反应详情

To a stirred solution of 3-(2,6-Dichloro-5-fluoropyridin-3-yl)-3 -oxo-propanoic acid ethyl ester (compound (1): 85.0 kg, 303 mol) in toluene (808 kg)was added Me2 NCH(OMe)2 (40.8 kg ) and acetic acid (4.56 kg). The mixture was stirred at room temperature for 50 minutes. Cyclopropylamine (22.53 kg) was added to the reaction mixture, and the mixture was stirred at 25 to 35° C. for 50 minutes. The reaction mixture was washed with 10% aqueous citric acid solution, and then water. After layer separation, the aqueous layer was discarded, and tetrabutylammonium bromide (4.88 kg) and 25% aqueous sodium hydroxide solution (53 kg) were added to the separated organic layer. The resulting mixture was stirred for 2 hours. 35% aqueous hydrochloric acid solution (142 kg) was added, and the resulting mixture was heated at reflux. After about 8 hours, the reaction mixture was cooled, and water (about 50 kg) was added thereto, and then the aqueous layer was separated off. The reaction solution was washed with water, and the solid compound present in the separated organic layer was filtered, and washed with isopropanol, water, and isopropanol in sequence. The resulting solid was dried under vacuum to give the title compound (77 kg) as a white crystal.

1. stirringthe mixture was stirred at 25 to 35° C. for 50 minutes
2. washThe reaction mixture was washed with 10% aqueous citric acid solution
3. customAfter layer separation
4. additiontetrabutylammonium bromide (4.88 kg) and 25% aqueous sodium hydroxide solution (53 kg) were added to the separated organic layer
5. stirringThe resulting mixture was stirred for 2 hours
6. addition35% aqueous hydrochloric acid solution (142 kg) was added
7. temperaturethe resulting mixture was heated
8. temperatureat reflux
9. waitAfter about 8 hours
10. temperaturethe reaction mixture was cooled
11. additionwater (about 50 kg) was added
12. customthe aqueous layer was separated off
13. washThe reaction solution was washed with water
14. filtrationthe solid compound present in the separated organic layer was filtered
15. washwashed with isopropanol, water, and isopropanol in sequence
16. customThe resulting solid was dried under vacuum