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Preparation method of platelet aggregation inhibitor ticagrelor

A technology of platelet aggregation and ticagrelor, applied in the direction of organic chemistry, can solve the problems of no conformational change and signal transmission, and achieve the effect of less impurities, less by-products, and simple post-processing

Inactive Publication Date: 2020-10-30
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the difference is that the interaction between ticagrelor and the platelet P2Y12ADP receptor is reversible, there is no conformational change and signal transmission, and the platelet function in the blood also recovers rapidly after drug withdrawal

Method used

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  • Preparation method of platelet aggregation inhibitor ticagrelor
  • Preparation method of platelet aggregation inhibitor ticagrelor

Examples

Experimental program
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Effect test

Embodiment 1

[0022] Add compound 2 (1.00g, 4.20mmol), compound 3 (2.76g, 4.62mmol) and 30mL isopropanol successively to a 100mL reaction flask, add triethylamine (1.61g, 15.94mmol) under stirring, and heat up to 80°C , keep the reaction for 20 hours, cool to room temperature, transfer the reaction solution to a 100mL reaction bottle, add 30mL water and 10mL ethyl acetate, stir and leave to separate layers, extract the water phase with 10mL ethyl acetate twice, combine the organic phase and wash with water , Wash with saturated saline. Dry over anhydrous sodium sulfate and filter. After concentration and spin-drying, 2.342 g of a dark red solid (compound 4) was obtained, with a yield of 86%. 1 H-NMR (CDCl 3 , 400MHz) δ: 0.94(t, J=7.2Hz, 3H), 1.60-1.66(m, 2H), 2.08-2.15(m, 1H), 2.92-3.01(m, 2H), 3.01-3.04(m, 2H), 3.13-3.15(m,1H), 3.46(m,1H), 3.68-3.71(m,2H), 3.77-3.80(m,2H), 4.31-4.32(m,1H), 4.65(d, 6H), 5.68(s,2H), 7.29-7.32(m,15H), 7.62(s,1H); ESI-MS m / z:C 35 h 41 ClN 4 o 4 S[M+H] ...

Embodiment 2

[0028] Add compound 2 (1.00kg, 4.20mol), compound 3 (3.01kg, 5.04mol) and 30L isopropanol successively in 50L enamel reaction kettle, add triethylamine (1.70kg, 16.80mol) under stirring, heat up to 80 ℃, heat preservation reaction for 30 hours, cooled to room temperature, transferred the reaction solution to a 100L reaction kettle, added 30L water and 10L ethyl acetate, stirred, left to stand for liquid separation, extracted the water phase twice with 10L ethyl acetate, and combined The organic phase was washed twice with 10 L of water and washed with 10 L of saturated brine. Dry over anhydrous sodium sulfate and filter. After concentration and spin-drying, 2.42 kg brick red solid (compound 4) was obtained, with a yield of 89%.

[0029] 50L of acetonitrile, compound 4 (2.42kg, 3.73mol) and isoamyl nitrite (0.55kg, 4.69mol) were sequentially added to a 100L reactor, stirred, and then heated to 75°C for 12 hours under reflux. After the reaction was detected by TLC, it was conc...

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Abstract

The invention discloses a preparation method of platelet aggregation inhibitor ticagrelor, and belongs to the field of drug synthesis. According to the method, a compound 2 and a compound 3 are used as raw materials, substitution reaction, cyclization reaction, amination reaction and deprotection are sequentially carried out, a crude product is recrystallized by ethyl acetate and normal hexane toobtain the ticagrelor, and the purity of the ticagrelor is up to 99.5% or above. Compared with methods reported in existing literatures, the method has the advantages that the reaction route is obviously shortened, the process stability is high, use of toxic solvents and high-pollution reagents is avoided, and the method is relatively more environmentally friendly and suitable for large-scale production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of a novel platelet aggregation inhibitor ticagrelor. Background technique [0002] Ticagrelor, chemical name: (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl] Amino]-5-propylthiotriazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol, molecular formula: C 23 h 28 f 2 N 6 o 4 S. [0003] The trade name of ticagrelor is Belinda, which belongs to the cyclopentyl triazolopyrimidine compound. It is a new type of small molecule anticoagulant drug developed by the British AstraZeneca Pharmaceutical Company. It is used to inhibit platelet aggregation. Its clinical efficacy Its safety and safety have been verified and supported by the Platelet Inhibition and Patient Outcome Study (PLATO Study) and its multiple subgroup studies. It was launched in Europe in 2010 and was approved by the US FDA in July 2011; the sales volume i...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 郝二军苏富赢官愉清尹梦娟张运巧刘玉侠
Owner HENAN NORMAL UNIV
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