a6) adding water to the following: optionally the compound or derivative of formula (1a), or a salt thereof (wherein R 1 is a TMS group), optionally the compound or derivative of formula (2), or a salt thereof, the TMSOTf, the organic solvent co-reagent, and the compound or derivative of formula (Ia), or a salt thereof or a solvate thereof (optionally wherein R 1is a TMS group); (a7) isolating the compound or derivative of formula (Ia), or a salt or solvate thereof; (a8) dissolving the compound or derivative of formula (Ia), or a salt or solvate thereof in methanol in a gas pressure tube; (a9) cooling the solution of the compound or derivative of formula (Ia), or a salt or solvate thereof in methanol to -78°C; (a10) bubbling ammonia gas into the solution of the compound or derivative of formula (Ia), or a salt or solvate thereof in methanol; solution; (a11) sealing the pressure tube; (a12) raising the temperature to -20°C; (a13) cooling the pressure tube at -20°C for about 12 hours to about 4 days to produce a compound or derivative of formula (VIII), or a salt or solvate thereof; (a14) unsealing the gas pressure tube; and (a15) isolating the compound or derivative of formula (VIII), or a salt or solvate thereof; wherein these steps (a1) to (a15) are performed sequentially before step (a).

[0467] In an embodiment, the present disclosure provides a novel crystalline Form I of nicotinamide riboside triacetate (NRTA) chloride according to formula (IX):

[0468]

[0469] In another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks at 19.6°, 22.1°, and 26.6° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks at 9.8°, 19.2°, 19.6°, 22.1°, and 26.6° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks at 9.8°, 14.5°, 18.6°, 19.2°, 19.6°, 22.1°, 22.5°, and 26.6° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks at 9.8°, 14.5°, 18.6°, 19.2°, 19.6°, 22.1°, 22.5°, and 26.6° 2θ ± 0.2° 2θ. Figure 18 In yet another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 2.

[0470] In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum at 626.8, 644.1, and 916.0 cm -1 ±0.2cm -1In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum with peaks at 626.8, 644.1, 916.0, 1058.8, 1101.2, and 1114.7 cm -1 ±0.2cm -1 In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum with peaks at 626.8, 644.1, 916.0, 1058.8, 1101.2, 1114.7, 1205.3, 1240.0, 1683.6, and 1737.6 cm -1 ±0.2cm -1 In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum substantially as follows: Figure 24 In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum having peaks ± 0.3 cm substantially as provided in Table 3. -1 .

[0471] In yet another embodiment, the above crystalline Form I may be characterized by a DSC thermogram substantially as follows Figure 31 In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10K / min includes an endothermic event wherein the onset temperature is 149°C ± 2°C. In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10K / min includes an endothermic event wherein the peak temperature is 156°C ± 2°C. In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10K / min includes an endothermic event wherein the onset temperature is 149°C ± 2°C and the peak temperature is 156°C ± 2°C. In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10K / min includes an endothermic event wherein the onset temperature is 149°C ± 2°C and the peak temperature is 156°C ± 2°C. In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10K / min includes an endothermic event wherein the onset temperature is 208°C ± 2°C. In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10K / min includes an endothermic event wherein the peak temperature is 215°C ± 2°C. In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the onset temperature is 208° C.±2° C. and the peak temperature is 215° C.±2° C. In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the onset temperature is 149° C.±2° C. and the peak temperature is 156° C.±2° C. and an endothermic event wherein the onset temperature is 208° C.±2° C. and the peak temperature is 215° C.±2° C.

[0472] In an embodiment, crystalline NRTA Form I can be prepared by a method which can include the following steps:

[0473] (a) adding a volume of acetonitrile to a compound or derivative of formula (IX), or a salt or solvate thereof, at room temperature to dissolve the compound or derivative of formula (IX), or a salt or solvate thereof in the volume of acetonitrile; (b) adding a volume of acetone at least equal to the volume of the acetonitrile to a solution of the compound or derivative of formula (IX), or a salt or solvate thereof in the volume of acetonitrile to precipitate the crystalline Form I; and (c) isolating the crystalline Form I.

[0474] In an alternative embodiment of the above method for preparing crystalline NRTA Form I, the method may further comprise the steps of:

[0475] (a1) providing a compound or derivative having the formula (2), or a salt thereof:

[0476]

[0477] wherein X′ is selected from the group consisting of fluorine, chlorine, bromine, iodine, HCO 2 , acetoxy, propionyloxy, butyryloxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoyloxy, HOCO 2 , citratoyloxy, carbamoyloxy, glucosyloxy, lactoyloxy, succinyloxy, sulfonyloxy, trifluoromethanesulfonyloxy, trichloromethanesulfonyloxy, tribromomethanesulfonyloxy, and trifluoroacetoxy;

[0478] R 6 、R 7 and R 8 each is -C(O)R';

[0479] R' is a methyl group;

[0480] (a2) treating a compound or derivative of formula (2), or a salt thereof, with a molar equivalent of a compound or derivative of formula (1a), or a salt thereof, and a molar equivalent of TMSOTf;

[0481]

[0482] where Z 2 It is NH;

[0483] n is 0;

[0484] R 1 It is hydrogen;

[0485] R 2 、R 3 、R4 and R 5 Each is hydrogen;

[0486] (a3) processing the compound or derivative of formula (2), or a salt thereof, the compound or derivative of formula (1a), or a salt thereof, and the TMSOTf to produce the compound or derivative of formula (IX), or a salt thereof, or a solvate thereof; and (a4) isolating the compound or derivative of formula (IX), or a salt thereof, or a solvate thereof; wherein these steps (a1) to (a4) are performed sequentially before step (a).

[0487] In an embodiment, the present disclosure provides a novel crystalline Form I of nicotinic acid riboside triacetate (NARTA) according to formula (X):

[0488]

[0489] In another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks at 4.7°, 9.5°, and 20.5° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks at 4.7°, 9.5°, 16.5°, 16.8°, and 20.5° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks at 4.7°, 9.5°, 12.0°, 16.5°, 16.8°, 19.9°, 20.5°, 23.7°, and 23.9° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern substantially as Figure 19 In yet another embodiment, the above crystalline Form I may be characterized by a powder X-ray diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 9.

[0490] In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum at 603.6, 684.6, 763.7, and 781.0 cm -1 ±0.2cm -1 In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum with peaks at 603.6, 684.6, 763.7, 781.0, 858.2, 894.8, 921.8, 1026.0, 1051.0, and 1066.5 cm -1 ±0.2cm -1In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum with peaks at 603.6, 684.6, 763.7, 781.0, 858.2, 894.8, 921.8, 1026.0, 1051.0, 1066.5, 1610.3, 1639.2, and 1743.4 cm -1 ±0.2cm -1 In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum substantially as follows: Figure 25 In yet another embodiment, the above crystalline Form I may be characterized by an IR spectrum having peaks ± 0.2 cm substantially as provided in Table 10. -1 .

[0491] In yet another embodiment, the above crystalline Form I may be characterized by a DSC thermogram substantially as follows Figure 33 In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the onset temperature is 148° C.±2° C. In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the peak temperature is 152° C.±2° C. In yet another embodiment, the above crystalline Form I may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the onset temperature is 148° C.±2° C. and the peak temperature is 152° C.±2° C.

[0492] In yet another embodiment, the above crystalline Form I can be prepared by a method which may include the following steps:

[0493] (a) dissolving a compound or derivative of formula (X), or a salt or solvate thereof; (b) adding a volume of acetone equal to the volume of methanol to the compound or derivative of formula (X), or a salt or solvate thereof in the volume of methanol; (c) precipitating the crystalline Form I; and (d) isolating the crystalline Form I.

