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Method for preparing trans-(1R, 2R)-2-(3, 4-difluoro phenyl)-1-cyclopropane formic acid

A technology of cyclopropanecarboxylic acid and difluorophenyl, which is applied in the field of preparation of trans--2--1-cyclopropanecarboxylic acid, can solve the problems of rare raw materials, difficult separation, heavy pollution, etc., and achieves a simple preparation method, three-dimensional The effect of good selectivity and easy availability of raw materials

Active Publication Date: 2014-04-23
ZHONGSHAN HAIHONG MEDICINE CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0021] In summary, although there are many studies on the preparation of trans-(1R, 2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxylic acid, there are more or less defects, such as The unfavorable factors such as long steps, rare raw materials, low yield, difficult separation, heavy pollution and high cost make the industrialization of the above process subject to certain restrictions.

Method used

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  • Method for preparing trans-(1R, 2R)-2-(3, 4-difluoro phenyl)-1-cyclopropane formic acid
  • Method for preparing trans-(1R, 2R)-2-(3, 4-difluoro phenyl)-1-cyclopropane formic acid
  • Method for preparing trans-(1R, 2R)-2-(3, 4-difluoro phenyl)-1-cyclopropane formic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0036] Example 1. Preparation of trans-(1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanemethanol:

[0037]

[0038] (E)-3-(3,4-difluorophenyl)prop-2-en-1-ol (1.70g, 10mmol) and (1R,2R)-1,2-N,N'-bis(3 , 5-dichlorobenzenesulfonamido)cyclohexane (5 mmol%) in 100 mL of anhydrous CH 2 Cl 2 solution, keep the temperature at -15-0°C, add Et 2 Zn (1mol / L n-hexane solution 20mL, 20mmol) and CH 2 I 2 (8.04g, 30mmol), keep the reaction for 5 hours, rise to room temperature, add 50mL of 2mol / L NaOH solution, and use 100mL CH 2 Cl 2After three extractions, the catalyst can be recovered by acidifying the aqueous layer. The organic layers were combined, washed once with saturated aqueous sodium chloride, dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure to obtain trans-(1R,2R)-2-(3,4-difluorophenyl)-1- Cyclopropanemethanol 1.66g, yield 90%, ee value: 97% (HPLC, chiral column, 3% isopropanol n-hexane). IR (KBr): 3450, 362, 3012, 2927, 1865, 1605, 149...

Embodiment 2

[0039] Example 2. Preparation of trans-(1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanemethanol:

[0040] (E)-3-(3,4-difluorophenyl)prop-2-en-1-ol (1.70g, 10mmol) and (1R,2R)-1,2-N,N'-bis(3 , 5-dichlorobenzenesulfonamido)cyclohexane (5 mmol%) in 100 mL of anhydrous CH 2 Cl 2 solution, keep the temperature at -15-0°C, add Et 2 Zn (1mol / L n-hexane solution 21mL, 21mmol) and CH 2 I 2 (8.04g, 30mmol), heat preservation reaction for 5 hours, refer to Example 1 for post-treatment process, yield 94%, ee value: 98.9%.

Embodiment 3

[0041] Example 3, Preparation of trans-(1R, 2R)-2-(3,4-difluorophenyl)-1-cyclopropanemethanol

[0042] (E)-3-(3,4-difluorophenyl)prop-2-en-1-ol (1.70g, 10mmol) and (1R,2R)-1,2-N,N'-bis(3 , 5-dichlorobenzenesulfonamido)cyclohexane (10 mmol%) in 100 mL of anhydrous CH 2 Cl 2 solution, keep the temperature at -15-0°C, add Et 2 Zn (1mol / L n-hexane solution 25mL, 25mmol) and CH 2 I 2 (9.4g, 35mmol), heat preservation reaction for 5 hours, refer to Example 1 for post-treatment process, yield 98%, ee value: 99.8%.

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Abstract

The invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for preparing trans-(1R, 2R)-2-(3, 4-difluoro phenyl)-1-cyclopropane formic acid. According to the method, (E)-3-(3, 4 difluoro phenyl) propyl-2-alkene-1-alcohol is taken as the starting material, due to the induction of chiral ligand, trans-(1R, 2R)-2-(3,4-difluoro phenyl)-1-cyclopropane methyl alcohol is obtained through high stereoselectivity reaction, the trans-(1R, 2R)-2-(3,4-difluoro phenyl)-1-cyclopropane methyl alcohol is oxidized so as to obtain the trans-(1R, 2R)-2-(3,4-difluoro phenyl)-1-cyclopropane formic acid. The method is simple and convenient, economical and environment-friendly, and easily available in raw materials, and has high yield; the prepared product has good purity and stereoselectivity.

Description

technical field [0001] The invention relates to a preparation method of trans-(1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxylic acid, which belongs to the technical field of medicine synthesis. Background technique [0002] Ticagrelor, whose chemical name is (1S, 2S, 3R, 5S)-3-[7-[(1R, 2S)-2-(3,4-dichlorophenyl)cyclopropylamino]-5-(sulfur Propyl)-3H-[1,2,3]triazol[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. The drug is a new type of selective small molecule anticoagulant drug developed by AstraZeneca. After oral use, it takes effect quickly and can effectively improve the symptoms of patients with acute coronary heart disease. The antiplatelet effect of ticagrelor is reversible, which is especially suitable for patients who need to undergo surgery after anticoagulant therapy. It is a promising anticoagulant drug. [0003] The synthesis route and preparation method of ticagrelor have been reported: CN1334816, CN1680340, CN101143864, CN102731467, ...

Claims

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Application Information

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IPC IPC(8): C07C61/40C07C51/16
CPCC07C29/44C07C51/16C07C2601/02C07C61/40C07C35/50
Inventor 唐国萍
Owner ZHONGSHAN HAIHONG MEDICINE CO LTD
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