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A kind of preparation method of high-purity ticagrelor

A high-purity technology of ticagrelor, applied in the field of drug synthesis, can solve the problems of high consumption, unfavorable environmental protection, high polarity of reaction solvent, poor reaction selectivity, etc., and achieve the effects of easier quality control, shortened reaction time, and increased activity

Active Publication Date: 2019-12-20
JIANGXI GUOYAO PHARMA LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The above background analysis is described in more detail in the Chinese patent CN105153167 authorized by Shenzhen Xinlitai Company, and CN107337675 applied by Hunan Tianji Caotang Pharmaceutical Co., Ltd. is also mentioned. The above two patents are used in the preparation of ticagrelor intermediate TG-1 Using ethylene glycol as the reaction solvent, the impact is that it is directly diluted with water and then extracted with an organic solvent during post-treatment. The large consumption is not conducive to environmental protection. The polarity of the reaction solvent and the high reaction temperature also have a greater impact on impurities.
[0010] The "one-pot method" in the following steps prepares ticagrelor, using toluene as the reaction solvent. After the reaction is completed, the simple organic phase is separated from the water phase, and then the next step is performed. However, a series of reactions are performed with this solvent, and the reaction temperature High, so the reaction selectivity is poor, and more organic impurities are produced

Method used

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  • A kind of preparation method of high-purity ticagrelor

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Embodiment 1

[0054] A preparation method of high-purity ticagrelor, comprising the following steps:

[0055] S1: Preparation of intermediate TG-1:

[0056] Add 8 mol of 1,4-dioxane, 1 mol of TG-SM-3, 1 mol of TG-SM-2 to the reactor in sequence, then add 1 mol of catalyst and 2 mol of N,N-diisopropylethylamine in sequence, and then blow nitrogen into it, and raise the temperature to 90°C Reflux, keep stirring for 8 hours, concentrate under reduced pressure to remove 1,4-dioxane, add dichloromethane and water after cooling down to room temperature, separate liquids, wash the organic layer with water and saturated sodium chloride solution in sequence, and wash the organic layer Concentrate under reduced pressure to obtain the crude product, add ethyl acetate and stir until completely dissolved, heat up and reflux, add n-hexane 4 times the mass of the crude product dropwise to the solution, cool to 15°C to crystallize for 2 hours, filter, and dry in vacuo to obtain off-white solid TG -1;

[...

Embodiment 2

[0074] A preparation method of high-purity ticagrelor, comprising the following steps:

[0075] S1: Preparation of intermediate TG-1:

[0076] Add 25 mol 1,4-dioxane, 1.5 mol TG-SM-3, 1 mol TG-SM-2 to the reactor in sequence, then add 3 mol catalyst and 6 mol N,N-diisopropylethylamine in sequence, pass in nitrogen, and raise the temperature by 100 Reflux at ℃, keep stirring for 10 hours, concentrate under reduced pressure to remove 1,4-dioxane, add dichloromethane and water after cooling down to room temperature, separate liquids, wash the organic layer with water and saturated sodium chloride solution in sequence, and the organic layer after washing Concentrate the layer under reduced pressure to obtain the crude product, add ethyl acetate and stir until it is completely dissolved, raise the temperature and reflux, add n-hexane 5 times the mass of the crude product dropwise to the solution, cool to 18°C ​​to crystallize for 2.5h, filter, and dry in vacuo to obtain off-white ...

Embodiment 3

[0094] A preparation method of high-purity ticagrelor, comprising the following steps:

[0095] S1: Preparation of intermediate TG-1:

[0096] Add 50mol 1,4-dioxane, 2mol TG-SM-3, 1mol TG-SM-2 to the reactor in turn, then add 5mol catalyst and 10mol N,N-diisopropylethylamine in turn, blow nitrogen into it, and raise the temperature to 110°C Reflux, keep stirring for 12 hours, concentrate under reduced pressure to remove 1,4-dioxane, add dichloromethane and water after cooling down to room temperature, separate liquids, wash the organic layer with water and saturated sodium chloride solution in sequence, and wash the organic layer Concentrate under reduced pressure to obtain the crude product, add ethyl acetate and stir until it dissolves completely, heat up and reflux, add n-hexane 6 times the mass of the crude product dropwise to the solution, cool to 20°C to crystallize for 3 hours, filter, and dry in vacuo to obtain off-white solid TG- 1;

[0097] Among them, the molar rati...

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Abstract

The invention discloses a preparation method of high-purity ticagrelor. The preparation method comprises the following steps: preparing intermediates TG-1, TG-2, TG-3 and TG-4; and refining the ticagrelor. According to the preparation method, matching of reactants is adjusted, the reaction time and temperature are optimized, and a post-processing manner is adopted; a specific catalyst and a specific devitrification solvent are selected, so that the reaction efficiency of the intermediates is improved, the reaction time is shortened and the purity of the intermediates is improved; after a crudeproduct of the ticagrelor is obtained, different devitrification solvents and a staged crystallization process are adopted to obtain the ticagrelor with high purity, so that the production cost is reduced, the advantages of being high efficiency and clean in production are achieved, and the operability is strong; and the purity of the obtained ticagrelor product is not lower than 99.8%, and no single impurity exceeds 0.06%.

Description

technical field [0001] The invention relates to a preparation method of high-purity ticagrelor, which belongs to the field of drug synthesis. Background technique [0002] Ticagrelor (also known as ticagrelor) is a new type of selective small molecule anticoagulant drug developed by AstraZeneca, and it is also the first oral P2Y12 adenosine diphosphate that can be combined Compared with clopidogrel, it can further significantly reduce the cardiovascular mortality or myocardial infarction rate in patients with acute coronary syndrome (ACS), and at the same time significantly reduce the heart rate. Vascular mortality. [0003] The drug was approved by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) in 2010 and 2011 in the European Union and the United States. At present, the imported preparation ticagrelor tablets has been listed in my country, and the trade name is Belinda. [0004] There are many reports on the synthetic routes and prepa...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 杨建国万义斌葛友群左飞鸿余承祥杨明李进进于莲欣刘威谢亮亮刘林华
Owner JIANGXI GUOYAO PHARMA LLC
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