Preparation method of ticagrelor

The 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 high product yield and product purity, and quick and convenient preparation process.

Active Publication Date: 2013-09-18
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

[0040]Add 1-[3aR-(3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadieno-1,3-dioxolane to the reaction flask -4-Oxy]ethanol]-6-yl]-5-amino-4-carboxamido-1,2,3-triazole (II) (3.27 g, 10 mmol), potassium carbonate (4.14 g, 30 mmol) ), 2 mL of water and 50 mL of dichloromethane. The temperature was lowered to 0° C., and a solution of carbon dichlorosulfide (III) (3.45 g, 30 mmol) in 25 mL of dichloromethane was slowly added dropwise, and the mixture was reacted 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 organic phases were combined, dried, and the solvent was removed under reduced pressure. The product was recrystallized from ethyl acetate to obtain off-white solid 9-[3aR-(3aα,4α,6α,6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadieno-1 , 3-dioxolane-4-oxy]ethanol]-6-yl]-2-thio-6-oxo-8-azapurine (IV) 3.14g, yield 85.1%.

Embodiment 2

[0042] Add 9-[3aR-(3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadieno-1,3-dioxolane to the reaction flask -4-Oxy]ethanol]-6-yl]-2-thio-6-oxo-8-azapurine (IV) (1.85 g, 5 mmol), potassium hydroxide solution (0.1 M, 10 mL) and To 25 mL of acetonitrile, a solution of bromopropane (V) (1.53 g, 12.5 mmol) in acetonitrile was added dropwise at room temperature. The reaction was stirred at room temperature for 15 hours. The solvent was recovered under reduced pressure, the residue was extracted three times with dichloromethane, the organic phases were combined, dried, and distilled under reduced pressure to obtain an oily substance 9-[3aR-(3aα, 4α, 6α, 6aα)-[[2,2-dimethylformaldehyde yl-tetrahydro-4H-cyclopentadieno-1,3-dioxolane-4-oxy]ethanol]-6-yl]-2-propylmercapto-6-oxo-8-aza Purine (VI) 1.83 g, yield 89.1%.

Embodiment 3

[0044] Add 9-[3aR-(3aα, 4α, 6α, 6aα)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadieno-1,3-dioxolane to the reaction flask -4-Oxy]ethanol]-6-yl]-2-propylmercapto-6-oxo-8-azapurine (VI) (1.95g, 5mmol), phosphorus oxychloride 7.5mL, start stirring, cool down At 0°C, 3.5 mL of 2,6-lutidine was added dropwise. The temperature was slowly raised to 100°C, and the reaction was stirred at this temperature for 9 hours. Phosphorus oxychloride was recovered under reduced pressure, and after the residue was cooled to room temperature, the reaction was quenched with ice water. Extract three times with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, recover the solvent under reduced pressure, dissolve the obtained oil in 25 mL of acetonitrile and transfer it to a reaction flask, add trans-(1R, 2S)-2-( 3,4-Difluorophenyl)cyclopropylamine (VII) (1.0 g, 6 mmol) and pyridine 1.5 mL. The reaction was stirred at room temperature for 12 hours, and the reaction was com...

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Abstract

The invention discloses a preparation method of ticagrelor. The preparation method comprises the following steps of: carrying out cyclization reaction between 5-amido-1,4-bis-substituent group-1,2,3-triazole (II) and a sulfur-containing cyclizing agent (III) to obtain 9-substitution-2-sulfo-6-oxo-8-azapurine (IV); carrying out substitution reaction between an intermediate (IV) and halogenated propane (V) to generate 9-substitution-2-propyl sulfydryl-6-oxo-8-azapurine (VI); chloridizing an intermediate (VI), and carrying out amination reaction between the intermediate (VI) and trans-(1R, 2S)-2-(3,4-difluorophenyl) rolicyprine (VII) to generate 9-substitution-6-amido substituendum-2-propyl sulfydryl-8-azapurine (VIII); and removing the propylidene acetonyl out of an intermediate (VIII) to obtain ticagrelor (I). The preparation method has the advantages of simple process and high chemical and chiral purity and provides a new preparation way for the industrialization 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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