[0494] In yet another embodiment, the above crystalline Form I can be prepared by a method which can further comprise the following steps:

[0495] (a) providing a compound or derivative of formula (1a), or a salt thereof:

[0496]

[0497] where Z 2 It is oxygen;

[0498] n is 0;

[0499] R 1 It is hydrogen;

[0500] wherein the compound or derivative of formula (1a) may optionally be in the form of a conjugated species of a carboxylate anion of the compound or derivative of formula (1a), further optionally associated with a positively charged counterion selected from the group consisting of a calcium cation, a magnesium cation, a potassium cation, a sodium cation, a zinc cation, and an ammonium cation;

[0501] R 2 、R 3 、R 4 and R 5 Each is hydrogen;

[0502] (a2) treating the compound or derivative of formula (1a), or a salt thereof, with an excess of one or more trimethylsilylating agents to produce a compound or derivative of formula (1a), or a salt thereof (wherein R 1 is a TMS group); (a3) ​​removing one or more trimethylsilylating agents; (a4) treating the compound or derivative of formula (1a), or its salt (wherein R 1 is a TMS group);

[0503]

[0504] wherein X′ is selected from the group consisting of fluorine, chlorine, bromine, iodine, HCO 2 , acetoxy, propionyloxy, butyryloxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoyloxy, HOCO 2 , citratoyloxy, carbamoyloxy, glucosyloxy, lactoyloxy, succinyloxy, sulfonyloxy, trifluoromethanesulfonyloxy, trichloromethanesulfonyloxy, tribromomethanesulfonyloxy, and trifluoroacetoxy;

[0505] R 6 、R 7 and R 8 each is -C(O)R';

[0506] R' is a methyl group;

[0507] (a5) processing the compound or derivative of formula (1a), or a salt thereof (wherein R 1 is a TMS group), the compound or derivative of formula (2), or a salt thereof, and the organic solvent co-reagent, so as to produce the compound or derivative of formula (Ia), or a salt thereof, or a solvate thereof (wherein R 1is a TMS group); (a6) adding water to the following: optionally the compound or derivative of formula (1a), or a salt thereof (wherein R 1 is a TMS group), optionally the compound or derivative of formula (2), or a salt thereof, the organic solvent co-reagent, and the compound or derivative of formula (Ia), or a salt thereof or a solvate thereof (optionally wherein R 1 is a TMS group); (a7) adjusting the pH of the aqueous phase; (a8) separating the organic phase from the aqueous phase; and (a9) freeze-drying the aqueous phase to provide the compound or derivative of formula (Ia), or a salt or solvate thereof; wherein these steps (a1) to (a9) are performed sequentially before step (a).

[0508] In yet another embodiment of the above method, in step (a4), the compound or derivative of formula (1a), or a salt thereof (wherein R 1 is a TMS group), the compound or derivative of formula (2), or a salt thereof, and the organic solvent co-reagent.

[0509] In an embodiment, the present disclosure provides a novel crystalline Form III of nicotinamide mononucleotide (NMN) according to formula (XI):

[0510]

[0511] In another embodiment, the above crystalline Form III may be characterized by a powder X-ray diffraction pattern having peaks at 7.9°, 22.9°, and 24.8° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form III may be characterized by a powder X-ray diffraction pattern having peaks at 7.9°, 15.6°, 17.2°, 22.9°, and 24.8° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form III may be characterized by a powder X-ray diffraction pattern having peaks at 7.9°, 15.6°, 17.2°, 17.9°, 21.3°, 21.9°, 22.9°, 24.8°, 25.2°, and 28.0° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form III may be characterized by a powder X-ray diffraction pattern substantially as Figure 20 In yet another embodiment, the above crystalline Form III may be characterized by a powder X-ray diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 13.

[0512] In yet another embodiment, the above crystalline Form III may be characterized by an IR spectrum at 624.8, 626.8, 671.1, 802.3, and 906.4 cm -1 ±0.2cm -1In yet another embodiment, the above crystalline Form III may be characterized by an IR spectrum with peaks at 624.8, 626.8, 671.1, 802.3, 906.4, 923.8, 952.7, 985.5, 1035.6, 1078.0, 1147.5, and 1182.2 cm -1 ±0.2cm -1 In yet another embodiment, the above crystalline Form III may be characterized by an IR spectrum with peaks at 624.8, 626.8, 671.1, 802.3, 906.4, 923.8, 952.7, 985.5, 1035.6, 1078.0, 1147.5, 1182.2, 1619.9, and 1689.4 cm -1 ±0.2cm -1 In yet another embodiment, the above crystalline Form III may be characterized by an IR spectrum substantially as follows: Figure 26 In yet another embodiment, the above crystalline Form III may be characterized by an IR spectrum having peaks ± 0.2 cm substantially as provided in Table 14. -1 .

[0513] In yet another embodiment, the above crystalline Form III may be characterized by a DSC thermogram substantially as follows Figure 35 In yet another embodiment, the above crystalline Form III may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the onset temperature is 105° C.±2° C. In yet another embodiment, the above crystalline Form III may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the peak temperature is 157° C.±2° C. In yet another embodiment, the above crystalline Form III may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the peak temperature is 157° C.±2° C. In yet another embodiment, the above crystalline Form III may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the onset temperature is 105° C.±2° C. and the peak temperature is 157° C.±2° C.

[0514] In yet another embodiment, the above crystalline Form III can be prepared by a method which may include the following steps:

[0515] (a) adding the compound or derivative of formula (XI), or its salt or solvate thereof, to a certain volume of methanol and water in a volume:volume ratio of 3:2 at room temperature; (b) stirring the compound or derivative of formula (XI), or its salt or solvate thereof, and the volume of methanol and water to dissolve the compound or derivative of formula (XI), or its salt or solvate thereof in the volume of methanol and water; (c) filtering the solution of the compound or derivative of formula (XI), or its salt or solvate thereof in the volume of methanol and water to remove (d) adding a volume of acetone to the solution of the compound of formula (XI) or derivative, or salt or solvate thereof, in the volume of methanol and water, wherein the volume of acetone is about 2 to about 5 times the combined volume of methanol and water; (e) cooling the compound of formula (XI) or derivative, or salt or solvate thereof, in the volume of acetone and the volume of methanol and water to -20°C to precipitate the crystalline Form III; (f) isolating the crystalline Form III; and (g) drying the crystalline Form III at room temperature.

[0516] In yet another embodiment, the above crystalline Form III can be prepared by a method which can further comprise the following steps:

[0517] (a1) providing a compound or derivative of formula (Ia-H), or a salt or solvate thereof:

[0518]

[0519] Among them, X as the counterion - is non-existent, or when X - When X exists, - selected from the group consisting of fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methylsulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;

[0520] Z 2 It is NH;

[0521] n is 0;

[0522] R 1 It is hydrogen;

[0523] R 2 、R 3 、R 4 and R 5Each is hydrogen;

[0524] R 6 、R 7 、R 8 Each is hydrogen;

[0525] (a2) treating the compound or derivative of formula (Ia-H), or its salt or solvate thereof, with a phosphorylating agent; (a3) ​​processing the compound or derivative of formula (Ia-H), or its salt or solvate thereof, and the phosphorylating agent to produce the compound or derivative of formula (XI), or its salt or solvate thereof; (a4) optionally adding the compound or derivative of formula (Ia-H), or its salt or solvate thereof, optionally the phosphorylating agent, and the compound or derivative of formula (XI), or its salt or solvate thereof to ice water; and (a5) isolating the compound or derivative of formula (XI), or its salt or solvate thereof; wherein these steps (a1) to (a5) are performed sequentially before step (a).

[0526] In yet another embodiment, the above crystalline Form III can be prepared by a method which can further comprise the following steps:

[0527] (a1) Provide a compound or derivative having the formula (Ia-H), or a salt or solvate thereof; (a2) Treat the compound or derivative having the formula (Ia-H), or a salt or solvate thereof, with a phosphitylating reagent and (0 < x ≤ 20) molar equivalents of a Bronsted base; (a3) Process the compound or derivative having the formula (Ia-H), or a salt or solvate thereof, the phosphitylating reagent, and the Bronsted base to produce a phosphitylated analogue of the compound or derivative having the formula (Ia-H), or a salt or solvate thereof; (a4) Add an oxidizing reagent to any of: optionally the compound or derivative having the formula (Ia-H), or a salt or solvate thereof, optionally the phosphitylating reagent, optionally the Bronsted base, and the phosphitylated analogue of the compound or derivative having the formula (Ia-H), or a salt or solvate thereof; (a5) Process the oxidizing reagent, optionally the compound or derivative having the formula (Ia-H), or a salt or solvate thereof, optionally the phosphitylating reagent, optionally the Bronsted base, and the phosphitylated analogue of the compound or derivative having the formula (Ia-H), or a salt or solvate thereof to produce the compound or derivative having the formula (XI), or a salt or solvate thereof; (a6) Optionally add the oxidizing reagent, optionally the compound or derivative having the formula (Ia-H), or a salt or solvate thereof, optionally the phosphitylating reagent, optionally the Bronsted base, optionally the phosphitylated analogue of the compound or derivative having the formula (Ia-H), or a salt or solvate thereof, and the compound or derivative having the formula (XI), or a salt or solvate thereof to ice water; (a7) Isolate the compound or derivative having the formula (XI), or a salt or solvate thereof; wherein steps (a1) to (a7) are carried out sequentially before step (a).

