Process for making spirolactone compounds

1. A process for preparing a compound of the formula IA, or a salt thereof,

wherein

T, U, V and W are each independently selected from the group consisting of

(1) nitrogen, and

(2) methine,

wherein the methine group is unsubstituted or optionally substituted with a substituent selected from the group consisting of

(a) halogen,

(b) lower alkyl,

(c) hydroxy, and

(d) lower alkoxy, and

wherein at least two of T, U, V, and W are methine;

comprising the steps of

(a) combining a strong base with a compound of formula A

in an aprotic solvent to form a solution;

(b) reacting a compound of formula B

 wherein

wherein R 2 is selected from the group consisting of:

(a) lower alkyl, and

(b) —CH 2 -phenyl, wherein the phenyl group is

unsubstituted or substituted with a substituent selected from the group consisting of

(1) lower alkyl,

(2) lower alkoxy, and

(3) —NO 2 ,

 with the solution of step (a) to form a solution;

(c) adjusting the pH of the solution of step (b) to between about 0 and 4 with an acid to form a compound of formula E

(d) contacting the compound of formula F of step (c), wherein at least one of T, U, V and W is nitrogen, with an acid to form a salt of compound E; and

(e) treating compound E, or a salt thereof, with an acid to form a salt of compound IA.

2. The process of claim 1 wherein steps (a) and (b) are run at a temperature of between about −50° C. and −80° C.

3. The process of claim 1 wherein the aprotic solvent of step (a) is selected from the group consisting of tetrahydrofuran, toluene, heptane, dimethoxyethane, benzene, and hexane, diethyl ether, xylene, or a mixture thereof.

4. The process of claim 3 wherein the aprotic solvent of step (a) is tetrahydrofuran.

5. The process of claim 1 wherein the strong base of step (a) is selected from the group consisting of n-BuLi, sec-BuLi, t-BuLi, LiHMDS, NaHMDS, KHMDS and LiTMP.

6. The process of claim 5 wherein the strong base of step (a) is n-BuLi.

7. The process of claim 1 wherein step (a) further comprises adding a salt selected from the group consisting of LiBr, LiCl, LiI, LiBF 4 , LiClO 4 , and CeCl 3 .

8. The process of claim 7 wherein the salt of step (a) is LiBr.

9. The process of claim 1 wherein the acid of step (c) is selected from the group consisting of camphor sulfonic acid, sulfuric acid, hydrochloric acid, methane sulfonic acid, acetic acid, trifluoromethane sulfonic acid, or a mixture thereof.

10. The process of claim 9 wherein the acid of step (c) is acetic acid.

11. The process of claim 1 wherein step (c) further comprises adding a solvent selected from the group consisting of C 1-6 alcohol, tetrahydrofuran and toluene.

12. The process of claim 11 wherein the solvent of step (c) is ethanol.

13. The process of claim 1 wherein the acid of step (d) is selected from the group consisting of camphor sulfonic acid, sulfuric acid, hydrochloric acid, methane sulfonic acid, trifluoromethane sulfonic acid, or a mixture thereof.

14. The process of claim 13 wherein the acid of step (d) is camphor sulfonic acid.

15. The process of claim 1 wherein step (d) is heated to a temperature of between about 50° C. to 80° C. to form the salt.

16. The process of claim 1 wherein R 2 is selected from the group consisting of: —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , and —CO 2 CH(CH 3 ) 3 .

17. The process of claim 16 wherein R 2 is —CH 2 CH 3 .

18. The process of claim 1 wherein the acid of step (e) is selected from the group consisting of hydrochloric acid, sulfuric acid, methane sulfonic acid, trifluoromethane sulfonic acid, or a mixture thereof.

19. The process of claim 18 wherein the acid of step (e) is sulfuric acid.

20. The process of claim 1 wherein the temperature of step (e) is between about 50° C. and 100° C.

21. The process of claim 1 further comprising the step (f) of treating the salt of compound IA with a base to form free acid IA in solution.

22. The process of claim 21 wherein the base of step (f) is selected from a group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, and sodium bicarbonate.

23. The process of claim 22 wherein the base of step (f) is sodium hydroxide.

24. The process of claim 23 further comprising the step (g) of isolating the compound of formula IA.

25. The process of claim 1 wherein T, V and W are methine, wherein the methine group is unsubstituted or optionally substituted with a substituent selected from the group consisting of

(a) halogen,

(b) lower alkyl,

(c) hydroxy, and

(d) lower alkoxy; and

U is nitrogen.

26. The process of claim 25 wherein T, V and W are unsubstituted methine; and U is nitrogen.

27. The process of claim 1 wherein T, U, V and W are methine, wherein the methine group is unsubstituted or optionally substituted with a substituent selected from the group consisting of

(a) halogen,

(b) lower alkyl,

(c) hydroxy, and

(d) lower alkoxy.

28. A process for preparing the compound of formula IA, or a salt thereof,

wherein

T, U, V and W are each independently selected from the group consisting of

(1) nitrogen, and

(2) methine,

wherein the methine group is unsubstituted or optionally substituted with a substituent selected from the group consisting of

(a) halogen,

(b) lower alkyl,

(c) hydroxy, and

(d) lower alkoxy, and

wherein at least two of T, U, V, and W are methine,

comprising the steps of

(a) contacting the compound of formula E

 wherein

R 2 is selected from the group consisting of:

(a) lower alkyl, and

(b) —CH 2 -phenyl, wherein the phenyl group is

unsubstituted or substituted with a substituent selected from the group consisting of

(1) lower alkyl,

(2) lower alkoxy, and

(3) —NO 2 , and

 wherein at least one of T, U, V and W is nitrogen,

 with an acid to form a salt of compound E; and

(b) treating compound E, or a salt thereof, with an acid to form compound IA, or a salt thereof.

29. The process of claim 28 wherein the acid of step (a) is selected from the group consisting of camphor sulfonic acid, sulfuric acid, hydrochloric acid, methane sulfonic acid, trifluoromethane sulfonic acid, or a mixture thereof.

30. The process of claim 28 wherein R 2 is selected from the group consisting of: —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 CH 3 , —CH(CH 3 ) 2 , —(CH 2 ) 3 CH 3 , and —CH(CH 3 ) 3 .

31. The process of claim 28 wherein the acid of step (b) is selected from the group consisting of hydrochloric acid, sulfuric acid, methane sulfonic acid, trifluoromethane sulfonic acid, or a mixture thereof.

32. The process of claim 28 further comprising the step (c) of isolating compound IA, or a salt thereof.