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Preparation method of ticagrelor

A technology of ticagrelor and synthetic method, which is applied in the field of synthesis of pharmaceutical compounds, and can solve problems such as difficult separation of impurities, long steps, and many residual intermediates

Inactive Publication Date: 2018-07-27
北京东旭利医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] There are many preparation methods of ticagrelor that have been disclosed, but they all have some defects to varying degrees, such as long steps, more intermediate residues, difficult separation of impurities, and difficult removal of solvent residues, etc.

Method used

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  • Preparation method of ticagrelor
  • Preparation method of ticagrelor
  • Preparation method of ticagrelor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Step 1: Synthesis of Intermediate Im-1

[0126] 1) Ratio of materials

[0127] Table 1 Step 1 Reaction Feeding Quantity

[0128] name

Molar mass

Feeding amount

moles

The molar ratio of

SM1

238.14

9.335kg

39.20mol

1.2

SM2

367.35

12kg

32.67mol

1

Triethylamine

101.19

16.529kg

163.35mol

5

Ethylene glycol

/

18L

/

/

ethyl acetate

/

72L

/

/

Isooctane

/

216L

/

/

purified water

/

120L

/

/

[0129] 2) Reaction equipment

[0130] 100L glass reactor, 200L reactor, 500L reactor, flat centrifuge, vacuum oven.

[0131] 3) Operation process

[0132] (1) Add 18L of ethylene glycol, 9.335kg of SM1, 12kg of SM2 and 16.529kg of triethylamine into the 100L reactor, stir and mix well;

[0133] (2) Heating the reaction solution to 90-100°C, the solid in the reaction solution dissolves, and the color...

Embodiment 2

[0202] Embodiment 2, another refining method of the present invention

[0203] 1) Ratio of materials

[0204] Table 5 Step 5 Reaction Feeding Amount

[0205] name

Molar mass

Feeding amount

moles

The molar ratio of

Crude ticagrelor

522.57

11.5kg

22.01mol

1

Dichloromethane

/

45L

/

/

tert-butanol

/

117L

/

/

[0206] 2) Reaction equipment

[0207] 200L crystallization kettle, filter device, vacuum drying oven.

[0208] 3) Operation process

[0209] (1) Add 45L dichloromethane and 117L tert-butanol in 200L crystallization kettle; Stir and add 11.5kg ticagrelor crude product,

[0210] (2) Heat to 50-60°C with stirring and keep for 1 hour; cool down to 20-30°C and stir for 1 hour;

[0211] (3) cooling down to 0~10°C and stirring for 2 hours;

[0212] (4) Centrifugal filtration, the reaction kettle and the filter cake are rinsed with water pre-cooled to 0-10°C;

[0213] (5) The f...

Embodiment 3

[0214] Embodiment 3, another refining method of the present invention

[0215] 1) Ratio of materials

[0216] Table 5 Step 5 Reaction Feeding Amount

[0217] name

Molar mass

Feeding amount

moles

The molar ratio of

Crude ticagrelor

522.57

11.5kg

22.01mol

1

Dichloromethane

/

45L

/

/

tert-butanol

/

112L

/

/

[0218] 2) Reaction equipment

[0219] 200L crystallization kettle, filter device, vacuum drying oven.

[0220] 3) Operation process

[0221] (1) Add 45L dichloromethane and 112L tert-butanol in 200L crystallization kettle; Stir and add 11.5kg ticagrelor crude product,

[0222] (2) Heat to 50-60°C with stirring and keep for 1 hour; cool down to 20-30°C and stir for 1 hour;

[0223] (3) cooling down to 0~10°C and stirring for 2 hours;

[0224] (4) Centrifugal filtration, the reaction kettle and the filter cake are rinsed with water pre-cooled to 0-10°C;

[0225] (5) The f...

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Abstract

The invention relates to synthesis of a pharmaceutical compound and in particular relates to a preparation method of ticagrelor. The method disclosed by the invention comprises the steps as follows: step 1, synthesizing an intermediate Im-1; step 2, synthesizing an intermediate Im-2; step 3, synthesizing an intermediate Im-3; step 4, synthesizing a crude product Im-4; and step 5, carrying out refining, namely recrystallizing the crude product of ticagrelor by using 10-15 times of mixed solution of dichloromethane and tertiary butanol, and carrying out washing, filtering and drying to obtain arefined product of ticagrelor, wherein the volume ratio of dichloromethane to tertiary butanol in the mixed solution of dichloromethane and tertiary butanol is 1:(2-3).

Description

technical field [0001] The present invention relates to the synthesis of a pharmaceutical compound, in particular to a preparation method of ticagrelor Background technique [0002] Ticagrelor is a pharmaceutical compound with the following structural formula, [0003] [0004] Chemical name: (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-propylthio Triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol. [0005] Ticagrelor is a platelet aggregation inhibitor. As acute coronary syndrome (ACS) continues to grow today, antiplatelet therapy is still one of the important treatment measures for ACS. Ticagrelor is a novel cyclopentyltriazole pyrimidine (CPTP) oral antiplatelet drug with ATC code B01AC24. Ticagrelor is a non-prodrug, which can directly take effect without being activated by liver metabolism, and reversibly binds to the P2Y12ADP receptor. The results of the PLATO study showed that ticagrelor treatment for 12 months fu...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D405/12
CPCC07D487/04C07D405/12
Inventor 鲍艺文王雅军
Owner 北京东旭利医药科技有限公司