A kind of preparation method of high-purity vardenafil hydrochloride trihydrate suitable for industrialization
A technology of vardenafil hydrochloride and trihydrate, which is applied in the direction of organic chemistry, can solve the problems of thionyl chloride hypertoxicity, sensitivity, and high product viscosity, and achieve simple and convenient industrial operation, simple and convenient operation process, and high product quality. The effect of low viscosity
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Embodiment 1
[0035] Add 2.5L of chlorosulfonic acid into a 10L reaction tank, protect it with nitrogen, and cool it down. Add 1kg of 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1- f] [1,2,4]-triazin-4-one was added to the reaction tank in batches, and the temperature was kept at -15~15°C during the feeding process, and then raised to room temperature and stirred for 8~10 hours. After the reaction is complete, mix 25 L of ice water and 20 L of dichloromethane, stir, and add the reaction solution after cooling, keeping the temperature at -5 to 10° C. non-sticky, in powder form), separate the organic phase, and extract the water phase once with 5 L of dichloromethane, mix the 25 L of the separated organic phase with the new 25 L system of ice water, stir mechanically, add the filtered solid to it, and stir for 15~ 30min until the solid is basically dissolved (there may be a very small amount of insoluble matter between the two phases), separate the organic phase, wash the organic phase ...
Embodiment 2
[0037] Dissolve the product (10kg) of Example 1 in 50L tetrahydrofuran, add 4.6L N-ethylpiperazine to the reaction solution at 0°C, keep the temperature not higher than 25°C, after the addition is completed, warm up to room temperature and stir for 10-30min, the solution It becomes cloudy (or the solution is clear with sticky material at the bottom), and the reaction is monitored by HPLC. After completion of the reaction, 150L of 0.5% sodium carbonate solution was added dropwise to the reaction solution, the solution became clear, and a large amount of solids were precipitated. Continue to stir at room temperature for 1h, filter, and wash the solid with 150L of water (the water volume is the same as the total volume of the sodium carbonate solution), and the washing solution pH ≈7, the solid was vacuum-dried at 45°C for 2 to 4 hours, measured by HPLC, and measured for moisture, and the moisture content was ≤7.0%. Re-dissolve the crude product (weight after deducting moisture) ...
Embodiment 3
[0039]Dissolve 6.0kg of the product of Example 2 (weight after deducting moisture) in 18L of acetone:water=12:1 solution, heat and stir at 40-45°C, add 1.16L of concentrated hydrochloric acid, stir, the solid dissolves immediately, and heat to 60 Reflux at around ℃ (10min), try to avoid solid precipitation, cool down to room temperature and stir for 30-60min, stir at -5-0℃ for 1.5-2h, filter, wash the solid with 3L acetone: water = 12:1 solution, solid sample test HPLC, dry the solid at room temperature or dry in a vacuum seal, measure the moisture and melting point. Dissolve the crude product (without deduction of water) in a solution of 5 times acetone: water = 9:1, heat to dissolve at 50-55°C, cool down to room temperature and stir for 30-60min, then stir at -5-0°C for 1.5-2h, Filter, wash the solid with a solution of acetone:water=9:1 (1 / 10 of the volume of the original acetone and water), sample the solid for HPLC, dry the solid at room temperature or dry it in a vacuum s...
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