Process-scale synthesis of urolithin A
Disclosed are methods for preparing a salt of urolithin A and, in turn, urolithin A. The methods are advantageous for the large-scale preparation of urolithin A or a pharmaceutically acceptable salt thereof.
1. A method of preparing a salt of urolithin A, comprising: combining in an alkaline aqueous solution a copper-containing catalyst, 2-bromo-5-hydroxybenzoic acid, and resorcinol, thereby forming the salt of urolithin A; wherein the amount of the copper-containing catalyst is at least a trace amount but no more than 0.01 molar equivalents relative to the amount of 2-bromo-5-hydroxybenzoic acid; and the molar ratio of resorcinol to 2-bromo-5-hydroxybenzoic acid is about 3.5:1 to about 5:1.
2. The method of claim 1 , wherein the copper-containing catalyst is selected from the group consisting of copper powder, copper-bronze couple, CuSO 4 pentahydrate, CuSO 4 hydrate, anhydrous CuSO 4 , Cu(acac) 2 , CuCl, CuCl 2 , CuBr, CuBr 2 , CuI, Cu 2 O, CuO, CuOTf, CuCN, and mixtures thereof.
3. The method of claim 1 , wherein the alkaline aqueous solution comprises LiOH, NaOH, KOH, CsOH, Na 2 CO 3 , CaCO 3 , or Cs 2 CO 3 .
4. The method of claim 1 , wherein the alkaline aqueous solution comprises LiOH, NaOH, KOH, CsOH, Na 2 CO 3 , CaCO 3 , or Cs 2 CO 3 ; and the molar ratio of LiOH, NaOH, KOH, CsOH, Na 2 CO 3 , CaCO 3 , or Cs 2 CO 3 to 2-bromo-5-hydroxybenzoic acid is about 2.8:1 to about 5:1.
5. The method of claim 1 , wherein the molar yield of the salt of urolithin A is at least about 40% relative to the amount of 2-bromo-5-hydroxybenzoic acid.
6. The method of claim 1 , wherein the salt of urolithin A is urolithin A monosodium salt.
7. The method of claim 1 , wherein the salt of urolithin A is urolithin A disodium salt.
8. The method of claim 1 , wherein the alkaline aqueous solution is heated at a temperature in the range of about 60° C. to about 90° C.
9. The method of claim 1 , further comprising isolating the salt of urolithin A, to give an isolated salt of urolithin A.
10. The method of claim 9 , wherein the isolated salt of urolithin A is isolated by filtration.
11. The method of claim 9 , wherein the isolated salt of urolithin A contains less than about 1 ppm copper.
12. The method of claim 9 , further comprising combining a Bronsted acid and the isolated salt of urolithin A, to give a slurry.
13. The method of claim 12 , wherein the Bronsted acid is a carboxylic acid.
14. The method of claim 13 , wherein the carboxylic acid is acetic acid.
15. The method of claim 13 , wherein the carboxylic acid is glacial acetic acid.
16. The method of claim 9 , wherein the isolated salt of urolithin A is urolithin A monosodium salt.
17. The method of claim 9 , wherein the isolated salt of urolithin A is urolithin A disodium salt.
18. The method of claim 9 , wherein the isolated salt of urolithin is at least 95% pure.
19. The method of claim 12 , wherein the slurry is heated at a temperature in the range of about 100° C. to about 130° C.
20. The method of claim 12 , wherein the slurry is maintained at a temperature in the range of about 10° C. to about 30° C.
21. The method of claim 12 , further comprising isolating urolithin A from the slurry.
22. The method of claim 21 , wherein the urolithin A is isolated by filtration.
23. The method of claim 21 , wherein the isolated urolithin A is at least 99% pure.