Efficient and scalable syntheses of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, adenylyl dinucleotide conjugates thereof, and novel crystalline forms thereof

1. A method of making a nicotinamide riboside, or a salt, or solvate thereof, as shown in the following:

wherein X − is a counterion that may be present or absent;

wherein, when X − is present, X − is 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, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, trifluoroacetate, malate, tartrate, glycolate, glucoronate, maleate, fumarate, pyruvate, anthranilate, 4-hydroxybenzoate, phenylacetate, mandelate, pamoate, methanesulfonate, ethanesulfonate, benzenesulfonate, panthothenate, trifluoroacetate, 2-hydroxyethanesulfonate, p-toluenesulfonate, sulfanilate, cyclohexylaminosulfonate, stearate, alginate, beta-hydroxybutyrate, salicylate, galactarate, and galacturonate;

the method comprising:

providing a volume of solvent comprising acetonitrile and nicotinamide riboside triacetate chloride, wherein the volume of solvent dissolves at least a portion of the nicotinamide riboside triacetate chloride;

adding a volume of acetone to the volume of solvent to precipitate crystalline Form I of the nicotinamide riboside triacetate chloride;

isolating the crystalline Form I of the nicotinamide riboside triacetate chloride from the solvent; and

preparing the nicotinamide riboside, or a salt, or solvate, thereof using the crystalline Form I of the riboside triacetate chloride.

2. The method of claim 1 , wherein preparing the nicotinamide riboside, or a salt, or solvate thereof using the crystalline Form I of the riboside triacetate chloride comprises treating the crystalline Form I of the nicotinamide riboside triacetate chloride with ammonium hydroxide or NH 3 .

3. The method of claim 1 , wherein preparing the nicotinamide riboside, or a salt, or solvate thereof using the crystalline Form I of the riboside triacetate chloride comprises treating the crystalline Form I of the nicotinamide riboside triacetate chloride with an inorganic acid.

4. The method of claim 1 , wherein the nicotinamide riboside, or a salt, or solvate thereof is a beta-anomer.

5. The method of claim 1 , further comprising:

(a) providing a compound of Formula (2), or salt thereof:

wherein X′ is selected from the group consisting of fluoro, chloro, bromo, iodo, or —C(O)R′;

R 6 , R 7 and R 8 each are —C(O)R′; and

R′ is methyl;

(b) treating the compound of Formula (2), or salt thereof, with a compound of Formula (1), or a salt thereof:

where

Z 2 is NH;

n is 0;

R 1 is hydrogen or a trimethylsilyl (“TMS”) group; and

R 2 , R 3 , R 4 , and R 5 are each hydrogen;

(c) processing the compound of formula (2) and the compound of formula (1) so as to produce nicotinamide riboside triacetate chloride; and

(d) isolating the nicotinamide riboside triacetate chloride.

6. The method of claim 5 , wherein the processing of step (c) is selected from the group consisting of batch processing, liquid-assisted mixing, milling, grinding, and extruding.

7. The method of claim 5 , wherein the compound or derivative having formula (2), or salt thereof, and the compound formula (1), or salt thereof, is further treated with a molar equivalent of a Lewis acid in step (b).

8. The method of claim 7 , wherein the Lewis acid is trimethylsilyl trifluoromethanesulfonate (TMSOTf).

9. The method of claim 1 , wherein alpha- and beta-anomers of the nicotinamide riboside triacetate chloride are separately isolated by selectively dissolving the alpha-anomer of nicotinamide riboside triacetate chloride or by selectively precipitating the beta-anomer of nicotinamide riboside triacetate chloride.

10. The method of claim 5 , wherein, after processing step (c), the alpha- and beta-anomers of nicotinamide riboside triacetate chloride are separately isolated by:

adding acetone to selectively dissolve the alpha-anomer of the nicotinamide riboside triacetate chloride;

filtering off solids to provide filtered solids and a filtrate;

washing the filtered solids with acetone;

wherein the filtered solids are enriched for the beta-anomer of the nicotinamide riboside triacetate chloride.

