Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Synthesis of 4-aminopyrimidine compounds

A compound, isobutylpyrimidine technology, applied in the field of organic compound manufacturing, can solve problems such as being unsuitable for modern industrial needs

Active Publication Date: 2020-07-28
帕劳制药有限公司
View PDF2 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, existing methods are not suitable for the needs of modern industry in terms of cost and environmental impact

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthesis of 4-aminopyrimidine compounds
  • Synthesis of 4-aminopyrimidine compounds
  • Synthesis of 4-aminopyrimidine compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0219] Example 1: Synthesis of compound (V) [6-amino-2-isobutylpyrimidin-4-ol]

[0220] Reaction: 3-methylbutyramide imide acetate [Compound (VI)] (20.0 g; 125 mmol; 1.0 equivalent) was suspended in EtOH (40 ml; 2 relative volumes). 21% by weight of NaOEt (60.7 g; 187 mmol; 1.5 equivalents) was added and heated to 70°C. A solution of ethyl 2-cyanoacetate [Compound (VII)] (16.2 g; 144 mmol; 1.15 equivalents) (about 4 hours) was slowly added to EtOH (20 ml; 2 volumes). After 40% addition of [Compound (V) 45%] and 100% addition of [Compound (V) 69%], the conversion rate was checked by GC. After reacting at 70°C for 21 hours [85% compound (V)], the conversion rate was checked by GC. The mixture was stirred overnight at 70°C.

[0221] Work-up and separation: The mixture was cooled to 50°C and then quenched with AcOH (0.55 equivalents; 4.13 g). Fill with water (8 volumes). The mixture was concentrated to about 7 volumes at 50°C to 55°C. The suspension was stripped with ACN (3 volum...

Embodiment 2

[0223] Example 2: Synthesis of compound (III) [6-chloro-2-isobutylpyrimidin-4-amine]

[0224] Reaction: The 6-amino-2-isobutylpyrimidin-4-ol [compound (V)] (30.0 g; 179 mmol; 1.0 equivalent) from Example 1 was suspended in ACN (150 ml; 5) at room temperature (RT) Volume). Join POCl 3 (138g; 897mmol; 5.0 equivalents). The suspension was gradually heated to 60°C, 65°C, then 70°C, and stirred at 70°C for 15 minutes. The suspension was further heated to 80°C and stirred overnight. After 19 hours at 80°C, the conversion rate ([Compound (III)] 98.9%) was checked by HPLC.

[0225] Work-up: Concentrate the mixture at 60°C to 70°C to about 3 relative volumes. The mixture was stripped 3 times with toluene (3 volumes) at 60°C to 70°C, diluted with toluene (2 volumes), and then the temperature was adjusted to ±50°C. The mixture was quenched with water (5 volumes). The temperature was adjusted to 60°C, and the mixture was stirred at 55°C to 65°C for at least 30 minutes. Phase separation...

Embodiment 3

[0228] Example 3: Compound (II') [(1-(6-amino-2-isobutylpyrimidin-4-yl)azetidin-3-yl) (formula Base) tert-butyl carbamate] synthesis

[0229] Reaction: The 6-chloro-2-isobutylpyrimidin-4-amine [compound (III)] (25.0 g; 135 mmol; 1.0 equivalent) from Example 2 was combined with K 2 CO 3 (22.3 g; 162 mmol; 1.2 equivalents) was added to the reactor. Add tert-butyl azetidine-3-yl (methyl) carbamate dissolved in dimethyl sulfoxide [Compound (IV')] (26.1 g, 140 mmol, 1.04 equivalent) (m Solution = 148g, 17.6% by weight), the mixture was heated to 110°C. The conversion rate was measured after 24 hours (compound (II') 93%).

[0230] Workup and separation: the mixture was cooled to 50°C to 60°C, then diluted with water (6 volumes) and EtOAc (10 volumes) and stirred for 5 minutes. Phase separation: Separate OL, then wash with water (2 volumes). Concentrate OL to about 6 relative volumes at 65°C to 75°C. The solution was stripped 3 times with iPAc (4 volumes). The solution was slowly c...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention relates to a process for manufacturing 2-isobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine of Formula (I) comprising starting from 6-chloro-2-isobutylpyrimidin-4-amine and tert-butyl azetidin-3-yl(methyl)carbamate, or another N-protected N-methylazetidin-3-amine, and performing the following steps: (a) coupling reaction of both compounds in dimethyl sulfoxide in presence of potassium carbonate to afford an intermediate protected compound; and (b) deprotection of the protected compound to afford 2-isobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine. The invention also relates to a process for manufacturing the intermediate protected compound, wherein deprotection step (b) is omitted. The invention also relates to the compounds obtained from the processes according to the invention.

Description

[0001] Invention field [0002] The present invention relates to the field of manufacturing organic compounds. The invention particularly relates to the synthesis of 2-isobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine. Background technique [0003] 4-aminopyrimidine derivatives are a class of compounds with general formula (A): [0004] [0005] It can be used as a therapeutic active ingredient, especially histamine H4 receptor antagonist. [0006] Among the 4-aminopyrimidine derivatives, 2-isobutyl-6-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine of formula (I) (hereinafter referred to as "compound (I)", abbreviated as "(I)") is of particular interest: [0007] [0008] WO 2009 / 080721 patent application describes the compound of formula (I) and several different synthetic methods, especially the chlorinated aromatic compound and tert-butoxycarbonyl (Boc) protected heterocyclic ring as shown in the following scheme 1. Base-assisted coupling of diamines: [0009] [0010] pla...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61P29/00A61P37/00A61K31/506
CPCC07D403/04A61P29/00A61P37/00
Inventor 达恩·乔普曼斯阿芒丁·莫尔莫里斯·休伯特·邦滕道恩·多伦多
Owner 帕劳制药有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com