反应详情

温度

90 °C

A stirred solution of 2-trifluoromethylpyridin-4-ol (12.5 g, 76.6 mmol) and dimethylformamide (3.00 mL) in phosphorus oxychloride (75 mL) is heated under reflux for 2 hours before excess phosphorus oxychloride is removed in vacuo. The residue is poured onto an ice-water mixture and extracted into ethyl acetate (×5). The combined organic extracts dried (sodium sulfate), filtered and concentrated in vacuo. The non-basic components of the mixture are eluted through a SCX column washing with a 1:1 mixture of methanol-dichloromethane. A stirred suspension of the residue, 1-t-butoxycarbonyl-4-[(methylamino)methyl]piperidine (1.11 g, 4.85 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in dimethylformamide (38 mL) is heated at 90° C. for 13 hours. Excess dimethylformamide is removed in vacuo, the residue is taken into chloroform and washed with 2.5% hydrogen chloride solution. The aqueous layer is extracted into chloroform (×3) and the combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. Flash column chromatography eluting with a gradient of 30% ethyl acetate-hexane to 50% ethyl acetate-hexane provides 1-t-butoxycarbonyl-4-{[(methyl)(2-trifluoromethylpyridin-4-yl)amino]methyl}piperidine (520 mg, 2%).

1. customis removed in vacuo
2. additionThe residue is poured onto an ice-water mixture
3. extractionextracted into ethyl acetate (×5)
4. dry with materialThe combined organic extracts dried (sodium sulfate)
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. washThe non-basic components of the mixture are eluted through a SCX column
8. washwashing with a 1:1 mixture of methanol-dichloromethane
9. customExcess dimethylformamide is removed in vacuo
10. washwashed with 2.5% hydrogen chloride solution
11. extractionThe aqueous layer is extracted into chloroform (×3)
12. dry with materialthe combined organic extracts are dried (sodium sulfate)
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. washFlash column chromatography eluting with a gradient of 30% ethyl acetate-hexane to 50% ethyl acetate-hexane