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Method for preparing ticagrelor intermediate

A technology of ticagrelor and intermediates, which is applied in the design of organic synthesis routes and the preparation of raw materials and intermediates, can solve the problems of long steps, difficult separation, rare raw materials and the like, and achieves the reaction conditions suitable for large-scale industrial production. Easy to control, mild reaction conditions effect

Active Publication Date: 2014-02-19
贺州市八步区市场监督管理局
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] It can be seen that although there are many research reports on the preparation of ticagrelor intermediate C, there are many defects, such as long steps, rare raw materials, low yield, difficult separation, heavy pollution, and safety restrictions. or high cost, etc., these unfavorable factors make the industrialization of the above-mentioned process subject to certain restrictions

Method used

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  • Method for preparing ticagrelor intermediate
  • Method for preparing ticagrelor intermediate
  • Method for preparing ticagrelor intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Add (1R,2R,3R.4R)-rel-1,2;3,4-dioxycyclopentane (I) (9.8g, 0.1mol), sodium azide (8.13g, 0.125mol) and acetone / water (1 / 1) mixed solvent 200mL, start stirring, raise the temperature to 45-50°C, react for 72 hours, and the reaction is completed by GC detection. Diethyl ether was added until the solution was separated and the organic phase was separated. The aqueous phase was extracted 5 times with 100 mL of ether and acetone (4:1). The organic phases were combined and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure, and the residue is subjected to column chromatography (ether / n-pentane=5 / 1) to obtain a white solid (3aR,4S,6R,6aS)-rel-6-azidotetrahydro-2,2-dimethyl 9.0 g of yl-4H-cyclopenta-1,3-dioxan-4-ol (II), yield 45.2%.

Embodiment 2

[0034]Under nitrogen protection, add (3aR,4S,6R,6aS)-rel-6-azidotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-diox Hetero-4-alcohol (II) (8.0g, 0.04mol), tetrabutylammonium bromide (phase transfer catalyst) 0.25g and dry toluene 100mL, add sodium hydride (1.92g, 0.08mol) in batches under stirring, drop Add 2-bromoethanol (9.92 g, 0.08 mol) and slowly warm to reflux. Keep the reflux reaction for about 24 hours, and TLC detects that the reaction is complete. Cool to room temperature, add water and stir for 15 minutes, separate layers. The organic phase was washed with brine and dried over anhydrous sodium sulfate. The solvent was recovered by distillation under reduced pressure, and the residual oil was recrystallized from n-hexane to obtain a white solid 2-[[(3aR,4S,6R,6aS)-rel-6-azidotetrahydro-2,2-dimethyl- 8.1 g of 4H-cyclopenta-1,3-dioxan-4-yl]oxy]ethanol (III), yield 83.3%.

Embodiment 3

[0036] Under nitrogen protection, add 2-[[(3aR,4S,6R,6aS)-rel-6-azidotetrahydro-2,2-dimethyl-4H-cyclopenta-1 into the reaction flask, 3-Dioxa-4-yl]oxy]-ethanol (III) (7.3g, 0.03mol), Hans ester 1,4-dihydropyridine (9.1g, 0.036mol), 10% palladium carbon 1.8g and ethanol 50mL, started stirring, heated to reflux and maintained reflux for 5 hours, and TLC detected that the reaction was complete. Cool to room temperature, filter, and recover the catalyst. Concentrate under reduced pressure, dissolve the residue in dichloromethane, and wash successively with 5% hydrochloric acid, saturated brine and water. Dry over anhydrous sodium sulfate, and recover the solvent by distillation under reduced pressure to obtain light yellow oil 2-[[(3aR,4S,6R,6aS)-rel-6-aminotetrahydro-2,2-dimethyl-4H-cyclo Penteno-1,3-dioxan-4-yl]oxy]ethanol (IV) 5.9 g, yield 90.6%.

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Abstract

The invention discloses a method for preparing a ticagrelor intermediate 2-[[(3aR, 4S, 6R, 6aS)-6-aminotetralin-2, 2-dimethyl-4H-cyclopenteno-1,3-dioxin-4-group]oxygroup] ethanol (intermediate C). The method comprises the following steps: using (1R, 2R, 3R.4R)-rel-1,2 and 3, 4 bicyclo oxacyclopentane (I) as raw materials and obtaining a target product sequentially through nitrine opening ring, aminolysis, ketone condensation, etherification, reduction, resolution and the like. The preparation method has the advantages of being easy to obtain raw materials and simple in process, can effectively control the production cost, increases the quality of products, and promotes economic and technological development of ticagrelor active pharmaceutical ingredients.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a ticagrelor intermediate 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2 - A process for the preparation of dimethyl-4H-cyclopenta-1,3-dioxan-4-yl]oxy]ethanol. 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) for marketing in the EU and the US in 2010 and 2011, respectively, and its imported preparation, ticagrelor tablets, has been ap...

Claims

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Application Information

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IPC IPC(8): C07D317/44
CPCC07D317/44
Inventor 许学农
Owner 贺州市八步区市场监督管理局
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