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Preparation method of Ticagrelor

A technology of ticagrelor and compounds, applied in the field of preparation of anti-platelet aggregation drug ticagrelor

Inactive Publication Date: 2015-06-03
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Preparation method of Ticagrelor

Examples

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Effect test

Embodiment 1

[0036] Example 1: Preparation of ticagrelor

[0037] M-1 (1kg), toluene (4.31kg) and acetic acid (0.86kg) were added to the reaction flask, and sodium nitrite (0.19kg) in water (0.5kg) was added dropwise with stirring, and the temperature was controlled not to exceed 30°C. After stirring for 3 hours, a solution of potassium carbonate (1.01 kg) in water (2.01 kg) was added dropwise, after dripping, the solution was allowed to stand for liquid separation, and the upper organic phase (intermediate M-2) was stored at low temperature.

[0038] Add SM1 [0.86kg (purity 98.5%, impurity X 0.25%)] treated with 5 times the amount of acetonitrile to the water (3.24kg) solution of potassium carbonate (0.88kg) for 1 h, under nitrogen protection, pour into the previous product In the intermediate M-2 solution, the reaction was stirred at 25°C for 2 hours. Let stand for liquid separation. The organic layer is washed twice with acetic acid (0.10kg) and sodium chloride (74.8g) in water (3.13kg) sol...

Embodiment 2

[0042] Add M-1 (4.2kg), toluene (18.1kg) and acetic acid (3.61kg) into the reaction flask, add dropwise sodium nitrite (0.8kg) in water (2.1kg) solution under stirring, and control the temperature not to exceed 30℃ . After stirring for 3 hours, a solution of potassium carbonate (4.24 kg) in water (8.44 kg) was added dropwise. After the dripping, the mixture was allowed to stand for liquid separation, and the upper organic phase (Intermediate M-2) was stored at low temperature.

[0043] Add SM1 [3.61kg (purity 99.0%, impurity X 0.18%)] treated with 10 times the amount of acetonitrile to the water (13.61kg) solution of potassium carbonate (3.7kg) for 1h, and pour into the product from the previous step under nitrogen In the intermediate M-2 solution, the reaction was stirred at 22°C for 2 hours. Let stand for liquid separation. The organic layer was washed twice with acetic acid (0.42kg) and sodium chloride (0.31kg) in water (13.15kg) solution, and sodium chloride (1.3kg) in water...

Embodiment 3

[0047] Example 3: Add M-1 (6.3kg), toluene (27.2kg) and acetic acid (5.42kg) into the reaction flask, add dropwise sodium nitrite (1.2kg) in water (3.15kg) solution under stirring, and control the temperature Does not exceed 30°C. After stirring for 3 hours, a solution of potassium carbonate (6.36 kg) in water (12.66 kg) was added dropwise, after dripping, the solution was allowed to stand for liquid separation, and the upper organic phase (intermediate M-2) was stored at low temperature.

[0048] Add SM1 [5.42kg (purity 99.5%, impurity X 0.11%)] treated with 15 times the amount of acetonitrile to the water (28.74kg) solution of potassium carbonate (5.55kg) for 1 h, under nitrogen protection, pour into the product of the previous step In the intermediate M-2 solution, the reaction was stirred at 20°C for 2 hours. Let stand for liquid separation. The organic layer was washed twice with acetic acid (0.63kg) and sodium chloride (0.46kg) in water (20.42kg) solution, and sodium chlor...

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Abstract

A preparation method of Ticagrelor comprises the following steps: (1) dissolving a compound shown in formula M-1 into methylbenzene and acetic acid, dropwise adding an aqueous solution of sodium nitrite, and keeping the temperature at 30DEG C or below to obtain a compound shown in formula M-2; (2) performing acetonitrile beating treatment on a compound shown in formula SM1, adding the treated compound shown in formula SM1 into an aqueous solution of potassium carbonate, under the protection of inert gas, adding the aqueous solution of potassium carbonate into the compound shown in formula M-2, which is obtained in step (1), and performing a condensation reaction to obtain a compound shown in formula M-3; (3) under the protection of inert gas, hydrolyzing the compound shown in formula M-3, which is obtained in step (2), into a mixed solution of concentrated hydrochloric acid and methyl alcohol to obtain coarse Ticagrelor shown in formula TGRL; and (4) recrystallizing the coarse Ticagrelor obtained in step (3) with ethyl acetate-isooctane to obtain high-purity Ticagrelor. Ticagrelor prepared according to the preparation method provided by the invention is up to the purity above 99.50% and contains 0.1wt% of TGRL-A to TGRL-D and less than 0.5wt% of total impurities.

Description

Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a preparation method of the antiplatelet aggregation drug ticagrelor, wherein the prepared ticagrelor has high purity. Background technique [0002] Ticagrelor (chemical structure see formula I), chemical name (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl) )Cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazole[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) ring Pentane-1,2-diol is a new type of small molecule anticoagulant drug developed by AstraZeneca to selectively treat acute coronary syndrome (ACS), which can reversibly act on vascular smooth muscle cells. Purine 2 receptor (P2) subtype P2Y12, does not require metabolic activation, has a significant inhibitory effect on platelet aggregation caused by adenosine diphosphate, has rapid onset and strong curative effect, significantly reduces the risk of bleeding events in patients, and reduces cardiovascular mortality Featu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 缪世峰张海波陈令武路显锋宋金翔施连勇梁慧兴骆宏鹏
Owner YANGTZE RIVER PHARM GRP CO LTD
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