Preparation method of ticagrelor

[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...

[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...

[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...