ChemicalBook CAS DataBase List TICAGRELOR

TICAGRELOR synthesis

5synthesis methods

Product Name:TICAGRELOR
CAS Number:274693-27-5
Molecular formula:C23H28F2N6O4S
Molecular Weight:522.57

Ticagrelor, also known as AZD-6140 and AR-C 126532XX, is a platelet aggregation inhibitor produced by AstraZeneca. The drug was approved in 2011. Ticagrelor is an antagonist of the P2Y12 receptor. Like the thienopyridines prasugrel, clopidogrel and ticlopidine, ticagrelor blocks adenosine diphosphate (ADP) receptors of subtype P2Y12. In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it an allosteric antagonist, and the blockage is reversible. Moreover, the drug does not need hepatic activation, which might work better for patients with genetic variants regarding the enzyme CYP2C19.

Synthetic Routes

ROUTE 1

ROUTE 2

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Zhang, Hao; Liu, Jun; Zhang, Luyong; Kong, Lingyi; Yao, Hequan; Sun, Hongbin. Synthesis and biological evaluation of ticagrelor derivatives as novel antiplatelet agents. Bioorganic & Medicinal Chemistry Letters. Volume 22. Issue 11. Pages 3598-3602. Journal; Online Computer File. (2012).

274693-26-4 Synthesis

2-[[(3aS,4R,6S,6aR)-4-[7-[[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy]ethanol

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Yield:274693-27-5 97.1%

Reaction Conditions:

with hydrogenchloride in methanol at -3 - 20; for 3 h;Large scale;

Steps:

3 Example 3 Preparation of ticagrelor

Methanol (105 L) and Stage II (21 kg) were charged to the reaction kettle at room temperature,Cool to -3 ° C at -3 ° CConcentrate hydrochloric acid (107.1 kg) in batches in two hours and below,Stir for 1 hour. Methyl tert-butyl ether was charged to the reaction vessel at -3 ° C105L,207 L sodium hydroxide solution was added to adjust the pH of the reaction mass to 8.0. After the reaction mass was stirred at 10 ° C for 30 minutes,Warm to room temperature and stir for another 30 minutes.Static stratification,The organic and aqueous phases are separated,The lower aqueous phase was extracted with methyl tert-butyl ether,The organic phase was washed with saturated sodium chloride solution and then extracted with methanol.Combined organic phase,Put into activated carbon 2.10kg,Heated to 40 ° C,Stir for 30 minutes,filter,Rinse with methyl tert-butyl ether.Vacuum distillation,The resulting residue was recrystallized from ethyl acetate and cyclohexane,Centrifuge,Vacuum dried at 55 ° C for 6 hours,Ticagrelor.The yield is about 97.1%Purity is about 99.6%.

References:

CN106866682,2017,A Location in patent:Paragraph 0045; 0046; 0047; 0048