Method for preparing (1R, 2R)-2-(3, 4-difluoro phenyl)cyclopropylamine

A technology of difluorophenyl and cyclopropylamine, applied in the field of preparing -2-cyclopropylamine, can solve the problems of loss of raw materials, expensive reagents and high cost

Active Publication Date: 2016-06-29
DAILY FAME TRADING LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the prior art, there are mainly two methods for synthesizing (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine: one is by synthesizing the racemate of 2-(3,4-difluoro Phenyl) cyclopropylamine, obtain (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine then by resolution; Can lose half of the raw material like this, cause very big waste, an

Method used

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  • Method for preparing (1R, 2R)-2-(3, 4-difluoro phenyl)cyclopropylamine
  • Method for preparing (1R, 2R)-2-(3, 4-difluoro phenyl)cyclopropylamine
  • Method for preparing (1R, 2R)-2-(3, 4-difluoro phenyl)cyclopropylamine

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Experimental program
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Embodiment 1

[0050] Embodiment one: the preparation of compound A

[0051]

[0052] 450 ml of dichloromethane and 133.5 g (1 mol) of aluminum trichloride were added to the reaction flask, followed by stirring. Under nitrogen protection, 113 g (1 mol) of chloroacetyl chloride was added dropwise to the reaction solution, and the dropwise addition time was not less than 10 minutes. After the dropwise addition, the reaction solution was heated to reflux for reaction. After 30 minutes of reflux reaction, 97 g (0.85 mol) of 1,2-difluorobenzene was added dropwise under reflux for no less than 2 hours. After the dropwise addition, the reflux reaction was continued for 1 hour. After the reaction was completed, the reaction solution was cooled to 20° C., then slowly poured into 500 g of ice water, and stirred for 30 minutes. After separating the layers, the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, saturated sodium bicarbonate and wa...

Embodiment 2

[0053] Embodiment two: the preparation of product B

[0054]

[0055] 50 ml of methanol and 7.6 g (0.04 mol) of compound A were added to the reaction flask. Under the condition of stirring, the reaction solution was cooled to 0°C. Slowly add 0.378 g (0.01 mol) of sodium borohydride to the reaction solution, and the temperature during the addition is less than 5°C. After sodium borohydride was added, the temperature of the reaction solution was raised to room temperature for reaction. After the reaction, the reaction solution was cooled to 0°C, dichloromethane was added, and 10% NH 4 Cl aqueous solution 75ml. After completion of the dropwise addition, the mixture was stirred for 30 minutes. layered. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine. The organic layer was dried and filtered. The organic layer was concentrated to obtain 7.42g of product B with a yield of 96%; 1 H-NMR: δ (ppm): 3.9 (2H, dd); 5.3 (2...

Embodiment 3

[0056] Embodiment three: the preparation of product C

[0057]

[0058] 10.5 g (0.02625 mol) of 10% aqueous sodium hydroxide solution, 4.813 g (0.025 mol) of product B and 50 ml of dichloromethane (DCM) were added to the reaction flask. React under stirring conditions at room temperature. After the reaction was finished, it was cooled to room temperature, and the layers were separated. The aqueous layer was extracted with dichloromethane; the combined organic layers were washed with water. Dry and concentrate the organic layer to obtain 3.8g of product C with a yield of 97.4%; 1 H-NMR: δ2.71-2.73 (1H, dd); 3.13-3.15 (1H, m); 3.82-3.83 (1H, m); 7.01-7.27 (3H, m).

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Abstract

A method for preparing (1R, 2R)-2-(3, 4-difluoro phenyl)cyclopropylamine includes the steps of: taking 1,2-difluorbenzene as a raw material, and introducing chloracetyl on a benzene ring through the Friedel-Crafts reaction; carrying out reduction by using a boron hydrogen compound, then carrying out a dead circulation reaction, and obtaining a racemate 3,4-difluoro phenyl epoxyethane; carrying out hydrolysis reaction on the racemate 3,4-difluoro phenyl epoxyethane and water in the action of a catalyst to form (s)-3,4-difluoro phenyl epoxyethane; and carrying out reaction on the (s)-3,4-difluoro phenyl epoxyethane and phosphoryl triethyl acetate, then carrying out ammonolysis and Hofmann degradation reactions, and obtaining the (1R, 2R)-2-(3, 4-difluoro phenyl)cyclopropylamine. The method can avoid using expensive reagents during chirality redox, and obtains the (s)-3,4-difluoro phenyl epoxyethane through the kinetic resolution. The raw material cost is low, and the catalyst can be recycled. The (s)-3,4-difluoro phenyl epoxyethane can be obtained by configuration conversion of resolution generated R-configuration, and intermediate cost can be reduced.

Description

technical field [0001] The invention relates to a method for preparing (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine, which belongs to the technical field of medicinal chemistry. Background technique [0002] Ticagrelor (ticagrelor) is a new type of small molecule anticoagulant drug with selective effects. It was approved for marketing in December 2010 and July 2011 by the European Union and the US Food and Drug Administration (FDA). At present, more than 40 countries including the European Union, the United States, Brazil, Canada, Australia and Russia have approved ticagrelor for the treatment of acute coronary syndrome (acute coronary syndrome, ACS). Clinical trials have confirmed that, unlike thienopyridine anticoagulants such as clopidogrel and prasugrel, ticagrelor can reversibly act on the adenosine diphosphate (ADP) receptor subtype P2Y12, significantly inhibiting the Platelet aggregation, and oral administration is quick, helps to improve the symptoms of ACS patien...

Claims

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Application Information

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IPC IPC(8): C07C211/40C07C209/58C07C209/56
CPCY02P20/584C07C209/58C07B2200/07C07C29/106C07C29/143C07C45/46C07C67/26C07C209/56C07C231/02C07D301/00C07D301/28C07D303/08C07F7/1804C07C49/80C07C33/46C07C69/743C07C233/58C07C211/40
Inventor 吕学烱
Owner DAILY FAME TRADING LTD
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