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 molar ratio of resorcinol to 2-bromo-5-hydroxybenzoic acid is about 3.8:1 to about 4.2:1; the alkaline aqueous solution comprises NaOH; the molar ratio of NaOH to 2-bromo-5-hydroxybenzoic acid is about 4.2:1 to about 4.6:1; and the copper-containing catalyst is CuSO 4 pentahydrate.
2. The method of claim 1 , 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.
3. The method of claim 1 , wherein the molar ratio of resorcinol to 2-bromo-5-hydroxybenzoic acid is about 4.0:1.
4. The method of claim 1 , wherein the molar ratio of NaOH to 2-bromo-5-hydroxybenzoic acid is about 4.4:1.
5. The method of claim 1 , wherein the salt of urolithin A is urolithin A monosodium salt.
6. The method of claim 1 , wherein the salt of urolithin A is urolithin A disodium salt.
7. The method of claim 1 , further comprising isolating the salt of urolithin A, to give an isolated salt of urolithin A.
8. The method of claim 7 , wherein the isolated salt of urolithin A is isolated by filtration.
9. The method of claim 7 , wherein the isolated salt of urolithin A contains less than about 1 ppm copper.
10. The method of claim 7 , further comprising combining a Bronsted acid and the isolated salt of urolithin A, to give a slurry; wherein the Bronsted acid is a carboxylic acid.
11. The method of claim 10 , wherein the carboxylic acid is glacial acetic acid.
12. The method of claim 7 , wherein the isolated salt of urolithin A is urolithin A monosodium salt.
13. The method of claim 7 , wherein the isolated salt of urolithin A is urolithin A disodium salt.
14. The method of claim 10 , further comprising heating the slurry at a temperature in the range of about 100° C. to about 130° C. for a period of time.
15. The method of claim 10 , further comprising maintaining the slurry at a temperature in the range of about 15° C. to about 25° C. for a period of time.
16. The method of claim 10 , further comprising isolating urolithin A from the slurry.
17. The method of claim 1 , wherein the molar ratio of resorcinol to 2-bromo-5-hydroxybenzoic acid is about 4.0:1; and the molar ratio of NaOH to 2-bromo-5-hydroxybenzoic acid is about 4.4:1.