Methods of preparing reduced nicotinamide riboside and derivatives thereof

Patent metadata

Field	Value
Publication number	US-2024239831-A1
Application number	US-202418598617-A
Country	US
Kind code	A1
Filing date	Mar 7, 2024
Priority date	Jul 29, 2013
Publication date	Jul 18, 2024
Grant date	—

Abstract

Methods of preparing nicotinamide riboside and derivatives thereof, are described. In an aspect, the invention relates to a method of making a compound of formula (II), or a salt, or solvate thereof:

wherein n is 0 or 1;
Y is O or S;
m is 1;
R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted primary or secondary amino, and substituted or unsubstituted azido; and
R 2 -R 5 are each H.

First claim

We claim:

1 . A method of making a compound of formula (IIA), or a salt, or solvate thereof:

the method comprising the steps of:
(a) providing a compound of formula (IVA):

wherein n is 0 or 1;
Y is O or S;
m is 1;
R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted primary or secondary amino, and azido;
R 2 -R 5 are each H;
X − is an anion, wherein the anion is selected from the group consisting of a substituted or unsubstituted carboxylic acid, a halide, a substituted or unsubstituted sulfonate, a substituted or unsubstituted phosphate, a substituted or unsubstituted sulfate, a substituted or unsubstituted carbonate, and a substituted or unsubstituted carbamate; and
R 6 , R 7 and R 8 are each independently selected from the group consisting of an ester-type protecting group, an ether-type protecting group, and a silyl protecting group;
(b) reducing the compound of formula (IVA) to provide a compound of formula (IIIA)

(c) processing the compound of formula (IIIA);
(d) optionally, isolating the compound of formula (IIIA);
(e) optionally, deprotecting the compound of formula (IIIA) so as to produce the compound of formula (IIA); and
(f) isolating the compound of formula (IIA).

2 . The method of claim 1 , wherein the reducing step (b) is carried out using sodium dithionite or sodium borohydride.

3 . The method of claim 1 , wherein the reducing step (b) includes sodium hydrogen carbonate.

4 . The method of claim 1 , wherein, in the compounds of formula (IIIA) and (IVA), R 6 , R 7 and R 8 are each ester protecting groups.

5 . The method of claim 1 , wherein Y n R 1 is NH 2 or OEt.

6 . The method of claim 1 , wherein X − is selected from the group consisting of chloride, bromide, and triflate.

7 . The method of claim 1 , wherein X − is a monocarboxylic acid or a dicarboxylic acid.

8 . The method of claim 1 , wherein R 1 is an alkyl comprising a linear, branched, or cyclic, aliphatic hydrocarbon, having from 1 to 12 carbon atoms.

9 . The method of claim 1 , wherein R 1 is an aryl which is a substituted or unsubstituted phenyl, or a substituted or unsubstituted heteroaryl.

10 . The method of claim 1 , wherein the reducing step (b) optionally comprises the simultaneous addition of a reducing agent, an aqueous solution, and an organic solvent; or the sequential addition of the reducing agent, aqueous solution, and organic solvent, in any order; or any combination thereof.

11 . The method of claim 1 , wherein the processing step (c) further comprises separation of an organic solvent from an aqueous solution, to extract the compound of formula (IIIA).

12 . The method of claim 11 , further comprising isolating the compound of formula (IIIA) from the organic solvent.

13 . The method of claim 10 , wherein the organic solvent is selected from the group consisting of ethyl acetate, dichloromethane, n-butyl acetate, and chloroform, or a combination thereof.

14 . The method of claim 10 , wherein the organic solvent is selected from the group consisting of butanol, hexane, 1,2-dichloroethane, cyclohexane, diethyl ether, heptane, methyl ethyl ketone, octane, diisopropyl ether, and methyl acetate, or a combination thereof.

15 . The method of claim 1 , wherein step (e) uses a deprotecting agent selected from an acid or a base.

16 . The method of claim 4 , wherein R 6 , R 7 and R 8 are unsubstituted acetate or unsubstituted benzoyl.

17 . The method of claim 15 , wherein the base is selected from ammonia, sodium carbonate or sodium hydroxide.

18 . The method of claim 15 , wherein step (e) is carried out in a polar protic solvent or an aprotic solvent, or a combination thereof.

19 . The method of claim 17 , wherein step (e) is carried out in a protic solvent selected from the group consisting of water, methanol, ethanol, and propanol, or a combination thereof.

20 . The method of claim 1 , which is performed at room temperature.

21 . The method of claim 1 , which is performed under an inert atmosphere.

22 . The method of claim 1 , wherein the reactants are subjected to mechanical grinding.

23 . The method of claim 1 , wherein reducing step (b) is carried out in a pH range of about 6 to about 8.

24 . The method of claim 1 , wherein the compound of formula (IIA) in step (f) is 1-(beta-D-ribofuranosyl)-1,4-dihydronicotinamide having the structure

25 . The method of claim 1 , wherein the compound of formula (IIA) in step (f) is 1,4-dihydronicotinic acid riboside having the structure

26 . The method of claim 1 , wherein the compound of formula (IIA) in step (f) is O-ethyl-1,4-dihydronicotinate riboside having the structure

27 . The method of claim 1 , wherein the compound having formula (IIIA) in step (d) is triacetyl-1,4-dihydronicotinamide riboside having the structure

28 . The method of claim 1 , wherein the compound of formula (IIIA) in step (d) is triacetyl-1,4-dihydronicotinic acid riboside having the structure

29 . The method of claim 1 , wherein the compound of formula (IIIA) in step (d) is triacetyl-O-ethyl-1,4-dihydronicotinate riboside having the structure

30 . The method of claim 1 , wherein the compound of formula (IIIA) in step (d) is tribenzoyl-1,4-dihydronicotinic acid riboside having the structure

31 . A nutritional supplement composition comprising a compound of formula (IIA) or (IIIA) made by the method of claim 1 .

32 . A method of making a dihydronicotinoyl riboside compound of formula (IIA), or a salt, or solvate thereof:

the method comprising the steps of:
(a) providing a compound of formula (IA):

wherein n is 0 or 1;
Y is O or S;
m is 1;
R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted

Assignees

• Univ Belfast

Inventors

• Migaud Marie
• Redpath Philip
• Crossey Kerri
• Doherty Mark

Classifications

• C07H1/06

  Separation; Purification · CPC title

• Y02P20/582

  Recycling of unreacted starting or intermediate materials · CPC title

• C07H1/00

  Processes for the preparation of sugar derivatives · CPC title

• C07H19/04

  Heterocyclic radicals containing only nitrogen atoms as ring hetero atom · CPC title

• A23L33/10

  using additives (addition of substantially indigestible substances A23L33/21) · CPC title