反应详情

温度

0 °C

A suspension of 2.000 kg (6.39 mol) of [4-(3-aminophenyl)-6,7-dimethoxyquinazolin-2-yl]methylamine in 71.14 kg of tetrahydrofuran was stirred in a nitrogen atmosphere while being cooled at 0° C. To the suspension was added dropwise 16.70 kg of “monomethyl terephthalate chloride/N,N-diisopropylethylamine” solution (monomethyl terephthalate chloride content: 1.40 kg, 7.03 mol) over 1 hour and 26 minutes, and the container was washed with 1.40 L of 1,2-dimethoxyethane. The mixture was stirred at 0° C. for 13 hours and 4 minutes. Under cooling at 0° C., 36.5 kg of ethyl acetate was added to the reaction mixture and then 80.1 kg of a 5% aqueous solution of sodium hydrogencarbonate was added dropwise, and the mixture was stirred at 20° C. for 1 hour and 10 minutes. Then, 37.3 kg of ethyl acetate was added into the mixture, the mixture was stirred, and the water layer was separated. The organic layer was washed with 40.0 kg of a 5% aqueous solution of sodium chloride, 40.2 kg of water, and 40.1 kg of water in this order. The organic layer was concentrated under reduced pressure at a jacket temperature of 40° C., 23.70 kg of methanol was added to the residue, and stirred for 1 hour and 1 minute while being heated to 60 to 66° C. 23.60 kg of 2-propanol was added dropwise to the suspension over 1 hour while stirring the suspension at a jacket temperature of 50° C. Then, the suspension was cooled at a cooling rate of 10° C./hour and stirred at 20° C. for 12 hours and 23 minutes. The precipitated crystals were filtered, rinsed with a mixed solution of 3.00 L of methanol and 3.00 L of 2-propanol and 6.00 L of 2-propanol in this order to yield 5.52 kg of a crude product (content of the target compound: 2.57 kg, 5.44 mol) as pale yellow crystals (yield: 85.3%).

1. wash26 minutes, and the container was washed with 1.40 L of 1,2-dimethoxyethane
2. stirringThe mixture was stirred at 0° C. for 13 hours and 4 minutes
3. temperatureUnder cooling at 0° C.
4. addition36.5 kg of ethyl acetate was added to the reaction mixture
5. addition80.1 kg of a 5% aqueous solution of sodium hydrogencarbonate was added dropwise
6. stirringthe mixture was stirred at 20° C. for 1 hour and 10 minutes
7. additionThen, 37.3 kg of ethyl acetate was added into the mixture
8. stirringthe mixture was stirred
9. customthe water layer was separated
10. washThe organic layer was washed with 40.0 kg of a 5% aqueous solution of sodium chloride, 40.2 kg of water, and 40.1 kg of water in this order
11. concentrationThe organic layer was concentrated under reduced pressure at a jacket temperature of 40° C., 23.70 kg of methanol
12. additionwas added to the residue
13. stirringstirred for 1 hour and 1 minute
14. temperaturewhile being heated to 60 to 66° C
15. addition23.60 kg of 2-propanol was added dropwise to the suspension over 1 hour
16. stirringwhile stirring the suspension at a jacket temperature of 50° C
17. temperatureThen, the suspension was cooled at a cooling rate of 10° C./hour
18. stirringstirred at 20° C. for 12 hours and 23 minutes
19. filtrationThe precipitated crystals were filtered
20. washrinsed with a mixed solution of 3.00 L of methanol and 3.00 L of 2-propanol and 6.00 L of 2-propanol in this order