反应详情

温度

0 °C

To a mixture of 1-[2-amino-3-chloro-4-(2,2-dimethoxyethoxy)phenyl]ethanone (13 g, 47.5 mmol) and isopropylaminothiazole-4-carboxylic acid hydrobromide (prepared as described in Ivanov, V., et. al.; EP1881001A1, p. 62-63; 12.6 g, 47.5 mmol) in pyridine (150 ml) was slowly added phosphorus oxychloride (9.47 g, 61.8 mmol) at −40° C. The mixture was then stirred at 0° C. for 4 h. Upon completion of the reaction, H2O (30 ml) was added dropwise to the mixture. The mixture was then stirred at 0° C. for another 15 min. The mixture was concentrated in vacuo. The residue was diluted with EtOAc, washed with a sat. NaHCO3 aqueous solution. The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in CH2Cl2, hexanes was added slowly to the solution, and a yellow solid started to crash out. More hexanes were added precipitation was complete to afford 2-isopropylaminothiazole-4-carboxylic acid [6-acetyl-2-chloro-3-(2,2-dimethoxyethoxy)phenyl]amide (18 g, 85% yield).

1. customat −40° C
2. additionwas added dropwise to the mixture
3. stirringThe mixture was then stirred at 0° C. for another 15 min
4. concentrationThe mixture was concentrated in vacuo
5. additionThe residue was diluted with EtOAc
6. washwashed with a sat. NaHCO3 aqueous solution
7. dry with materialThe organic layer was dried (Na2SO4)
8. concentrationconcentrated in vacuo
9. dissolutionThe residue was dissolved in CH2Cl2
10. additionhexanes was added slowly to the solution
11. additionMore hexanes were added
12. customprecipitation