Method for preparing elagolix intermediate and composition thereof

Patent metadata

Field	Value
Publication number	US-11365178-B2
Application number	US-201816957685-A
Country	US
Kind code	B2
Filing date	Dec 25, 2018
Priority date	Dec 27, 2017
Publication date	Jun 21, 2022
Grant date	Jun 21, 2022

Abstract

The present invention relates to a method for preparing an intermediate (Formula IV) of sodium elagolix. The intermediate is prepared by the following route. The method has advantages of simple and safe operation, high yield, less environmental pollution, good economic effect and suitability for industrial production, wherein R represents C1-C4 substituted or unsubstituted benzyl or allyl.

First claim

The invention claimed is:

1. A method for preparing a compound of Formula IV, an intermediate of elagolix, comprising steps of: carrying out ammonolysis reaction of a compound of Formula I and a compound of Formula II in mixed solvent of organic solvent and water, and then carrying out cyclization reaction catalyzed by acid to obtain the compound of Formula IV;
wherein the volume ratio of the organic solvent to water is 1:0.001-2;

wherein R is selected from a group consisting of linear or branched C 1 -C 4 substituent or benzyl.

2. The method according to claim 1 , wherein the linear or branched C 1 -C 4 substituents is selected from alkyl or alkenyl.

3. The method according to claim 1 , wherein the organic solvent is an aprotic organic solvent.

4. The method according to claim 1 , wherein the organic solvent is toluene.

5. The method according to claim 1 , wherein the volume ratio of the organic solvent to water is 1:0.1-1.0.

6. The method according to claim 1 , wherein the mass ratio of the compound of Formula I to the compound of Formula II is 1:0.66-4.

7. The method according to claim 1 , wherein the ratio of the mass of the compound of Formula II to the volume of the mixed solvent is 1:8 to 1:20 with a unit of g/ml.

8. The method according to claim 1 , wherein the reaction temperature of the ammonolysis reaction is 80° C. to 150° C.

9. The method according to claim 1 , wherein the reaction temperature of the cyclization reaction catalyzed by the acid to prepare the compound of Formula IV is 40° C. to 150° C.

10. The method according to claim 1 , wherein the acid is selected from a group consisting of p-toluenesulfonic acid, methanesulfonic acid, and sodium dihydrogen phosphate.

11. The method according to claim 1 , wherein the mass ratio of the compound of Formula II to the acid is 1:0.5-1.5.

12. The method according to claim 2 , wherein the alkyl is selected from a group consisting of methyl, ethyl, isopropyl and tert-butyl; and the alkenyl is selected from allyl.

13. The method according to claim 3 , wherein the organic solvent is selected from a group consisting of toluene, chlorobenzene, xylene, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and combinations thereof.

14. The method according to claim 6 , wherein the mass ratio of the compound of Formula I to the compound of Formula II is 1:1.5-2.0.

15. The method according to claim 8 , wherein the reaction temperature of the ammonolysis reaction is 100° C. to 120° C.

16. The method according to claim 9 , wherein the reaction temperature of the cyclization reaction catalyzed by the acid to prepare the compound of Formula IV is 60° C. to 120° C.

Assignees

• Zhejiang Huahai Pharm Co Ltd
• Shanghai Syncores Tech Inc

Inventors

• Su Hu
• Guo Xiaowen
• Liang Yukun
• Shi Kaiqiang
• Yang Jintao
• He Kang
• Tao Anping
• Huang Luning
• An Jianguo
• Chen Xi
• Gu Hong

Classifications

• C07D239/54 Primary

  as doubly bound oxygen atoms or as unsubstituted hydroxy radicals · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title