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Synthesis of (1r,2s)-1-amino-(3,4-difluorophenyl)-cyclopropane

A technology of difluorophenyl and cyclopropane, which is applied in the field of synthesizing ticagrelor intermediate-1-amino-cyclopropane, can solve the problems of low yield, long reaction steps, harsh reaction conditions and the like, and achieves easy availability of raw materials. Inexpensive, low production cost, and the effect of improving yield

Inactive Publication Date: 2018-04-24
NORTH CHINA UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] This route also has long reaction steps, the acid chloride used has a corrosive effect on the equipment, and the obtained product is a racemized product, which needs to be further resolved, which is not conducive to industrialization
[0014] In summary, although there are many studies on the preparation of (1R,2S)-1-amino-(3,4-difluorophenyl)-cyclopropane, there are many defects, such as long steps and harsh reaction conditions. , a large amount of chiral reagents are used, the cost is high, the yield is low, etc., the art still needs a better preparation method of (1R,2S)-1-amino-(3,4-difluorophenyl)-cyclopropane to solve the problem above question

Method used

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  • Synthesis of (1r,2s)-1-amino-(3,4-difluorophenyl)-cyclopropane
  • Synthesis of (1r,2s)-1-amino-(3,4-difluorophenyl)-cyclopropane
  • Synthesis of (1r,2s)-1-amino-(3,4-difluorophenyl)-cyclopropane

Examples

Experimental program
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Embodiment 1

[0035] Synthesis of (1R,2S)-1-cyano-2-(3,4-difluorophenyl)cyclopropane

[0036]Mix 14.2g (100mmol) of 3,4-difluorobenzaldehyde and 25.4g (100mmol) of bis-linked pinacol borate in 50ml of tetrahydrofuran and stir at 30°C for 3 hours to obtain mixture A; 12g (300mmol) of sodium hydroxide and 28.1g (150mmol) of 2-iodopropionitrile were added to mixture A and stirred at 60°C for 4 hours. After monitoring the completion of the reaction, the temperature was lowered to room temperature, 50ml of water was added, extracted with ethyl acetate, the organic phase was washed with water, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure and recrystallize from petroleum ether to obtain 15.6 g of (1R,2S)-1-cyano-2-(3,4-difluorophenyl)cyclopropane with a yield of 87.3% and an HPLC purity of 99.20% (area normalized Law).

Embodiment 2

[0038] Synthesis of (1R,2S)-1-cyano-2-(3,4-difluorophenyl)cyclopropane

[0039] 14.2g (100mmol) of 3,4-difluorobenzaldehyde and 20.3g (80mmol) of bis-linked pinacol borate were mixed in 60ml of tetrahydrofuran and stirred at 35°C for 4 hours to obtain mixture A; 8.0g (200mmol) of sodium hydroxide ) and 28.1g (150mmol) of 2-iodopropionitrile were added to mixture A and stirred at 50°C for 4 hours. After monitoring the completion of the reaction, cool down to room temperature, add 50ml of water, extract with ethyl acetate, wash the organic phase with water, and dry over anhydrous sodium sulfate. , concentrated under reduced pressure, recrystallized petroleum ether to obtain (1R,2S)-1-cyano-2-(3,4-difluorophenyl)cyclopropane 15.5g, yield 86.6%, HPLC purity 98.95% (area normalized one method).

Embodiment 3

[0041] Synthesis of (1R,2S)-1-cyano-2-(3,4-difluorophenyl)cyclopropane

[0042] 14.2g (100mmol) of 3,4-difluorobenzaldehyde and 22.8g (90mmol) of bis-linked pinacol borate were mixed in 50ml of tetrahydrofuran and stirred at 40°C for 3 hours to obtain mixture A; 16g (400mmol) of sodium hydroxide Add 21.7g (120mmol) of 2-iodopropionitrile into mixture A and stir at 45°C for 4 hours, monitor the completion of the reaction, cool down to room temperature, add 50ml of water, extract with ethyl acetate, wash the organic phase with water, and dry over anhydrous sodium sulfate. Concentration under reduced pressure and recrystallization from petroleum ether gave (1R,2S)-1-cyano-2-(3,4-difluorophenyl)cyclopropane 15.6g, yield 87.1%, HPLC purity 98.67% (area normalized Law).

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Abstract

The present invention relates to a method for synthesizing (1R,2S)-1-amino-(3,4-difluorophenyl)-cyclopropane. The method is characterized by comprising: 1) mixing 3,4-difluorobenzaldehyde and bis(pinacolato)diboron in tetrahydrofuran to obtain a mixture A; 2) adding an alkali and 2-iodopropionitrile to the mixture A, and carrying out a stirring reaction to obtain (1R,2S)-1-cyano-2-(3,4-difluorophenyl)cyclopropane; 3) carrying out alkaline hydrolysis on the product obtained in the step 2) to obtain (1R,2S)-1-amido-2-(3,4-difluorophenyl)cyclopropane; and 4) in a sodium hydroxide aqueous solution, carrying out a downgrade reaction to obtain the (1R,2S)-1-amino-(3,4-difluorophenyl)-cyclopropane. According to the present invention, the method provides the new synthesis approach for ticagrelor and the intermediate thereof, has characteristics of high stereoselectivity, low production cost, high yield and simple operation, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis and relates to a method for synthesizing ticagrelor intermediate (1R,2S)-1-amino-(3,4-difluorophenyl)-cyclopropane. Background technique [0002] Ticagrelor (also known as ticagrelor) is a new type of selective small molecule anticoagulant, and it is also the first reversible binding oral P2Y12 adenosine diphosphate receptor antagonist. The platelet aggregation caused by ADP has obvious inhibitory effect, which can effectively improve the symptoms of patients with acute coronary heart disease. The drug has been approved for marketing by the European Medicines Agency (EMEA), the US Food and Drug Administration (FDA), and the China Food and Drug Administration (SFDA). Ticagrelor was developed by AstraZeneca, the chemical name is: (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl) ring Propylamino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane -1...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C209/62C07C211/40C07C231/06C07C233/58C07C253/30C07C255/46
CPCC07C209/62C07C231/06C07C253/30C07C211/40C07C233/58C07C255/46
Inventor 孙泽林戚晓渊沈海涛戚素银韩晓燕
Owner NORTH CHINA UNIVERSITY OF SCIENCE AND TECHNOLOGY