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Synthesizing method of ticagrelor

A technology of ticagrelor and a synthesis method, applied in the field of synthesis of pharmaceutical compounds, can solve the problems of long steps, difficult separation of impurities, and many residual intermediates, etc.

Inactive Publication Date: 2018-07-13
河北凯威制药有限责任公司
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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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  • Synthesizing method of ticagrelor
  • Synthesizing method of ticagrelor
  • Synthesizing 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] (5) Centrifugal filtration, the reaction kettle and the filter cake are rinsed with water pre-cooled to 0-10°C;

[0213] (6) 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] (5) Centrifugal filtration, the reaction kettle and the filter cake are rinsed with water pre-cooled to 0-10°C;

[0225] (6) The f...

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Abstract

The invention relates to synthesis of a medicine compound, in particular to a synthesizing method of ticagrelor. The synthesizing method comprises the following steps of S1, synthesizing an intermediate Im-1; S2, synthesizing an intermediate Im-2; S3, synthesizing an intermediate Im-3; S4, synthesizing a crude product Im-4; S5, refining: recrystallizing a crude product of the ticagrelor by a mixedsolution of dichloromethane and tertiary butanol, washing, filtering, and drying, so as to obtain a refined product of the ticagrelor.

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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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04C07B2200/07
Inventor 庞玉宁
Owner 河北凯威制药有限责任公司