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Method for preparing trans-(1R,2S)-2-(3,4-difluorophenyl) cyclopropylamine

A technology of difluorophenyl and cyclopropylamine, which is applied in the field of preparation of ticagrelor intermediate trans--2-cyclopropylamine, can solve the problems of long steps, rare raw materials, heavy pollution, etc., and is suitable for large-scale industrialization The production and reaction conditions are mild and the preparation method is simple

Inactive Publication Date: 2013-08-14
SUZHOU MIRACPHARMA TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] As mentioned above, although there are many studies on the preparation of ticagrelor intermediate B, there are many defects, such as long steps, rare raw materials, low yield, difficult separation, heavy pollution, safety restrictions and high cost. High, these unfavorable factors make the industrialization of the above process subject to certain restrictions

Method used

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  • Method for preparing trans-(1R,2S)-2-(3,4-difluorophenyl) cyclopropylamine
  • Method for preparing trans-(1R,2S)-2-(3,4-difluorophenyl) cyclopropylamine
  • Method for preparing trans-(1R,2S)-2-(3,4-difluorophenyl) cyclopropylamine

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Experimental program
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Effect test

Embodiment 1

[0036] Add 3,4-difluorobenzaldehyde (I) (7.1g, 0.05mol), nitromethane (7.7g, 0.1mol) and 50mL of ethanol into the reaction flask, start stirring, and add ammonium acetate (3.85g, 0.05mol) , acetic acid (4.2g, 0.07mol) and phase transfer catalyst cetyltrimethylammonium bromide (0.9g, 2.5mmol, 5%eq), warming up to 75-80 ° C, reflux reaction for 5 hours, TLC detection reaction Finish. Concentrate under reduced pressure to 1 / 3 of the volume, add 100 mL of water, cool to 10°C, and stir to crystallize. After filtration and drying, 7.8 g of light yellow solid β-(3,4-difluorobenzene)nitroethylene (II) was obtained, with a yield of 84.3%.

Embodiment 2

[0038] Add trans-1,2-cyclohexanediamine (0.34g, 3mmol), 3,5-tert-butyl salicylaldehyde (0.70g, 3mmol) and 25mL of dioxane in the reaction flask, start stirring, keep The reaction was stirred at 55°C for 1 hour. Diethylzinc (2.5 g, 30 mmol) and diiodomethane (12.1 g, 45 mmol) were added to the reaction flask and stirring was continued for 30 minutes. Dissolve β-(3,4-difluorobenzene)nitroethylene (II) (2.8g, 15mmol) in 10mL of dioxane, drop it into the above reaction system within 30 minutes, and keep it at 55°C for 5 hours. TLC detects that the reaction is complete. Cool to room temperature, add ethyl acetate and water, and separate layers. The organic phase was washed with brine and dried over anhydrous sodium sulfate. The solvent was recovered by distillation under reduced pressure, and the residual oil was recrystallized from n-hexane to obtain 2.6 g of trans-2-(3,4-difluorophenyl)nitrocyclopropane (III) as a light yellow solid, with a yield of 87.0%.

Embodiment 3

[0040] Add trans-2-(3,4-difluorophenyl)nitrocyclopropane(III) (3.0g, 15mmol), sodium dithionite (15.7g, 90mmol), 50mL of toluene and 50mL of water into the reaction flask, At the same time, 0.25 g of tetrabutylammonium bromide was added. Start stirring, keep stirring at 65° C. for 4 hours, and TLC detects that the reaction is complete. Cool to room temperature, separate the organic layer, wash the water layer twice with toluene, combine the organic phases, wash with 5% sodium bicarbonate and water successively, dry, and recover the solvent by distillation under reduced pressure, and dissolve the residual oily matter with ethyl acetate. Add S-mandelic acid (2.28g, 15mmol), stir at room temperature for 6-8 hours, cool down to 0°C, filter, and the obtained solid is S-mandelic acid salt of the target product. The solid was placed in 50 mL of water, the pH was adjusted to 12-13 with 30% sodium hydroxide, extracted three times with ethyl acetate, and the organic phases were combined....

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Abstract

The invention discloses a method for preparing ticagrelor intermediate trans-(1R,2S)-2-(3,4-difluorophenyl) cyclopropylamine (intermediate B). The method comprises the following steps of: carrying out condensation reaction between 3,4-difluorobenzaldehyde and nitromethane to obtain trans-beta-(3,4-difluorobenzene)nitroethylene (II); carrying ou cyclopropanation reaction of the compound (II), with zinc iodide and diethyl zinc under catalytic action of chiral ligand, thus generating trans-2-(3,4-difluorophenyl)nitrocyclopropylamine (III), and finally, carrying out nitroreduction reaction of the compound (III), thus obtaining the intermediate B. The preparation method provided by the invention is simple and convenient, economical and environment-friendly, and advantageous for industrial production of the drug; besides, the preparation method is also capable of promoting the development of the economic technology of the crude drug.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, in particular to a trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine intermediate of ticagrelor method of preparation. Background technique [0002] Ticagrelor (also known as ticagrelor) is a new type of selective small molecule anticoagulant drug developed by AstraZeneca, and it is also the first reversible conjugated oral P2Y12 adenosine di The phosphate receptor antagonist has obvious inhibitory effect on ADP-induced platelet aggregation, and can effectively improve the symptoms of patients with acute coronary heart disease. The drug was approved by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) for marketing in the EU and the US in 2010 and 2011 respectively, and its imported preparation, ticagrelor tablets, has been approved by the SFDA for marketing in my country. [0003] Tica...

Claims

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Application Information

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IPC IPC(8): C07C211/37C07C209/34
Inventor 许学农
Owner SUZHOU MIRACPHARMA TECH
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