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Ticagrelor impurity preparation method

A technology for ticagrelor and impurities, which is applied in the field of preparation of ticagrelor impurities, can solve the problems of low preparation efficiency and few reports on preparation methods of impurities, and achieves high chromatographic purity, easy separation and purification, and short synthesis route. Effect

Pending Publication Date: 2019-04-02
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] There are many studies on the synthesis method of ticagrelor, but there are few reports on the preparation method of its impurities
Although the patent CN104059069B discloses the preparation method of impurity E, unfortunately, in this method, impurity E is obtained in the form of by-products, the content is only about 0.08%, and the preparation efficiency is extremely low

Method used

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Embodiment 1

[0038] 6-Chloro-N4-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-2-(propylthio)pyrimidine-4,5-diamine (Compound III) synthesis

[0039](1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (R)-mandelate (compound II, 3.31g, 10mmol) and 4,6-dichloro-2-(propylthio Base)-5-aminopyrimidine (Compound I, 2g, 13mmol) was placed in a 50mL three-necked flask, and ethylene glycol (10mL) and triethylamine (4.24g, 42mmol) were added. The reaction mixture was heated to 100°C and stirred for 7 hours. Turn off the heating and cool down to 40°C naturally. Isopropyl acetate (10 mL) and water (10 mL) were added and stirred for 1 hour. Stop stirring, cool to room temperature, and let stand for liquid separation. The organic phase was separated, washed with water (10 mL), and dried over anhydrous sodium sulfate for 30 minutes. Suction filtration, the desiccant was filtered off, and the residue was separated by silica gel column chromatography (200-300 mesh column chromatography silica gel, eluent 0-5...

Embodiment 2

[0041] 7-Chloro-3-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylthio)-3H-[1,2,3]triazolo Synthesis of [4,5-d]pyrimidine (Compound IV)

[0042] Compound III (2.6g, 7mmol) was placed in a 50mL single-necked bottle, toluene (10mL) and acetic acid (0.5g) were added, stirred to dissolve, and cooled to 5°C. A solution of sodium nitrite (0.8g) in water (5mL) was added dropwise, and the internal temperature did not exceed 10°C during the dropwise addition. After the addition was complete, the reaction system continued to react at 5-10°C for 1 hour. After the reaction was complete, a solution of potassium carbonate (2.8 g) in water (5 mL) was added dropwise. Stir for 15 minutes. Stop stirring, let stand for liquid separation, discard the aqueous phase, and use the organic phase directly for the next reaction.

Embodiment 3

[0044] (2-(((3aR,4S,6R,6aS)-6-((3-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylthio Base)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)amino)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][ Synthesis of 1,3]dioxol-4-yl)oxy)ethanol (impurity E)

[0045] 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxan-4-yl)oxy base) ethanol L-(+)-tartrate (compound V, 2.75g, 7.5mmol), potassium carbonate (2.47g, 18mmol) were placed in water (10mL), and stirred. This mixture was added to the toluene solution from step 2 at 5°C. After the addition was complete, the reactants were reacted at 20°C for 1 hour. Stop stirring and let stand to separate the liquid. The organic phase was washed twice with saturated sodium chloride solution (10 mL) added with 0.2 mL of acetic acid, then washed twice with saturated sodium chloride solution (10 mL), and dried over anhydrous sodium sulfate for 30 minutes. Suction filtration, filter out desiccant. The residue was evaporated t...

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Abstract

The invention discloses a ticagrelor impurity preparation method, wherein 4,6-dichloro-2-(propylthio)-5-aminopyrimidine and (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine(R)-mandelate are used as starting raw materials, and are subjected to a nucleophilic substitution reaction under alkaline conditions, a diazotization ring-closing reaction is performed to prepare a triazole intermediate, the triazole intermediate and 2-(((3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aH- cyclopentyl[d][1,3]dioxa-4-yl)oxy)ethanol L-(+)-tartrate are subjected to C-N coupling to obtain a ticagrelor impurity E,and the impurity E is hydrolyzed under acidic conditions to remove acetonylidene protection so as to obtain an impurity A. According to the present invention, the preparation method has characteristics of short synthesis route, simple operation and high product purity, and the obtained target product can be used as the impurity reference substance for controlling the purity of the ticagrelor raw materials or preparations.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, and in particular relates to a preparation method and application of ticagrelor impurities. Background technique [0002] Ticagrelor (Ticagrelor), trade name Brilinta (Brilinta), is a new type of small molecule anticoagulant drug developed by AstraZeneca to selectively treat acute coronary syndrome (ACS) , is a novel cyclopentyltriazole pyrimidine oral P2Y12 receptor antagonist, which was approved for marketing in the EU in December 2010, and was approved for marketing by the US FDA in July 2011. After listing, it has been recommended by many international treatment guidelines for the treatment of ACS patients, including the guidelines of the European Society of Cardiology (ESC), the American College of Cardiology (ACC) and the American Heart Association (AHA). In November 2012, ticagrelor obtained the import drug license issued by CFDA and was approved to be officially launche...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 缪世峰徐浩宇蔡伟张海波吕慧敏孙春艳牟聪王德国刘景龙刘晶胡涛
Owner YANGTZE RIVER PHARM GRP CO LTD
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