Intermediate of Ticagrelor and preparation method therefor, and preparation method for Ticagrelor

Patent metadata

Field	Value
Publication number	US-9359366-B2
Application number	US-201414781803-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Apr 10, 2013
Publication date	Jun 7, 2016
Grant date	Jun 7, 2016

Abstract

Disclosed are intermediates of Ticagrelor and a preparation method therefor, and a preparation method for Ticagrelor. Specifically, disclosed is an intermediate, namely, a compound of Formula (VI), for preparing Ticagrelor. Further disclosed is a method for preparing the intermediate and a method for preparing Ticagrelor by using the intermediate. Ticagrelor is prepared by using the intermediate, so that the synthesis process is simple, and a defect that long reaction times under high temperature that are required in the existing methods are avoided. The method is suitable for mass production in industry, energy consumption is reduced, pollution of the environment is reduced, and discharge of waste is reduced.

First claim

We claim:

1. A compound of Formula (VI):

wherein R is hydrogen or a hydroxyl protecting group.

2. A preparation method for the compound of Formula (VI) according to claim 1 , comprising a step of reacting a compound of Formula (VIII) with a compound of Formula (VII) or a salt thereof:

3. The preparation method according to claim 2 , wherein the method further comprises a step of removing the hydroxyl protecting group from the compound of Formula (VI) in the presence of an acid to produce a compound of Formula (VI′):

wherein R is a hydroxyl protecting group.

4. The preparation method according to claim 2 , wherein the reaction is carried out in the presence of a base.

5. The preparation method according to claim 2 , wherein a reaction temperature ranges from 0° C. to 100° C.

6. The preparation method according to claim 2 , wherein the reaction is carried out in a solvent; and the solvent is selected from the group consisting of methylbenzene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethyl formamide, N,N-dimethyl acetamide, acetonitrile, dichloromethane, trichloromethane, dichloroethane, dimethylbenzene, trimethylbenzene, methyl tertiary-butyl ether, cyclopentyl methyl ether, and any combination thereof.

7. The preparation method according to claim 2 , wherein the method further comprises a step of reacting a compound of Formula (IX) with a trifluoroacetylation reagent to produce the compound of Formula (VIII):

wherein said trifluoroacetylation reagent is selected from the group consisting of trifluoroethyl acetate, trifluoroacetic anhydride, trifluoroacetoxy succinimide, (trifluoroacetyl)benzotriazole, pentafluorophenyl trifluoroacetate, and 2-(trifluoroacetoxy)pyridine.

8. The preparation method according to claim 7 , wherein the reaction is carried out in the presence of a base; and the base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 2,3,4-monoalkylated pyridine, anhydrous potassium carbonate, anhydrous sodium carbonate, anhydrous sodium bicarbonate, anhydrous sodium phosphate and anhydrous potassium phosphate.

9. The preparation method according to claim 7 , wherein the reaction is carried out in a solvent; and the solvent is selected from the group consisting of methylbenzene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethyl formamide, N,N-dimethyl acetamide, dichloromethane, trichloromethane, dichloroethane, ethyl acetate, dimethylbenzene, trimethylbenzene, diethyl ether, isopropyl ether, methyl tertiary-butyl ether, cyclopentyl methyl ether, and any combination thereof.

10. A compound of Formula (VIII):

11. A preparation method for a compound of formula (I):

wherein the method comprises a step of preparing the compound of Formula (VI) according to claim 2 and a step of preparing the compound of formula (I) from the compound of Formula (VI); wherein in Formula (VI), R is a hydroxyl protecting group.

12. The preparation method according to claim 11 , wherein the step of preparing the compound of Formula (I) from the compound of Formula (VI) is a multi-step reaction, comprising a step of reacting the compound of Formula (VI) with a base to produce a compound of Formula (V) and a subsequent step of preparing the compound of Formula (I) from the compound of Formula (V):

13. The preparation method according to claim 12 , wherein the base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 2,3,4-monoalkylated pyridine, anhydrous potassium carbonate, anhydrous sodium carbonate, anhydrous sodium bicarbonate, anhydrous sodium phosphate, and anhydrous potassium phosphate.

14. The preparation method according to claim 12 , wherein the compound of Formula (VI) is reacted with the base in a solvent; and the solvent is selected from the group consisting of methylbenzene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethyl formamide, N,N-dimethyl acetamide, dichloromethane, trichloromethane, dichloroethane, ethyl acetate, dimethylbenzene, trimethylbenzene, diethyl ether, isopropyl ether, methyl tertiary-butyl ether, cyclopentyl methyl ether, and any combination thereof.

15. The preparation method according to claim 12 , wherein the step of further preparing the compound of Formula (I) from the compound of Formula (V) comprises the following steps:

(i) reacting the compound of Formula (V) with an alkali metal nitrite to produce a compound of Formula (IV);
(ii) reacting the compound of Formula (IV) with a (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine or a salt thereof to produce a compound of Formula (II); and
(iii) deprotecting the compound of Formula (II) to prepare the compound of Formula (I).

16. A preparation method for a compound of Formula (I):

wherein the method comprises a step of preparing the compound of Formula (VI′) according to claim 3 , and a step of preparing the compound of Formula (I) from the compound of Formula (VI′).

17. The preparation method according to claim 16 , wherein the step of preparing the compound of Formula (I) from the compound of Formula (VI′) is a multi-step reaction, comprising a step of reacting the compound of Formula (VI′) with a strong acid or a base to produce the compound of Formula (IV′), and a further step of preparing the compound of Formula (I) from the compound of Formula (IV′):

18. The preparation method according to claim 17 , wherein the strong acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid and sulfuric acid; and the base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 2,3,4-monoalkylated pyridine, N-methylmorpholine, anhydrous potassium carbonate, anhydrous sodium carbonate, anhydrous sodium bicarbonate, anhydrous sodium phosphate, anhydrous potassium phosphate, sodium hydroxide, and lithium hydroxide.

19. The preparation method according to claim 17 , wherein the compound of Formula (IV′) is reacted with the base in a solvent; and the solvent is selected from the group consisting of methylbenzene, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, N,N-dimethyl formamide, N,N-dimethyl acetamide, dichloromethane, trichloromethane, dichloroethane, ethyl acetate, dimethylbenzene, trimethylbenzene, diethyl ether, isopropyl ether, methyl tertiary-butyl ether, cyclopentyl methyl ether, and any combination thereof.

20. The preparation method according to cl

Assignees

• Jiangsu Hengrui Medicine Co
• Suncadia Pharmaceuticals Co Ltd

Inventors

• Sun Shaoguang
• Song Defu
• He Biao
• Lai Xiaobo

Classifications

• C07D239/47

  One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D405/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D239/48

  Two nitrogen atoms · CPC title