Process for preparing thienopyrimidine compound and intermediates used therein

Patent metadata

Field	Value
Publication number	US-10392403-B2
Application number	US-201615770794-A
Country	US
Kind code	B2
Filing date	Oct 31, 2016
Priority date	Oct 30, 2015
Publication date	Aug 27, 2019
Grant date	Aug 27, 2019

Abstract

The present invention relates to a novel method for preparing thienopyrimidine compound having an activity of selectively inhibiting tyrosine kinase, specifically the mutant epidermal growth factor receptor tyrosine kinase; and a novel intermediate used therein. According to the method of the present invention, the industrial mass-production of the compound of Formula 1, which is useful as a therapeutic agent for non-small cell lung cancer induced by the mutant epidermal growth factor receptor tyrosine kinase, can be implemented more conveniently and efficiently than the conventional technology.

First claim

The invention claimed is:

1. A method for preparing the compound of Formula 1, comprising steps of:
1) subjecting the compound of Formula 3 to a reaction with the compound of Formula 4 in an organic solvent under the presence of a base to obtain the compound of Formula 2; and
2) subjecting the compound of Formula 2 to a reaction with the compound of Formula 5 in an organic solvent under the presence of an acid to obtain the compound of Formula 1:

2. The method of claim 1 , wherein the organic solvent used in step 1) is selected from the group consisting of acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, N′,N′-dimethylformamide, N′,N-dimethylacetamide, dimethylsulfoxide, and a mixture thereof.

3. The method of claim 1 , wherein the base is selected from the group consisting of potassium carbonate, calcium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, and a mixture thereof.

4. The method of claim 1 , which further comprises, after step 1), the step of precipitating the compound of formula 2 obtained in step 1) in a mixed solvent of an organic solvent and water.

5. The method of claim 4 , wherein the organic solvent is selected from the group consisting of acetone, methanol, ethanol, isopropanol, acetonitrile, and a mixture thereof.

6. The method of claim 5 , wherein the organic solvent is acetone or isopropanol.

7. The method of claim 4 , wherein the mixed solvent comprises the organic solvent and water in a volume ratio of 3:1 to 1:3.

8. The method of claim 1 , wherein the organic solvent used in step 2) is selected from the group consisting of tetrahydrofuran, dioxane, acetonitrile, methanol, ethanol, butanol, 2-butanol, isopropanol, N′,N-dimethylformamide, N′,N′-dimethylacetamide, dimethylsulfoxide, and a mixture thereof.

9. The method of claim 1 , wherein the acid is an inorganic or organic acid.

10. The method of claim 9 , wherein the inorganic acid is selected from the group consisting of hydrochloric acid, nitric acid, sulfuric acid, and a mixture thereof.

11. The method of claim 9 , wherein the organic acid is selected from the group consisting of benzoic acid, toluene, sulfonic acid, benzene sulfonic acid, methane sulfonic acid, acetic acid, trifluoroacetic acid, and a mixture thereof.

12. The method of claim 11 , wherein the organic acid is trifluoroacetic acid.

13. The method of claim 1 , which further comprises, after step 2), the step of precipitating the compound of formula 1 obtained in step 2) in a mixed solvent of an organic solvent and water.

14. The method of claim 13 , wherein the organic solvent is selected from the group consisting of acetone, methanol, ethanol, isopropanol, acetonitrile, and a mixture thereof.

15. The method of claim 14 , wherein the organic solvent is acetone or isopropanol.

16. The method of claim 13 , wherein the mixed solvent comprises the organic solvent and water in a volume ratio of 1:3 to 1:9.

17. The compound of Formula 2:

Assignees

• Hanmi Pharm Ind Co Ltd

Inventors

• Jang Wook
• Moon Young Ho
• Ha Tae Hee
• Suh Kwee Hyun

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title