Chlorotrimethylsilane → Ethyl 2,2-difluoro-3-[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]propanoate

Temperature

50 °C

A mixture of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole (0.51 g, 1.5 mmol, EXAMPLE 2, Step 2) and 1H-benztriazole-1-methanol (0.22 g, 1.5 mmol) in ethanol (6 mL) was stirred at 50° C. for 20 min. The mixture was concentrated in vacuo to give a solid. The residual solid was dissolved with tetrahydrofuran (2 mL) and this solution was added to a mixture of zinc powder (0.20 g, 3.0 mmol), trimethylsilylchloride (0.19 mL, 1.5 mmol), and ethyl bromodifluoroacetate (0.46 g, 2.3 mmol) in tetrahydrofuran (6 mL) at room temperature. The mixture was refluxed for 2 h and then cooled to room temperature. The mixture was filtered and the filtrate was diluted with ethyl acetate and sat. aq. sodium hydrogencarbonate (30 mL). The mixture was extracted with ethyl acetate (50 mL×2) and washed with brine. The combined extract was dried over magnesium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 4:1) to give 0.34 g (49%) of the title compound as a colorless oil.

1. concentrationThe mixture was concentrated in vacuo
2. customto give a solid
3. temperatureThe mixture was refluxed for 2 h
4. temperaturecooled to room temperature
5. filtrationThe mixture was filtered
6. additionthe filtrate was diluted with ethyl acetate and sat. aq. sodium hydrogencarbonate (30 mL)
7. extractionThe mixture was extracted with ethyl acetate (50 mL×2)
8. washwashed with brine
9. extractionThe combined extract
10. dry with materialwas dried over magnesium sulfate
11. concentrationconcentrated in vacuo
12. customto give an oil
13. customThe residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 4:1)

ORD record

ord-4746181122a24da79859ccddd03f7f3f

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08816090B2