A kind of synthetic method of Sofosbuvir intermediate
A synthetic method and intermediate technology, applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of not being able to adapt to large-scale industrial production, poor stereoselectivity, and low yield, and achieve good application prospects and market potential, simple steps, and low cost. cheap effect
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Embodiment 1
[0033] The synthesis of embodiment 1 compound VI II
[0034]
[0035] Add 200 g of compound II and 1.0 L of ethanol into a 2 L reaction flask, stir and dissolve to form a clear solution. At room temperature, 200 g of acetic acid was slowly added dropwise. After the dropwise addition, the temperature of the reaction mixture was raised to 80° C., and the reaction was stirred for 15 hours. After the reaction was completed, it was concentrated under reduced pressure, and the solvent ethanol was distilled off. Then add 400mL of acetone, stir, and raise the temperature to 50°C. After a clear solution formed, 20 mL of water was slowly added dropwise. After the dropwise addition, the temperature was slowly lowered to 10° C., and crystallization was carried out with stirring. The solid formed was Buchner filtered and the filter cake was washed twice with pre-cooled acetone. The obtained solid was dried to obtain compound VIII (108 g, 82%). 1 H NMR (400MHz, DMSO-d6) δ: 5.81(s, ...
Embodiment 2
[0037] The synthesis of embodiment 2 compound IX
[0038]
[0039]Under the protection of nitrogen, 200 g of compound VIII, 1.0 L of 2-methyltetrahydrofuran and 390 g of pyridine were added into a 5.0 L reaction flask, stirred and dissolved to form a clear solution. The temperature of the reaction solution was lowered to 5° C., and 295 g of benzoyl chloride was slowly added dropwise. During the dropwise addition, the reaction temperature is controlled between 10-15°C. After the dropwise addition, the reaction solution was stirred and reacted at 15° C. for 30 minutes. After the completion of the reaction was confirmed by high performance liquid chromatography, 2.0 L of hydrochloric acid (6.0 N) and 5.0 L of dichloromethane were added. Stand to separate layers and take the organic phase. The aqueous phase was extracted twice with 2.0 L of dichloromethane. Combine the organic phases, wash once with 1.0L hydrochloric acid (1.0N), and wash twice with 1.0L saturated sodium bi...
Embodiment 3
[0041] The synthesis of embodiment 3 compound I
[0042]
[0043] Add 50 g of compound IX and 600 mL of acetonitrile into a 2.0 L reaction flask, stir and dissolve to form a clear solution. 100 mL of triethylamine trihydrofluoride and 68 g of triethylamine were added. The temperature of the reaction mixture was lowered to 0° C., and a solution of thionyl chloride (13.3 g) in acetonitrile (100 mL) was slowly added dropwise with stirring. After the dropwise addition, the temperature was maintained for 2 h. After the completion of the reaction was confirmed by high performance liquid chromatography, the reaction was also concentrated to dryness under reduced pressure. Add 250 mL of isopropanol to the obtained crude product, raise the temperature to 55°C, and stir to dissolve. Stirring was continued overnight during which time the temperature slowly fell to room temperature. Continue to cool down to 0°C and stir for one hour. The solid formed was Buchner filtered and the fi...
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