Preparation method of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide

Patent metadata

Field	Value
Publication number	US-10081599-B2
Application number	US-201515532374-A
Country	US
Kind code	B2
Filing date	Nov 9, 2015
Priority date	Dec 24, 2014
Publication date	Sep 25, 2018
Grant date	Sep 25, 2018

Abstract

The present invention relates to a preparation method of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide capable of enabling 4-chlorine-N-methylpyridine-2-formamide to react with 4-amino-3-fluorophenol in the presence of an inorganic base. The present invention employs the inorganic base to replace potassium t-butoxide in the prior art, thus effectively solving the problem of a potential safety hazard of the potassium t-butoxide in industrial production. In addition, after the reaction is completed, the present invention employs a crystallization method for separation to obtain a reaction product; thus compared with the methods of extraction, concentration and column isolation and purification employed in the prior art, the present invention has a simpler operation and a lower cost, results in less environment pollution and a higher yield, and is very suitable for industrial production.

First claim

The invention claimed is:

1. A process for preparing 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide shown in the formula below,

wherein the process comprises:
(a) under an inert gas atmosphere, in the presence of an inorganic base, reacting 4-chloro-N-methylpyridine-2-formamide shown in the formula below

with 4-amino-3-fluorophenol shown in the formula below

2. The process according to claim 1 , wherein the inorganic base is sodium hydroxide or potassium hydroxide.

3. The process according to claim 1 , wherein a ratio of 4-chloro-N-methylpyridine-2-formamide, 4-amino-3-fluorophenol and the inorganic base is 1.0: 0.9 to 1.5: 0.9 to 1.5.

4. The process according to claim 1 , wherein the reaction is carried out in an organic solvent.

5. The process according to claim 4 , wherein the organic solvent is selected from the group consisting of N, N-dimethyl acetamide, N, N-dimethyl formamide and N-methyl pyrrolidone.

6. The process according to claim 1 , wherein a reaction temperature of the reaction is from 40 to 160° C.

7. The process according to claim 1 , wherein a reaction time for the reaction is from 1 to 24 h.

8. The process according to claim 1 , wherein the process further comprises:
(b) after completion of the reaction, adding a suitable amount of water to the reaction solution obtained in step (a), and then cooling to a temperature from −20 to 20° C. for crystallization, so as to obtain 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide.

9. The process according to claim 8 , wherein a ratio by volume of the water added in step (b) to the reaction solution obtained in step (a) is 0.5 to 3:1.

10. The process according to claim 1 , wherein the inorganic base is sodium hydroxide.

11. The process according to claim 1 , wherein a ratio of 4-chloro-N-methylpyridine-2-formamide, 4-amino-3-fluorophenol and the inorganic base is 1.0: 1.1 to 1.3: 1.1 to 1.3.

12. The process according to claim 4 , wherein the organic solvent is N, N-dimethyl acetamide.

13. The process according to claim 1 , wherein a reaction temperature of the reaction is from 80 to 140° C.

14. The process according to claim 1 , wherein a reaction temperature of the reaction is from 90 to 110° C.

15. The process according to claim 1 , wherein a reaction time for the reaction is from 1 to 6 h.

16. The process according to claim 1 , wherein the process further comprises:
(b) after completion of the reaction, adding a suitable amount of water to the reaction solution obtained in step (a), and then cooling to a temperature from 0 to 10° C. for crystallization, so as to obtain 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide.

17. The process according to claim 8 , wherein a ratio by volume of the water added in step (b) to the reaction solution obtained in step (a) is from 1 to 2: 1.

Assignees

• Zhejiang Hisun Pharm Co Ltd

Inventors

• Wang Guan
• Yu Xufeng
• Wei Guo
• Chai Jian
• Yang Zhiqing

Classifications

• C07D213/127

  Preparation from compounds containing pyridine rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D213/81 Primary

  Amides; Imides · CPC title

• C01D1/04

  Hydroxides · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title