New synthesis method of hepatitis C drug velpatasvir
A synthesis method and velpatasvir technology are applied in the field of new method synthesis of hepatitis C virus new drug velpatasvir and its series of intermediates, which can solve the problems of high cost, increased pressure for subsequent reaction purification, and low efficiency.
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Embodiment 1
[0045]
[0046] Add compound 31 (45.01g, 100mmol), compound 3 (35.04, 100mmol), N,N-dimethylformamide (225mL) into the three-necked flask, stir well, add potassium carbonate (27.64g, 200mmol), and react at room temperature 6 -8 hours. Add water (450mL) and ethyl acetate (450mL) after the reaction, separate the layers, extract the aqueous layer once with ethyl acetate (225mL), combine the organic phases and wash with water (225mL) twice, dry over anhydrous sodium sulfate, filter, and concentrate Most of the ethyl acetate was removed, petroleum ether (450 mL) was added to make a slurry, filtered, and vacuum-dried to obtain intermediate 4 (56.13 g, yield 78%). MS(ESI)m / z 719[M+H] + , 1 H NMR(CDCl3,400MHz)7.95-7.80(m,2H),7.75-7.65(m,2H),7.50-7.40(m,2H),7.40-7.25(m,4H),6.20-5.90(m,1H ),5.55-5.45(m,2H),5.34-5.22(m,1H),5.16(s,2H),4.77-4.50(m,2H),3.85-3.77(m,1H),3.65-3.61(m ,3H), 3.40-3.15(m,6H), 2.98-2.88(m,2H), 2.65-2.45(m,3H), 1.98-1.83(m,2H).
Embodiment 2
[0048]
[0049]Add compound 4 (35.98g, 50mmol) in the three-necked flask, compound 5 (15.03g, 52.5mmol), N,N-dimethylformamide (180mL), stir well and add cesium carbonate (32.58g, 100mmol), heat React at 50°C for 4-6 hours, cool to room temperature after the reaction, add saturated ammonium chloride (360mL), ethyl acetate (360mL), separate the layers, extract the water layer with ethyl acetate (180mL) once more, combine the organic phases and wash with water (180mL) twice, dried over anhydrous sodium sulfate, filtered, concentrated to remove most of the ethyl acetate, added petroleum ether (360mL) for slurry, filtered, and vacuum-dried to give intermediate 6 (34.69g, yield 75%). MS(ESI)m / z 925[M+H] + , 1 H NMR(CDCl3,400MHz)8.00-7.60(m,4H),7.58(s,1H),7.47-7.25(m,5H),6.25-5.95(m,1H),5.63-5.45(m,3H), 5.30-5.22(m,2H),5.16(s,2H),4.75-4.55(m,2H),4.35-4.15(m,1H),3.86-3.77(m,1H),3.72-3.58(m,6H ), 3.40-3.05(m,7H), 2.91(m,1H), 2.62-1.80(m,10H), 1.45-1.35(m,3H), 1.05-0.80(m,6H).
Embodiment 3
[0051]
[0052] Add compound 4 (35.98g, 50mmol) in the three-necked flask, compound 9 (12.04g, 52.5mmol), N,N-dimethylformamide (180mL), stir well and add cesium carbonate (32.58g, 100mmol), heat React at 50°C for 4-6 hours, cool to room temperature after the reaction, add saturated ammonium chloride (360mL), ethyl acetate (360mL), separate the layers, extract the water layer with ethyl acetate (180mL) once more, combine the organic phases and wash with water (180mL) twice, dried over anhydrous sodium sulfate, filtered, concentrated to remove most of the ethyl acetate, added petroleum ether (360mL) for slurry, filtered, and vacuum-dried to give intermediate 10 (31.96g, yield 72%). MS(ESI)m / z 868[M+H] + , 1 HNMR(CDCl3,400MHz)δ7.98-7.80(m,2H),7.98-7.59(m,3H),7.44(d,J=7.6Hz,2H),7.37-7.27(m,3H),6.24-5.90 (m,1H),5.65-5.45(m,3H),5.28-5.21(m,1H),5.17(s,2H),4.76-4.63(m,1H),3.90-3.70(m,1H),4.52 -4.30(m,1H),4.11-3.90(m,1H),3.85-3.77(m,1H),3.70-3.60(m,3H),3.40-3.10(m,7H),2.95-2.87(...
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