N-methyl-2-pyrrolidone → N-(4-(6-Cyano-7-benzyloxy-4-quinolyl)oxyphenyl)-N'-(4-methoxyphenyl)urea

Temperatur

130 °C

After adding 1-methylpyrrolidone (3.4 ml) and diisopropylethylamine (3.6 ml, 20.78 mmol) to N-(4-hydroxyphenyl)-N′-(4-methoxyphenyl)urea (4.25 g, 16.46 mmol), the mixture was heated and stirred at 130° C. to complete dissolution, and then 4-chloro-6-cyano-7-benzyloxyquinoline (5.10 g, 17.32 mmol) was added and the mixture was stirred at 130° C. for 1.5 hours and at 150° C. for 1 hour. Upon addition of diisopropylethylamine (1.2 ml, 6.93 mmol), the mixture was further stirred for 1 hour. After cooling and adding tetrahydrofuran and ethyl acetate, the mixture was washed with saturated bicarbonate water and saturated saline and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtain crystals were washed with diethyl ether/hexane, acetonitrile/diethyl ether/hexane, methanol and dimethylsulfoxide/water, in that order. The obtained crystals were dissolved in tetrahydrofuran, filtered with silica gel (200 cc silica gel) and flushed with 3000 ml of tetrahydrofuran, and the solvent was distilled off under reduced pressure. The crystals were then washed with diethyl ether, acetonitrile and diethyl ether:ethanol=5:1 and dried by aspiration to obtain the title compound (3.70 g, 7.1627 mmol, 43.52%) as brown crystals.

1. temperaturethe mixture was heated
2. dissolutiondissolution
3. stirringthe mixture was stirred at 130° C. for 1.5 hours and at 150° C. for 1 hour
4. stirringthe mixture was further stirred for 1 hour
5. temperatureAfter cooling
6. washthe mixture was washed with saturated bicarbonate water and saturated saline
7. dry with materialdried over magnesium sulfate
8. distillationthe solvent was distilled off under reduced pressure
9. washThe obtain crystals were washed with diethyl ether/hexane, acetonitrile/diethyl ether/hexane, methanol and dimethylsulfoxide/water, in that order
10. dissolutionThe obtained crystals were dissolved in tetrahydrofuran
11. filtrationfiltered with silica gel (200 cc silica gel)
12. customflushed with 3000 ml of tetrahydrofuran
13. distillationthe solvent was distilled off under reduced pressure
14. washThe crystals were then washed with diethyl ether, acetonitrile and diethyl ether
15. dry with materialethanol=5:1 and dried by aspiration

ORD-Eintrag

ord-c3b5f4489b3e47faa4a237ae7b820a1f

Quelldatensatz

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08372981B2