[0528] In an embodiment, the present disclosure provides a novel crystalline Form IV of nicotinamide mononucleotide (NMN) according to Formula (XI). In another embodiment, the above crystalline Form IV may be characterized by a powder X-ray diffraction pattern having peaks at 9.6°, 22.8°, and 25.3° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form IV may be characterized by a powder X-ray diffraction pattern having peaks at 9.6°, 16.2°, 22.0°, 22.8°, 25.3°, and 25.6° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form IV may be characterized by a powder X-ray diffraction pattern having peaks at 9.6°, 16.2°, 16.5°, 17.4°, 18.9°, 19.9°, 22.0°, 22.8°, 25.3°, 25.6°, 27.1°, and 28.7° 2θ ± 0.2° 2θ. In yet another embodiment, the above crystalline Form IV may be characterized by a powder X-ray diffraction pattern substantially as follows Figure 28 In yet another embodiment, the above crystalline Form IV may be characterized by a powder X-ray diffraction pattern having peaks ±0.2° 2θ substantially as provided in Table 15.

[0529] In yet another embodiment, the above crystalline Form IV may be characterized by an IR spectrum at 624.8, 640.3, 665.3, 725.1, 813.8, and 840.8 cm -1 ±0.2cm -1 In yet another embodiment, the above crystalline Form IV may be characterized by an IR spectrum with peaks at 624.8, 640.3, 665.3, 725.1, 813.8, 840.8, 867.8, 921.8, 948.8, 985.8, 1029.8, and 1076.1 cm -1 ±0.2cm -1 In yet another embodiment, the above crystalline Form IV may be characterized by an IR spectrum with peaks at 624.8, 640.3, 665.3, 725.1, 813.8, 840.8, 867.8, 921.8, 948.8, 985.8, 1029.8, 1076.1, 1625.7, 1646.9, and 1687.4 cm -1 ±0.2cm -1 In yet another embodiment, the above crystalline Form IV may be characterized by an IR spectrum substantially as follows: Figure 29 In yet another embodiment, the above crystalline Form IV may be characterized by an IR spectrum having peaks ± 0.2 cm substantially as provided in Table 16. -1 .

[0530] In yet another embodiment, the above crystalline Form IV may be characterized by a DSC thermogram substantially as follows Figure 36 In yet another embodiment, the above crystalline Form IV may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the onset temperature is 144° C.±2° C. In yet another embodiment, the above crystalline Form IV may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the peak temperature is 165° C.±2° C. In yet another embodiment, the above crystalline Form IV may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the peak temperature is 165° C.±2° C. In yet another embodiment, the above crystalline Form IV may be characterized in that a DSC thermogram obtained using a heating rate of 10 K / min includes an endothermic event wherein the onset temperature is 144° C.±2° C. and the peak temperature is 165° C.±2° C.

[0531] In yet another embodiment, the above crystalline Form IV can be prepared by a method which may comprise the following steps:

[0532] (a) adding the compound of formula (XI) or derivative, or salt or solvate thereof, to a volume of ethanol and water in a 3:2 volume:volume ratio at room temperature, wherein the compound of formula (XI) or derivative, or salt or solvate thereof is added in an amount of about 200 mg per milliliter of the volume of ethanol and water; (b) stirring the compound of formula (XI) or derivative, or salt or solvate thereof, and the volume of ethanol and water to dissolve the compound of formula (XI) or derivative, or salt or solvate thereof in the volume of ethanol and water; (c) filtering the solution of the compound of formula (XI) or derivative, or salt or solvate thereof in the volume of ethanol and water to remove any undissolved solids; (d) cooling the compound of formula (XI) or derivative, or salt or solvate thereof in the volume of ethanol and water to -10°C for about 48 hours to precipitate the crystalline Form IV; (e) isolating the crystalline Form IV; and (f) drying the crystalline Form IV at room temperature.

[0533] In yet another embodiment, the above crystalline Form IV can be prepared by a process which can further comprise the following steps:

[0534] (a1) providing a compound or derivative of formula (Ia-H), or a salt or solvate thereof:

[0535]

[0536] Among them, X as the counterion - is non-existent, or when X - When X exists, -selected from the group consisting of fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methylsulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;

[0537] Z 2 It is NH;

[0538] n is 0;

[0539] R 1 It is hydrogen;

[0540] R 2 、R 3 、R 4 and R 5 Each is hydrogen;

[0541] R 6 、R 7 、R 8 Each is hydrogen;

[0542] (a2) treating the compound or derivative of formula (Ia-H), or its salt or solvate thereof, with a phosphorylating agent; (a3) ​​processing the compound or derivative of formula (Ia-H), or its salt or solvate thereof, and the phosphorylating agent to produce the compound or derivative of formula (XI), or its salt or solvate thereof; (a4) optionally adding the compound or derivative of formula (Ia-H), or its salt or solvate thereof, optionally the phosphorylating agent, and the compound or derivative of formula (XI), or its salt or solvate thereof to ice water; and (a5) isolating the compound or derivative of formula (XI), or its salt or solvate thereof; wherein these steps (a1) to (a5) are performed sequentially before step (a).

[0543] In yet another embodiment, the above crystalline Form IV can be prepared by a process which can further comprise the following steps:

[0544] (a1) Provide a compound or derivative having the formula (Ia-H), or a salt or solvate thereof; (a2) Treat the compound or derivative having the formula (Ia-H), or a salt or solvate thereof, with a phosphitylating reagent and (0 < x ≤ 20) molar equivalents of a Bronsted base; (a3) Process the compound or derivative having the formula (Ia-H), or a salt or solvate thereof, the phosphitylating reagent, and the Bronsted base to produce a phosphitylated analogue of the compound or derivative having the formula (Ia-H), or a salt or solvate thereof; (a4) Add an oxidizing reagent to any of: optionally the compound or derivative having the formula (Ia-H), or a salt or solvate thereof, optionally the phosphitylating reagent, optionally the Bronsted base, and the phosphitylated analogue of the compound or derivative having the formula (Ia-H), or a salt or solvate thereof; (a5) Process the oxidizing reagent, optionally the compound or derivative having the formula (Ia-H), or a salt or solvate thereof, optionally the phosphitylating reagent, optionally the Bronsted base, and the phosphitylated analogue of the compound or derivative having the formula (Ia-H), or a salt or solvate thereof to produce a compound or derivative having the formula (XI), or a salt or solvate thereof; (a6) Optionally add the oxidizing reagent, optionally the compound or derivative having the formula (Ia-H), or a salt or solvate thereof, optionally the phosphitylating reagent, optionally the Bronsted base, optionally the phosphitylated analogue of the compound or derivative having the formula (Ia-H), or a salt or solvate thereof, and the compound or derivative having the formula (XI), or a salt or solvate thereof to ice water; (a7) Isolate the compound or derivative having the formula (XI), or a salt or solvate thereof; wherein steps (a1) to (a7) are carried out sequentially before step (a).

[0545] In yet another embodiment of the above method for preparing a compound or derivative having the formula (I-H), or a salt, solvate, or prodrug thereof, the compound or derivative having the formula (I-H), or a salt, solvate, or prodrug thereof can be nicotinamide riboside (NR) chloride having the formula (VII):

[0546]

[0547] In yet another embodiment of the above method for preparing a compound or derivative of formula (IH), or a salt, solvate, or prodrug thereof, the reagent of step (b) can be a Bronsted mineral acid. In yet another alternative embodiment of the above method, the Bronsted mineral acid can be at least three molar equivalents of HCl in methanol at about 5°C. In yet another embodiment of the above method, the acetamide content of nicotinamide riboside (NR) chloride can be less than 10 ppm as measured by gas chromatography. In yet another embodiment of the above method, the acetamide content of nicotinamide riboside (NR) chloride can be less than 5 ppm as measured by gas chromatography. BRIEF DESCRIPTION OF THE DRAWINGS

[0548] Figure 1 The reaction product mixture of the procedure described in Part A of Example 1 is depicted. 1 H NMR spectrum. Part A of this Example 1 was performed according to one embodiment of the method for preparing the compound or derivative of formula (2) or a salt thereof.

