Processes for the production of isomerically pure or enriched cis-clomiphene
The present disclosure relates to methods for the production of the isomerically pure or isomerically enriched cis-clomiphene and salts thereof.
1. A process for the production of isomerically enriched cis-clomiphene free base or a salt thereof from isomerically pure or isomerically enriched trans-clomiphene hydrobromide comprising:
(a) reacting hydrobromic acid with the isomerically pure or isomerically enriched trans-clomiphene hydrobromide in the absence of organic solvent to provide isomerically enriched cis-clomiphene hydrobromide, and
(b) optionally converting the isomerically enriched cis-clomiphene hydrobromide to isomerically enriched cis-clomiphene free base or a salt thereof other than hydrobromide.
2. The process according to claim 1 wherein the isomerically enriched cis-clomiphene free base or a salt thereof is isomerically pure cis-clomiphene free base or salt thereof, the process further comprising:
(b) converting the isomerically enriched cis-clomiphene hydrobromide obtained in step (a) to an isomerically enriched cis-clomiphene free base;
(c) reacting hydrobromic acid with the isomerically enriched cis-clomiphene free base obtained in step (b) in acetone to selectively crystallize isomerically pure cis-clomiphene hydrobromide;
(d) optionally converting the isomerically pure cis-clomiphene hydrobromide obtained in step (c) to isomerically pure cis-clomiphene free base;
(e) optionally converting the isomerically pure cis-clomiphene hydrobromide obtained in step (c) or the isomerically pure cis-clomiphene free base obtained in step (d) to an isomerically pure cis-clomiphene salt other than the isomerically pure cis-clomiphene hydrobromide.
3. The process according to claim 2 for preparing isomerically pure cis-clomiphene citrate comprising:
(a) reacting hydrobromic acid with isomerically pure or isomerically enriched trans-clomiphene hydrobromide in the absence of organic solvent to provide isomerically enriched cis-clomiphene hydrobromide;
(b) converting the isomerically enriched cis-clomiphene hydrobromide obtained in step (a) to an isomerically enriched cis-clomiphene free base;
(c) reacting hydrobromic acid with the isomerically enriched cis-clomiphene free base obtained in step (b) in acetone to selectively crystallize isomerically pure cis-clomiphene hydrobromide;
(d) converting the isomerically pure cis-clomiphene hydrobromide obtained in step (c) in isomerically pure cis-clomiphene free base;
(e) converting the isomerically pure cis-clomiphene free base obtained in step (d) to isomerically pure cis-clomiphene citrate.
4. The process according to claim 3 wherein step (d) is performed by reacting the isomerically pure cis-clomiphene hydrobromide with a base.
5. The process according to claim 3 wherein step (e) is performed by reacting citric acid with isomerically pure cis-clomiphene free base.
6. The process according to claim 2 wherein step (c) is performed by reacting from 0.9 to 1.2 equivalents, of hydrobromic acid relative to isomerically enriched cis-clomiphene free base.
7. The process according to claim 1 wherein step (a) is performed at a temperature ranging from about 45 to about 80° C.
8. The process according to claim 1 wherein step (a) is performed by reacting from four to ten volumes of hydrobromic acid relative to the isomerically pure or isomerically enriched trans-clomiphene hydrobromide.
9. The process according to claim 3 wherein step (c) is performed by reacting from 0.9 to 1.2 equivalents of hydrobromic acid relative to isomerically enriched cis-clomiphene free base.
10. The process according to claim 2 wherein step (a) is performed at a temperature ranging from about 45 to about 80° C.
11. The process according to claim 3 wherein step (a) is performed at a temperature ranging from about 45 to about 80° C.
12. The process according to claim 2 wherein step (a) is performed by reacting four to ten volumes of hydrobromic acid relative to the isomerically pure or isomerically enriched trans-clomiphene hydrobromide.
13. The process according to claim 3 wherein step (a) is performed by reacting from four to ten volumes of hydrobromic acid relative to the isomerically pure or isomerically enriched trans-clomiphene hydrobromide.
14. The process according to claim 3 wherein step (d) is performed by reacting the isomerically pure cis-clomiphene hydrobromide with a base in a mixture comprising an organic solvent and water.
15. The process according to claim 3 wherein step (e) is performed by reacting citric acid with isomerically pure cis-clomiphene free base in acetone.
16. The process according to claim 1 wherein step (a) is performed at about 70° C.
17. The process according to claim 2 wherein step (c) is performed by reacting one equivalent of hydrobromic acid relative to isomerically enriched cis-clomiphene free base.