IP Library › Granted Patent US 7,514,466

Granted Patent B2

US 7,514,466 · App. 11/113,730 · Granted Apr 7, 2009

Purification of progesterone receptor modulators

Assignee: Wyeth

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Quick Facts

Patent No.: US 7,514,466
App. No.: 11/113,730
Granted: Apr 7, 2009
Kind: B2

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Abstract

Methods for purifying a compound of formula I are provided, wherein A, B X, Q, and R 1 are defined herein. The methods include mixing the compound of formula I and a solvent; adding a base to the solvent; and precipitating purified compound of formula I.

Claims (143)

1. A method for purifying a compound of formula I:

wherein:

A and B are joined to form a ring comprising (i), (ii), or (iii):

(i) a carbon-based 3 to 8 membered saturated spirocyclic ring;

(ii) a carbon-based 3 to 8 membered spirocyclic ring containing in its backbone one or more carbon-carbon double bonds; or

(iii) a 3 to 8 membered heterocyclic ring containing in its backbone one to three heteroatoms selected from the group consisting of O, S and N;

the rings of (i), (ii) and (iii) being optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 thioalkyl, CF 3 , OH, CN, NH 2 , NH(C 1 to C 6 alkyl), and N(C 1 to C 6 alkyl) 2 ;

T is absent;

Q is O, S, or NR 3 ;

R 1 is (iv), (v), or (vi):

(iv) halogen;

(v) a substituted benzene ring containing the substituents X, Y and Z as shown below:

wherein:

X is selected from the group consisting of H, halogen, CN, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 thioalkoxy, substituted C 1 to C 3 thioalkoxy, amino, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, SO 2 NH 2 , COR C , OCOR C , and NR D COR C ;

R C is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;

R D is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , amino, aminoalkyl, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy; or

(vi) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 2 and containing one or two substituents independently selected from the group consisting of H, halogen, CN, NO 2 , amino, C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, SO 2 NH 2 , COR E , and NR F COR E ;

R E is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;

R F is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

R 2 is H, absent, O, or C 1 to C 4 alkyl; and

R 3 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, CN, C(O)R 4 , SO 2 R 4 , SCN, OR 4 , SR 4 , C(O)OR 4 , C(S)OR 4 , C(O)SR 4 , or C(S)SR 4 ;

R 4 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, or substituted aryl;

wherein said method comprises:

(a) treating a sample of a compound of formula I which contains greater than about 1% by weight impurities with a base in the presence of a solvent to form a basic salt; and

(b) converting said basic salt to a purified form of a compound of formula I by treating said basic salt with water, acid, or heat.

2. The method according to claim 1 , wherein said compound of formula I is selected from the group consisting of an indol-2-one, indol-2-thione, indol-2-ylidene cyanamide.

3. The method according to claim 1 , wherein said solvent is selected from the group consisting of tetrahydrofuran, methanol, diethylamine, acetone, and water.

4. The method according to claim 1 , wherein said base is selected from the group consisting of an alkoxide salt, diethylamine, a hydroxide salt, tetramethylguanidine, and diazabicycloundecene.

5. The method according to claim 4 , wherein said hydroxide salt is sodium hydroxide, choline hydroxide, or potassium hydroxide.

6. The method according to claim 4 , wherein said alkoxide salt is selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-pentoxide, and potassium tert-pentoxide.

7. The method according to claim 1 , wherein said basic salt is soluble in said solvent.

8. The method according to claim 1 , wherein said basic salt is insoluble in said solvent.

9. The method according to claim 8 , further comprising isolating said basic salt.

10. The method according to claim 9 , wherein said isolation is performed using filtration.

11. The method according to claim 9 , wherein said isolated basic salt is dissolved in a solubilizing solvent.

12. The method according to claim 11 , wherein said solubilizing solvent is acetone or aqueous acetone.

13. The method according to claim 1 , further comprising filtering the product of step (a).

14. The method according to claim 1 , wherein said purified compound of formula I is precipitated.

15. The method according to claim 14 , wherein said precipitation is performed using an acid.

16. The method according to claim 15 , wherein said acid is an organic acid or a mineral acid.

17. The method according to claim 15 , wherein said acid is selected from the group consisting of hydrochloric acid and acetic acid.

18. The method according to claim 14 , wherein said precipitation is performed using water.

19. The method according to claim 14 , wherein said precipitation is performed using heat.

20. The method according to claim 1 , further comprising isolating said purified compound of formula I.

21. The method according to claim 1 , further comprising recrystallizing said purified compound of formula I.

22. The method according to claim 1 , further comprising converting said purified compound of formula I to a pharmaceutically acceptable salt thereof.

23. The method according to claim 1 , wherein said compound of formula I is selected from the group consisting of 5-(2-thioxospiro[cyclohexane-1,3-[3H]-indol]-1-methyl-2-pyrrole-2-carbonitrile, 5-bromo-spiro[cyclohexane-1,3′-[3H]-indol-2(1H)-one, and 5-bromo-spiro[cyclohexane-1,3′-[3H]-indol-2(1H)-thione.

24. The method according to claim 1 , wherein said basic salt is selected from the group consisting 5′-(5-cyano-1-methyl-1H-pyrrole-2-yl)spiro[cyclohexane-1,3′-[3H]-indol]-2′-ylidenecyanamide choline salt and 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]-indol]-2′-ylidenecyanamide choline salt.

