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Preparation method of important intermediate of ticagrelor (1r, 2s)-2-(3,4-difluorophenyl)cyclopropylamine

A technology of difluorophenyl and ticagrelor, which is applied in the fields of organic synthesis and chemical medicine preparation, can solve the problems of poor reaction stereoselectivity, accidental damage, environmental pollution, explosive and harmful reagents, etc., and achieves excellent economic efficiency, The effect of shortening the process route and reducing the risk of accidental injury

Active Publication Date: 2016-05-11
ZHEJIANG YONGTAI TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although the two synthetic routes reported above have been developed and improved for several years, they still have the disadvantages of long routes, poor reaction stereoselectivity, high production costs, explosive and harmful reagents, and accidental injuries and injuries in the production process. The shortcomings that are difficult to overcome, such as environmental pollution, are not conducive to large-scale industrial production

Method used

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  • Preparation method of important intermediate of ticagrelor (1r, 2s)-2-(3,4-difluorophenyl)cyclopropylamine
  • Preparation method of important intermediate of ticagrelor (1r, 2s)-2-(3,4-difluorophenyl)cyclopropylamine
  • Preparation method of important intermediate of ticagrelor (1r, 2s)-2-(3,4-difluorophenyl)cyclopropylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0042] Add camphorsulfonium ylide I (24.4g, 0.06mol), THF (300mL) and acrylonitrile (2.65g, 0.05mol) successively into a 500mL three-neck flask, place at -10°C, add potassium tert-butoxide (16.8 g, 0.15mol), after the addition was completed, the reaction was continued at -10°C, and the reaction was monitored by TLC. After the reaction was completed for about 12 hours, the reaction mixture was first filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. Color oily product II 7.6g. The yield was 85.0%.

Embodiment 1-2

[0043] Embodiment 1-2. (1R,2R)-2-(3,4-difluorophenyl) the synthesis of cyclopropyl nitrile compound II

[0044] Add camphorsulfonium ylide I (24.4g, 0.06mol), THF (200mL) and acrylonitrile (2.65g, 0.05mol) successively into a 500mL three-neck flask, place at -78°C, add potassium tert-butoxide (16.8 g, 0.15mol), after the addition was completed, the reaction was continued at -78°C, and the reaction was monitored by TLC. After the reaction was completed for 24 hours, the reaction mixture was first filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was colorless after simple removal of impurities. Oily product II 7.3 g. The yield was 82.0%.

Embodiment 1-3

[0045]Embodiment 1-3. (1R,2R)-2-(3,4-difluorophenyl) the synthesis of cyclopropyl nitrile compound II

[0046] Add camphorsulfonium ylide I (20.3g, 0.05mol), methyltetrahydrofuran (200mL) and acrylonitrile (2.65g, 0.05mol) in sequence in a 500mL three-neck flask, place at -50°C, and add potassium tert-butoxide (16.8g, 0.15mol), after the addition was completed, the reaction was continued at -50°C, and the reaction was monitored by TLC. After the reaction was completed for 20 hours, the reaction mixture was first filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was obtained by simple removal of impurities. Colorless oily product II 8.5g. The yield was 84%.

[0047] Then use the (1R,2R)-2-(3,4-difluorophenyl)cyclopropylnitrile compound II prepared in any of the above Examples 1-1~1-3 for the synthesis of (1R,2R)- 2-(3,4-difluorophenyl) cyclopropyl formamide III, specific examples are as follows:

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Abstract

The invention relates to a method for preparing important midbody (1R,2S)-2-(3,4-difluorinated phenyl) cyclopropylamine of ticagrelor. The method mainly comprises the following steps: performing cyclopropane reaction on camphor sulfonium ylide I and acrylonitrile, synthesizing (1R, 2S)-2-(3,4-difluorinated phenyl) cyclopropyl nitrile II in a stereoselectivity manner, and further performing hydrolysis and holfman degradation reaction, thereby obtaining a target product IV. The method has the characteristics of cheap initial materials, high yield, good stereoselectivity, high enantioselectivity, low production cost and the like, and has important significance in industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis and chemical medicine preparation, and relates to a preparation method of (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine, in particular to a method for preparing anticoagulant The preparation method of the important intermediate (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine of the drug ticagrelor. technical background [0002] Ticagrelor is a novel, small molecule anticoagulant drug developed by AstraZeneca, and is the first reversibly binding, direct-acting, orally administered platelet adenosine diphosphate P2Y12 receptor antagonist. (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine as shown in formula IV is an important intermediate for the synthesis of anticoagulant drug ticagrelor, and its synthesis method research has been very active, There are many literature and patent reports. So far, there are two main synthetic routes of (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine reporte...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C211/40C07C209/56
Inventor 何人宝管月清周国斌
Owner ZHEJIANG YONGTAI TECH CO LTD
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