11. The method of claim 10 , further comprising:

combining the acetone from the filtering and washing steps; and

removing the acetone under reduced pressure to provide a residue;

wherein the residue is enriched for the alpha-anomer of the nicotinamide riboside triacetate chloride.

12. A method of making a nicotinamide riboside, or a salt, or solvate thereof, as shown in the following structure:

wherein X − is a counterion or is absent;

wherein when X − is present, X − is 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, trifluoromethanesulfonate, trichloromethanesulfonate, tribromomethanesulfonate, trifluoroacetate, malate, tartrate, glycolate, glucoronate, maleate, fumarate, pyruvate, anthranilate, 4-hydroxybenzoate, phenylacetate, mandelate, pamoate, methanesulfonate, ethanesulfonate, benzenesulfonate, panthothenate, trifluoroacetate, 2-hydroxyethanesulfonate, p-toluenesulfonate, sulfanilate, cyclohexylaminosulfonate, stearate, alginate, beta-hydroxybutyrate, salicylate, galactarate, and galacturonate;

the method comprising:

preparing a salt of nicotinamide riboside triacetate in a solvent;

collecting solid crystalline Form I of nicotinamide riboside triacetate salt from the solvent; and

preparing the nicotinamide riboside, or a salt, or solvate thereof using the crystalline Form I of nicotinamide riboside triacetate salt.

13. The method of claim 12 , wherein the solid crystalline Form I of nicotinamide riboside triacetate salt is precipitated from the solvent by adding acetone to the solvent.

14. The method of claim 12 , wherein the crystalline Form I of nicotinamide riboside triacetate salt is suspended in the solvent prior to collecting the solid crystalline Form I of nicotinamide riboside triacetate salt.

15. The method of claim 12 , wherein preparing the nicotinamide riboside, or a salt, or solvate thereof comprises treating nicotinamide riboside triacetate salt with NH 3 or ammonium hydroxide.

16. The method of claim 15 , wherein the NH 3 or ammonium hydroxide is methanolic.

17. The method of claim 12 , wherein preparing the nicotinamide riboside, or a salt, or solvate, or prodrug thereof comprises treating nicotinamide riboside triacetate halogen salt with inorganic acid.

18. The method of claim 17 , wherein the inorganic acid is hydrogen bromide or hydrogen chloride.

19. The method of claim 18 , wherein the hydrogen bromide or hydrogen chloride is methanolic.

20. The method of claim 12 , wherein the salt of nicotinamide riboside triacetate is the chloride salt.

21. The method of claim 12 , further comprising:

(a) providing a compound of formula (2), or salt thereof:

wherein X′ is selected from the group consisting of —OAc, fluoro, chloro, bromo, or iodo;

R 6 , R 7 and R 8 each are —C(O)R′; and

R′ is methyl;

(b) treating the compound of formula (2), or salt thereof, with a compound or derivative having formula (1), or a salt thereof;

R 1 is hydrogen or trimethylsilyl (“TMS”) group; and

(c) processing the compound of formula (2) and the compound of formula (1) so as to produce nicotinamide riboside triacetate or a salt, or solvate thereof; and

(d) isolating the nicotinamide riboside triacetate or a salt, or solvate thereof.

22. The method of claim 21 , wherein, after processing step (c), alpha- and beta-anomers of nicotinamide riboside triacetate, or a salt, or solvate thereof are optionally separately isolated by:

adding acetone to selectively dissolve the alpha-anomer of the nicotinamide riboside triacetate, or a salt, or solvate thereof;

filtering off solids to provide filtered solids and a filtrate;

washing the filtered solids with acetone;

wherein the filtered solids are enriched for the beta-anomer of the nicotinamide riboside triacetate, or a salt, or solvate thereof.

23. The method of claim 22 , further comprising:

removing the filtrate, the acetone from the washing steps, or both under reduced pressure to provide a residue;

wherein the residue is enriched for the alpha-anomer of the nicotinamide riboside triacetate, or a salt, or solvate thereof.