25. The method according to claim 1 , wherein said electron withdrawing group of R 3 is CN.

26. A method for purifying a compound of formula I:

wherein:

A and B are independently selected from the group consisting of C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , and NR B COR A;

R A is selected from the group consisting of H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, amino, C 1 to C 3 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;

R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

T is absent;

Q is O, S, or NR 3 ;

R 1 is (iv) or (v):

(iv) a substituted benzene ring containing the substituents X, Y and Z as shown below:

wherein:

R C is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;

R D is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , amino, aminoalkyl, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy; or

(v) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 2 and containing one or two substituents independently selected from the group consisting of H, halogen, CN, NO 2, amino, C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, SO 2 NH 2 , COR E , and NR F COR E ;

R E is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;

R F is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

R 2 is H, absent, O, or C 1 to C 4 alkyl; and R 3 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, CN, C(O)R 4, SO 2 R 4 , SCN, OR 4 , SR 4 , C(O)OR 4 , C(S)OR 4 , C(O)SR 4 , or C(S)SR 4 ;

R 4 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, or substituted aryl;

wherein said method comprises:

(a) treating a sample of a compound of formula I which contains greater than about 1% by weight impurities with a base in the presence of a solvent to form a basic salt; and

(b) converting said basic salt to a purified form of a compound of formula I by treating said basic salt with water, acid, or heat.

27. A method for purifying a compound of formula I:

wherein:

R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

T is absent;

Q is S or NR 3;

R 1 is (iv), (v), or (vi):

(iv) halogen;

(v) a substituted benzene ring containing the substituents X, Y and Z as shown below:

wherein:

R c is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;

R D is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , amino, aminoalkyl, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy; or

(vi) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 2 and containing one or two substituents independently selected from the group consisting of H, halogen, CN, NO 2, amino, C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, SO 2 NH 2 , COR E , and NR F COR E ;

R E is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;

R F is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

R 2 is H, absent, O, or C 1 to C 4 alkyl; and

R 3 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, CN, C(O)R 4, SO 2 R 4 , SCN, OR 4 , SR 4 , C(O)OR 4 , C(S)OR 4 , C(O)SR 4 , or C(S)SR 4 ;

R 4 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, or substituted aryl;

wherein said method comprises:

(a) treating a sample of a compound of formula I which contains greater than about 1% by weight impurities with a base in the presence of a solvent to form a basic salt; and

(b) converting said basic salt to a purified form of a compound of formula I by treating said basic salt with water, acid, or heat.

28. A method for purifying a compound of formula I:

wherein:

A and B are independently selected from the group consisting of C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, C 3 to C 8 cycloalkyl, aryl, heterocyclic, substituted heterocyclic, COR A , and NR B COR A ;

R B is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

T is absent;

Q is O;

R 1 is (iv), (v) or (vi):

(iv) halogen;

(v) a substituted benzene ring containing the substituents X, Y and Z as shown below:

wherein:

R C is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;

R D is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , amino, aminoalkyl, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy; or

(vi) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 2 and containing one or two substituents independently selected from the group consisting of H, halogen, CN, NO 2, amino, C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, SO 2 NH 2 , COR E , and NR F COR E ;

R E is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;

R F is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

R 2 is H, absent, O, or C 1 to C 4 alkyl; and

R 3 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, CN, C(O)R 4, SO 2 R 4 , SCN, OR 4 , SR 4 , C(O)OR 4 , C(S)OR 4 , C(O)SR 4 , or C(S)SR 4 ;

R 4 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, or substituted aryl;

wherein said method comprises:

(a) treating a sample of a compound of formula I which contains greater than about 1% by weight impurities with a base in the presence of a solvent to form a basic salt; and

(b) converting said basic salt to a purified form of a compound of formula I by treating said basic salt with water, acid, or heat.

29. A method for purifying a compound of formula I:

wherein:

A and B are independently selected from the group consisting of C 1 to C 6 alkyl and substituted C 1 to C 6 alkyl; or

A and B are joined to form a carbon-based 3 to 8 membered saturated spirocyclic ring, which is optionally substituted by from 1 to 4 groups selected from the group consisting of fluorine, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 1 to C 6 thioaikyi, CF 3 , OH, CN, NH 2 , NH(C 1 to C 6 alkyl), and N(C 1 to C 6 alkyl) 2 ;

T is absent;

Q is O, S, or NR 3;

R 1 is (iv), (v), or (vi):

(iv) halogen;

(v) a substituted benzene ring containing the substituents X, Y and Z as shown below:

wherein:

R C is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;

R D is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

Y and Z are independently selected from the group consisting of H, halogen, CN, NO 2 , amino, aminoalkyl, C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkoxy; or

(vi) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 2 and containing one or two substituents independently selected from the group consisting of H, halogen, CN, NO 2, amino, C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, SO 2 NH 2 , COR E , and NR F COR E ;

R E is H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, or substituted C 1 to C 3 aminoalkyl;

R F is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;

R 2 is H, absent, O, or C 1 to C 4 alkyl; and

R 3 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, substituted aryl, CN, C(O)R 4, SO 2 R 4 , SCN, OR 4 , SR 4 , C(O)OR 4 , C(S)OR 4 , C(O)SR 4 , or C(S)SR 4 ;

R 4 is C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, or substituted aryl;

wherein said method comprises:

(a) treating a sample of a compound of formula I which contains greater than about 1% by weight impurities with a base in the presence of a solvent to form a basic salt; and

(b) converting said basic salt to a purified form of a compound of formula I by treating said basic salt with water, acid, or heat.

Assignments (2)

CHANGE OF NAME Recorded Sep 6, 2012

From: WYETH

To: WYETH LLC

Reel/Frame 028916/0842 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 17, 2005

From: WILK, BOGDAN KAZIMIERZ; RUBEZHOV, ARKADIY ZINOVIY; HELOM, JEAN LOUISE

To: WYETH

Reel/Frame 016220/0643 →

Continuity (2)

Provisional Application 6056565900 · Apr 27, 2004

Related Publication 20050250766A1 · Nov 10, 2005