Processes for the production of isomerically pure or enriched cis-clomiphene
AssigneePcas
InventorsSergio Kreimerman, Sandrine Gauthier, Quentin Llopis
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Abstract
The present disclosure relates to methods for the production of the isomerically pure or isomerically enriched cis-clomiphene and salts thereof.
Claims20
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.
A process for selectively crystallizing isomerically pure cis-clomiphene hydrobromide from a mixture of trans- and cis-clomiphene free base which comprises the step of reacting hydrobromic acid with the mixture of trans- and cis-clomiphene free base in acetone, wherein the mixture of trans- and cis-clomiphene free base comprises at least 40 wt. % of cis-clomiphene free base relative to the total weight of the mixture of trans- and cis-clomiphene free base.
A process for preparing isomerically pure cis-clomiphene free base or a salt thereof 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) 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.
A process for preparing cis-clomiphene citrate as crystalline form I, which comprises the step of crystallizing cis-clomiphene citrate in acetone.
A process for preparing cis-clomiphene citrate as crystalline form VI, which comprises the step of crystallizing cis-clomiphene citrate in a solvent selected from the group consisting of butan-2-ol, methanol, isopropyl alcohol and methyl tert-butyl ether or in a mixture acetone/water.
A process for converting crystalline form I of cis-clomiphene citrate to crystalline form VI of cis-clomiphene citrate which comprises the step of adding crystalline form I of cis-clomiphene citrate in a mixture consisting of acetone and water in order to obtain a slurry, heating the slurry at a temperature ranging from about 40 to 55° C., preferably for about 5 days, and collecting cis-clomiphene citrate as crystalline form VI.
Dependencies are inferred from the claim text.