Ammonium Chloride → (2S,3R)-1-tert-Butoxycarbonyl-3-(3-hydroxypropyn-1-yl)-2-phenylpiperidin-3-ol

Temperature

0 °C

O-Trimethylsilylpropargyl alcohol (24.51 mL, 20.47 g, 160 mL) was added slowly to a cooled (-10° C.) solution of ethylmagnesium bromide (1M in tetrahydrofuran, 160 mL, 160 mmol). The mixture was stirred at 0° C. for 20 min., then at room temperature for 2 h. The mixture was cooled to -10° C. and a solution of (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Description 1; 42.3 g) in tetrahydrofuran (200 mL) was added dropwise over 30 min. (Internal temperature below -5° C.). The mixture was stirred at room temperature for 14 h., poured into water (300 mL) and saturated aqueous ammonium chloride (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic fractions were washed with brine (300 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL) and a solution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 160 mL, 160 mmol) was added dropwise. The mixture was stirred at room temperature for 30 min., water (300 mL) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×300 mL) and the combined organic fractions were washed with water (300 mL) and brine (300 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the crude title compound as an orange oil (45 g). The crude material was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10 increasing to 25:75) to give the title compound as an amber oil (32.2 g). 1H NMR (CDCl3) δ7.53-7.55 (2H, m), 7.19-7.35 (3H, m), 5.56 (1H, s), 4.27 (2H, s), 3.99-4.03 (1H, m), 3.25 (1H, br s), 2.77-2.81 (1H, m), 2.77 (1H, br s), 2.12-2.20 (1H, m), 1.91-1.99 (2H, m), 1.77-1.83 (1H, m), and 1.39 (9H, s).

1. waitat room temperature for 2 h
2. temperatureThe mixture was cooled to -10° C.
3. stirringThe mixture was stirred at room temperature for 14 h.
4. extractionextracted with ethyl acetate (2×300 mL)
5. washThe combined organic fractions were washed with brine (300 mL)
6. dry with materialdried (MgSO4)
7. customthe solvent was evaporated under reduced pressure
8. dissolutionThe residue was dissolved in ethyl acetate (500 mL)
9. stirringThe mixture was stirred at room temperature for 30 min.
10. customthe layers were separated
11. extractionThe aqueous layer was extracted with ethyl acetate (2×300 mL)
12. washthe combined organic fractions were washed with water (300 mL) and brine (300 mL)
13. dry with materialdried (MgSO4)
14. customthe solvent was evaporated under reduced pressure
15. customto give the crude title compound as an orange oil (45 g)
16. customThe crude material was purified by flash column chromatography on silica gel
17. washeluting with hexane/EtOAc (90:10 increasing to 25:75)

ORD record

ord-63d40f9557d245c08427eb81e0fa4b63

Source dataset

uspto-grants-2000_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06071927