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 crystalline Form I of nicotinic acid riboside triacetate (NARTA) according to formula (X):

2. The crystalline Form I of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks at 4.7, 9.5, and 20.5 degrees two theta±0.2 degrees two theta.

3. The crystalline Form I of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks at 4.7, 9.5, 16.5, 16.8, and 20.5 degrees two theta±0.2 degrees two theta.

4. The crystalline Form I of claim 1 that is 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 degrees two theta±0.2 degrees two theta.

5. The crystalline Form I of claim 1 that is characterized by a powder X-ray diffraction pattern substantially as shown in FIG. 19 .

6. The crystalline Form I of claim 1 that is characterized by a powder X-ray diffraction pattern having peaks substantially as provided in Table 9±0.2 degrees two theta.

7. The crystalline Form I of claim 1 that is characterized by an IR spectrum having peaks at 603.6, 684.6, 763.7, and 781.0 cm −1 ±0.2 cm −1 .

8. The crystalline Form I of claim 1 that is characterized by an IR spectrum having 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 ±0.2 cm −1 .

9. The crystalline Form I of claim 1 that is characterized by an IR spectrum having 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 ±0.2 cm −1 .

10. The crystalline Form I of claim 1 that is characterized by an IR spectrum substantially as shown in FIG. 25 .

11. The crystalline Form I of claim 1 that is characterized by an IR spectrum having peaks substantially as provided in Table 10±0.2 cm −1 .

12. The crystalline Form I of claim 1 that is characterized by a DSC thermogram substantially as shown in FIG. 33 .

13. The crystalline Form I of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K/min comprising an endothermic event with an onset temperature of 148° C.±2° C.

14. The crystalline Form I of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K/min comprising an endothermic event with a peak temperature of 152° C.±2° C.

15. The crystalline Form I of claim 1 that is characterized by a DSC thermogram obtained using a heating rate of 10 K/min comprising an endothermic event with an onset temperature of 148° C.±2° C. and a peak temperature of 152° C.±2° C.

16. The crystalline Form I of claim 1 that is prepared by a method comprising the steps of:

(a) dissolving the compound or derivative having formula (X), or salt or solvate thereof, in a volume of methanol;

(b) adding a volume of acetone, of an equal volume to the volume of methanol, to the compound or derivative having formula (X), or salt or solvate thereof, in the volume of methanol;

(c) precipitating the crystalline Form I; and

(d) isolating the crystalline Form I.

17. The crystalline Form I of claim 16 that is prepared by a method further comprising the steps of:

(a1) providing a compound or derivative having formula (Ia), or a salt thereof:

wherein Z 2 is oxygen;

n is 0;

R 1 is hydrogen;

wherein the compound or derivative having formula (Ia) may optionally take the form of the carboxylate anion conjugate base species of the compound or derivative having formula (Ia), further optionally associated with a positively charged counterion selected from the group consisting of calcium, magnesium, potassium, sodium, zinc, and ammonium cations;

each of R 2 , R 3 , R 4 , and R 5 is hydrogen;

(a2) treating the compound or derivative having formula (Ia), or salt thereof, with excess trimethylsilylating reagent(s) so as to produce a compound or derivative having formula (Ia), or salt thereof, wherein R 1 is a TMS group;

(a3) removing the trimethylsilylating reagent(s);

(a4) treating the compound or derivative having formula (Ia), or salt thereof, wherein R 1 is a TMS group, with a molar equivalent amount of a compound or derivative having formula (2), or a salt thereof, in an organic solvent co-reagent:

wherein X′ is selected from the group consisting of fluoro, chloro, bromo, iodo, HCO 2 , acetoxy, propionoxy, butyroxy, glutamyloxy, aspartyloxy, ascorbyloxy, benzoxy, HOCO 2 , citryloxy, carbamyloxy, gluconyloxy, lactyloxy, succinyloxy, sulfoxy, trifluoromethanesulfoxy, trichloromethanesulfoxy, tribromomethanesulfoxy, and trifluoroacetoxy;

each of R 6 , R 7 , and R 8 is C(O)R′;

R′ is methyl;

(a5) processing the compound or derivative having formula (Ia), or salt thereof, wherein R 1 is a TMS group, the compound or derivative having formula (2), or salt thereof, and the organic solvent co-reagent so as to produce the compound or derivative having formula (Ia), or salt or solvate thereof, wherein R 1 is a TMS group;

optionally wherein X − as counterion is absent, or 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, and trifluoroacetate;

and Z 2 , n, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R′ as defined above;

(a6) adding water to, optionally, the compound or derivative having formula (Ia), or salt thereof, wherein R 1 is a TMS group, optionally, the compound or derivative having formula (2), or salt thereof, the organic solvent co-reagent, and the compound or derivative having formula (Ia), or salt or 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;

(a9) freeze-drying the aqueous phase to provide the compound or derivative having formula (X), or salt or solvate thereof;

wherein the steps (a1) to (a9) are performed sequentially, before step (a).

18. The method of claim 17 , wherein the compound or derivative having formula (Ia), or salt thereof, wherein R 1 is a TMS group, the compound or derivative having formula (2), or salt thereof, and the organic solvent co-reagent are further treated with a Lewis acid in step (a4).

19. The crystalline Form I of claim 17 , wherein the processing of step (a5) is selected from the group consisting of batch processing, liquid-assisted mixing, milling, grinding, and extruding.