[0549] Figure 2 The reaction product mixture of the procedure described in Part B of Example 1 is depicted. 1 H NMR spectrum, Part B of Example 1 was performed according to one embodiment of the method for preparing a compound or derivative having the general formula (I), or a salt, a solvate, or a prodrug thereof.

[0550] Figure 3 The reaction product mixture of the procedure described in Part B of Example 1 is depicted. 1 H NMR spectrum, part B of Example 1 according to one embodiment of the method for preparing a compound or derivative of formula (I), or a salt, solvate, or prodrug thereof, after removing the polar organic solvent co-reagent.

[0551] Figure 4 Depicts the precipitation and separation of the reaction product from the reaction product mixture of the procedure described in Part B of Example 1. 1 H NMR spectrum, part B of Example 1 was performed according to one embodiment of the method for preparing the compound or derivative of formula (I), or a salt, solvate, or prodrug thereof.

[0552] Figure 5 Depicted is the recovery of nucleoside tetraacetates from the reaction product mixture of the procedure described in Part A of Example 1. 1 H NMR spectrum (bottom) compared to a nucleoside tetraacetate standard (top). Part A of Example 1 was performed according to one embodiment of the method for preparing a compound or derivative of formula (2) or a salt thereof.

[0553] Figure 6 Depicts the reaction product isolated from the reaction product mixture of the procedure described in Part B of Example 1. 1 HNMR spectrum, Part B of Example 1 was performed according to one embodiment of the method for preparing the compound or derivative of general formula (I), or a salt, a solvate, or a prodrug thereof.

[0554] Figure 7 The purification and subsequent isolation of the compound or derivative of formula (I) from the reaction product mixture of the procedure described in part B of Example 1 is depicted. 1 H NMR spectrum, part B of Example 1 was performed according to one embodiment of the method for preparing the compound or derivative of formula (I), or a salt, solvate, or prodrug thereof.

[0555] Figure 8 Depicted are compounds of formula (I) or derivatives thereof as starting materials. 1 H NMR spectrum (bottom) of the reaction product mixture after treatment with a base addition salt at low temperature according to the procedure described in Part D of Example 1. 1 H NMR spectrum (middle), and the purified desired product 1 Comparison of H NMR spectra (top), Part D of Example 1 according to the method for preparing a compound or derivative of the general formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 is hydrogen).

[0556] Figure 9 Depicted are compounds of formula (I) or derivatives thereof as starting materials. 1 H NMR spectrum (bottom) of the reaction product mixture after treatment with a base addition salt according to the procedure described in Part D of Example 1 at room temperature. 1 H NMR spectrum (middle), and the purified desired product 1 Comparison of H NMR spectra (top), Part D of Example 1 according to the method for preparing a compound or derivative of the general formula (IH), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 is hydrogen).

[0557] Figure 10 Depicted are compounds of formula (I) or derivatives thereof as starting materials. 1H NMR spectra (bottom) of the reaction product mixture after treatment with acid at two different concentrations at room temperature according to the procedure described in Part D of Example 1. 1 H NMR spectrum (middle), and the purified desired product 1 Comparison of H NMR spectra (top), Part D of Example 1 according to the method for preparing a compound or derivative having the general formula (Ia-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 is hydrogen).

[0558] Figure 11(a) depicts the product filtrate of a compound or derivative having the general formula (Ia-H) 1 H NMR spectrum, which is used to prepare a compound or derivative having the general formula (Ia-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 is hydrogen).

[0559] FIG11(b) depicts the 1 The H NMR spectrum of the product filtrate shows the supernatant containing impurities remaining after filtration. 1 H NMR spectrum, which is used to prepare a compound or derivative having the general formula (Ia-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 is hydrogen).

[0560] Figure 12 Depicts the reaction mixture according to the procedure described in Part C of Example 1. 1 H NMR spectrum, part C of Example 1 according to the method for preparing a compound or derivative having the general formula (Ia-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen) wherein the reaction is carried out at 50 RPM for 10 minutes.

[0561] Figure 13 Depicts the reaction mixture according to the procedure described in Part C of Example 1. 1 H NMR spectrum, part C of Example 1 according to the method for preparing a compound or derivative having the general formula (Ia-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6、R 7 and R 8 Each is hydrogen) wherein the reaction is carried out at 100 RPM for 10 minutes.

[0562] Figure 14 Depicts the reaction mixture according to the procedure described in Part C of Example 1. 1 H NMR spectrum, part C of Example 1 according to the method for preparing a compound or derivative having the general formula (Ia-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen) wherein the reaction is carried out at 250 RPM for 15 minutes.

[0563] Figure 15 Provided is an X-ray powder diffraction pattern of Form I of the previously described crystalline nicotinamide riboside chloride (NR-Cl), the compound of formula (VII) for use in preparing a compound of formula (Ia-H) or a derivative thereof, or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen).

[0564] Figure 16 Provided is an X-ray powder diffraction pattern of NR methanol salt form II of crystalline nicotinamide riboside chloride (NR-Cl) disclosed herein, wherein the compound of formula (VII) is used in the preparation of a compound or derivative of general formula (Ia-H) according to the disclosed method, or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen).

[0565] Figure 17 Provided is an X-ray powder diffraction pattern of Form I of the crystalline nicotinic acid riboside (NAR) disclosed herein, wherein the compound of formula (VIII) is used in the preparation of a compound of formula (Ia-H) or a derivative thereof, or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen).

[0566] Figure 18Provided is an X-ray powder diffraction pattern of Form I of crystalline nicotinamide riboside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-nicotinamide, "NR triacetate" or "NRTA") of the present disclosure, which is prepared according to an embodiment of the method of preparing a compound or derivative of the general formula (Ia), or a salt, solvate, or prodrug thereof, of the present disclosure.

[0567] Figure 19 Provided is an X-ray powder diffraction pattern of Form I of crystalline nicotinate riboside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-nicotinic acid, "NAR triacetate" or "NARTA") of the present disclosure, which is prepared according to an embodiment of the method of preparing a compound or derivative of the general formula (Ia) or a salt, solvate, or prodrug thereof of the present disclosure.

[0568] Figure 20 Provided is an X-ray powder diffraction pattern of Form III of crystalline nicotinamide mononucleotide (NMN) of the present disclosure, wherein the compound of formula (XI) is prepared according to an embodiment of the method of preparing a compound or derivative of formula (IIa), or a salt, solvate, or prodrug thereof of the present disclosure.

[0569] Figure 21 Provided is an X-ray powder diffraction pattern of an amorphous solid form of nicotinamide mononucleotide (NMN) of the present disclosure, wherein the compound of formula (XI) is prepared according to an embodiment of the method for preparing a compound of formula (IIa) or a derivative thereof, or a salt, solvate, or prodrug thereof of the present disclosure.

[0570] Figure 22 Provided is a solid-state IR spectrum of NR methoxide Form II of crystalline nicotinamide riboside chloride (NR-Cl) of the present disclosure, the compound having Formula (VII).

[0571] Figure 23 Provided is a solid-state IR spectrum of Form I of crystalline nicotinic acid riboside (NAR) of the present disclosure, the compound having Formula (VIII).

[0572] Figure 24 Provided is a solid-state IR spectrum of Form I of crystalline nicotinamide riboside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-nicotinamide, "NR triacetate" or "NRTA") of the present disclosure, which has Formula (IX).

[0573] Figure 25Provided is a solid-state IR spectrum of Form I of crystalline nicotinic acid riboside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-nicotinic acid, "NAR triacetate" or "NARTA") of the present disclosure, the compound having Formula (X).

[0574] Figure 26 Provided is a solid-state IR spectrum of Form III of crystalline nicotinamide mononucleotide (NMN) of the present disclosure, the compound having Formula (XI).

[0575] Figure 27 Provided is a solid-state IR spectrum of an amorphous solid form of nicotinamide mononucleotide (NMN) of the present disclosure, the compound having formula (XI).

[0576] Figure 28 Provided is an X-ray powder diffraction pattern of Form IV of crystalline nicotinamide mononucleotide (NMN) of the present disclosure, wherein the compound of formula (XI) is prepared according to an embodiment of the method of preparing a compound or derivative of formula (IIa), or a salt, solvate, or prodrug thereof, of the present disclosure.

[0577] Figure 29 Provided is a solid-state IR spectrum of Form IV of crystalline nicotinamide mononucleotide (NMN) of the present disclosure, the compound having Formula (XI).

[0578] Figure 30 Provided is a DSC thermogram of a sample of the crystalline NR methoxide Form II of nicotinamide riboside chloride of the present disclosure, which was heated at a rate of 10 K / min.

