Purification of progesterone receptor modulators

Abstract

Processes are provided for purifying a compound of the structure:

Description

Claims

1. A process for purifying a compound of the structure:

2. A process for purifying 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile, comprising: (a) dissolving 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile in a solution comprising acetone, water and a base at about 30° C.;(b) filtering the solution of step (a) at about 30° C.;(c) precipitating said purified 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile by adjusting the solution of step (b) to an acidic pH.

3. The process according to claim 1, wherein said compound is 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile.

4. The process according to claim 1, wherein said compound is tanaproget.

5. The process according to any one of claims 1 to 4, wherein said base is sodium hydroxide, potassium hydroxide, or calcium hydroxide.

6. The process according to any one of claims 1 to 5, wherein said base is sodium hydroxide.

7. The process according to any one of claims 1 to 6, wherein said filtration is performed using charcoal.

8. The process according to any one of claims 1 to 7, wherein said filtration is performed using a filtration device comprising alternating layers of charcoal and the diatomaceous earth.

9. The process according to any one of claims 1 to 8, wherein said filtration device contains a first layer comprising diatomaceous earth, a second layer comprising charcoal, and a third layer comprising diatomaceous earth.

10. The process according to any one of claims 1 to 9, wherein said acidic pH is about 4.5 to about 7.

11. The process according to any one of claims 1 to 10, wherein said purified compound is collected by filtration.

12. The process according to claim 11, wherein said purified compound is collected at about 20° C.

13. The process according to any one of claims 1 to 12, which is performed under inert conditions.

14. The process according to any one of claims 1 to 13, wherein said precipitation is performed using hydrochloric acid.

15. The process according to any one of claims 1 to 14, wherein the product of step (a) is a sodium salt.

16. The process according to claim 1 or 2, wherein the product of step (a) is:

17. The process according to any one of claims 1 to 16, wherein said purified compound is isolated in greater than an about 90% yield.

18. The process according to any one of claims 1 to 17, wherein said purified compound contains less than about 1% acetone.

19. The process according to any one of claims 1 to 18, wherein said purified compound contains less than about 1.5% water.

20. The process according to any one of claims 1 to 19, wherein said process is performed on a kilogram scale.

21. A process for purifying 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile, comprising: (a) dissolving 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile in acetone, water and sodium hydroxide at about 30° C.;(b) filtering the solution of step (a) through charcoal at about 30° C.;(c) precipitating the purified 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile by adjusting the solution of step (b) to a pH of about 4.5 to about 7 using hydrochloric acid; and(d) collecting purified 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile by filtration at about 20° C.

22. A process for purifying 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile, comprising: (a) dissolving 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile in a solution comprising acetone, water and sodium hydroxide at about 30° C.;(b) filtering the solution of step (a) at about 30° C.; and(c) precipitating purified 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile by adjusting the solution of step (b) to a pH of about 4.5 to about 7;wherein said process is performed in the absence of acetone distillation.

23. A process for purifying 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile, comprising: (a) dissolving 5-(2-thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile in a solution comprising acetone, water and sodium hydroxide at about 30° C.;(b) filtering the solution of step (a) at about 30° C.; and(c) precipitating purified 5-(2-Thioxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1-methylpyrrole-2-carbonitrile by adjusting the solution of step (b) to a pH of about 4.5 to about 7;wherein said process is performed in the absence of THF.