1,4-dichlorobut-2-yne

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of hydroxymethylphosphonic acid diethylester (3.35 g, 20 mmol), 1,4-dichloro-2-butyne (3.8 g, 30 mmol) and tetra-n-butylammonium iodide,(0.75 g, 2 mmol) in anhydrous tetrahydrofuran (100 ml), sodium hydride (0.95 g, 24 mmol, 60% in oil) is added in portions at 0° C. The resulting mixture is stirred overnight at 0° C. Then the reaction mixture is stirred overnight at 20° C., hydrolyzed with a saturated solution of ammonium chloride and extracted with diethylether. The title product is obtained by flash chromatography on silica gel (2.3 g, 30%). is added in portions at 0° C extracted with diethylether

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5.0 g 4-hydroxy-2-isopropylidenecoumaran-3-one, 4.6 g potassium carbonate, 3.3 ml 1,4-dichloro-but-2-yne and 100 ml dimethylformamide is warmed to 50° C. for 3 hours, then evaporated, mixed with water and extracted with dichloromethane. After evaporation of the extract, the residue (9.2 g) is purified by silica gel chromatography (eluent isohexane/ethyl acetate 9:1) to give 2.2 g of the desired intermediate. evaporated mixed with water extracted with dichloromethane After evaporation of the extract the residue (9.2 g) is purified by silica gel chromatography (eluent isohexane/ethyl acetate 9:1)

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of phenol (50.8 g), potassium hydroxide (30 g), ethanol (200 ml) and water (50 ml) was stirred and heated under reflux for 1 hour, then cooled to 30° C. A solution of 1,4-dichlorobut-2-yne (100 g) in ethanol (60 ml) was added dropwise over 3.5 hours, then the mixture was stirred at ambient temperature for 18 hours and filtered. The filter cake was washed with ethanol (60 ml), and the filtrate and washings were combined. The solvents were removed in vacuo, and the residue was distilled to give 1-chloro-4-phenoxybut-2-yne as a colourless oil (52.5 g), b.p. 92°-98° C. at 0.53 mbar. heated under reflux for 1 hour the mixture was stirred at ambient temperature for 18 hours filtered The filter cake was washed with ethanol (60 ml) The solvents were removed in vacuo the residue was distilled

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The intermediate 5-(5-chloro-3-pentynyl)-3-methylisoxazole was prepared from 3,5-dimethylisoxazole and 1,4-dichloro-2-butyne in the presence of n-butyllithium.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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+). the solvent was evaporated under reduced pressure The residue was dissolved in N,N-dimethylformamide (3 ml) The mixture was stirred at room temperature for 16 hours the mixture was stirred at 50° C. for 2 hours the mixture was stirred at 50° C. for 1 hours The mixture was cooled to room temperature 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) 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)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of [2S,3S]-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol-5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine hydrochloride (270 mg) in N,N-dimethylformamide (3.0 ml) was slowly added to a solution of 1,4-dichlorobut-2-yne (189 ml) and potassium carbonate (269 mg) in N,N-dimethylformamide (5.0 ml). The solution was stirred for 18 hours at room temperature and the solvent removed under reduced pressure. To the residue was added water (40 ml) and the product was extracted with ethyl acetate (3×10 ml). The combined organic fractions were washed with water, saturated brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by MPLC (40% ethyl acetate/hexane) to give [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol-5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a yellow oil (142 mg). 1H NMR (360 MHz,CDCl3) δ 1.52 (2H, m), 2.16 (2H, m), 2.64 (1H, m), 3.00 (1H, m), 3.30 (2H, m), 3.48 (1H, br s), 3.57 (1H, s), 3.98 (3H, s), 4.11 (1H, d, J=11.0 Hz), 4.15 (1H, s) 4.52 (2H, d, J=11.0 Hz), 7.17-7.26 (4H, m), 7.40-7.47 (4H, m), 7.68 (1H, s). the solvent removed under reduced pressure To the residue was added water (40 ml) the product was extracted with ethyl acetate (3×10 ml) The combined organic fractions were washed with water, saturated brine dried over MgSO4 filtered the solvent removed under reduced pressure The residue was purified by MPLC (40% ethyl acetate/hexane)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir: