Intermediates useful for the synthesis of a selective inhibitor against protein kinase and processes for preparing the same

Patent metadata

Field	Value
Publication number	US-11198684-B2
Application number	US-201816633756-A
Country	US
Kind code	B2
Filing date	Jul 25, 2018
Priority date	Jul 28, 2017
Publication date	Dec 14, 2021
Grant date	Dec 14, 2021

Abstract

The present invention provides intermediates useful for the synthesis of an aminopyrimidine derivative or pharmaceutically acceptable salt thereof having a selective inhibitory activity against protein kinases, especially against the protein kinases for mutant epidermal growth factor receptors; and processes for preparing the same. And also, the present invention provides novel intermediates useful for said process and processes for preparing the same.

First claim

The invention claimed is:

1. A process for preparing N-(5-(4-(4-formyl-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-4-methoxy-2-morpholinophenyl)acrylamide, the process comprising reacting tert-butyl (5-acrylamido-2-methoxy-4-morpholinophenyl)carbamate or N-(5-amino-4-methoxy-2-morpholinophenyl)acrylamide with a compound of Formula 13:

wherein, Z is halogen.

2. The process according to claim 1 , wherein the N-(5-amino-4-methoxy-2-morpholinophenyl)acrylamide is obtained by reacting tert-butyl (5-acrylamido-2-methoxy-4-morpholinophenyl)carbamate with an acid.

3. The process according to claim 2 , wherein the acid is one or more selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid and p-toluenesulfonic acid.

4. The process according to claim 1 , wherein the reacting of tert-butyl (5-acrylamido-2-methoxy-4-morpholinophenyl)carbamate with the compound of Formula 13 is carried out in the presence of an acid.

5. The process according to claim 4 , wherein the acid is one or more selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid and p-toluenesulfonic acid.

6. The process according to claim 1 , wherein the reacting of the N-(5-amino-4-methoxy-2-morpholinophenyl)acrylamide with the compound of Formula 13 is carried out in the presences of a metal catalyst, a ligand, and a base.

7. The process according to claim 6 , wherein the metal catalyst is one or more selected from the group consisting of palladium, copper, iron, cadmium, zinc, and nickel.

8. The process according to claim 7 , wherein the metal catalyst is palladium acetate, palladium acetylacetonate, bis(dibenzylideneacetone)palladium, or tris(dibenzylideneacetone)dipalladium.

9. The process according to claim 6 , wherein the ligand is one or more selected from the group consisting of 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene, 1,1′-bis(diphenylphosphino)ferrocene, and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

10. The process according to claim 6 , wherein the base is one or more selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, cesium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, triethylamine, diisopropylamine, and diisopropylethylamine.

11. The process according to claim 1 , wherein the reacting of N-(5-amino-4-methoxy-2-morpholinophenyl)acrylamide with the compound of Formula 13 is carried out in the presence of an acid.

12. The process according to claim 11 , wherein the acid is one or more selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid and p-toluenesulfonic acid.

13. The process according to claim 1 , wherein the tert-butyl (5-acrylamido-2-methoxy-4-morpholinophenyl)carbamate is obtained by a process comprising
(i) reacting tert-butyl (5-amino-2-methoxy-4-morpholinophenyl)carbamate with a compound of Formula 11 to form a compound of Formula 5; and
(ii) reacting the compound of Formula 5 with a base to obtain tert-butyl (5-acrylamido-2-methoxy-4-morpholinophenyl)carbamate:

wherein, X and Y are, independently of each other, halogen.

14. The process according to claim 13 , wherein Step (i) and Step (ii) are carried out in a one-pot reaction without isolating the compound of Formula 5.

15. The process according to claim 13 , wherein the reacting of Step (i) or the reacting of Step (ii) is carried out in the presence of one or more base(s) selected from the group consisting of potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, sodium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, triethylamine, diisopropylamine and diisopropylethylamine.

16. The process according to claim 13 , wherein the tert-butyl (5-amino-2-methoxy-4-morpholinophenyl)carbamate is obtained by performing a reduction of tert-butyl (2-methoxy-4-morpholino-5-nitrophenyl)carbamate.

17. The process according to claim 16 , wherein the reduction is carried out with a reducing agent selected from the group consisting of formic acid and ammonium formate.

18. The process according to claim 16 , wherein the reduction is carried out in the presence of a catalyst selected from the group consisting of palladium, palladium/carbon, zinc, copper, magnesium, and platinum.

19. The process according to claim 16 , wherein the tert-butyl (2-methoxy-4-morpholino-5-nitrophenyl)carbamate is obtained by reacting tert-butyl (4-fluoro-2-methoxy-5-nitrophenyl)carbamate with morpholine.

20. The process according to claim 19 , wherein the reacting is carried out in the presence of one or more base(s) selected from the group consisting of sodium hydride, sodium C 1 ˜C 6 alkoxide, potassium C 1 ˜C 6 alkoxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, pyridine, dimethylaminopyridine, triethylamine, and diisopropylethylamine.

21. The process according to claim 19 , wherein the tert-butyl (4-fluoro-2-methoxy-5-nitrophenyl)carbamate is obtained by reacting 4-fluoro-2-methoxy-5-nitroaniline with dibutyl dicarbonate.

22. The process according to claim 1 , wherein the compound of Formula 13 is obtained by reacting a compound of Formula 14 with 3-phenyl-1H-pyrazole-4-carbaldehyde:

wherein, Z and Z′ are, independently of each other, halogen.

23. A compound, wherein said compound is N-(5-amino-4-methoxy-2-morpholinophenyl)acrylamide.

24. A compound, wherein said compound is tert-butyl (5-acrylamido-2-methoxy-4-morpholinophenyl)carbamate.

25. A compound of Formula 5 or salt thereof:

wherein, Y is halogen.

26. A compound, wherein said compound is tert-butyl (5-amino-2-methoxy-4-morpholinophenyl)carbamate.

27. A compound, wherein said compound is tert-butyl (2-methoxy-4-morpholino-5-nitrophenyl)carbamate.

Assignees

• Yuhan Corp

Inventors

• Oh Sang-Ho
• Khoo Ja-Heouk
• Lim Jong-Chul
• Lee Doo-Byung
• Lee Jung-Ae
• Lee Jun-Sup
• Ju Hyun
• Shin Woo-Seob
• Jeon Sang-Seol

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D295/155 Primary

  with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• C07D295/135 Primary

  with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title