[0579] Figure 31 Provided is a DSC thermogram of a Form I sample of crystalline nicotinamide riboside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-nicotinamide, "NR triacetate" or "NRTA") of the present disclosure, the compound having Formula (IX), the sample being heated at a rate of 10 K / min.

[0580] Figure 32 Provided is a DSC thermogram of a Form I sample of crystalline nicotinic acid riboside (NAR) of the present disclosure, the compound having Formula (VIII), the sample being heated at a rate of 10 K / min.

[0581] Figure 33 Provided is a DSC thermogram of a Form I sample of crystalline nicotinic acid riboside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-nicotinic acid, "NAR triacetate" or "NARTA") of the present disclosure, the compound having Formula (X), the sample being heated at a rate of 10 K / min.

[0582] Figure 34 Provided is a DSC thermogram of a sample of an amorphous solid form of nicotinamide mononucleotide (NMN) of the present disclosure, the compound having formula (XI), the sample being heated at a rate of 10 K / min.

[0583] Figure 35 Provided is a DSC thermogram of a Form III sample of crystalline nicotinamide mononucleotide (NMN) of the present disclosure, the compound having Formula (XI), the sample being heated at a rate of 10 K / min.

[0584] Figure 36 Provided is a DSC thermogram of a Form IV sample of crystalline nicotinamide mononucleotide (NMN) of the present disclosure, the compound having Formula (XI), the sample being heated at a rate of 10 K / min.

[0585] Figure 37 Provided is an X-ray powder diffraction pattern of an amorphous solid form of reduced nicotinamide riboside (NRH, compound 9, hereinafter) disclosed herein, which is used in the preparation of a compound or derivative having the general formula (IVa-H), or a salt, a solvate, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen).

[0586] Figure 38 Provided is an X-ray powder diffraction pattern of an amorphous solid form of reduced nicotinic acid riboside (NARH, compound 9, hereinafter) disclosed herein, which is used in the preparation of a compound or derivative having the general formula (IVa-H), or a salt, a solvate, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen).

[0587] Figure 39 Provided is an X-ray powder diffraction pattern of an amorphous solid form of crystalline reduced nicotinamide riboside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-1,4-dihydronicotinamide, "NRH triacetate" or "NRH-TA," Compound 7, hereinafter) of the present disclosure, which is prepared according to an embodiment of the method for preparing a compound or derivative having the general formula (IVa), or a salt, solvate, or prodrug thereof, of the present disclosure.

[0588] Figure 40Provided is an X-ray powder diffraction pattern of an amorphous solid form of crystalline reduced nicotinate triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-1,4-dihydronicotinic acid, "NARH triacetate" or "NARH-TA," Compound 8, hereinafter) of the present disclosure, which is prepared according to an embodiment of the method of the present disclosure for preparing a compound or derivative having the general formula (IVa), or a salt, solvate, or prodrug thereof.

[0589] Figure 41 The reduced nicotinamide riboside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-1,4-dihydronicotinamide, "NRH triacetate" or "NRH-TA", compound 7, hereinafter) (prepared using common solvent-based laboratory techniques) is depicted. 1 H NMR spectrum (top), compared with reduced nicotinamide riboside triacetate (NRH-TA) (performed according to one embodiment of the method for preparing a compound or derivative of formula (IVa), or a salt, solvate, or prodrug thereof) 1 Comparison of H NMR spectra (bottom).

[0590] Figure 42 The reduced nicotinic acid riboside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-1,4-dihydronicotinic acid, "NARH triacetate" or "NARH-TA", compound 7, hereinafter) (prepared using common solvent-based laboratory techniques) is depicted. 1 H NMR spectrum (top), compared with reduced nicotinic acid riboside triacetate (NARH-TA) (performed according to one embodiment of the method for preparing a compound or derivative of formula (IVa), or a salt, solvate, or prodrug thereof) 1 Comparison of H NMR spectra (bottom).

[0591] Figure 43 The reduced nicotinamide riboside (1-(β-D-ribofuranosyl)-1,4-dihydronicotinamide, "NRH," Compound 9, hereinafter) (prepared using common solvent-based laboratory techniques) is depicted. 1 H NMR spectrum (top), compared with reduced nicotinamide riboside (NRH) (used according to the method for preparing a compound or derivative having the general formula (IVa-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen) is carried out in accordance with an embodiment of the method 1 Comparison of H NMR spectra (bottom).

[0592] Figure 44 Depicted is the reduced nicotinic acid riboside (1-β-D-ribofuranosyl)-1,4-dihydronicotinic acid, "NARH," Compound 10, hereinafter) (prepared using common solvent-based laboratory techniques). 1 H NMR spectrum (top), compared with reduced nicotinic acid riboside (NARH) (used according to the method for preparing a compound or derivative having the general formula (IVa-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 Each is hydrogen) is carried out in accordance with an embodiment of the method 1 Comparison of H NMR spectra (bottom).

[0593] Figure 45 The product nicotinic acid riboside (NAR) is depicted 19 F NMR spectrum, which shows the absence of any fluorine-containing species in the product and the absence of any fluorine transfer, the compound has the formula (VIII), according to which the compound or derivative of the general formula (Ia-H), or a salt thereof, a solvate thereof, or a prodrug thereof (wherein R 6 、R 7 and R 8 are each hydrogen), and wherein the process comprises using a Lewis acid comprising a trifluoromethanesulfonate ("triflate") species.

[0594] Figure 46 The product nicotinic acid riboside triacetate (NARTA) is depicted. 19 F NMR spectrum showing the absence of any fluorine transfer corresponding to the absence of any fluorine-containing species in the product, the compound having formula (X), prepared according to an embodiment of the method for preparing a compound or derivative having general formula (Ia), or a salt, solvate, or prodrug thereof, and wherein the method comprises using a Lewis acid comprising a trifluoromethanesulfonate ("triflate") species. DETAILED DESCRIPTION

[0595] In one embodiment, the present disclosure relates to a synthetic sequence that is capable of efficiently producing nicotinoyl riboside, its triacetate, its phosphorylated analog, and its adenosine dinucleotide conjugate, or a salt thereof, a solvate thereof, or a prodrug thereof, by a process enabled by processing reagents through liquid-assisted mixing, grinding, milling, and / or extrusion.

[0596] In another embodiment, the present disclosure relates to a synthetic sequence that is capable of efficiently producing reduced nicotinoyl riboside, its triacetate, its phosphorylated analog, and its adenosine dinucleotide conjugate, or a salt thereof, a solvate thereof, or a prodrug thereof, by a process enabled by processing reagents through liquid-assisted mixing, grinding, milling, and / or extrusion.

[0597] In yet another embodiment, the present disclosure relates to a scalable process for preparing nicotinamide riboside (NR) and nicotinic acid riboside (NAR) and derivatives thereof, or salts thereof, solvates thereof, or prodrugs thereof by liquid-assisted mixing, milling, and / or extrusion.

[0598] In yet another embodiment, the present disclosure relates to a scalable method for preparing reduced nicotinamide riboside (NRH) and reduced nicotinic acid riboside (NARH) and derivatives thereof, or salts thereof, solvates thereof, or prodrugs thereof by liquid-assisted mixing, milling and / or extrusion.

[0599] In yet another embodiment, the present disclosure relates to a scalable process for preparing reduced nicotinamide riboside triacetate (NRH-TA) and reduced nicotinic acid riboside triacetate (NARH-TA) and derivatives thereof, or salts thereof, solvates thereof, or prodrugs thereof by two-phase liquid-assisted mixing, milling and / or extrusion.

[0600] In yet another embodiment, the present disclosure relates to a batch process capable of producing nicotinamide riboside (NR) and nicotinic acid riboside (NAR), or salts thereof, solvates thereof, or prodrugs thereof, whereby the use of solvents is kept to a minimum, and whereby conversion and reaction times are optimized through the use of containment conditions and / or mechanochemistry, and optimized purification sequences.

[0601] In yet another embodiment, the present disclosure relates to batch and semi-continuous processes capable of producing reduced nicotinamide riboside (NRH) and reduced nicotinic acid riboside (NARH) and triacetate derivatives thereof, or salts thereof, solvates thereof, or prodrugs thereof, wherein the use of solvents is kept to a minimum and thereby conversion and reaction times are optimized by using containment conditions, continuous liquid-liquid extraction and / or mechanochemistry, and optimized purification sequences.

