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Preparation method for ticagrelor intermediate

A technology for ticagrelor and intermediates, applied in the direction of organic chemistry, etc., can solve the problems of many steps in the preparation method, unsatisfactory yield, and few steps, and achieve the effects of short steps, reduced production costs, and high reaction yield

Inactive Publication Date: 2017-03-15
QINGDAO YUNTIAN BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The purpose of the present invention is to overcome the existing ticagrelor intermediate 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopentena- The preparation method of 1,3-dioxa-4-yl]oxyethanol has defects such as many steps, high cost and unsatisfactory yield, and provides a new ticagrelor intermediate 2-[[(3aR,4S , 6R, 6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopentena-1,3-dioxan-4-yl]oxyethanol preparation method, the preparation method step Less, high stereoselective products can be obtained without adding or using chiral compounds, and also have a higher yield, and the raw materials used in the preparation method are easy to obtain, effectively controlling the production cost of ticagrelor intermediates

Method used

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  • Preparation method for ticagrelor intermediate
  • Preparation method for ticagrelor intermediate
  • Preparation method for ticagrelor intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The preparation of the compound shown in formula I

[0032] In a 150ml flask, 142.0g (10mmol) of AlCl 3 , 16.61g (100mmol) 2-nitrobenzaldehyde oxime, 9.28g (95mmol) cyclopentadiene were added to 1,4-dioxane, stirred and reacted at 20°C for 4 hours, the reaction was completed, the reaction solution was concentrated, poured Rinse in water, filter, and then recrystallize from petroleum ether to obtain 18.58 g of the compound represented by formula I, with a yield of 84.2% and an HPLC purity of 98.58% (area normalization method).

Embodiment 2

[0034] The preparation of the compound shown in formula I

[0035] In a 150ml flask, 1.36g (10mmol) ZnCl 2, 16.61g (100mmol) 2-nitrobenzaldehyde oxime, 5.29g (80mmol) cyclopentadiene were added to 1,4-dioxane, stirred and reacted at 30°C for 4 hours, the reaction was completed, the reaction solution was concentrated, poured Rinse in water, filter, and then recrystallize from petroleum ether to obtain 15.18 g of the compound represented by formula I, with a yield of 81.7% and a HPLC purity of 98.58% (area normalization method).

Embodiment 3

[0037] The preparation of the compound shown in formula I

[0038] In a 150ml flask, 2.66g (20mmol) AlCl 3 , 14.62g (100mmol) 2-cyanobenzaldehyde oxime, 5.95g (90mmol) cyclopentadiene were added to 1,4-dioxane, stirred and reacted at 10°C for 4 hours, the reaction was completed, the reaction solution was concentrated, poured Washed in water three times, filtered, and then recrystallized from petroleum ether to obtain 15.78 g of the compound represented by formula I, with a yield of 82.6% and an HPLC purity of 98.58% (area normalization method).

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Abstract

The invention discloses a preparation method for a ticagrelor intermediate. The preparation method comprises the following steps: 1) subjecting o-substituted benzaldoxime and cyclopentadiene to a contact reaction so as to obtain a compound as shown in a formula I; 2) oxidizing the compound as shown in the formula I with hydrogen peroxide under the catalysis of osmium tetroxide so as to obtain a compound as shown in a formula II; 3) reacting the compound as shown in the formula II with acetone under the catalysis of p-toluenesulfonic acid so as to obtain a compound as shown in a formula III; 4) reacting the compound as shown in the formula III with 2-bromoethanol in the presence of alkali so as to obtain a compound as shown in a formula IV; and 5) reducing the compound as shown in the formula IV so as to obtain the ticagrelor intermediate. The method provided by the invention uses cheap and easily available raw material, reduces production cost, and does not need any chiral raw material; a cycloaddition reaction enables a highly stereoselective product to be obtained; and the method is short in steps and high in reaction yield and provides a novel approach for synthesis of ticagrelor.

Description

technical field [0001] The present invention relates to a preparation method of ticagrelor intermediate, in particular to a 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclo A preparation method of penteno-1,3-dioxan-4-yl]oxyethanol. Background technique [0002] Ticagrelor (Ticagrelor), the chemical name 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 -diol, which is the first reversible binding oral P2Y12 adenosine diphosphate receptor antagonist, has a significant inhibitory effect on ADP-induced platelet aggregation, and can effectively improve the symptoms of patients with acute coronary heart disease. The compound was developed by AstraZeneca and approved for marketing in the European Union and the United States in 2010 and 2011 respectively. In addition, the imported tablet has also been approved by the China Food and Drug Administration (SFDA...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/44
CPCC07D317/44
Inventor 刘同祥
Owner QINGDAO YUNTIAN BIOTECH