Macitentan related substance d, its preparation method and use
A technology of impurity and high performance liquid chromatography, which is applied in the field of drug synthesis and can solve problems affecting product quality
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Embodiment 1
[0031] The preparation of embodiment 1 impurity D
[0032] Take 10.0g V-1 and 80ml ethylene glycol dimethyl ether into a one-mouth bottle, add 6.9g ethylene glycol and 14.6g potassium tert-butoxide, reflux and stir for 15 hours, after the reaction is complete, cool down to room temperature, and pour the filtrate into 500ml 10% citric acid aqueous solution was stirred for 4 hours, filtered with suction, and the filter cake was placed in blast drying to obtain 8.1 g of the intermediate. Add 48ml of methanol to the above solid, reflux and stir until dissolved, turn off the heating, cool down to room temperature, filter with suction, and dry the filter cake to obtain 4.1g of solid.
[0033] 1.6g of sodium hydrogen was washed twice with tetrahydrofuran and then added to a single-necked bottle, with 40ml of tetrahydrofuran as the solvent, and stirred. Slowly add the intermediate obtained above, stir for 1 hour, then add 16ml of DMF and 5.4g of raw material IIc, heat to 65°C and sti...
Embodiment 2
[0034] The preparation of embodiment 2 impurity D
[0035] Take 10.0g V-1 and 80ml tetrahydrofuran into a single-necked bottle, add 6.9g ethylene glycol and 10.4g lithium tert-butoxide, reflux and stir the reaction, after the reaction is complete, cool down to room temperature, pour the filtrate into 500ml 10% citric acid aqueous solution and stir After 4 hours, filter with suction, and place the filter cake in forced air to dry to obtain 7.8 g of the intermediate. Add 50 mL of methanol to the above solid, reflux and stir until dissolved, cool down to room temperature, suction filter, and dry the filter cake to obtain 3.8 g of solid.
[0036] 1.6g of sodium hydrogen was washed twice with tetrahydrofuran and then added to a single-necked bottle, with 40ml of tetrahydrofuran as the solvent, and stirred. Slowly add the intermediate obtained above, stir for 0.5, then add 16ml of toluene and 5.4g of raw material IIc, heat to 65°C and stir for 4h. Cool down to 25°C, pour the filtr...
Embodiment 3
[0037] The preparation of embodiment 3 impurity D
[0038] Take 10.0g V-1 and 80ml DMF into a single-necked bottle, add 6.9g ethylene glycol and 14.5g potassium tert-butoxide, reflux and stir the reaction, after the reaction is complete, turn off the heating, cool down to room temperature, pour the filtrate into 500ml 10% lemon The acid aqueous solution was stirred for 4 hours, filtered with suction, and the filter cake was placed in blast drying to obtain 7.5 g of the intermediate. Add 50 mL of methanol to the above solid, reflux and stir until dissolved, cool down to room temperature, filter with suction, and dry the filter cake to obtain 3.6 g of solid.
[0039] Add 4.5 g of potassium tert-butoxide into a single-necked bottle, add 40 ml of toluene and stir. Slowly add the intermediate obtained above, stir for 1 hour, then add 16ml of toluene and 5.4g of raw material IIc, heat to 65°C and stir for 4 hours. Cool down to 25°C, pour the filtrate into 400ml of 10% citric acid ...
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