[0602] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide riboside (NR), including but not limited to Form I of nicotinamide riboside chloride ("NR-Cl"), and methods of making the same.

[0603] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide riboside (NR), including but not limited to "NR methoxide Form II" of nicotinamide riboside chloride (NR-Cl), and methods for their preparation.

[0604] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinic acid riboside (NAR), including but not limited to "Form I" of nicotinic acid riboside (NAR), and methods of making the same.

[0605] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide riboside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-nicotinamide, "NR triacetate" or "NRTA"), including but not limited to "Form I" of nicotinamide riboside triacetate (NRTA) chloride, and methods for their preparation.

[0606] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinoside triacetate (1-(2',3',5'-triacetyl-β-D-ribofuranosyl)-nicotinic acid, "NAR triacetate" or "NARTA"), including but not limited to "Form I" of nicotinoside triacetate (NARTA), and methods of making the same.

[0607] In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide mononucleotide ("NMN") (including but not limited to "Form III" of nicotinamide mononucleotide (NMN)) and methods for their preparation. In yet another embodiment, the present disclosure relates to amorphous solid forms of nicotinamide mononucleotide (NMN) and methods for their preparation. In yet another embodiment, the present disclosure relates to crystalline forms of nicotinamide mononucleotide (NMN) (including but not limited to "Form IV" of nicotinamide mononucleotide (NMN)) and methods for their preparation.

[0608] In yet another embodiment, the present disclosure relates to a crystalline form of a compound or derivative having formula (III), or a salt, solvate, or prodrug thereof, and methods for preparing the same.

[0609] In yet another embodiment, the present disclosure relates to a crystalline form of a compound or derivative having formula (IV), or a salt, solvate, or prodrug thereof, and methods for preparing the same.

[0610] In yet another embodiment, the present disclosure relates to a compound or derivative having formula (IV-H), or a crystalline form of a salt, solvate, or prodrug thereof and methods for preparing the same.

[0611] In yet another embodiment, the present disclosure relates to a compound or derivative having formula (V), or a crystalline form of a salt, solvate, or prodrug thereof, and methods for preparing the same.

[0612] In yet another embodiment, the present disclosure relates to a compound or derivative having formula (VI), or a crystalline form of a salt, solvate, or prodrug thereof and a method for preparing the same.

[0613] According to one embodiment, the present disclosure provides a novel method whereby sealed conditions and / or mechanical force are used to minimize the amount of solvent, reduce reaction time, increase overall conversion, and facilitate product purification in a multi-step synthetic sequence, thereby minimizing the formation of by-products and thereby producing primarily by-products that can be easily removed by filtration or evaporation.

[0614] Additionally, the methods of the present disclosure address the limitations of the prior art to produce compounds or derivatives, such as nicotinoyl riboside, reduced nicotinoyl riboside, triacetate thereof, derivatives thereof, phosphorylated analogs thereof, and adenosine dinucleotide conjugates thereof, or salts thereof, solvates thereof, or prodrugs thereof.

[0615] According to one embodiment, the present disclosure provides a novel method for preparing the following substances in commercial quantities: a compound or derivative having formula (I), or a salt thereof, a solvate thereof, or a prodrug thereof, such as nicotinoyl riboside and its derivatives, and including but not limited to NR-Cl (nicotinamide riboside chloride salt form) and triacetylated form of NAR (nicotinoic acid riboside) (a compound or derivative having formula (I) wherein R 6 、R 7 and R 8 Each is acetyl), and fully deprotected forms thereof (compounds or derivatives of formula (I) wherein R 6 、R 7 and R 8 Each is hydrogen). According to this embodiment, the present disclosure provides a novel method whereby mechanical force and / or sealed conditions are used to minimize the amount of solvent and reagents, reduce reaction time, increase overall conversion, and facilitate product purification in a multi-step synthetic sequence, thereby minimizing the formation of by-products and thereby producing primarily by-products that can be easily removed by filtration or evaporation. Prototype product nicotinoyl riboside compounds include compounds or derivatives having formula (I), or salts thereof, solvates thereof, or prodrugs thereof:

[0616]

[0617] Optionally, wherein X as a counterion - is non-existent, or when X - When X exists, - selected from the group consisting of fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methylsulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;

[0618] Optionally, when X - When absent, optionally the counterion is an inner salt;

[0619] Optionally, X - is an anion of a substituted or unsubstituted carboxylic acid selected from a monocarboxylic acid, a dicarboxylic acid, or a polycarboxylic acid; and

[0620] Optionally, X - is an anion of a substituted monocarboxylic acid, further optionally an anion of a substituted propionic acid (propanoate or propionate), or an anion of a substituted acetic acid (acetate), or an anion of a hydroxy-propionic acid, or an anion of a 2-hydroxypropionic acid (being lactic acid, the anion of which is lactate), or a trihaloacetate selected from trichloroacetate, tribromoacetate and trifluoroacetate; and,

[0621] Optionally, X - is an anion of an unsubstituted monocarboxylic acid selected from formic acid, acetic acid, propionic acid, or butyric acid, which are formate, acetate, propionate, and butyrate, respectively; and

[0622] Optionally, X - is the anion of a substituted or unsubstituted amino acid (i.e., an amino-monocarboxylic acid or an amino-dicarboxylic acid, optionally selected from glutamic acid and aspartic acid), glutamate and aspartate, respectively; and

[0623] Optionally, X - is the anion of ascorbic acid, which is ascorbate; and,

[0624] Optionally, X - is a halide ion selected from fluoride, chloride, bromide or iodide; and

[0625] Optionally, X - is a substituted or unsubstituted sulfonate anion, further optionally a trihalomethanesulfonate selected from trifluoromethanesulfonate, tribromomethanesulfonate or trichloromethanesulfonate; and

[0626] Optionally, X - is an anion of substituted or unsubstituted carbonate, further optionally bicarbonate; and

[0627] Optionally, X - is the anion of substituted or unsubstituted glutathione or glutathione disulfide;

[0628] wherein the substituted carboxylic acids, substituted monocarboxylic acids, substituted propionic acids, substituted acetic acids, substituted amino acids, substituted sulfonates, substituted carbonates, substituted glutathionse, and substituted glutathione disulfides are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0629] Z 1 and Z 2 are independently NH or oxygen;

[0630] n is 0 or 1;

[0631] R 1 Selected from the group consisting of: hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0632] Among them, when R 1 It is hydrogen, Z 2 When is oxygen, and n is 0, the compound of formula (I) or derivative may optionally be in the form of a carboxylate anion conjugate base species of the compound of formula (I) or derivative, further optionally associated with a positively charged counterion selected from the group consisting of an alkali metal, an alkaline earth metal, a transition metal, and a base addition cation;

[0633] R ASelected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0634] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0635] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0636] R 2 、R 3 、R 4 and R 5 are each independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0637] R 6 selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 esters, vitamin B2 esters, vitamin B6 esters, choline esters, biotin esters, vitamin A esters, resveratrol esters, glutathione esters, glutathione disulfide esters, aryl (C1-C4)alkyl, heterocyclic (C1-C4)alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(RA )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0638] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R Bwherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0639] R 7 and R 8 independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)ORC 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0640] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0641] According to such embodiments, suitable starting materials for the disclosed methods for preparing compounds or derivatives of formula (I), or salts, solvates, or prodrugs thereof, include compounds or derivatives of formula (1), or salts thereof:

[0642]

[0643] where Z 1 and Z 2 independently nitrogen or oxygen;

[0644] m is 1 or 2;

[0645] n is 0 or 1;

[0646] Each R 1 independently selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A)-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0647] Among them, when R 1 It is hydrogen, Z 2 When m is oxygen, m is 1, and n is 0, the compound or derivative of formula (1) may optionally be in the form of a carboxylate anion conjugate base species of the compound or derivative of formula (1), further optionally associated with a positively charged counterion selected from the group consisting of an alkali metal, an alkaline earth metal, a transition metal, and a base addition cation;

[0648] R ASelected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0649] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0650] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0651] R 2 、R 3 、R 4 and R 5 are each independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0652] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0653] According to such embodiments, suitable starting materials for the disclosed methods of preparing compounds or derivatives of formula (I), or salts, solvates, or prodrugs thereof, include compounds or derivatives of formula (2), or salts thereof:

[0654]

