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The preparation method of ticagrelor

A technology of ticagrelor and dimethyl, which is applied in the field of preparation of new anticoagulant drug ticagrelor, can solve the problems of difficult control of coupling position, avoid the use of hazardous chemicals, the preparation process is fast and convenient, and the Suitable for large-scale industrial production

Active Publication Date: 2015-08-05
铜陵三十九度创客公园管理有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the directionality of the triazole ring, it is difficult to control the coupling position

Method used

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  • The preparation method of ticagrelor
  • The preparation method of ticagrelor
  • The preparation method of ticagrelor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Add 1-[3aR-(3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadiene-1,3-dioxolane to the reaction flask -4-oxyl]ethanol]-6-yl]-5-amino-4-formamido-1,2,3-triazole (II) (3.27g, 10mmol), potassium carbonate (4.14g, 30mmol ), water 2mL and dichloromethane 50mL. Cool down to 0°C, slowly add a solution of carbon dichlorosulfur (III) (3.45 g, 30 mmol) in 25 mL of dichloromethane dropwise, and react for 2 hours. The reaction solution was poured into ice water to quench the reaction, and the organic phase was separated. The aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried and the solvent was removed under reduced pressure. The crude product was recrystallized from ethyl acetate to obtain off-white solid 9-[3aR-(3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadiene-1, 3-dioxolane-4-oxyl]ethanol]-6-yl]-2-thioxo-6-oxo-8-azapurine (IV) 3.14g, yield 85.1%.

Embodiment 2

[0043] Add 9-[3aR-(3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadiene-1,3-dioxolane to the reaction flask -4-oxyl]ethanol]-6-yl]-2-thioxo-6-oxo-8-azapurine (IV) (1.85g, 5mmol), potassium hydroxide solution (0.1M, 10mL) and Acetonitrile 25mL, room temperature was added dropwise bromopropane (V) (1.53g, 12.5mmol) in acetonitrile solution. The reaction was stirred at room temperature for 15 hours. The solvent was recovered under reduced pressure, the residue was extracted 3 times with dichloromethane, the organic phases were combined, dried, and distilled under reduced pressure to obtain the oily substance 9-[3aR-(3aα, 4α, 6α, 6aα)-[[2,2-dimethyl Base-tetrahydro-4H-cyclopentadiene-1,3-dioxol-4-oxyl]ethanol]-6-yl]-2-propylmercapto-6-oxo-8-aza Purine (VI) 1.83g, yield 89.1%.

Embodiment 3

[0045] Under nitrogen protection, add 9-[3aR-(3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadiene-1,3-di Oxolane-4-oxyl]ethanol]-6-yl]-2-propylmercapto-6-oxo-8-azapurine (VI) (1.95g, 5mmol), benzotriazole-1 -Oxyloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (3.32 g, 7.5 mmol) and acetonitrile 25 mL. Under stirring, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (1.14 g, 7.5 mmol) was added dropwise, and the reaction was carried out at room temperature for 12 hours. The temperature was raised to 60° C., and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, dissolved in 100 mL of ethyl acetate, and washed with 20 mL of 2M sodium hydroxide. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in 50 mL of tetrahydrofuran, and trans-(1R, 2S)-2-(3,4-difluorophenyl)cyclopropylamine (VII) (1.0 g, 6 mmol) and sodium hydride (0.16 g, 6.5 mmol) were added ), the tempe...

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Abstract

The invention discloses a preparation method of ticagrelor. The preparation method comprises the following steps of: carrying out a cyclization reaction between 5-amino-1,4-di-substituted-1,2,3-triazole (II) and a sulfur-containing cyclizing agent (III), thereby obtaining 9-substituted-2-sulfo-6-oxo-8-azaguanine (IV), carrying out a substitution reaction between the intermediate (IV) and halogenated propane (V) to generate 9-substituted-2-propylthiol-6-oxo-8-azaguanine (VI), carrying out condensation between the intermediate (VI) and trans-(1R,2S)-2-(3,4-difluorophenyl) cyclopropylamine (VII) to generate 9-substituted-6-amino substituent-2-propylthiol-8-azaguanine (VIII), and depriving an idene acetone protecting group from the intermediate (VIII) to obtain the ticagrelor (I). The preparation method disclosed by the invention is simple in process, economic and environment-friendly, and high in chemical and chiral purity, and provides a new preparation way for industrial production of the ticagrelor.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of a novel anticoagulant drug ticagrelor. 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. 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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCY02P20/55
Inventor 许学农
Owner 铜陵三十九度创客公园管理有限公司
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