反应详情

温度

20 °C

A reaction flask with stirrer was charged with 20.0 g of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide and 180 g of tetrahydrofuran as solvent. A solution of 18.7 g of 4-chloro-3-trifluoromethyl-phenylisocyanate and 21.1 g of toluene was added dropwise within approximately 90 minutes at room temperature. The resulting solution was stirred for 3 hours to complete the reaction. After then 30 g of tetrahydrofuran and 7.8 g of methanol were added to the reaction mixture. Following 9.0 g of acetyl chloride were added dropwise within 15 minutes to the reaction mixture. After additional stirring for approximately 2 hours the suspension was filtered and the solid was washed with tetrahydofuran (18.2 g) and acetone (136.4 g). The solid was added to a mixture of acetone (268.6 g), water (55.8 g) and an aqueous sodium hydroxide solution (8.2 g, 45% w/w) at 40° C. The mixture was stirred for additional 30 minutes. Then the crystallization was initiated by seeding with crystals of 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide monohydrate. After cooling to 20° C. 31.6 g of water were added. The suspension was cooled down to approx. 3° C. and stirred for 30 minutes. The product was filtered off, washed with a cold mixture of acetone (106 g) and water (44 g) and dried under reduced pressure (30° C., 80 mbar). In this way 31.8 g (83% of theory) of 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide monohydrate were obtained as white crystals.

1. customthe reaction
2. additionwere added dropwise within 15 minutes to the reaction mixture
3. stirringAfter additional stirring for approximately 2 hours the suspension
4. filtrationwas filtered
5. washthe solid was washed with tetrahydofuran (18.2 g) and acetone (136.4 g)
6. additionThe solid was added to a mixture of acetone (268.6 g), water (55.8 g)
7. customat 40° C
8. stirringThe mixture was stirred for additional 30 minutes
9. customThen the crystallization
10. addition31.6 g of water were added
11. temperatureThe suspension was cooled down to approx. 3° C.
12. stirringstirred for 30 minutes
13. filtrationThe product was filtered off
14. washwashed with a cold mixture of acetone (106 g) and water (44 g)
15. customdried under reduced pressure (30° C., 80 mbar)