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
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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

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  • 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...

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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

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Application Information

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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
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