A kind of preparation method of ticagrelor

A technology of ticagrelor and its compound, which is applied in the field of preparation of the small molecule anticoagulant ticagrelor, can solve the problems of being unsuitable for industrial production, and achieve the effects of cost reduction, mild reaction conditions, and shortened reaction steps

Active Publication Date: 2017-05-17
SHANGHAI JINGXIN BIOLOGICAL MEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] However, diethyl azodicarboxylate (DEAD), triphenylphosphine, and the triphenoxyphosphine and hydrazine diester compounds introduced therefrom, which are required for the Mitsunobu reaction, are difficult to remove in an easy way, and therefore, this method does not Suitable for industrial production

Method used

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  • A kind of preparation method of ticagrelor
  • A kind of preparation method of ticagrelor
  • A kind of preparation method of ticagrelor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Add formula II compound (4,6-dichloro-2-(propylthio)pyrimidin-5-amine) (2.68 g, 20 mmol) and dichloromethane (25 ml) into a 100 ml three-necked flask, cool to 0°C, add the compound of formula III ([3αR-(3aα,4α,6α,6aα)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopentadiene-1,3-dioxo Heterocyclopent-4-ol) tartrate (3.65 g, 10 mmol), and 10 ml of an aqueous solution of potassium carbonate (4.2 g, 30 mmol) was added dropwise. After the dropwise addition, keep warm at 0°C and stir for 30 minutes, then raise the temperature to room temperature (25°C), and continue stirring for 2 hours. The dichloromethane layer was separated, the water layer was washed with 10 ml of dichloromethane, the dichloromethane layers were combined, dried with anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation, and the residue was separated by column chromatography (eluent: Ethyl acetate: dichloromethane volume ratio = 0-20%: 1 gradient elution), to obtain 1.25 g of pr...

Embodiment 2

[0046] Add compound II (5.4 g, 20 mmol) in a 150 ml three-necked flask, tartrate (7.2 g, 20 mmol) of compound III, dichloromethane (50 ml), cool to -20°C, drop potassium carbonate ( 8.2 g, 30 mmol) in 30 ml of aqueous solution. After the dropwise addition was completed, the temperature was raised to 0° C. and stirred for 2 hours. Separate the dichloromethane layer, dry the dichloromethane layer with anhydrous sodium sulfate, filter, remove the solvent by rotary evaporation, and separate the residue by column chromatography (eluent: ethyl acetate:dichloromethane volume ratio=0- 20%:1 gradient elution), to obtain 2.5 g of product compound IV, based on the amount of compound III, the yield was 28%.

[0047] The product that present embodiment makes confirms to be formula IV compound through detection

Embodiment 3

[0049] Compound II (5.4 g, 20 mmol) and dichloromethane (50 ml) were added to a 150 ml three-necked flask, cooled to 0°C, and 4.1 g of potassium carbonate was added. The tartrate (3.65 g, 10 mmol) of compound III was added to 20 ml of dichloromethane, and 20 ml of an aqueous solution of potassium carbonate (4.1 g, 15 mmol) was added dropwise to prepare the free matter, and the dichloromethane containing the free matter was Layer separation. Slowly add dropwise to the reaction flask of compound II and potassium carbonate, after the dropwise addition is completed, keep warm at 0°C and stir for 2 hours. Separate the dichloromethane layer, dry the dichloromethane layer with anhydrous sodium sulfate, filter, remove the solvent by rotary evaporation, and separate the residue by column chromatography (eluent: ethyl acetate:dichloromethane volume ratio=0- 20%: 1 gradient elution), to obtain 3.5 grams of product compound IV, based on the amount of compound III, the yield was 78%.

[...

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Abstract

The invention provides a preparation method for ticagrelor. The method comprises the reaction steps shown in the specification, and concretely comprises the following steps: (1) in the presence of an alkali, coupling a formula II compound with a formula III compound to generate a formula IV compound; (2) under an acidic condition, performing reduction and deprotection on the formula IV compound, so as to obtain a formula V compound; (3) performing diazotization and ring closure on the formula V compound, so as to generate a formula VI compound; and (4) under an alkali condition, coupling the formula VI compound with a formula VII compound, so as to obtain ticagrelor shown as a formula I. The method is mild in reaction conditions and simple in post-treatment, is capable of effectively controlling impurities and improving the optical purity of the product, is suitable for industrialized production and has relatively large application value.

Description

technical field [0001] The invention relates to the preparation of medicines, in particular to a preparation method of ticagrelor, a small molecule anticoagulant. Background technique [0002] (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-[ 1,2,3]triazol[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentyl-1,2-diol (ticagrelor, ticagrelor ), the CAS number is 274693-27-5, shown in the following structural formula: [0003] [0004] Ticagrelor is a new type of selective small molecule anticoagulant drug developed by AstraZeneca. The drug can reversibly act on the purine 2 receptor subtype P2Y12 on vascular smooth muscle cells (VSMC). Ticagrelor is not a prodrug, so it does not require metabolic activation. Obvious inhibitory effect, and rapid onset after oral administration, can effectively improve the symptoms of patients with acute coronary heart disease. Unlike thienopyridine drugs (clopidogrel, prasugrel, etc.), ticagrelor is...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 黄悦张涛
Owner SHANGHAI JINGXIN BIOLOGICAL MEDICAL
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