Method for preparing s-citalopram from r-diol
A technology of diol and dichloromethane, which is applied in the field of preparation of S-citalopram, can solve the problems of non-compliance with atom economy, increase production cost, pollute the environment, etc., and achieve the effect of improving atom economy
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Embodiment 1
[0018] Embodiment 1: the preparation of R-diol (refer to CN103342664B, Zhai Jisheng etc.)
[0019] 20.0kg of RS-diol hydrobromide, 80L of dichloromethane, 10kg of 30% sodium hydroxide, and 20L of water were added to the reaction tank, and the reaction was stirred. After standing, the water layer was separated, the organic layer was washed with water, and the dichloromethane was evaporated to obtain RS-diol oil.
[0020] Add 80L of isopropanol, 0.2kg of water, stir, add 9.5kg of D-(+)-di-p-toluoyltartaric acid (hereinafter referred to as "(+)-DTTA") at 40°C, and stir for crystallization. Cool, centrifuge. Wash with isopropanol and dry to obtain S-diol tartrate.
[0021] The centrifuged mother liquor (the main component is R-diol tartrate) was evaporated to remove the solvent, 40L of dichloromethane, 5kg of 30% sodium hydroxide, 10L of water were added, and the reaction was stirred. It was left to stand, the water layer was separated, the organic layer was washed with water, ...
Embodiment 2
[0023] (1) Chlorination: 8.0 kg of R-diol oil and 4.8 kg of phosphorus trichloride were put into the reaction tank, and the temperature was raised to 75° C. for reflux reaction for 4 hours. Cool, add 16L dichloromethane, 15kg sodium bicarbonate, 30L water, and layer. The organic layer was washed with water, and the layers were separated. The organic layer was evaporated to dichloromethane to obtain an oily product as (S)-4-[4-dimethylamino-1-(4-fluorophenyl)-1-chlorobutyl]-3-chloromethylbenzonitrile (below referred to as "S-dichloro").
[0024] (2) Ringing: add 1.1kg sodium hydroxide and 0.4kg water to the reaction tank containing S-dichloro oil. The temperature was raised to 80°C for 6h. Cool down, add 16L of dichloromethane and 30L of water, and separate the layers. The organic layer was washed with water, and the layers were separated. The organic layer was evaporated to dichloromethane to obtain 7.3 kg of oil as S-citalopram. The content is 97.1%, and the yield is 94...
Embodiment 3
[0026] (1) Chlorination: 8.0 kg of R-diol oil and 4.2 kg of thionyl chloride were put into the reaction tank, and the temperature was raised to 75° C. for reflux reaction for 4 hours. Cool, add 16L dichloromethane, 15kg sodium bicarbonate, 30L water, and layer. The organic layer was washed with water, and the layers were separated. The organic layer was evaporated to dichloromethane to obtain an oily product as (S)-4-[4-dimethylamino-1-(4-fluorophenyl)-1-chlorobutyl]-3-chloromethylbenzonitrile (below referred to as "S-dichloro").
[0027] (2) Ringing: add 1.6kg potassium hydroxide and 0.4kg water to the reaction tank containing S-dichloro oil. The temperature was raised to 80°C for 6h. Cool down, add 16L of dichloromethane and 30L of water, and separate the layers. The organic layer was washed with water, and the layers were separated. The organic layer was evaporated to dichloromethane to obtain 7.2 kg of oil as S-citalopram. The content is 97.4%, and the yield is 93%. ...
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