Hydrochloric Acid → [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine

A solution of HCl in ethanol (5M, 4 ml) was added to a stirred solution of [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine (125 mg, 0.24 mmol) in ethanol (2 ml). The mixture was stirred at room temperature for 90 minutes and the solvent was evaporated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 ml) and potassium carbonate (100 mg, 0.72 mmol) and 1,4-dichlorobut-2-yne (47 ml, 59 mg, 0.48 mmol) were added. The mixture was stirred at room temperature for 16 hours. Further potassium carbonate (100 mg, 0.72 mmol) and 1,4-dichlorobut-2-yne (47 ml, 59 mg, 0.48 mmol) were added and the mixture was stirred at 50° C. for 2 hours. Further potassium carbonate (100 mg, 0.72 mmol) and 1,4-dichlorobut-2-yne (47 ml, 59 mg, 0.48 mmol) were added and the mixture was stirred at 50° C. for 1 hours. The mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate (20 ml) and water (10 ml) were added and and the mixture was extracted with ethyl acetate (3×20 ml). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (4×20 ml) and brine (20 ml), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (50:50 increasing to 80:20) to give [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[3-(5-methyltetrazol-1-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a yellow oil (90 mg, 74%) 1H (CDCl3) δ 7.54 (2H, s), 7.44-7.06 (6H, m), 4.63 (1H, d, J=12.9 Hz), 4.16 (3H, m), 3.61-3.22 (4H, m), 3.04 (1H, m), 2.65 (1H, m), 2.55 (3H, s), 2.21 (2H, m), and 1.63 (2H, m). m/z 504 (M+H+).

1. customthe solvent was evaporated under reduced pressure
2. dissolutionThe residue was dissolved in N,N-dimethylformamide (3 ml)
3. stirringThe mixture was stirred at room temperature for 16 hours
4. stirringthe mixture was stirred at 50° C. for 2 hours
5. stirringthe mixture was stirred at 50° C. for 1 hours
6. temperatureThe mixture was cooled to room temperature
7. extractionthe mixture was extracted with ethyl acetate (3×20 ml)
8. washThe combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (4×20 ml) and brine (20 ml)
9. dry with materialdried (MgSO4)
10. customthe solvent was evaporated under reduced pressure
11. customThe residue was purified by flash column chromatography on silica gel
12. washeluting with ethyl acetate/hexane (50:50 increasing to 80:20)

ORD record

ord-84ab9ce41c8144398f9cbb77d5db98fb

Source dataset

uspto-grants-1998_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05830892