|
In water; acetone; at 50℃;Purification / work up; |
Example 1Preparation of the Anhydrate Crystal Form: Form D (Preparation 1)Solid 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol (0.2 g) was dissolved in acetone (2 ml) at about 50 C. The suspension was filtered. To the solution, with stirring, was added water (6 ml) in one portion. The solid formed was filtered off and dried at 45-55 C., 5-10 mm Hg, to give the targeted crystalline form (Form D). Fast addition of the filtrate solution to water followed by drying at 45-55 C., 5-10 mm Hg, yielded the same crystalline form (Form D). |
|
|
Example 5Preparation of the Anhydrate Crystal Form: Form D (Preparation 5)Solid 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol (1 g) was added in acetonitrile (3 ml) at 70 C. and stirred for 24 hrs. The suspension was filtered. To the filtrate, with stirring, was added water (8 ml) in one portion. The solid formed was filtered off and dried at 45-55 C., 5-10 mm Hg. Alternatively, the solid was formed by fast addition of the filtrate solution to water, and the solid was dried at 45-55 C., 5-10 mm Hg, The solid formed (and dried) was a mixture of the crystalline form discussed herein (Form D) and the hydrate crystal form of the compound of Formula (I) disclosed in U.S. patent application Ser. No. 11/369,405, filed Mar. 06, 2006. |
|
|
Example 2Preparation of the Anhydrate Crystal Form: Form D (Preparation 2)Solid 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol (1 g) was added to methanol (3 ml) at 50 C. and stirred for 24 hrs. The resulting suspension was filtered. To the filtrate, with stirring, was added water at room temperature (6 ml) in one portion. The solid formed was filtered off and dried at 45-55 C., 5-10 mm Hg, to give the targeted crystalline form (Form D). Fast addition of the filtrate solution to water, followed by drying at 45-55 C., 5-10 mm Hg, yielded the same crystalline form (Form D). |
|
In water; isopropyl alcohol; at 70℃;Purification / work up; |
Example 4Preparation of the Anhydrate Crystal Form: Form D (Preparation 4)Solid 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol (0.28 g) was dissolved in isopropanol (2 ml) at 70 C. To the solution, with stirring, was added water (6 ml) in one portion. The solid formed was filtered off and dried at 45-55 C., 5-10 mm Hg, to give the targeted crystalline form (Form D). Fast addition of the filtrate solution to water, followed by drying at 45-55 C., 5-10 mm Hg, yielded the same crystalline form (Form D). |
|
In ethanol; water; at 20 - 70℃;Purification / work up; |
Example 3Preparation of the Anhydrate Crystal Form: Form D (Preparation 3)Solid 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol (0.36 g) was dissolved in ethanol (2 ml) at 70 C. To the solution, with stirring, was added water (at room temperature 6 ml) in one portion. The solid formed was filtered off and dried at 45-55 C., 5-10 mm Hg, to give the targeted crystalline form (Form D). Fast addition of the filtrate solution to water, followed by drying at 45-55 C., 5-10 mm Hg, yielded the same crystalline form (Form D). |
|
|
... depletion, comprising: providing to a mammal in need thereof, a therapeutically effective amount of one or more estrogenic agents, wherein at least one of said one or more estrogenic agents is selected from a gluocuronide derivative, a sulfate derivative, or a glucuronide-sulfate derivative of: 2-(5-hydroxy-1,3-benzoxazol-2-yl)benzene-1,4-diol; 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol; 3-(5-hydroxy-1,3-benzoxazol-2-yl)benzene-1,2-diol; 2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; 2-(3-chloro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; 2-(2-chloro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; 2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-ol; 2-(3-tert-butyl-4-hydroxyphenyl)-1,3-benzoxazol-6-ol; 2-(6-hydroxy-1,3-benzoxazol-2-yl)benzene-1,4-diol; ... |
|
|
claim 4 , wherein at least one of said one or more estrogenic agents is selected from: 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol; 2-(2-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol; 2-(2,3-difluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol; 5-hydroxy-2-(4-hydroxyphenyl)-1,3-benzoxazole-7-carbonitrile; 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; 4-bromo-2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol; 4,6-dibromo-2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol; 7-(1-bromovinyl)-2-(2-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; 7-(1-bromovinyl)-2-(2,3-difluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; ... |
|
|
claim 4 , wherein at least one of said one or more estrogenic agents is selected from: 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol; 7-bromo-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol; 5-hydroxy-2-(4-hydroxyphenyl)-1,3-benzoxazole-7-carbonitrile; 3-(3-fluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile; 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol; 2-(2-fluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol; and 2-(2,3-difluoro-4-hydroxyphenyl)-7-vinyl-1,3-benzoxazol-5-ol. |