Ticagrelor crystal and medicinal composition comprising same

A ticagrelor crystallization technology, which is applied in the field of ticagrelor crystallization and pharmaceutical compositions containing the crystallization, can solve problems such as difficulty in obtaining ticagrelor products that meet the purity requirements, improve quality, increase yield, The effect of simple process steps

Active Publication Date: 2015-12-16
HUIZHOU XINLITAI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This reaction only objectively describes the removal of the propylidene protecting group, and methanol is used as the reaction solvent to obtain the chemical product of ticagrelor. Since there are a variety of intermediate raw materials and acid-base agents in this reaction, it is difficult to obtain a product that meets the purity and low impurity N Limited ticagrelor product

Method used

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  • Ticagrelor crystal and medicinal composition comprising same
  • Ticagrelor crystal and medicinal composition comprising same
  • Ticagrelor crystal and medicinal composition comprising same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1 "One-pot" preparation of ticagrelor

[0049] Preparation of TGRL-4

[0050]

[0051] Add TGRL-3 (7.00kg), TGRL-2 (5.46kg), ethylene glycol (19.6kg) and triethylamine (6.77kg) into the reactor respectively, heat to 100°C and stir for 8h. Cool down to room temperature, add ethyl acetate and water, stir and separate phases. The organic phase was decolorized by adding activated carbon, filtered, and the filtrate was concentrated to a solid. Add ethyl acetate and stir until the solid is completely dissolved, add n-hexane dropwise, stir for 2-3h, and filter. Dry to obtain TGRL-4 solid with a purity of 99.4% and a yield of 81.5%.

[0052] Preparation of TGRL-5:

[0053]

[0054] Add TGRL-4 (6.7kg) toluene (26.5kg) and glacial acetic acid (5.76kg) to the reaction kettle. Stir to dissolve, add dropwise an aqueous solution of sodium nitrite, and stir for 1h. Then add K dropwise to the reaction system 2 CO 3 aqueous solution. After stirring, the lower aque...

Embodiment 2

[0061] Example 2 "One-pot" preparation of ticagrelor

[0062] According to the feeding and method of Example 1, in the preparation of TGRL-4, the reaction temperature is 110°C, and the reaction time is 9h;

[0063] Preparation of TGRL-5: room temperature, reaction time: 2h;

[0064] Preparation of TGRL-6: room temperature, reaction time: 5h;

[0065] Preparation of TGRL-1: Reaction temperature: 15°C, reaction time: 4h, 5.6kg of ticagrelor was obtained, the total yield was 56%, the purity was 96.65%, and the impurity N was 1.0%.

Embodiment 3

[0066] The refined preparation of embodiment 3 ticagrelor

[0067] Crystallization of Crude TGRL-1

[0068] Add methanol (67 L) to the TGRL-1 solid obtained in Example 1, and stir to dissolve. Water (26.8 L) was added dropwise with stirring, and stirred for 10 minutes. Continue to add water (37.5L) dropwise at a rate of 5ml / s, and crystallize for 2-3h. Cooled to 0-5 ° C crystallization 0.5h. Filter and wash the filter cake with water. The solid was dried under vacuum at 30°C to obtain the crude product of TGRL-1. Yield 90%, purity 98.26%, impurity N0.1%.

[0069] Refinement of TGRL-1

[0070] The TGRL-1 crude solid (6.0 kg) from the previous step was added to the reaction kettle. Ethyl acetate (60 L) was added. Stir and heat at 40-45°C to dissolve. Add n-hexane (78L) dropwise, crystallize at room temperature for 2-3h after the dropwise addition, and then cool to 0-5°C for 0.5h. After filtering, the filter cake was double-cone dried at 30°C to obtain a refined product...

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Abstract

The invention provides a ticagrelor crystal and a medicinal composition comprising the same. The purity of the ticagrelor crystal is greater than 99 percent, and an impurity N is less than 0.1 percent. The crystal is prepared by adopting a one-pot method and is obtained by adopting a further crystal refining method. By adopting the methods, the ticagrelor with the purity being obviously improved can be obtained, and the raw material and medicinal composition with excellent quality are further acquired.

Description

technical field [0001] The invention belongs to the technical field of chemical medicines, and relates to a ticagrelor crystal and a pharmaceutical composition containing the crystal. 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 reversible conjugated oral P2Y12 adenosine di The phosphate receptor antagonist has obvious inhibitory effect on ADP-induced platelet aggregation, and can effectively improve the symptoms of patients with acute coronary heart disease. [0003] The drug was approved by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) in 2010 and 2011, respectively, and was launched in the EU and the US under the trade name Brilinta. Its imported preparation, ticagrelor tablets, has been approved by the China Food and Drug Administration (SFDA) to be launched in my country, and its Chinese product name...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519
CPCC07D487/04
Inventor 许文杰汪尚文刘俊光李松华怀杰
Owner HUIZHOU XINLITAI PHARMA
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