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Preparation method of ticagrelor key intermediate aromatic cyclopropanamide

A technology of cyclopropaneamide and ticagrelor, which is applied in the field of preparation of aromatic cyclopropaneamide, a key intermediate of ticagrelor, can solve the problems of potential safety hazards in large-scale production, achieve easy purchase, save reaction steps, The effect of cheap reagents

Active Publication Date: 2019-11-12
KAIYUAN HENGTAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This synthesis scheme requires the use of pressure vessels, and there are potential safety hazards in large-scale production

Method used

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  • Preparation method of ticagrelor key intermediate aromatic cyclopropanamide
  • Preparation method of ticagrelor key intermediate aromatic cyclopropanamide
  • Preparation method of ticagrelor key intermediate aromatic cyclopropanamide

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Experimental program
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Effect test

Embodiment 1

[0029] A preparation method of the key intermediate aromatic cyclopropaneamide of ticagrelor, comprising the steps of:

[0030] Dissolve ethyl (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropylcarboxylate (I) (20g, 88.496mmol, 1.0eq) in formamide (100ml ), added tetrabutylammonium bromide (1.43g, 4.425mmol, 0.05eq), added ethyl formate (3.278g, 44.248mmol, 0.5eq), and slowly added methanol solution (25wt%) of sodium methoxide under stirring ( 36.8g, 176.992mmol, 2.0eq), heat up to 55°C, keep warm for 2 hours, then seal the reaction bottle and draw negative pressure to -0.08MPa~-0.09MPa, keep warm for 5 hours, TLC (PE / EA, 5:1, V / V) Track the end of the reaction, cool the reaction solution to 0-5°C, add dropwise the prepared acetic acid (10.63g, 176.992mmol, 2.0eq) water (200ml) solution, stir for 30 minutes, filter, and rinse twice with 100ml of water , drained, put the wet product into the reaction flask, add dichloromethane (80ml), stir and heat up to reflux, stir for 1 hour, coo...

Embodiment 2

[0032] A preparation method of the key intermediate aromatic cyclopropaneamide of ticagrelor, comprising the steps of:

[0033]Dissolve ethyl (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropylcarboxylate (I) (40g, 176.992mmol, 1.0eq) in formamide (200ml ), add tetrabutylammonium bromide (2.86g, 8.85mmol, 0.05eq), add ethyl formate (6.56g, 88.496mmol, 0.5eq), slowly add ethanol solution (20wt%) of sodium ethylate under stirring (120.44g, 353.984mmol, 2.0eq), heat up to 60°C, keep warm for 2 hours, then seal the reaction bottle and draw negative pressure to -0.08MPa~-0.09MPa, keep warm for 5.5 hours, TLC (PE / EA, 5:1, V / V) Tracking the end of the reaction, cooling the reaction solution to 0-5°C, adding dropwise the prepared acetic acid (21.26g, 353.984mmol, 2.0eq) water (400ml) solution, stirring for 30 minutes, filtering, 150ml of water twice Wash, drain, put the wet product into a reaction bottle, add dichloromethane (160ml), stir and heat up to reflux, stir for 1 hour, cool down to...

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Abstract

The invention discloses a preparation method of a ticagrelor key intermediate, aromatic cyclopropanamide. The method comprises the following steps: with (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropyl formate (I) as an initial raw material, carrying out transesterification with formamide under the action of alkali, and meanwhile, maintaining negative pressure or normal pressure to generate a target product, namely, (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropyl formamide (II). According to the invention, the three-step synthesis reaction in the prior art is simplified by a one-step reaction, and amide is directly generated by formate reaction; therefore, according to the method, reaction steps are saved, the reaction period is shortened, reaction conditions are milder, high-temperature and high-pressure reaction conditions are avoided, and potential safety hazards are greatly reduced. Meanwhile, the raw materials and reagents of the method are low in price, easy to purchase and high in reaction yield, so that the method is low in reaction cost, and industrial production is easy to achieve.

Description

technical field [0001] The invention relates to the technical fields of organic synthesis and chemical medicine preparation, in particular to a method for preparing an aromatic cyclopropane amide, a key intermediate of ticagrelor. Background technique [0002] Ticagrelor (Ticagrelor) is a new type of small molecule anticoagulant drug developed by AstraZeneca. body antagonists. (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropylcarboxamide is an important intermediate in the synthesis of the anticoagulant drug ticagrelor, and the research on its synthesis method has been very active. There are many literature and patent reports. So far, there are three main synthetic routes of (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropylcarboxamide reported in the literature: [0003] Route 1: WO2008018822A1 reported the synthesis of this compound. This route uses (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropyl carboxylate (intermediate Ⅰ) as raw material, through Hydrolyzed into carboxylic acid, m...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C233/58
CPCC07C231/12C07B2200/07C07C2601/02C07C233/58
Inventor 孟强董学军荀凤强
Owner KAIYUAN HENGTAI PHARMA
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