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Preparation method of ticagrelor

A technology for ticagrelor and compounds, applied in the field of preparation of ticagrelor, capable of solving problems such as long route, low total yield, and unsuitability

Active Publication Date: 2014-12-10
SHANGHAI HAOYUAN CHEMEXPRESS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This route also has the shortcoming that the route is long and the total yield is low, so it is not suitable as the optimal route for large-scale industrial production.

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

[0024] Preparation of Compound Via

[0025]

[0026] Compound VIIa (615 g, 2 mol) was added into 3.5 L of tetrahydrofuran, and potassium tert-butoxide solid (269.5 g, 2.4 mol) was added in portions. The mixture was stirred for 10 minutes, and a 1L tetrahydrofuran solution of 2-bromoethoxy tert-butyldimethylsilane (573.5g, 2.4mol) was added dropwise at 0°C. The reaction solution was stirred for 1.5 hours. TLC showed that the reaction was complete, and 2L of water was added to the reaction solution. , ethyl acetate 2L, the organic phase was separated, dried, and concentrated to obtain compound VIa857.3g, with a yield of 92%.

[0027] Preparation of compound Va

[0028]

[0029] Compound VIa (838.2g, 1.8mol) was added to 5L of ethanol, 10% palladium carbon (40g) was added, the reaction solution was replaced with hydrogen to remove air, pressurized at 1.5 Pa, and reacted at 50°C for 10 hours. TLC showed that the reaction was complete. Palladium carbon was removed by filtra...

Embodiment 2

[0043] Preparation of compound VIb

[0044]

[0045] Compound VIIb (615 g, 2 mol) was added to 3 L of N,N-dimethylformamide, and 40% solid sodium hydride (144 g, 2.4 mol) was added in portions. The mixture was stirred for 10 minutes, and 2-iodoethoxytriethylsilane (687g, 2.4mol) in 1L N,N-dimethylformamide solution was added dropwise at zero degree, and the reaction solution was stirred for 1 hour, TLC showed that the reaction was complete, and the reaction 2 L of water and 2 L of ethyl acetate were added to the solution, the organic phase was separated, dried and concentrated to obtain 47.5 g of compound VIb with a yield of 91%.

[0046] Preparation of Compound Vb

[0047]

[0048] Compound VIb (838.2g, 1.8mol) was added to 5L of methanol, 15% palladium hydroxide (40g) was added, the reaction solution was replaced with hydrogen to remove air, pressurized at 2 Pa, and reacted at 50°C for 12 hours. TLC showed that the reaction was complete. The liquid was filtered to remo...

Embodiment 3

[0062] Preparation of Compound VIc

[0063]

[0064] Compound VIIc (615 g, 2 mol) was added to 5 L of methyl tert-butyl ether, and sodium tert-amylate solid (264 g, 2.4 mol) was added. The mixture was stirred for 10 minutes, and a 1L solution of 1-chloro-2-methoxymethylethane (299 g, 2.4 mol) was added dropwise at zero degree, and the reaction solution was stirred for 1 hour. TLC showed that the reaction was complete, and the reaction solution 2 L of water and 2 L of ethyl acetate were added, and the organic phase was separated, dried, and concentrated to obtain 704.9 g of compound VIc with a yield of 89%.

[0065] Preparation of compound Vc

[0066]

[0067] Compound VIc (672.3g, 1.7mol) was added to 4L of isopropanol, 10% palladium carbon (30g) was added, the reaction solution was replaced with hydrogen to remove air, pressurized at 1.5Pa, and reacted at 50°C for 12 hours. TLC showed that the reaction was complete. The reaction solution was filtered to remove palladi...

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Abstract

The invention provides a preparation method of ticagrelor, belonging to the technical field of medicine manufacturing. According to the method, a compound VII is taken as a raw material, and the method comprises the steps of: carrying out a nucleophilic substitution reaction on the raw material to obtain a compound VI; hydrogenating the VI, removing carbamazepine (Cbz) protection to obtain a compound V; carrying out a reaction on the V and 4, 6-dichloro-2-(allyl sulfide)-5-amio-pyrimidine to obtain a compound IV; carrying out a reaction on the IV and nitrite of alkali metal to obtain a compound III; carrying out a reaction on the III and (1R, 2S)-2-(3, 4-difluoro phenyl) cyclopropylamine to obtain a compound II; and finally, removing protecting group of the II to obtain a compound I.

Description

technical field [0001] The invention relates to the technical field of medicine manufacture, in particular to a preparation method of ticagrelor. Background technique [0002] Ticagrelor, chemical name (1S, 2S, 3R, 5S)-3-[7-[(1R, 2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylsulfanyl)-3H-[ 1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol, CAS NO: 274693-27-5, Has the structural formula of formula I: [0003] [0004] I Ticagrelor is a new type of selective anticoagulant and the first reversible binding P2Y12 adenosine diphosphate receptor (ADP) antagonist, which can reversibly act on vascular smooth muscle cells (VSMC ) on the purine 2 receptor subtype P2Y12, which can significantly inhibit the platelet aggregation caused by ADP, and can effectively improve the symptoms of patients with acute coronary heart disease. This product is developed and produced by AstraZeneca, and the trade name is Brilinta. The tablet was first launched in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCY02P20/55
Inventor 郑保富薛吉军高强张宪恕刘树芳刘海旺
Owner SHANGHAI HAOYUAN CHEMEXPRESS
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