[0655] wherein X′ is selected from the group consisting of fluorine, chlorine, bromine, iodine, HCO 2 , acetoxy, propionyloxy, butyryloxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoyloxy, HOCO 2 , citratoyloxy, carbamoyloxy, glucosyloxy, lactoyloxy, methyl bromide, methylsulfonyloxy, nitrate, phosphate, diphosphate, succinyloxy, sulfonyloxy, trifluoromethanesulfonyloxy, trichloromethanesulfonyloxy, tribromomethanesulfonyloxy, and trifluoroacetyloxy;

[0656] Optionally, wherein X as a counterion - is non-existent, or when X - When X exists, - selected from the group consisting of fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methylsulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;

[0657] Optionally, when X - When absent, optionally the counterion is an inner salt;

[0658] Optionally, X - is an anion of a substituted or unsubstituted carboxylic acid selected from a monocarboxylic acid, a dicarboxylic acid, or a polycarboxylic acid; and

[0659] Optionally, X - is an anion of a substituted monocarboxylic acid, further optionally an anion of a substituted propionic acid (propanoate or propionate), or an anion of a substituted acetic acid (acetate), or an anion of a hydroxy-propionic acid, or an anion of a 2-hydroxypropionic acid (being lactic acid, the anion of which is lactate), or a trihaloacetate selected from trichloroacetate, tribromoacetate and trifluoroacetate; and,

[0660] Optionally, X - is an anion of a substituted monocarboxylic acid selected from formic acid, acetic acid, propionic acid, or butyric acid, which are formate, acetate, propionate, and butyrate, respectively; and

[0661] Optionally, X - is the anion of a substituted or unsubstituted amino acid (i.e., an amino-monocarboxylic acid or an amino-dicarboxylic acid, optionally selected from glutamic acid and aspartic acid), glutamate and aspartate, respectively; and

[0662] Optionally, X -is the anion of ascorbic acid, which is ascorbate; and,

[0663] Optionally, X - is a halide ion selected from fluoride, chloride, bromide or iodide; and

[0664] Optionally, X - is a substituted or unsubstituted sulfonate anion, further optionally a trihalomethanesulfonate selected from trifluoromethanesulfonate, tribromomethanesulfonate or trichloromethanesulfonate; and

[0665] Optionally, X - is an anion of substituted or unsubstituted carbonate, further optionally bicarbonate; and

[0666] Optionally, X - is the anion of substituted or unsubstituted glutathione or glutathione disulfide;

[0667] wherein the substituted carboxylic acids, substituted monocarboxylic acids, substituted propionic acids, substituted acetic acids, substituted amino acids, substituted sulfonates, substituted carbonates, substituted glutathionse, and substituted glutathione disulfides are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0668] R 6 selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 esters, vitamin B2 esters, vitamin B6 esters, choline esters, biotin esters, vitamin A esters, resveratrol esters, glutathione esters, glutathione disulfide esters, aryl (C1-C4)alkyl, heterocyclic (C1-C4)alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0669] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0670] R ASelected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0671] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0672] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B 、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0673] R 7 and R 8 independently selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl(C1-C4)alkyl, and substituted or unsubstituted heterocycle(C1-C4)alkyl; wherein the Substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, substituted heterocycle, substituted aryl (C1-C4) alkyl, and substituted heterocycle (C1-C4) alkyl are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0674] The premise is that the absolute configuration of C** is R or S, or a mixture of R and S.

[0675] According to alternative embodiments, the prototype product nicotinoyl riboside compound includes a compound or derivative having formula (Ia), or a salt, solvate, or prodrug thereof:

[0676]

[0677] Optionally, wherein X as a counterion - is non-existent, or when X - When X exists, - selected from the group consisting of fluoride, chloride, bromide, iodide, formate, acetate, propionate, butyrate, glutamate, aspartate, ascorbate, benzoate, carbonate, citrate, carbamate, gluconate, lactate, methyl bromide, methylsulfate, nitrate, phosphate, diphosphate, succinate, sulfonate, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, and trifluoroacetate;

[0678] Optionally, when X - When absent, optionally the counterion is an inner salt;

[0679] Optionally, X - is an anion of a substituted or unsubstituted carboxylic acid selected from a monocarboxylic acid, a dicarboxylic acid, or a polycarboxylic acid; and

[0680] Optionally, X - is an anion of a substituted monocarboxylic acid, further optionally an anion of a substituted propionic acid (propanoate or propionate), or an anion of a substituted acetic acid (acetate), or an anion of a hydroxy-propionic acid, or an anion of a 2-hydroxypropionic acid (being lactic acid, the anion of which is lactate), or a trihaloacetate selected from trichloroacetate, tribromoacetate and trifluoroacetate; and,

[0681] Optionally, X - is an anion of an unsubstituted monocarboxylic acid selected from formic acid, acetic acid, propionic acid, or butyric acid, which are formate, acetate, propionate, and butyrate, respectively; and

[0682] Optionally, X - is the anion of a substituted or unsubstituted amino acid (i.e., an amino-monocarboxylic acid or an amino-dicarboxylic acid, optionally selected from glutamic acid and aspartic acid), glutamate and aspartate, respectively; and

[0683] Optionally, X - is the anion of ascorbic acid, which is ascorbate; and,

[0684] Optionally, X -is a halide ion selected from fluoride, chloride, bromide or iodide; and

[0685] Optionally, X - is a substituted or unsubstituted sulfonate anion, further optionally a trihalomethanesulfonate selected from trifluoromethanesulfonate, tribromomethanesulfonate or trichloromethanesulfonate; and

[0686] Optionally, X - is an anion of substituted or unsubstituted carbonate, further optionally bicarbonate; and

[0687] Optionally, X - is the anion of substituted or unsubstituted glutathione or glutathione disulfide;

[0688] wherein the substituted carboxylic acids, substituted monocarboxylic acids, substituted propionic acids, substituted acetic acids, substituted amino acids, substituted sulfonates, substituted carbonates, substituted glutathionse, and substituted glutathione disulfides are substituted with one to five substituents independently selected from the group consisting of: -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0689] Z 1 and Z 2 are independently NH or oxygen;

[0690] n is 0 or 1;

[0691] R 1 Selected from the group consisting of: hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, pterostilbene ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C 2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0692] Among them, when R 1 It is hydrogen, Z 2 When is oxygen, and n is 0, the compound of formula (Ia) or derivative may optionally be in the form of a carboxylate anion conjugate base species of the compound of formula (Ia) or derivative, further optionally associated with a positively charged counterion selected from the group consisting of an alkali metal, an alkaline earth metal, a transition metal, and a base addition cation;

[0693] R A Selected from the group consisting of: -H, -(C1-C6)alkyl, -(CH2)3-NH-C(NH2)(=NH), -CH2C(=O)NH2, -CH2COOH, -CH2SH, -(CH2)2C(=O)-NH2, -(CH2)2COOH, -CH2-(2-imidazolyl), -CH(CH3)-CH2-CH3, -CH2CH(CH3)2, -(CH2)4-NH2, -(CH2)2-S-CH3, phenyl, -CH2-phenyl, -CH2-OH, -CH(OH)-CH3, -CH2-(3-indolyl), -CH2-(4-hydroxyphenyl), -CH(CH3)2, -NH2, and -CH2-CH3;

[0694] Each R B are independently hydrogen or -(C1-C8)alkyl;

[0695] Each R C independently selected from the group consisting of hydrogen, -(C1-C8)alkyl, substituted or unsubstituted pyridyl, substituted or unsubstituted 1,4-dihydropyridyl, a group of a compound or derivative of formula (I), and vitamin B7 ester (biotinyl); wherein the substituted pyridyl and substituted 1,4-dihydropyridyl are substituted by one to five substituents independently selected from the group consisting of -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, halogen, -CN, -NO2, -C(O)R B 、-C(O)OR B 、-C(O)NR B 2. -C(=NR B )NR B 2. -OR B 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR B 2. -(C1-C6)alkylene-NR B 2. -NR B 2. -NR B C(O)R B、-NR B C(O)O(C1-C6)alkyl, -NR B C(O)NR B 2. -NR B SO2NR B 2. -SR B 、-S(O)R B 、-SO2R B 、-OSO2(C1-C6)alkyl、-SO2NR B 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR B ;

[0696] R 2 、R 3 、R 4 and R 5 Each is hydrogen;

