Purification of progesterone receptor modulators
View Patent ↗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.
1. A method for purifying a compound of formula I:
wherein:
A and B are independently selected from the group consisting of H, 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 ; or
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 ;
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 O or S;
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 crude form of a compound of formula I 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.
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; benzoxazine-2-one, benzoxazine-2-thione, benzoxazin-2-ylidene cyanamide; benzothiazin-2-one, benzothiazine-2-thione, and a benzothiazin-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 1 , wherein said basic salt is soluble in said solvent.
6. The method according to claim 1 , wherein said basic salt is insoluble in said solvent.
7. The method according to claim 1 , further comprising isolating said basic salt.
8. The method according to claim 7 , wherein said isolated basic salt is dissolved in a solubilizing solvent.
9. The method according to claim 8 , wherein said solubilizing solvent is acetone or aqueous acetone.
10. The method according to claim 1 , further comprising filtering the product of step (a).
11. The method according to claim 1 , wherein said purified compound of formula I is precipitated.
12. The method according to claim 11 , wherein said precipitation is performed using an acid.
13. The method according to claim 12 , wherein said acid is an organic acid or a mineral acid.
14. The method according to claim 11 , wherein said precipitation is performed using water.
15. The method according to claim 11 , wherein said precipitation is performed using heat.
16. The method according to claim 1 , wherein said step (b) comprises treating said basic salt with an agent that converts said basic salt to said purified compound of formula I.
17. The method according to claim 16 , wherein said agent is selected from the group consisting of water, an acid, and heat.
18. The method according to claim 1 , further comprising isolating said purified compound of formula I.
19. The method according to claim 1 , further comprising recrystallizing said purified compound of formula I.
20. The method according to claim 1 , wherein said compound of formula I is selected from the group consisting of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-benzoxazin)-1-methyl-1H-pyrrole-2-carbonitrile, 5-(4,4-dimethyl-2-oxo-1,4-dihydro-benzoxazin)-3-chloro-benzonitrile, 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-benzoxazin)-1-methyl-1H-pyrrole-2-carbonitrile, 6-bromo-4,4-dimethyl-1,4-dihydro-benzoxazin-2-one, 5-(4,4-dimethyl-2-oxo-1,4-dihydro-benzoxazin)-3-fluoro-benzonitrile, and 5-(4,4-diethyl-2-oxo-1,4-dihydro-benzoxazin)-3-chloro-4-fluoro-benzonitrile.
21. The method according to claim 1 , wherein said basic salt is selected from the group consisting of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile sodium salt, 6-bromo-4,4-dimethyl-benzoxazin-2-one sodium salt, and 6-bromo-4,4-dimethyl-benzoxazin-2-one lithium salt.