Process for preparing aminopyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-11286253-B2
Application number	US-202017115037-A
Country	US
Kind code	B2
Filing date	Dec 8, 2020
Priority date	Jul 28, 2017
Publication date	Mar 29, 2022
Grant date	Mar 29, 2022

Abstract

The present invention provides an improved process for preparing 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. Additional, the present invention provides novel intermediates useful for said process and processes for preparing the same.

First claim

What is claimed is:

1. A process for preparing N-(544-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide or a pharmaceutically acceptable salt thereof, the process comprising
(a) reacting N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine with a compound of Formula 4 in acetonitrile in the presence of sodium hydroxide to obtain a compound of Formula 2; and
(b) reacting the compound of Formula 2 with triethylamine in n-propanol to obtain N-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamide:

wherein, X is halogen.

2. The process according to claim 1 , wherein Step (a) and Step (b) are carried out in a one-pot reaction.

3. The process according to claim 1 , wherein the N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine in Step (a) is obtained by a process comprising
(i) reacting 4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine with tin chloride dihydrate in the presence of hydrochloric acid and water to obtain a complex of Formula 5 and
(ii) reacting the complex of Formula 5 with sodium hydroxide to obtain N1-(4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-methoxy-4-morpholinobenzene-1,3-diamine:

4. The process according to claim 3 , wherein the 4-(4-((dimethylamino)methyl)-3-phenyl-1H-pyrazol-1-yl)-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine is obtained by reacting 1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde with dimethylamine hydrochloride, N,N-diisopropylethylamine, and sodium triacetoxyborohydride in N,N-dimethylacetamide and acetonitrile.

5. The process according to claim 4 , wherein the 1-(2-((2-methoxy-4-morpholino-5-nitrophenyl)amino)pyrimidin-4-yl)-3-phenyl-1H-pyrazole-4-carbaldehyde is obtained by reacting 4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine with 3-phenyl-1H-pyrazole-4-carbaldehyde in N,N-dimethylformamide under basic conditions using potassium carbonate.

6. The process according to claim 5 , wherein the 4-chloro-N-(2-methoxy-4-morpholino-5-nitrophenyl)pyrimidin-2-amine is obtained by reacting N-(2-methoxy-4-morpholino-5-nitrophenyl)formamide with 4-chloro-2-(methyl sulfonyl)pyrimidine.

7. The process according to claim 6 , wherein the N-(2-methoxy-4-morpholino-5-nitrophenyl)formamide is obtained by performing a formylation of 2-methoxy-4-morpholino-5-nitroaniline.

8. The process according to claim 7 , wherein the formylation is carried out with a mixture of acetic acid and formic acid.

9. The process according to claim 6 , wherein the 4-chloro-2-(methylsulfonyl)pyrimidine is obtained by performing an oxidation of 4-chloro-2-(methylthio)pyrimidine.

10. The process according to claim 9 , wherein the oxidation is carried out with one or more oxidizing agent(s) selected from the group consisting of potassium permanganate, chromic acid, oxygen, hydrogen peroxide and 3-chloroperbenzoic acid.

Assignees

• Yuhan Corp

Inventors

• Oh Sang-Ho
• Khoo Ja-Heouk
• Lim Jong-Chul
• Lee Seong-Ran
• Ju Hyun
• Shin Woo-Seob
• Park Dae-Gyu
• Park su-min
• Hwang Yoon-Ah

Classifications

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07F7/2284 Primary

  Compounds with one or more Sn-N linkages · CPC title

• C07D403/04

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