反应详情

温度

-10 °C

4.6 g 4-Chloro-5-(2,2-difluorocyclopropylmethoxy)-2-fluoroaniline was suspended in a mixture of 9.7 ml concentrated sulphuric acid and 41.5 ml water and cooled to -10° C. A solution of 1.38 g sodium nitrite in 4.2 ml water was added dropwise at such a rate that the temperature of the reaction mixture did not rise above -5° C. After the addition it was stirred for a further hour at -5° C. and excess nitrous acid destroyed with urea until a test with iodine-starch paper was negative. The solution thus obtained was warmed to 0° C. and added dropwise to an ice-cold solution of 2.3 g pipecolic acid and 8.3 ml triethylamine in 27.7 ml water. After the addition it was stirred for a further hour at 0° C. and the reaction mixture extracted several times with methylene chloride. The organic phases were combined, dried over magnesium sulphate and the solvent evaporated. The residue was taken up in 40 ml ether and treated with 4.14 ml acetic anhydride and 2.07 ml pyridine. The mixture was stirred overnight at room temperature, then poured into ice-water and extracted with ethyl acetate. The organic phases were dried over magnesium sulphate and the solvent evaporated. The residue was chromatographed on silica gel using 95 parts ethyl acetate and 5 parts methanol as eluent.

1. customdid not rise above -5° C
2. additionAfter the addition it
3. customexcess nitrous acid destroyed with urea until a test with iodine-starch paper
4. customThe solution thus obtained
5. temperaturewas warmed to 0° C.
6. additionAfter the addition it
7. stirringwas stirred for a further hour at 0° C.
8. extractionthe reaction mixture extracted several times with methylene chloride
9. dry with materialdried over magnesium sulphate
10. customthe solvent evaporated
11. additiontreated with 4.14 ml acetic anhydride and 2.07 ml pyridine
12. stirringThe mixture was stirred overnight at room temperature
13. additionpoured into ice-water
14. extractionextracted with ethyl acetate
15. dry with materialThe organic phases were dried over magnesium sulphate
16. customthe solvent evaporated
17. customThe residue was chromatographed on silica gel using 95 parts ethyl acetate and 5 parts methanol as eluent