A kind of preparation method of chlorcaserin hydrochloride
The technology of greencaserin and catalyst is applied in the field of preparation of greencaserin hydrochloride, which can solve the problems of long route, unfavorable equipment maintenance by waste gas and waste acid, etc., and achieve the effects of shortening reaction steps, being beneficial to equipment protection and convenient post-processing.
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Embodiment 1
[0040] (1) Preparation of (4-chlorophenethyl) tert-butyl carbamate (V)
[0041] Place 2-(4-chlorophenyl)ethylamine (50.0g, 321.3mmol) in a 1L three-necked flask, add 200mL of dichloromethane, stir to dissolve, and add Boc anhydride (77.1g, 353.3mmol) at 0°C. ) The solution obtained by dissolving in 300mL dichloromethane, a large amount of white solid precipitated, after the addition, warm to room temperature, add a catalytic amount of DMAP, the solution gradually becomes colorless and clear, stir the reaction for about 5h (TLC monitors the reaction is complete), pour into 400mL Separate the organic layer into water, extract the aqueous layer twice with dichloromethane (200 mL×2), combine the organic phases, wash with water and saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to After drying, 80.9 g of white solid was obtained with a yield of 98.5%. mp: 60-63°C.
[0042] 1 H-NMR (300MHz,...
Embodiment 2
[0059] Preparation of racemic chlorocaserin (II)
[0060] Take anhydrous aluminum trichloride (22.5g, 168.7mmol) and grind it into a powder, add it to a 500mL three-necked flask, add 1,2-dichlorobenzene (90mL), stir to form a suspension, and cool to 0~ in an ice bath 5°C. Intermediate IV (20.0g, 67.6mmol) was dissolved in 1,2-dichlorobenzene (50mL) and then slowly added dropwise to the above reaction solution. After the addition, under nitrogen protection, the temperature was raised to 120°C for reaction, and the reaction was carried out for 1-2h, TLC After detecting the completion of the reaction, stop heating and cool to room temperature. Slowly poured into 150 g of ice-water mixture to quench the reaction. Adjust pH=1~2 with 1mol / L dilute hydrochloric acid, separate the water layer, extract the organic layer once with water (100mL), combine the water layers, wash twice with ethyl acetate (100mL×2), and water layer with 30% hydroxide Adjust pH=10-12 with sodium solution, ext...
Embodiment 3
[0062] Preparation of racemic chlorocaserin (II)
[0063] Take anhydrous aluminum trichloride (13.5g, 101.2mmol) and grind it into a powder, add it to a 250mL three-necked reaction flask, add chlorobenzene (50mL), stir to form a suspension, and cool to 0-5°C in an ice bath. Intermediate IV (10.0g, 33.8mmol) was dissolved in chlorobenzene (30mL) and slowly added dropwise to the above suspension. After the addition, under nitrogen protection, the temperature was raised to 100°C for the reaction, and the reaction was completed by TLC detection (about 2h) , Stop heating and cool to room temperature. Pour slowly into 100 mL of ice-water mixture to quench the reaction. Adjust pH=1~2 with dilute hydrochloric acid, extract, separate the water layer, and then extract the organic layer with water (50mL), combine the water layers, wash twice with n-hexane (50mL×2), adjust the water layer with 30% sodium hydroxide solution pH=10-11, extraction with ethyl acetate (100 mL×2), combined ethyl ...
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