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Preparation method of ticagrelor

A technology of ticagrelor and amino group is applied in the field of preparation of new anticoagulant drug ticagrelor, which can solve the problems of difficult control of coupling position, and achieve the effects of quick and convenient preparation, high product yield and high product purity

Active Publication Date: 2013-09-11
鄄城县人民医院
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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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  • Preparation method of ticagrelor
  • Preparation method of ticagrelor
  • Preparation method of ticagrelor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042]Under dry and nitrogen atmosphere, add 1-[3aR-(3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadiene-1,3 -Dioxolane-4-oxyl]ethanol]-6-yl]-5-amino-4-carboxamido-1,2,3-triazole (II) (3.27g, 10mmol), ethanol Sodium (2.72g, 40mmol) and absolute ethanol 100mL were slowly heated to reflux and reacted for 3 hours. Dimethyl carbonate (2.7 g, 30 mmol) was added dropwise over half an hour and reflux was continued for 6 hours. Ethanol was distilled off at atmospheric pressure, and the distillation was repeated once with fresh ethanol. Cool down to room temperature, add 50 mL of water, adjust the pH to 6 with dilute acid while stirring, slowly crystallize for 2 hours, filter, and recrystallize the filter cake with 50% methanol to obtain off-white solid 9-[3aR-(3aα, 4α, 6α ,6aα)-[[2,2-Dimethyl-tetrahydro-4H-cyclopentadiene-1,3-dioxol-4-oxyl]ethanol]-6-yl]-2, 2.55 g of 6-dihydroxy-8-azapurine (IV), yield 72.5%.

Embodiment 2

[0044] 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]-2,6-dihydroxy-8-azapurine (IV) (1.77g, 5mmol), phosphorus oxychloride 15mL, start stirring, and cool down to 0°C , 3.5 mL of 2,6-lutidine was added dropwise. The temperature was slowly raised to 100°C, and the reaction was maintained at this temperature with stirring for 9 hours. Phosphorus oxychloride was recovered under reduced pressure, and the residue was cooled to room temperature, and the reaction was quenched with ice water. Extracted 3 times with dichloromethane, combined the organic phases, dried over anhydrous sodium sulfate, and recovered the solvent under reduced pressure to obtain the oil 9-[3aR-(3aα, 4α, 6α, 6aα)-[[2,2-dimethyl -Tetrahydro-4H-cyclopentadieno-1,3-dioxol-4-oxyl]ethanol]-6-yl]-2,6-dichloro-8-azapurine (V) 1.7 g, yield 87.5%.

Embodiment 3

[0046] 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]-2,6-dichloro-8-azapurine (V) (1.95g, 5mmol), trans-(1R,2S)-2-(3, 4-Difluorophenyl)cyclopropylamine (VI) (1.0g, 6mmol) and 25mL of acetonitrile were stirred at room temperature, and 1.5mL of triethylamine was added. Keep stirring at room temperature for 12 hours, and TLC detects that the reaction is complete. Concentrate under reduced pressure, add ethyl acetate and water to the residue, and adjust pH=4 with dilute acid. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined, washed with pure water and brine successively, dried, and the solvent was recovered by distillation under reduced pressure to obtain the oil 9-[3aR-(3aα, 4α, 6α, 6aα)-[[2,2-dimethyl- Tetrahydro-4H-cyclopentadiene-1,3-dioxol-4-oxyl]ethanol]-6-yl]-6-[[(1R,2S)-2-(3,4 -Difluorophenyl)cyclopropyl...

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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 dialkyl carbonate (III), thereby obtaining 9-substituted-2,6-dihydroxy-8-azaguanine (IV), chlorinating the intermediate (IV) to obtain 9-substituted-2,6-dichloro-8-azaguanine (V), carrying out an amination reaction between the intermediate (V) and trans-(1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (VI) to generate 9-substituted-6-amino substituent-2-chloro-8-azaguanine (VII), and carrying out a propylthiolation reaction between the intermediate (VII) and propanethiol (VIII) to obtain the ticagrelor (I). The preparation method disclosed by the invention is simple in process, 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. Its imported preparation ticagrelor tablets has been approved by the China Food and Drug Administration. (SFDA) approved for listing in my country. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 许学农
Owner 鄄城县人民医院
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