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Method for preparing ticagrelor

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

Active Publication Date: 2015-07-01
铜陵尚东高新科创有限公司
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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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  • Method for preparing ticagrelor
  • Method for preparing ticagrelor
  • Method for preparing ticagrelor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Add 1-[(3aR, 4S, 6R, 6aS)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadiene-1,3-dioxol-4 to the reaction flask -Oxy]ethyl acetate]-6-yl]-5-amino-4-carboxamido-1,2,3-triazole (II) (3.69g, 10mmol), thiourea (1.0g, 13mmol ) and toluene 25mL. Slowly raise the temperature to 100° C., and react for 10 hours under the protection of nitrogen. The solvent was removed under reduced pressure to give oil 9-[(3aR,4S,6R,6aS)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadieno-1,3-dioxane Pent-4-oxyl]ethyl acetate]-6-yl]-2-thio-6-oxo-8-azapurine (or named: 2-{[(3aR, 4S, 6R, 6aS) -6-{7-oxo-5-oxo-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-2,2-dimethyl-tetrahydro -3aH-cyclopentadiene[d][1,3]-dioxol-4-yl]oxy}ethyl acetate) (III) 3.5g, yield 85.2% (can be directly used in the following step reaction).

Embodiment 2

[0038] Add 9-[(3aR, 4S, 6R, 6aS)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadiene-1,3-dioxol-4 to the reaction flask -Oxy]ethyl acetate]-6-yl]-2-thioxo-6-oxo-8-azapurine (III) (2.10g, 5mmol), potassium hydroxide solution (0.1M, 10mL) and Acetonitrile 25mL, room temperature was added dropwise bromopropane (1.53g, 12.5mmol) 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 oil 9-[(3aR, 4S, 6R, 6aS)-[[2,2-dimethyl- Tetrahydro-4H-cyclopentadieno-1,3-dioxol-4-oxy]ethyl acetate]-6-yl]-2-propylmercapto-6-oxo-8-aza Purine (or named: 2-{[(3aR, 4S, 6R, 6aS)-6-{7-oxo-5-propylmercapto-3H-[1,2,3]triazolo[4,5- d]pyrimidin-3-yl}-2,2-dimethyl-tetrahydro-3aH-cyclopentadieno[d][1,3]-dioxol-4-yl]oxy}acetic acid Ethyl ester) (IV) 2.1g, yield 92.7%.

Embodiment 3

[0040] Under nitrogen protection, add 9-[(3aR, 4S, 6R, 6aS)-[[2,2-dimethyl-tetrahydro-4H-cyclopentadiene-1,3-dioxa Cyclopent-4-oxyl]ethyl acetate]-6-yl]-2-propylmercapto-6-oxo-8-azapurine (IV) (1.13g, 2.5mmol), benzotriazole- 1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1.7 g, 3.75 mmol) and acetonitrile 25 mL. Under stirring, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (0.6 g, 3.75 mmol) was added and reacted 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 25 mL of ethyl acetate, and washed with 10 mL of 2M sodium hydroxide. The organic phase was separated, dried and concentrated under reduced pressure. The residue was dissolved in 25 mL of tetrahydrofuran, and trans-(1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (0.5 g, 3 mmol) and sodium hydride (0.1 g, 4 mmol) were added, and the temperature was raised to 50° C., st...

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Abstract

The invention discloses a method for preparing ticagrelor, which comprises the following steps of by taking 1-[(3aR,4S,6R,6aS)-[[2,2- dimethyl-tetralin-4H-cyclopentadiene-1,3-dioxo heterocyclelane-4-oxygroup] ethyl acetate-6-base]-5-amidogen-4-formamido-1,2,3- triazole(II) as the raw material, sequentially carrying out cyclizing, replacement, condensation and reduction reactions, and removing the protecting group, so as to prepare the ticagrelor. The method is concise, environment-friendly and economic, has high chemical and chirality purity, and provides the new preparation method of ticagrelor industrialized production.

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 铜陵尚东高新科创有限公司
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