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A kind of preparation technology of (1r, 2s)-1-cyano-2-(3,4-difluorophenyl) cyclopropane

A technology for the preparation of difluorophenyl, which is applied in the field of preparation of ticagrelor intermediate 1-cyano-2-cyclopropane, achieving high stereoselectivity, high overall yield, and easy operation of the preparation process Effect

Inactive Publication Date: 2018-03-20
杨绮红 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] At present, there is no report on the preparation of (1R,2S)-1-cyano-2-(3,4-difluorophenyl)cyclopropane to obtain chiral target products through chemical stereoselection by using achiral raw materials

Method used

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  • A kind of preparation technology of (1r, 2s)-1-cyano-2-(3,4-difluorophenyl) cyclopropane
  • A kind of preparation technology of (1r, 2s)-1-cyano-2-(3,4-difluorophenyl) cyclopropane
  • A kind of preparation technology of (1r, 2s)-1-cyano-2-(3,4-difluorophenyl) cyclopropane

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Effect test

Embodiment 1

[0026] Preparation of (2S)-2-(3,4-difluorophenyl)oxirane

[0027] Under the protection of nitrogen, mix (S)-binaphthol phosphate 7g (20mmol) and 3,4-difluorostyrene 14.0g (100mmol) in tetrahydrofuran for 10-15min, then keep 20°C and add hydrogen peroxide (30% , 300mmol), continue to maintain the temperature and stir the reaction for 4 hours. After the reaction is completed, add water to the reaction solution, separate layers, wash the organic layer with water, concentrate under reduced pressure, and recrystallize petroleum ether to obtain (2S)-2-(3,4-difluoro Phenyl)oxirane 14.7g, yield 94.1%, ee value 99.15%. 1 H NMR (400MHz, CDCl3) δ: 7.03-7.28 (m, 4H), 3.81-3.84 (m, 1H), 3.10-3.15 (m, 1H), 2.69-2.72 (dd, J=2.45Hz, 1H).

Embodiment 2

[0029] Preparation of (2S)-2-(3,4-difluorophenyl)oxirane

[0030] Under the protection of nitrogen, mix 20.9g (60mmol) of (S)-binaphthol phosphate and 28g (200mmol) of 3,4-difluorostyrene in tetrahydrofuran for 10-15min, then add hydrogen peroxide (30% , 500mmol), continue to maintain the temperature and stir the reaction for 3 hours. After the reaction is completed, add water to the reaction solution, separate layers, wash the organic layer with water, concentrate under reduced pressure, and recrystallize petroleum ether to obtain (2S)-2-(3,4-difluoro Phenyl)oxirane 14.6g, yield 93.2%, ee value 99.01%.

Embodiment 3

[0032] Preparation of (2S)-2-(3,4-difluorophenyl)oxirane

[0033] Under nitrogen protection, mix 7g (20mmol) of (S)-binaphthol phosphate and 14g (100mmol) of 3,4-difluorostyrene in tetrahydrofuran for 10-15min, then add 142.0g (30mmol) of hydrogen peroxide dropwise at 10°C %, 200mmol), continue to maintain the temperature and stir the reaction for 4 hours, after the reaction is completed, add water to the reaction solution, separate layers, wash the organic layer with water, concentrate under reduced pressure, and recrystallize petroleum ether to obtain (2S)-2-(3,4-di Fluorophenyl)oxirane 14.9g, yield 95.5%, ee value 98.92%.

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Abstract

The invention discloses a preparation process for (1R,2S)-1-cyano-2-(3,4-difluoro-phenyl)cyclopropane. The preparation process comprises the following steps: 1) in the presence of (S)-(+)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate, performing a contact reaction on 3,4-difluorostyrene and hydrogen peroxide to obtain (2S)-2-(3,4-diflurophenyl)-ethylene oxide; 2) in the presence of alkali, making the (2S)-2-(3,4-diflurophenyl)-ethylene oxide react with diethyl cyanomethylphosphonate in 1,4-dioxane to obtain a target product. By adopting the preparation process, the use of chiral raw materials is avoided, and the reaction cost is lowered; moreover, the (1R,2S)-1-cyano-2-(3,4-difluoro-phenyl)cyclopropane is synthesized conveniently through the diethyl cyanomethylphosphonate, so that high overall yield and three-dimensional selectivity are achieved; furthermore, the method is easy and convenient to operate, and is suitable for industrial expandable production.

Description

technical field [0001] The invention relates to a synthesis technology of a drug intermediate, in particular to a preparation process of a ticagrelor intermediate (1R,2S)-1-cyano-2-(3,4-difluorophenyl)cyclopropane. Background technique [0002] Ticagrelor (Ticagrelor) is a new type of selective small molecule anticoagulant drug developed by AstraZeneca, and it is also the first reversible binding oral P2Y12 adenosine diphosphate receptor antagonist, It has obvious inhibitory effect on platelet aggregation caused by ADP, and can effectively improve the symptoms of patients with acute coronary heart disease. As a small molecule anticoagulant drug, the drug has been marketed in many countries around the world. [0003] The chemical name of ticagrelor is: (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5- (Propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-di Alcohol, the specific structural formula is as follows: [0...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C253/30C07C255/46
CPCC07B2200/07C07C253/30C07D301/26C07D303/08C07C255/46
Inventor 杨绮红张维爱
Owner 杨绮红
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