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Preparation method, detection method and application for ticagrelor-related substances

A kind of technology of ticagrelor and detection method, applied in the field of medicine

Active Publication Date: 2016-01-13
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the oxidative degradation test of ticagrelor, sulfur is oxidized to generate sulfoxide and sulfone derivatives, namely (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2- (3.4-Difluorophenyl)cyclopropyl]amino}-5-(propylsulfinyl)-3H-[1,2,3]triazolo-[4,5-d]pyrimidin-3-yl ]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (ticagrelor sulfoxide, structural formula Ⅰ) and (1S,2S,3R,5S)-3-[7-{ [(1R,2S)-2-(3.4-Difluorophenyl)cyclopropyl]amino}-5-(propylsulfonyl)-3H-[1,2,3]triazolo-[4,5 -d] pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol (ticagrelor sulfone, structural formula Ⅱ), Hassane SadouYaye et al reported in Identification of the major degradation pathway soft icagrelor The mechanism of oxidative degradation of Rylo, but for the specific preparation method of oxidized impurities, there is no literature to disclose

Method used

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  • Preparation method, detection method and application for ticagrelor-related substances
  • Preparation method, detection method and application for ticagrelor-related substances
  • Preparation method, detection method and application for ticagrelor-related substances

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1 Preparation of ticagrelor oxidized impurity compounds I and II

[0071] (1) Dissolve 15g of the intermediate in 225mL of toluene, cool in an ice-water bath to -2°C, add dropwise 210mL of toluene solution in which 18.06g of m-chloroperoxybenzoic acid is dissolved, and keep stirring at 0°C for 2.5 hours.

[0072] (2) Add 6.8g (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (R)-mandelate to the reaction solution, add 150mL of 0.8mol / L K 2 CO 3 The aqueous solution was stirred and reacted for 6 hours. After the reaction was completed, the layers were separated, and the toluene phase was taken for the next reaction.

[0073] (3) 120 mL of 0.3 mol / L concentrated hydrochloric acid methanol solution was added dropwise to the toluene phase. After the reaction, the mixture was allowed to stand for stratification, and the aqueous and organic phases were concentrated and evaporated to dryness respectively to obtain 7.9 g of light yellow solid and 1 white solid.

[0074...

Embodiment 2

[0077] Example 2 Preparation of ticagrelor oxidized impurity compounds I and II

[0078] (1) Dissolve 15g of the intermediate in 225mL of toluene, cool in an ice-water bath to -2°C, add dropwise 320mL of toluene solution in which 30g of m-chloroperoxybenzoic acid is dissolved, and keep stirring at 0°C for 1 hour.

[0079] (2) Add 11g (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (R)-mandelate to the reaction liquid, add 120mL of 0.8mol / L K 2 CO 3 The aqueous solution was stirred and reacted for 6 hours. After the reaction was completed, the layers were separated, and the toluene phase was taken for the next reaction.

[0080] (3) 220 mL of 0.6 mol / L concentrated hydrochloric acid methanol solution was added dropwise to the toluene phase. After the reaction was completed, the mixture was allowed to stand for stratification, and the aqueous phase and the organic phase were concentrated and evaporated to dryness to obtain 14.9 g of light yellow solid and 1 white solid.

[00...

Embodiment 3

[0084] Example 3 Preparation of ticagrelor oxidized impurity compounds I and II

[0085] (1) Dissolve 15g of the intermediate in 225mL of toluene, cool in an ice-water bath to -2°C, add dropwise 150mL of a methanol solution in which 12g of m-chloroperoxybenzoic acid is dissolved, and keep stirring at 0°C for 5 hours.

[0086] (2) Add 5.6g (1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (R)-mandelate to the reaction solution, add 120mL of 1mol / L K 2 CO 3 The aqueous solution was stirred and reacted for 6 hours. After the reaction was completed, the layers were separated, and the toluene phase was taken for the next reaction.

[0087] (3) 80 mL of 0.5 mol / L methanol solution of concentrated hydrochloric acid was added dropwise to the toluene phase. After the reaction was completed, the mixture was allowed to stand for stratification, and the aqueous phase and the organic phase were concentrated and evaporated to dryness respectively to obtain 4.02 g of light yellow solid and 1...

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Abstract

The invention provides a preparation method and detection method for oxides of ticagrelor, i.e., (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3.4-difluorophenyl)cyclopropyl]amino}-5-(propylthionyl)-3H-[1,2,3]triazolo-[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol and (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3.4-difluorophenyl)cyclopropyl]amino}-5-(propylthioacyl)-3H-[1,2,3]triazolo-[4,5-d]pyrimidine-3-yl]-5-(2-hydroxyethoxyl)cyclopentane-1,2-diol, and application of the oxides in the quality control research of ticagrelor.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a group of oxides of ticagrelor, a preparation method, a detection method and application thereof. Background technique [0002] Ticagrelor (Ticagrelor), chemical name: (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3.4-difluorophenyl)cyclopropyl]amino}- 5-(Propanylthio)-3H-[1,2,3]triazolo-[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane- 1,2-diol is a new type of antiplatelet drug that inhibits thrombus formation by selectively inhibiting P2Y12 receptors. Compared with clopidogrel, ticagrelor can inhibit the P2Y12 receptor faster, stronger and more stably, significantly reducing the incidence of death, myocardial infarction or stroke caused by vascular causes, thereby reducing thrombotic cardiovascular events The specific structural formula is as follows. [0003] [0004] At present, the literature on ticagrelor pharmacy is quite abundant, mainly focusing on the synthetic routes of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04G01N30/02
CPCC07D487/04G01N30/02
Inventor 李志华吴舰钱修文柴雨柱朱谧徐丹朱春霞田舟山
Owner NANJING CHIA TAI TIANQING PHARMA
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