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A kind of preparation method of ticagrelor and its new intermediate

A technology for ticagrelor and its compounds, which is applied in the field of intermediate preparation, can solve the problems of expensive starting materials, high cost, and long routes, and achieve easy and effective separation, reduced usage, and cheap and easy-to-obtain starting materials Effect

Active Publication Date: 2015-08-19
GINKGO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] In addition, after searching, it can be seen that there are many documents describing the synthesis of ticagrelor, but these routes have disadvantages such as relatively expensive starting materials, relatively high cost, long routes, and difficult purification.

Method used

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  • A kind of preparation method of ticagrelor and its new intermediate
  • A kind of preparation method of ticagrelor and its new intermediate
  • A kind of preparation method of ticagrelor and its new intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Preparation of 2-propylthio-4-hydroxy-5-nitro-6-chloropyrimidine (compound of formula 2)

[0061]

[0062] Add raw material 1 (30.0g, 129.7mmol) and solvent toluene (300ml) into a 500ml three-neck flask, add DIPEA (18.4g, 142.7mmol) and PCl3 (19.6g, 142.7mmol) under stirring, and stir at room temperature for 2 hours after the addition . Pour the reaction solution into ice water (150ml) to quench, extract with EA (2×150ml), combine the EA layers, wash with water (150ml), wash with saturated brine (150ml), dry over anhydrous sodium sulfate, filter, concentrate and add PE Recrystallization gave light yellow solid 2 (26.2 g, yield 80.9%).

[0063] 1 H NMR (CDCl 3 ,400MHz)δ3.23(2H,J=7.2Hz,t),1.81-1.76(2H,m),1.06(3H,J=7.2Hz,t).

[0064] Compounds of formula 2 can also be prepared using other chlorination reagents.

[0065]

[0066] Add raw material 1 (10.0g, 43.2mmol) and solvent toluene (100ml) into a 250ml three-neck flask, add DIPEA (6.1g, 47.6mmol) and POCl3 (7...

Embodiment 2

[0070] 6-((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-3aH-cyclopentyl[d][1,3]dioxo -4-amino)-5-nitro-2-(propylthio)pyrimidine-4-hydroxyl (formula 4a compound) preparation

[0071]

[0072] Add compound 3a (1.0g, 4.6mmol) and solvent ethylene glycol (5ml) into a 100ml single-necked flask, add base TEA (1.4g, 13.8mmol) and compound 2 (1.2g, 4.6mmol) under stirring, and put The temperature of the reaction system was raised to 110° C., and the reaction was stirred for 2 hours. Cool the reaction solution to room temperature, add water (10ml) and EA (10ml) to quench, stir for 10 minutes, separate the organic layer, extract the aqueous layer with EA (10ml), combine the EA layers, wash with water (2×20ml), and saturated salt Washed with water (20ml), concentrated and added PE to precipitate the solid product 4a (1.6g, yield 81.3%), which was directly used in the next reaction.

[0073] 1 H NMR (CDCl 3 ,400MHz)δ11.63(1H,s),10.08(1H,J=7.6Hz,d),4.76-4.68(2H,m),4.58(...

Embodiment 3

[0078] 6-((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-3aH-cyclopentyl[d][1,3]dioxo -4-amino)-5-amino-2-(propylthio)pyrimidine-4-hydroxyl (compound of formula 5a)

[0079]

[0080] Add compound 4a (1.0g, 2.3mmol) and solvent methanol (10ml) into a 50ml single-necked bottle, stir to dissolve, add the catalyst Raney nickel (0.3g), and react overnight at room temperature under hydrogen balloon pressure (0.1MPa). After filtration, the filtrate was concentrated to dryness to obtain the reduced product 5a (0.88 g, yield 94.6%), which was directly used in the next reaction.

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PUM

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Abstract

The invention relates to a preparation method of ticagrelor and novel intermediates of ticagrelor, and the method belongs to the technical field of medicine synthesis. The preparation method provided by the invention relates to the novel intermediates 2, 4, 5, 6 and 9, the technical route is novel, the operation is simple, the production cost is relatively low, the steps of separation and purification are easy, the yield is high, and the method is applicable to large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, more specifically, the invention relates to a selective anticoagulant drug compound ticagrelor and a preparation method of a new intermediate thereof. Background technique [0002] Ticagrelor (formerly known as ticagrelor) is a new, selective and reversible P2Y12 adenosine diphosphate receptor (ADP) antagonist developed by AstraZeneca. The drug does not require metabolic activation, has a significant inhibitory effect on platelet aggregation induced by adenosine diphosphate (ADP), and takes effect quickly after oral administration, and can effectively improve the symptoms of patients with acute coronary syndrome. Unlike thienopyridines, ticagrelor is a reversible inhibitor of P2Y12 receptors, so it is especially suitable for patients who need anticoagulant therapy before surgery. The imported preparation of ticagrelor has been approved by SFDA to be launched in my country, and the Chinese...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/56C07D487/04C07D405/12
CPCC07D239/56C07D405/12C07D487/04
Inventor 李本陈力文小伟
Owner GINKGO PHARMA
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