[0697] R 6 selected from the group consisting of hydrogen, -C(O)R', -C(O)OR', -C(O)NHR', substituted or unsubstituted (C1-C8)alkyl, substituted or unsubstituted (C1-C8)cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycle, vitamin B1 esters, vitamin B2 esters, vitamin B6 esters, choline esters, biotin esters, vitamin A esters, resveratrol esters, glutathione esters, glutathione disulfide esters, aryl (C1-C4)alkyl, heterocyclic (C1-C4)alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substituted (C1-C8) alkyl, substituted (C1-C8) cycloalkyl, substituted aryl, substituted heteroaryl, and substituted heterocycle are substituted by one to five substituents independently selected from the group consisting of: -(C1-C6) alkyl, -(C2-C6) alkenyl, -(C2-C6) alkynyl, halogen, -CN, -NO2, -C(O)R C 、-C(O)OR C 、-C(O)NR C 2. -C(=NR C )NR C 2. -OR C 、-OC(O)(C1-C6)alkyl、-OC(O)O(C1-C6)alkyl、-OC(O)NR C2. -(C1-C6)alkylene-NR C 2. -NR C 2. -NR C C(O)R C 、-NR C C(O)O(C1-C6)alkyl, -NR C C(O)NR C 2. -NR C SO2NR C 2. -SR C 、-S(O)R C 、-SO2R C 、-OSO2(C1-C6)alkyl、-SO2NR C 2. -(C1-C6)perfluoroalkyl and -(C1-C6)alkylene-OR C ;

[0698] R' is selected from the group consisting of hydrogen, substituted or unsubstituted (C1-C8) alkyl, substituted or unsubstituted (C1-C8) cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, vitamin B1 ester, vitamin B2 ester, vitamin B6 ester, choline ester, biotin ester, vitamin A ester, resveratrol ester, aryl (C1-C4) alkyl, heterocyclic (C1-C4) alkyl, -N(R A )-CO2R C 、-N(R A )-CO2R B 、-C**H-(R A )-NH2、-C**H-(R A )-CO2R B wherein the substitut...

Claims

1. A method for preparing a compound having formula (I) or a salt thereof: Where X - It is chloride ion; Z 2 It is NH; n is 0; R 1 It is hydrogen; R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of: hydrogen and -(C1-C3)alkyl; R 6 , R 7 and R 8 are each independently selected from the group consisting of: hydrogen and -C(O)(C1-C8)alkyl; The method comprises the following steps: (a) providing a compound having the formula (2) or a salt thereof: wherein X' is chlorine; R 6 , R 7 and R 8 Each is independently selected from the group consisting of: -C(O)(C1-C8)alkyl; (b) treating the compound of formula (2) or its salt with a stoichiometric equivalent of the compound of formula (1) or its salt; Where Z 2 It is nitrogen; m is 2; n is 0; Each R 1 It is hydrogen; R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of: hydrogen and -(C1-C3)alkyl; (c) extruding the compound of formula (2) or its salt and the compound of formula (1) or its salt in an extruder device to produce the compound of formula (I) or its salt in a yield greater than 0%, wherein the rotation speed of the extruder is 100 RPM, the temperature is 50° C. or 70° C., 1 equivalent of MeCN is present, and the molar ratio of the β-anomer of compound (2) to the nicotinamide compound (1) is 1:1; and (d) isolating the compound of formula (I) or a salt thereof.

2. The method of claim 1, wherein in step (b) the compound of formula (2) or a salt thereof is further treated with a molar equivalent of Lewis acid.

3. The method of claim 1, wherein the compound of formula (I) or a salt thereof is produced as a mixture of an α-anomer and a β-anomer at an anomeric ratio of α-anomer to β-anomer of from 1.5:1 to 1:1 in % by weight.

4. The method of claim 2, wherein the compound of formula (I) or a salt thereof is produced as the β-anomer.

5. The method of claim 1, wherein the α-anomer and β-anomer of the compound having formula (I) or a salt thereof are separately isolated.

6. The method of claim 1, further comprising the steps of: (b1) providing a compound having the formula (1) or a salt thereof: Where Z 2 It is nitrogen; m is 2; n is 0; R 1 It is hydrogen; R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of: hydrogen and -(C1-C3)alkyl; (b2) treating the compound of formula (1) or a salt thereof with an excess of one or more trimethylsilylating agents to produce a compound wherein each R in formula (1) 1 A compound substituted with a TMS group or a salt thereof; (b3) Separating each R in formula (1) 1 A compound substituted with a TMS group or a salt thereof; wherein steps (b1) to (b3) are sequentially performed before step (b).

7. The method of claim 1, further comprising the steps of: (d1) treating the compound of formula (I) or a salt thereof with (3 < x < 100) molar equivalents of an alcohol and a reagent selected from the group consisting of: at least a submolar equivalent of a Bronsted inorganic base, (x ≤ 20) molar equivalents of a Bronsted inorganic acid, and (3 ≤ x < 20) molar equivalents of an acid chloride; (d2) processing the compound of formula (I) or a salt thereof, the alcohol and the reagent to produce a compound wherein R 6 , R 7 and R 8 each being hydrogen, a compound of formula (I) or a salt thereof; as well as (d3) Separation of R 6 , R 7 and R 8 each being hydrogen, the compound of formula (I) or a salt thereof; wherein these steps (d1) to (d3) are performed sequentially after step (d).

8. The method of claim 7, wherein when the processing of step (d2) is selected from the group consisting of batch processing, liquid-assisted mixing, milling, grinding, and extrusion.

9. The method of claim 7, wherein when the reagent in step (d1) is a Bronsted inorganic base, the method further comprises the following steps: (d2a) neutralizing the Brønsted inorganic base using a concentrated acid solution under controlled conditions; The step (d2a) is performed after the step (d2).

10. The method of claim 7, further comprising the steps of: (d4) at room temperature 6 , R 7 and R 8 Each of the compounds of formula (I) or their salts is hydrogen, and a certain volume of methanol and water in a weight:weight ratio of 95:5 is added to make 15% of R 6 , R 7 and R 8 The compound of formula (I) or a salt thereof, each of which is hydrogen, is dissolved in the volume of methanol and water; (d5) stirring at 50°C wherein R 6 , R 7 and R 8 Each of the compounds of formula (I) or a salt thereof is hydrogen, until R 6 , R 7 and R 8 The compound of formula (I) or a salt thereof, each of which is hydrogen, is substantially dissolved in the volume of methanol and water; (d6) R 6 , R 7 and R 8 A solution of the compound of formula (I) or a salt thereof, each of which is hydrogen, in the volume of methanol and water is cooled to -10°C to precipitate 6 , R 7 and R 8 each being hydrogen, a crystalline form of the compound of formula (I) or a salt thereof; (d7) Filter the volume of methanol and water and R 6 , R 7 and R 8 said crystalline form of said compound of formula (I) or a salt thereof, each being hydrogen; as well as (d8) Drying R 6 , R 7 and R 8 said crystalline form of said compound of formula (I) or a salt thereof, each being hydrogen; wherein these steps (d4) to (d8) are performed sequentially after step (d3).

11. The method of claim 10, wherein: Where R 6 , R 7 and R 8 The crystalline form of the compound of formula (I) or a salt thereof, each of which is hydrogen, is crystalline Form I of nicotinamide riboside chloride having the following formula (XII): 。 12. The method of claim 1, wherein the isolated compound of formula (I) is nicotinamide riboside triacetate chloride.

13. The method of claim 12, wherein the α-anomer and the β-anomer of the compound of formula (I) or a salt thereof are separated separately, the method further comprising the following steps: (c1) adding acetone to the following: optionally the compound having formula (2) or a salt thereof, optionally the compound having formula (1) or a salt thereof, optionally wherein each R in formula (1) 1 a compound or a salt thereof substituted with a TMS group, and the compound of formula (I) or a salt thereof, so as to precipitate the β-anomer of the compound of formula (I) or a salt thereof; (c2) filtering the following: optionally the compound having formula (2) or a salt thereof, optionally the compound having formula (1) or a salt thereof, optionally wherein each R in formula (1) 1 A compound or a salt thereof substituted with a TMS group, and the compound or a salt thereof having the formula (I) so as to separate the β-anomer of the compound or a salt thereof having the formula (I); (c3) washing the β-anomer of the compound of formula (I) or its salt with acetone; (c4) combining the acetone from these addition and washing steps; as well as (c5) removing the acetone under reduced pressure; wherein these steps (c1) to (c5) are performed sequentially after step (c).

14. The method of claim 13, further comprising: combining the acetone from the filtration step and the washing step; as well as removing the acetone under reduced pressure to provide a residue; wherein the residue is enriched in the α-anomer of the nicotinamide riboside triacetate chloride.

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