Process-scale synthesis of urolithins
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.
1. A method of preparing a compound of formula I, comprising the step of combining in an aqueous alkaline solvent mixture a copper-containing catalyst, a compound of formula II, and a compound of formula III, thereby forming the compound of formula I;
wherein
the compound of formula I is represented by:
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 and OR;
wherein, if two OR are present at adjacent positions, then the two R groups taken together may represent a methylene (—CH 2 —) group;
R is selected from the group consisting of H and lower alkyl;
the compound of formula II is represented by:
or an alkyl or aryl ester thereof; wherein X is selected from the group consisting of Cl, Br, and I; and
the compound of formula III is represented by:
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 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 copper-containing catalyst is CuSO 4 hydrate or anhydrous CuSO 4 .
4. The method of claim 1 , wherein the amount of copper-containing catalyst is at least a trace amount but less than 0.01 equivalents relative to either formula II or formula III.
5. The method of claim 1 , wherein the aqueous alkaline solvent comprises LiOH, NaOH, KOH, CsOH, Na 2 CO 3 , CaCO 3 , or Cs 2 CO 3 .
6. The method of claim 1 , wherein the aqueous alkaline solvent comprises NaOH or KOH.
7. The method according to claim 1 , wherein the yield of formula I is at least about 40% relative to the limiting reagent between formula II and formula III.
8. The method of claim 1 , wherein formula I contains less than about 1 ppm copper.
9. The method of claim 1 , wherein X is Cl.
10. The method of claim 1 , wherein X is Br.
11. The method of claim 1 , wherein R 2 is H or OMe.
12. The method of claim 1 , wherein R 1 , R 4 , R 5 , R 6 , and R 8 are each H.
13. The method of claim 1 , wherein R 2 is OMe; and R 3 , R 7 , and R 8 are each OH or OMe.
14. The method of claim 1 , wherein
R 1 , R 3 , R 4 , R 5 , R 6 , and R 8 are each H; R 2 is OMe; and R 7 is OH;
R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each H; and R 2 is OMe;
R 1 , R 4 , R 5 , R 6 , and R 8 are each H; R 2 is OMe; and R 3 and R 7 are each OH; or
R 1 , R 4 , R 5 , and R 6 are each H; R 2 is OMe; and R 3 , R 7 , and R 8 are each OH.
15. The method of claim 1 , wherein R 1 , R 3 , R 4 , R 5 , R 6 , and R 8 are H; R 2 is OMe; and R 7 is OH.
16. The method of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 8 are H; and R 7 is OH.