Synthesis for thiazolidinedione compounds
The present invention provides novel methods for synthesizing PPARγ sparing compounds, e.g., thiazolidinediones, that are useful for preventing and/or treating metabolic disorders such as diabetes, obesity, hypertension, and inflammatory diseases.
1. A method for preparing a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein
Each of R 1 and R 2 is independently selected from H, halo, aliphatic, and alkoxy, wherein the aliphatic or alkoxy is optionally substituted with 1-3 of halo;
comprising the step of:
reducing a compound of Formula 2A:
to form a compound of Formula 3A; and
converting the compound of Formula 3A to a compound of Formula I.
2. The method of claim 1 , further comprising converting a compound of Formula 4A
into a compound of Formula 2A.
3. The method of claim 2 , further comprising treating the compound of Formula 4A with a reagent comprising HONH 2 .HCl, HONH 2 , TMSNHOTMS, (H 2 NOH) 2 .H 2 SO 4 , or any combination thereof to generate the compound of Formula 2A.
4. The method of claim 2 , further comprising reacting a compound of Formula 5A
wherein X is a leaving group, with the compound of Formula 6A
to form a compound of Formula 4A.
5. The method of claim 4 , wherein X is a leaving group selected from —Br, —Cl, —I, —OMs, —OTs, —OTf, —OBs, —ONs, —O-tresylate, or —OPO(OR 4 ) 2 , wherein each R 4 is independently C 1-4 alkyl or two of R 4 together with the oxygen and phosphorous atoms to which they are attached form a 5-7 membered ring.
6. The method of claim 4 , wherein the compound of Formula 5A comprises
wherein R 1 is selected from a C 1-6 alkyl or C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is —H or halo.
7. The method of claim 4 , wherein the compound of Formula 5A comprises
wherein R 1 is selected from a C 1-6 alkyl or C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
8. The method of claim 4 , wherein the compound of Formula 5A comprises
9. The method of claim 4 , further comprising halogenating a compound of Formula 7A
to form a compound of Formula 5A.
10. The method of claim 9 , wherein R 1 is selected from a C 1-6 alkyl or C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is —H or halo.
11. The method of claim 10 , wherein R 1 is C 1-6 alkoxy optionally substituted with 1-3 halo, and R 2 is —H.
12. The method of claim 4 , wherein X is selected from —Br and —Cl.
13. The method of claim 4 , further comprising reacting the compound
with the compound
under condensation conditions to form a compound of Formula 6A.
14. The method of claim 1 , wherein the compound of Formula 2A is reduced to a compound of Formula 3A in the presence of a reagent comprising NaBH 4 , LiBH 4 , KBH 4 , or any combination thereof and a catalyst comprising CoCl 2 .
15. The method of claim 1 , wherein the compound of Formula 3A is converted to a compound of Formula I in the presence of an aqueous acid.
16. The method of claim 15 , wherein the aqueous acid comprises aqueous HCl or aqueous H 2 SO 4 .
17. The method of claim 1 , further comprising reacting a compound of Formula 5B
wherein X is a leaving group, with a compound of Formula 6A
to form a compound of Formula 2A.
18. The method of claim 17 , further comprising converting a compound of Formula 5A
to form a compound of Formula 5B.
19. The method of claim 18 , wherein the compound of Formula 5A comprises
wherein R 1 is selected from a C 1-6 alkyl or C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is —H or halo.
20. The method of claim 19 , wherein the compound of Formula 5A comprises
wherein R 1 is selected from a C 1-6 alkyl or C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
21. The method of claim 20 , wherein the compound of Formula 5A comprises
22. The method of claim 18 , further comprising halogenating a compound of Formula 7A
to form a compound of Formula 5A.
23. The method of claim 22 , wherein R 1 is selected from a C 1-6 alkyl or C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is —H or halo.
24. The method of claim 23 , wherein R 1 is selected from methoxy, ethoxy, or propoxy, any of which is optionally substituted with 1-3 halo.
25. The method of claim 17 , wherein X is selected from —Br and —Cl.
26. The method of claim 25 , further comprising reacting the compound
with the compound
under condensation conditions to form a compound of Formula 6A.
27. The method of claim 17 , wherein the compound of Formula 2A is reduced to a compound of Formula 3A in the presence of a reagent comprising NaBH 4 , LiBH 4 , KBH 4 , or any combination thereof and a catalyst comprising CoCl 2 .
28. The method of claim 27 , wherein the compound of Formula 3A is converted to a compound of Formula I in the presence of an aqueous acid.
29. The method of claim 28 , wherein the aqueous acid comprises aqueous HCl or aqueous H 2 SO 4 .
30. The method of claim 2 , further comprising reacting a compound of Formula 8A
with the compound
under condensation conditions to form a compound of Formula 4A.
31. The method of claim 30 , further comprising reacting a compound of Formula 5A
wherein X is a leaving group, with 4-hydroxybenzaldehyde to form a compound of Formula 8A.
32. The method of claim 31 , wherein the compound of Formula 5A comprises
wherein R 1 is selected from a C 1-6 alkyl or C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is —H or halo.
33. The method of claim 32 , wherein the compound of Formula 5A Comprises
wherein R 1 is selected from a C 1-6 alkyl or C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
34. The method of claim 33 , wherein the compound of Formula 5A comprises
35. The method of claim 34 , further comprising halogenating a compound of Formula 7A
to form a compound of Formula 5A.
36. The method of claim 35 , wherein R 1 is selected from a C 1-6 alkyl or C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is —H or halo.
37. The method of claim 36 , wherein R 1 is selected from methoxy, ethoxy, or propoxy, any of which is optionally substituted with 1-3 halo.
38. The method of claim 31 , wherein X is selected from —Br and —Cl.
39. The method of claim 1 , further comprising reacting a compound of Formula 8B
with the compound
to generate the compound of Formula 2A.
40. The method of claim 39 , further comprising reacting a compound of Formula 5B
wherein X is a leaving group, with 4-hydroxybenzaldehyde to form a compound of Formula 8B.
41. The method of claim 40 , wherein the compound of Formula 5B comprises
wherein R 1 is selected from a C 1-6 alkyl or C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is —H or halo.
42. The method of claim 41 , wherein the compound of Formula 5B comprises
wherein R 1 is selected from a C 1-6 alkyl or C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo.
43. The method of claim 41 , wherein the compound of Formula 5B comprises
44. The method of claim 40 , further comprising halogenating a compound of Formula 7B
to form a compound of Formula 5B.
45. The method of claim 44 , wherein R 1 is selected from a C 1-6 alkyl or C 1-6 alkoxy, either of which is optionally substituted with 1-3 halo, and R 2 is —H or halo.
46. The method of claim 45 , wherein R 1 is selected from methoxy, ethoxy, or propoxy, any of which is optionally substituted with 1-3 halo.
47. The method of claim 43 , wherein X is selected from —Br and —Cl.