Preparation method of dacomitinib (I)
A technology of dacomitinib and amino group, which is applied in the field of preparation of dacomitinib, can solve the problems of low total yield, many steps, unsuitable requirements for industrialization, etc., achieves easy availability of raw materials, and is beneficial to industrial production. , the effect of simple process
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Embodiment 1
[0028] At room temperature, add 6-amino-7-hydroxy-3,4-dihydroquinazolin-4-one (II) (2.66 g, 15 mmol) and 20 mL of 50% sodium hydroxide solution to the reaction flask, and heat to 50 -60°C, stir until no particles are present. Slowly lower the temperature to 5°C and precipitation will occur. Filter and vacuum dry to obtain light red solid. Under the protection of nitrogen, the solid was added to the pre-added 1-butyl-3-methylimidazole tetrafluoroborate ([Bmin]BF 4 ) In the reaction flask, heat up to 80-90°C. Add iodomethane (2.56g, 18mmol) dropwise to the above reaction system, and after the dropwise addition is complete, the reaction is stirred for 6 hours with heat preservation. Cool, separate the upper ionic liquid. The lower layer was extracted with 1,2,-dichloroethane, and washed twice with water. The organic phase was dried with anhydrous sodium sulfate, the solvent was recovered by distillation under reduced pressure, and the residue was recrystallized with ethyl acet...
Embodiment 2
[0030] Add 6-amino-7-methoxy-3,4-dihydroquinazolin-4-one (III) (1.91g, 10mmol), triethylamine (1.0g, 10mmol) and dichloro in the reaction flask Methane 50mL, heat to 40-45°C, stir until the system is uniformly dissolved. After dropping to below 10℃, slowly add 4-(1-piperidinyl)-2-butenoyl chloride (2.24g, 12mmol) in dichloromethane 15mL solution, after dripping, continue the reaction at room temperature for 6 hours, TLC detects the completion of the reaction . The reaction solution was washed with 10% sodium bicarbonate solution and water, and dried with anhydrous sodium sulfate. The solvent was recovered under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain a white solid 6-[4-(1-piperidinyl)-1-oxo-2-buten-1-yl]amino-7-methoxy Benzyl-3,4-quinazolin-4-one (IV) 3.03 g, yield 88.6%.
Embodiment 3
[0032] Under the protection of nitrogen, add 6-[4-(1-piperidinyl)-1-oxo-2-buten-1-yl]amino-7-methoxy-3,4-quinazole into a three-necked flask Lin-4-one (IV) (3.42g, 10mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (6.63g, 15mmol) and acetonitrile 50mL. Under stirring, 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise, after dropping, the reaction was carried out at room temperature for 12 hours. The temperature was raised to 60°C, and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, 100 mL of ethyl acetate was added to dissolve, and it was washed with 20 mL of 2M sodium hydroxide. The organic phase was separated, dried, and concentrated under reduced pressure. The residue was dissolved in 100 mL of tetrahydrofuran, 4-fluoro-3-chloroaniline (1.89 g, 13 mmol) and sodium hydride (0.32 g, 13 mmol) were added, the temperature was raised to 50° C., and the reaction was st...
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