Preparation method of chiral aryl cyclopropylamine derivative
A technology for arylcyclopropylamine and derivatives, which is applied in the field of preparation of chiral arylcyclopropylamine derivatives, can solve the problems of cumbersome operation and low conversion rate of raw materials, and achieve high reaction yield, high yield, and shortened reaction route effect
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Embodiment 1
[0032] a. Preparation of intermediate IN-1: add 1000mL dichloromethane and 200g (1.5mol, 1.5eq) aluminum trichloride to the reaction flask, stir, then add dropwise 136g (1.2mol, 1.2 eq) Chloroacetyl chloride; after dropping, stir, heat up to reflux, add dropwise 114g (1.0mol, 1eq) 1,2-difluorobenzene; after dropping, reflux reaction; then cool down to 25°C, pump in 500g of ice water, Stir, stand still for liquid separation, extract the aqueous layer with dichloromethane (500mL×2), combine the organic phases, wash with water (800mL×2), saturated sodium bicarbonate solution (800mL) and saturated sodium chloride solution (800mL), Dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain 175.3 g of the product. Molar yield: 92%;
[0033] b. Preparation of intermediate IN-2: put 200mL toluene and 12.7g S-CBS-4 (0.05mol, 0.05eq) into the reaction bottle, stir; under nitrogen protection, put 9.5g trimethyl borate (0.09mol, 0.1eq), heat up to about 50°C, kee...
Embodiment 2
[0041] a. Preparation of intermediate IN-1: Add 500mL of dichloromethane, 90.1g (0.9mol, 1.8eq) of zinc chloride, 2g of cuprous iodide into the reaction flask, stir, and then add dropwise at 0-5°C 84.8g (0.75mol, 1.5eq) chloroacetyl chloride; after dropping, stir, heat up to reflux, add dropwise 65g (0.5mol, 1eq) o-chlorofluorobenzene; 300g of ice water, stirred, left to stand for liquid separation, the aqueous layer was extracted with dichloromethane (300mL×2), the organic phase was combined, water (300mL×2), saturated sodium bicarbonate solution (200mL) and saturated sodium chloride solution ( 200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 93.2g of the product. Molar yield: 90%;
[0042] b. Preparation of intermediate IN-2: put 200mL tetrahydrofuran and 5.1g S-CBS-4 (0.02mol, 0.05eq) into the reaction bottle, stir; under nitrogen protection, put 5.2g trimethyl borate (0.05mol, 0.1eq), heat up to about 50°C, keep warm for reac...
Embodiment 3
[0050] a. Preparation of intermediate IN-1: Add 1000mL dichloromethane and 240g (1.8mol, 1.8eq) aluminum trichloride to the reaction flask, stir, then add 170g (1.5mol, 1.5 eq) Chloroacetyl chloride; after dropping, stir, heat up to reflux, add 96g (1.0mol, 1eq) of fluorobenzene dropwise; solution, the aqueous layer was extracted with dichloromethane (500mL×2), the organic phases were combined, washed with water (800mL×2), saturated sodium bicarbonate solution (800mL) and saturated sodium chloride solution (800mL), dried over anhydrous sodium sulfate , and concentrated under reduced pressure to obtain 160.5 g of product. Molar yield: 93%;
[0051] b. Preparation of intermediate IN-2: put 300mL toluene and 12.7g S-CBS-4 (0.05mol, 0.05eq) into the reaction bottle, stir; under nitrogen protection, put 9.6g trimethyl borate (0.09mol, 0.1 eq), heat up to about 50°C, keep warm for reaction, then add 186mL 10mol / L borane dimethyl sulfide (1.86mol, 2.0eq) dropwise; after dropping, r...
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