Process-scale synthesis of urolithins

Patent metadata

Field	Value
Publication number	US-9573922-B2
Application number	US-201615212979-A
Country	US
Kind code	B2
Filing date	Jul 18, 2016
Priority date	Dec 23, 2013
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

Disclosed is a method of preparing a urolithin, or an intermediate or analog thereof, having a dibenzo[b,d]pyran-6-one core. The method is especially advantageous for the large-scale preparation of urolithins or intermediates or analogs thereof. The method may optionally include the preparation of a urolithin, or an intermediate or analog thereof, as a pharmaceutically acceptable salt.

First claim

What is claimed is:

1. A method of preparing a compound of formula IV, comprising the step of combining an inert organic solvent, a compound of formula V, and a Lewis acid selected from the group consisting of AlCl 3 , AlBr 3 , BeCl 2 , FeCl 3 , and SiCl 4 ; thereby forming the compound of formula IV;
wherein
the compound of formula IV is represented by:

wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are, independently for each occurrence, selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, halogen, and OR; and
R is selected from the group consisting of H, acyl, aracyl, sulfate, monosaccharide, and oligosaccharide; and

the compound of formula V is represented by:

wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are, independently for each occurrence, selected from the group consisting of H, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, halogen, and OR; wherein, if two OR are present at adjacent positions, then the two R groups taken together may be a methylene (—CH 2 —) group; and
R is selected from the group consisting of H, lower alkyl, lower haloalkyl, acyl, aracyl, sulfate, monosaccharide, and oligosaccharide;

with the provisos that (i) at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 in formula IV is OH; and (ii) at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 in formula V is O-alkyl.

2. The method of claim 1 , wherein the Lewis acid is AlCl 3 or AlBr 3 .

3. The method of claim 1 , wherein the Lewis acid is AlCl 3 .

4. The method of claim 1 , further comprising an additive selected from the groups consisting of a C 2 -C 24 thiol, LiCl, NaI, tetrabutylammonium iodide (Bu 4 NI), NaOMe, and trimethylamine hydrochloride.

5. The method of claim 4 , wherein the additive is ethanethiol.

6. The method of claim 1 , wherein the mixture is heated to a temperature of about 50 to about 120° C.

7. The method of claim 1 , wherein the starting material is contacted with the Lewis acid for about 30 minutes to about 5 hours.

8. The method of claim 1 , wherein the compound of formula IV is formed in at least 40% yield relative to the compound of formula V.

9. The method of claim 1 , wherein the inert organic solvent is selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, diethyl ether, 1,4-dioxane, tert-butyl methyl ether (TBME), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), diglyme, nitromethane, 1,2-dimethoxyethane (DME), pyridine, ethyl acetate, acetone, acetonitrile, benzene, o-xylene, m-xylene, p-xylene, xylenes, hexanes, cyclohexane, heptane, octane, nonane, and decane.

10. The method of claim 1 , wherein the inert organic solvent is selected from the group consisting of chlorobenzene, 1,4-dioxane, tert-butyl methyl ether (TBME), tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), pyridine, benzene, toluene, o-xylene, m-xylene, p-xylene, and xylenes.

11. The method of claim 1 , wherein the inert organic solvent is toluene.

12. The method of claim 1 , further comprising the step of recrystallizing the compound of formula IV from an organic acid selected from the group consisting of formic acid, acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, and trifluoroacetic acid.

13. The method of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are, independently for each occurrence, selected from the group consisting of H, alkyl, haloalkyl, and OR.

14. The method of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are, independently for each occurrence, H or OR; and R is H or lower alkyl.

15. The method of claim 1 , wherein R 2 is H or OMe.

16. The method of claim 1 , wherein R 1 , R 4 , R 5 , R 6 , and R 8 are each H.

17. The method of claim 1 , wherein R 2 is OMe; and R 3 , R 7 , and R 8 are each OH or OMe.

18. The method of claim 1 , wherein, in the compound of formula IV:
R 1 , R 3 , R 4 , R 5 , R 6 , and R 8 are each H; R 2 and R 7 are both OH;
R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each H; and R 2 is OH;
R 1 , R 4 , R 5 , R 6 , and R 8 are each H; and R 2 , R 3 , and R 7 are each OH; or
R 1 , R 4 , R 5 , and R 6 are each H; R 2 , R 3 , R 7 , and R 8 are each OH.

19. The method of claim 1 , wherein, in the compound of formula IV: R 1 , R 3 , R 4 , R 5 , R 6 , and R 8 are H, and R 2 and R 7 are both OH.

20. The method of claim 1 , wherein, in the compound of formula IV: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 8 are H; and R 7 is OH.

Assignees

• Amazentis Sa

Inventors

• Rinsch Christopher
• Mueller Roland
• Skranc Wolfgang

Classifications

• A61K31/366

  having six-membered rings, e.g. delta-lactones · CPC title

• A61K33/34

  Copper; Compounds thereof · CPC title

• C07D311/80 Primary

  Dibenzopyrans; Hydrogenated dibenzopyrans · CPC title