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:
converting a compound of Formula 2A to a compound of Formula I
wherein R 3 is hydrogen or an optionally substituted C 1-6 alkyl.
2. The method of claim 1 , further comprising reacting a compound of Formula 3A with a compound of Formula 4A:
wherein X 1 is a leaving group, to generate the compound of Formula 2A.
3. The method of claim 2 , wherein the compound of Formula 4A comprises
4. The method of claim 3 , wherein R 3 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, each of which is optionally substituted.
5. The method of claim 4 , wherein the compound of Formula 4A comprises
6. The method of claim 5 , wherein the compound of Formula 4A comprises
7. The method of claim 2 , further comprising converting a compound of Formula 5A
wherein X 1 is a leaving group, to a compound of Formula 4A.
8. The method of claim 7 , wherein X 1 is a halo or triflyl group.
9. The method of claim 7 , wherein the compound of Formula 5A comprises
wherein X 1 is Cl or Br.
10. The method of claim 7 , further comprising converting a compound of Formula 6A
to a compound of Formula 5A.
11. The method of claim 10 , further comprising halogenating the compound of Formula 6A to generate the compound of Formula 5A.
12. The method of claim 10 , wherein the compound of Formula 6A 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.
13. The method of claim 12 , wherein R 1 is a C 1-6 alkyl optionally substituted with 1-3 halo.
14. The method of claim 13 , wherein R 1 is selected from methyl, ethyl, or propyl, any of which is optionally substituted with 1-3 halo.
15. The method of claim 10 , wherein the compound of Formula 6A comprises
16. The method of claim 2 , further comprising reacting the compound
with the compound
under condensation conditions to form a compound of Formula 3B
and reducing the compound of Formula 3B to form a compound of Formula 3A.
17. The method of claim 1 , further comprising converting a compound of Formula 7A into a compound of Formula 2A:
18. The method of claim 17 , wherein the compound of Formula 7A is converted to a compound of Formula 2A under reduction conditions.
19. The method of claim 17 , wherein the compound of Formula 2A is generated by treating the compound of Formula 7A with a reducing reagent comprising NaBH 4 .
20. The method of claim 17 , wherein the compound of Formula 7A comprises
21. The method of claim 17 , further comprising reacting a compound of Formula 8A
with the compound
to generate a compound of Formula 7A.
22. The method of claim 21 , wherein the compound of Formula 8A is reacted with the compound
under condensation conditions.
23. The method of claim 22 , wherein the compound of Formula 8A is reacted with the compound
in the presence of an acid and heat.
24. The method of claim 21 , wherein the compound of Formula 8A comprises
25. The method of claim 21 , further comprising reacting a compound of Formula 4A
with the compound
, wherein X 1 is a leaving group, to generate a compound of Formula 8A.
26. The method of claim 25 , wherein the compound of Formula 4A comprises
27. The method of claim 26 , wherein R 3 is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, each of which is optionally substituted.
28. The method of claim 27 , wherein the compound of Formula 4A comprises
29. The method of claim 27 , wherein the compound of Formula 4A comprises
30. The method of claim 25 , further comprising converting a compound of Formula 5A
to a compound of Formula 4A.
31. The method of claim 30 , wherein X 1 is a halo or triflyl group.
32. The method of claim 30 , wherein the compound of Formula 5A comprises
wherein X 1 is Cl or Br.
33. The method of claim 30 , further comprising converting a compound of Formula 6A
to a compound of Formula 5A.
34. The method of claim 33 , further comprising halogenating the compound of Formula 6A to generate the compound of Formula 5A.
35. The method of claim 33 , wherein the compound of Formula 6A 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.
36. The method of claim 35 , wherein R 1 is a C 1-6 alkyl optionally substituted with 1-3 halo.
37. The method of claim 36 , wherein R 1 is selected from methyl, ethyl, or propyl, any of which is optionally substituted with 1-3 halo.
38. The method of claim 33 , wherein the compound of Formula 6A comprises