Method for preparing thienopyrimidine compound and intermediates used therein

Patent metadata

Field	Value
Publication number	US-10040801-B2
Application number	US-201515540757-A
Country	US
Kind code	B2
Filing date	Dec 30, 2015
Priority date	Dec 30, 2014
Publication date	Aug 7, 2018
Grant date	Aug 7, 2018

Abstract

The present invention provides a novel method for preparing a thienopyrimidine compound of Formula 1, which is a selective inhibitor of tyrosine kinase activity, in particular, of mutant epidermal growth factor receptor tyrosine kinase, and novel intermediates used in the method.

First claim

The invention claimed is:

1. A method for preparing a compound of Formula 1, comprising the steps of:
a. allowing a compound of Formula 3 or a salt thereof to react with a chlorinating agent to obtain a compound of Formula 2 or a salt thereof; and
b. allowing the compound of Formula 2 or the salt thereof to react with a compound of Formula 8 or a salt thereof and a base:

2. The method of claim 1 , wherein the compound of Formula 3 or the salt thereof is obtained by a step of:
c. allowing a compound of Formula 4 or a salt thereof to react with a compound of Formula 9 or a salt thereof and an organic acid:

wherein L is

 or halogen and R 1 is C 1-10 alkyl or benzyl.

3. The method of claim 2 , wherein the organic acid in step c. is selected from the group consisting of acetic acid, trifluoroacetic acid, and a mixture thereof.

4. The method of claim 1 , wherein the compound of Formula 4 or the salt thereof, where L is

is obtained by the steps of:
d. allowing a compound of Formula 7 or a salt thereof to react with an alkylating agent and a base to obtain a compound of Formula 6 or a salt thereof; and
e. allowing the compound of Formula 6 or the salt thereof to react with an oxidizing agent:

wherein R 1 is C 1-10 alkyl or benzyl.

5. The method of claim 4 , wherein the base in step d. is selected from the group consisting of sodium hydroxide, potassium hydroxide, and a mixture thereof.

6. The method of claim 4 , wherein the reaction of step d. is performed in the presence of an organic solvent selected from the group consisting of acetonitrile, methanol, ethanol, butanol, 2-butanol, isopropanol, and a mixture thereof with water.

7. The method of claim 4 , wherein the alkylating agent in step d. is R 1 —R 2 or R 1 —O—S(O) 2 —O—R 1 , where R 1 is C 1-10 alkyl or benzyl, and R 2 is halogen.

8. The method of claim 7 , wherein the alkylating agent in step d. is selected from the group consisting of dimethyl sulfate, methyl iodide, ethyl iodide, benzyl bromide, benzyl chloride and a mixture thereof.

9. The method of claim 4 , wherein the oxidizing agent in step e. is selected from the group consisting of hydrogen peroxide solution, metachloroperoxybenzoic acid, peroxyacetic acid, magnesium monoperoxyphthalate, oxone, and a mixture thereof.

10. The method of claim 1 , wherein the compound of Formula 4 or the salt thereof, where L is halogen, is obtained by the step of:
f. hydrolyzing a compound of Formula 5 or a salt thereof in the presence of a base:

wherein L is halogen.

11. The method of claim 10 , wherein the base in step f. is selected from the group consisting of sodium hydroxide, potassium hydroxide, and a mixture thereof.

12. The method of any one of claim 10 , wherein the reaction in step f. is performed in the presence of an organic solvent selected from the group consisting of tetrahydrofuran, dioxane, acetonitrile, methanol, ethanol, butanol, 2-butanol, isopropanol, and a mixture thereof with water.

13. The method of claim 10 , wherein L is chlorine.

14. The method of claim 1 , wherein step a. is performed in the presence of an organic solvent selected from the group consisting of acetonitrile, dichloromethane, chloroform, dioxane, N′N′-dimethyl formamide, N′N-dimethyl acetamide, and a mixture thereof.

15. The method of claim 1 , wherein the chlorinating agent in step a. is selected from the group consisting of phosphorus oxychloride (POCl 3 ), phosphorus trichloride (PCl 3 ), phosphorus pentachloride (PCl 5 ), phosgene (COCl 2 ), diphosgene (ClCO 2 CCl 3 ), triphosgene (Cl 3 CCO 2 CCl 3 ), chlorine (Cl 2 ), oxalyl chloride ((COCl) 2 ), thionyl chloride (SOCl 2 ), sulfuryl chloride (SO 2 Cl 2 ), and a mixture thereof.

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

17. The method of claim 1 , wherein the reaction of step b. is performed in the presence of an organic solvent selected from the group consisting of acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, N′-dimethyl formamide, N′N-dimethyl acetamide, dimethyl sulfoxide, and a mixture thereof.

Assignees

• Hanmi Pharm Ind Co Ltd

Inventors

• Baek Jong Ouk
• Jung Jae Hyuk
• Kim Ho Seok
• Ha Tae Hee
• Suh Kwee Hyun

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title