Processes for the preparation of zuclomiphene and intermediates thereof

Patent metadata

Field	Value
Publication number	US-11046638-B2
Application number	US-202017095707-A
Country	US
Kind code	B2
Filing date	Nov 11, 2020
Priority date	Nov 14, 2019
Publication date	Jun 29, 2021
Grant date	Jun 29, 2021

Abstract

The present invention provides processes for the preparation of zuclomiphene, as well as intermediates useful in the preparation thereof. In particular, processes are provided for the carbometallation of diphenylacetylene with a compound of Formula (3) to afford either zuclomiphene or an intermediate which is converted to zuclomiphene.

First claim

What is claimed is:

1. A process for the preparation of zuclomiphene (1-A):

or a salt thereof, comprising:
(i) reacting diphenylacetylene, in the presence of a nickel(II) catalyst, with a compound of Formula (3):

followed by a chlorinating agent,
wherein
A is —OCH 2 CH 2 NEt 2 or G;
M is zinc or magnesium; and
X is halide;

to provide either zuclomiphene (1-A) when A is —OCH 2 CH 2 NEt 2 or, when A is G, a compound of Formula (2-A):

wherein
G is OPG or X 1 ;
PG is an alcohol protecting group;
X 1 is halide; and

(ii) when A is G, converting the G group in the compound of Formula (2-A) to the —OCH 2 CH 2 NEt 2 group of zuclomiphene (1-A).

2. The process of claim 1 , wherein M is magnesium and X is bromide or chloride.

3. The process of claim 2 , wherein the chlorinating agent is selected from the group consisting of chlorine, N-chlorosuccinimide, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, hexachloroethane, and 1,3-dichloro-5,5-dimethylhydantoin.

4. The process of claim 3 , wherein the chlorinating agent is 1,3-dichloro-5,5-dimethylhydantoin.

5. The process of claim 2 , wherein the nickel(II) catalyst is selected from the group consisting of nickel(II) chloride, nickel(II) chloride hexahydrate, nickel(II) bromide, nickel(II) chloride ethylene glycol dimethyl ether complex, nickel(II) bromide ethylene glycol dimethyl ether complex, nickel(II) acetylacetonate, and nickel(II) acetate tetrahydrate.

6. The process of claim 5 , wherein the nickel(II) catalyst is nickel(II) chloride hexahydrate.

7. The process of claim 2 , wherein the reaction of diphenylacetylene and the compound of Formula (3) is conducted in the presence of a solvent (S1) selected from the group consisting of aromatic hydrocarbons, ethers, and mixtures thereof.

8. The process of claim 2 , wherein the reaction of diphenylacetylene and the compound of Formula (3) is conducted at a temperature in the range of about 50° C. to about 80° C.

9. The process of claim 2 , wherein the compound of Formula (2-A) is a compound of Formula (2-A1):

and the process of converting the compound of Formula (2-A) to zuclomiphene (1-A), or a salt thereof, comprises reacting the compound of Formula (2-A1) with Et 2 NCH 2 CH 2 OH.

10. The process of claim 9 , wherein the reaction of the compound of Formula (2-A1) with Et 2 NCH 2 CH 2 OH is conducted in the presence of a base (B1) that is selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, sodium hydride, and potassium hydride and a solvent (S3) that is an ether.

11. The process of claim 10 , wherein the solvent (S3) is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane and the base (B1) is potassium tert-butoxide.

12. The process of claim 2 , wherein the compound of Formula (2-A) is a compound of Formula (2-A3):

wherein
PG is an alcohol protecting group,

and the process of converting the compound of Formula (2-A) to zuclomiphene (1-A), or a salt thereof, comprises deprotecting the compound of Formula (2-A3) and alkylating the resulting intermediate with a compound of Formula Et 2 NCH 2 CH 2 LG, or a salt thereof, wherein LG is a leaving group.

13. The process of claim 12 , wherein PG is methyl.

14. The process of claim 13 , wherein the deprotecting is conducted in the presence of boron tribromide.

15. The process of claim 14 , wherein LG is chloride.

16. The process of claim 1 , wherein the isomeric purity of zuclomiphene (1-A), or a salt thereof, that is produced is at least about 80%.

17. The process of claim 1 , wherein the zuclomiphene (1-A) that is produced is further converted to zuclomiphene (1-A) citrate.

Assignees

• Apotex Inc

Inventors

• Karadeolian Avedis
• Souza Fabio E S
• Emmett Michael R
• Rey Allan W

Classifications

• C07B2200/07

  Optical isomers · CPC title

• C07C17/00 Primary

  Preparation of halogenated hydrocarbons · CPC title

• C07C217/60

  linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring · CPC title

• C07C213/02 Primary

  by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups · CPC title

• B01J23/755

  Nickel · CPC title