Zuclomiphene salts and crystalline forms thereof
The present invention provides zuclomiphene salts, zuclomiphene binaphthyl hydrogen phosphate salt (1-A)·(BPA) and zuclomiphene oxalate salt (1-A)·(OXL), crystalline forms thereof and processes for the preparation thereof.
1. A process for the preparation of a solid that is isomerically enriched in zuclomiphene of Formula (1-A) relative to enclomiphene of Formula (1-B):
or a salt thereof, the process comprising:
(i) crystallizing and isolating a solid, from a mixture comprising enclomiphene binaphthyl hydrogen phosphate salt and zuclomiphene binaphthyl hydrogen phosphate salt in a solvent (S1), that is isomerically enriched in the enclomiphene binaphthyl hydrogen phosphate salt to afford a first solution;
and either:
(ii-a) crystallizing and isolating a solid from the first solution that is isomerically enriched in the zuclomiphene binaphthyl hydrogen phosphate salt; or
(ii-b)(a) treating the first solution with a base to liberate binaphthyl phosphate salt and removing it from the first solution to afford a second solution;
(b) treating the second solution with oxalic acid; and
(c) crystallizing and isolating a solid from the second solution that is isomerically enriched in the zuclomiphene oxalate salt;
wherein the mixture is enriched in enclomiphene binaphthyl hydrogen phosphate salt relative to zuclomiphene binaphthyl hydrogen phosphate salt.
2. The process of claim 1 , wherein step (i) comprises combining a composition comprising zuclomiphene and enclomiphene, or a composition comprising salts thereof, with binaphthyl hydrogen phosphate in a solvent (S1) and maintaining the mixture at a suitable temperature for a suitable time.
3. The process of claim 2 , wherein the composition comprises zuclomiphene citrate and enclomiphene citrate.
4. The process of claim 1 , wherein the solvent (S1) is methanol.
5. The process of claim 1 , wherein the process comprises steps (ii-b)(a), (ii-b)(b), and (ii-b)(c).
6. The process of claim 5 , wherein the base is solid potassium carbonate.
7. The process of claim 5 , wherein solid potassium binaphthyl phosphate salt is generated and is removed from the first solution by filtration.
8. The process of claim 5 , wherein solvent (S1) is methanol and step (ii-b)(a) comprises replacing a portion of the methanol with ethyl acetate and water such that the solvent composition comprises, with respect to ethyl acetate, about 10-15 mole % water and less than about 20 mole % methanol, prior to filtration.
9. The process of claim 1 , wherein the zuclomiphene binaphthyl hydrogen phosphate salt or the zuclomiphene oxalate salt that is isolated is further converted to zuclomiphene citrate salt.