Zuclomiphene salts and crystalline forms thereof

Patent metadata

Field	Value
Publication number	US-11440871-B2
Application number	US-202017095684-A
Country	US
Kind code	B2
Filing date	Nov 11, 2020
Priority date	Nov 14, 2019
Publication date	Sep 13, 2022
Grant date	Sep 13, 2022

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Apotex Inc

Inventors

• Raheem Mohammed Abdul
• Kakani Siva Ramarao
• Nguyen Minh T N
• Zhao Yajun
• Green Stuart P
• Souza Fabio E S
• Stirk Alexander J
• Mohammadpourmir Fatemeh

Classifications

• C07C15/24

  containing two rings · CPC title

• C07C59/265 Primary

  Citric acid · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07C213/08 Primary

  by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups · CPC title

• C07C55/06

  Oxalic acid · CPC title