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Method for preparing ticagrelor solution

A technology of ticagrelor and solution, applied in chemical instruments and methods, blood diseases, pharmaceutical formulations, etc., can solve the problems of reduced yield, increased complexity of preparation process, increased annual production cost and raw material cost, etc.

Inactive Publication Date: 2016-08-17
SHANGHAI FANGNAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although compound (I) is easy to recrystallize, because the existing recrystallization system is not effective in removing some specific impurities, it needs multiple purifications
Repeated purification processes increase the complexity of the preparation process and greatly reduce the yield
The annual production cost and raw material cost of the process will also be greatly increased

Method used

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  • Method for preparing ticagrelor solution
  • Method for preparing ticagrelor solution
  • Method for preparing ticagrelor solution

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1 P = Trityl, P 1 = Hydrogen, P 2 = hydrogen, the preparation method of ticagrelor solution

[0057] The reaction scheme is as follows:

[0058]

[0059] The crude product of ticagrelor is prepared according to the method of Chinese patent CN1200940C, with a purity of 90% (HPLC analysis purity) and a content of 88% (mass fraction).

[0060] In the three-necked round-bottomed flask of 100ml, add content and be 88% ticagrelor crude product (5.94g, 10.0mmol), triphenylchloromethane (3.62g, 13.0mmol) and dichloromethane (60ml), stir well mixed. The temperature was raised to 25-30° C., triethylamine (1.32 g, 13.0 mmol) was added dropwise, and the reaction was stirred at this temperature. After reacting for 3-4 hours, HPLC traced the completion of the reaction, and added saturated ammonium chloride solution (50 ml) to quench the reaction. The organic phase was separated and the aqueous phase was extracted once with dichloromethane (50ml). The combined organic...

Embodiment 2

[0062] Example 2 P = tert-butyldiphenylsilyl, P 1 = Hydrogen, P 2 = hydrogen, the preparation method of ticagrelor solution

[0063] The reaction scheme is as follows:

[0064]

[0065]The crude product of ticagrelor is prepared according to the method of Chinese patent CN1200940C, with a purity of 90% (HPLC analysis purity) and a content of 88% (mass fraction).

[0066] In a 100ml three-necked round-bottomed flask, the content of 88% crude ticagrelor (5.94g, 10.0mmol), tert-butyldiphenylchlorosilane (3.30g, 12.0mmol) and dichloromethane (60ml) was added , and mix well under stirring. The temperature was raised to 25-30° C., triethylamine (1.21 g, 12.0 mmol) was added dropwise, and the reaction was stirred at this temperature. After reacting for 2 to 3 hours, HPLC traced the completion of the reaction, and added saturated ammonium chloride solution (50 ml) to quench the reaction. The organic phase was separated and the aqueous phase was extracted once with dichlorometh...

Embodiment 3

[0068] Example 3 P=4-phenylbenzoyl, P 1 = Hydrogen, P 2 = hydrogen, the preparation method of ticagrelor solution

[0069] The reaction scheme is as follows:

[0070]

[0071] The crude product of ticagrelor is prepared according to the method of Chinese patent CN1200940C, with a purity of 90% (HPLC analysis purity) and a content of 88% (mass fraction).

[0072] In a 100ml three-necked round-bottomed flask, add ticagrelor crude product (5.94g, 10.0mmol), triethylamine (1.21g, 12.0mmol), 4-(N,N-dimethylamino) with a content of 88% Pyridine (0.05g) and dichloromethane (50ml) were mixed evenly under stirring. The temperature was raised to 25-30° C., a dichloromethane solution of 4-phenylbenzoyl chloride (2.60 g, 12.0 mmol) was added dropwise, and the reaction was stirred at this temperature. After reacting for 4 hours, HPLC traced the completion of the reaction, and added saturated ammonium chloride solution (50 ml) to quench the reaction. The organic phase was separated ...

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Abstract

The invention discloses a method for preparing a ticagrelor solution. According to the invention, hydroxy of a ticagrelor I crude product is protected by a protective group, then a crude product of a compound II is separated and purified to obtain the high purity compound II; the hydroxy protective group of the high purity compound II is removed under proper reaction conditions, a reaction mixture is post-processed and then the by-product is removed to obtain the high purity ticagrelor I, the ticagrelor I, a solvent or / and pharmaceutic adjuvant form a solution, after the solvent is removed, ticagrelor or a mixture containing ticagrelor and accessory with medicinal requirement can be obtained. The method has the advantages of mild reaction condition, simple operation, low cost, and environmental protection, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a purification method of an anticoagulant drug, in particular to a preparation method of a ticagrelor solution. Background technique [0002] Ticagrelor, trade name Brilinta, chemical name: (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4 -Difluorophenyl)cyclopropyl]amino}-5-(propylthiouracil)-3H-[1,2,3]-triazolphos[4,5-d]pyrimidin-3-yl]-5 -(2-hydroxyethyl) cyclopentane-1,2-diol, its structure is as shown in formula (I): [0003] [0004] Ticagrelor (Ticagrelor) is a new type of platelet aggregation inhibitor developed by AstraZeneca, which is used for acute coronary syndrome (unstable angina, non-ST-segment elevation myocardial infarction or ST-segment elevation). Myocardial infarction) patients, including patients receiving drug therapy and percutaneous coronary intervention (PCI) to reduce the incidence of thrombotic cardiovascular events, was approved by the US Food and Drug Administration (FDA) in July 2011. Ticagrelor is a novel...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07F5/04A61K31/519A61K9/08A61P7/02
CPCY02P20/55
Inventor 熊志刚资春鹏胡涛张席妮
Owner SHANGHAI FANGNAN PHARMA
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