4-(difluoromethoxy)piperidine

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

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

Procedure: 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), 4-(difluoromethoxy)piperidine (18) (0.101 g, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (0.381 g, 1.01 mmol) were added to N,N-dimethylformamide (30 mL). To this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and the reaction was stirred for 2 hours before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.266 g, 92%); 1H NMR (400.132 MHz, DMSO) δ 1.53-1.45 (1H, m), 1.65-1.56 (1H, m), 1.83-1.74 (1H, m), 1.98-1.92 (1H, m), 3.15-3.09 (1H, m), 3.40-3.26 (2H, m), 4.01-3.91 (1H, m), 4.33 (2H, s), 4.41-4.35 (1H, m), 6.75 (1H, t), 7.22 (1H, t), 7.38-7.36 (1H, m), 7.44-7.40 (1H, m), 7.83 (1H, t), 7.88 (1H, t), 7.97 (1H, d), 8.27 (1H, d), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.98 (M+H 432). before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.266 g, 92%) m/z (LC-MS, ESI+), RT=1.98 (M+H 432)

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

Procedure: 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), 4-(difluoromethoxy)piperidine (18) (0.101 g, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (0.381 g, 1.01 mmol) were added to N,N-dimethylformamide (30 mL). To this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and the reaction was stirred for 2 hours before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.266 g, 92%); 1H NMR (400.132 MHz, DMSO) δ 1.53-1.45 (1H, m), 1.65-1.56 (1H, m), 1.83-1.74 (1H, m), 1.98-1.92 (1H, m), 3.15-3.09 (1H, m), 3.40-3.26 (2H, m), 4.01-3.91 (1H, m), 4.33 (2H, s), 4.41-4.35 (1H, m), 6.75 (1H, t), 7.22 (1H, t), 7.38-7.36 (1H, m), 7.44-7.40 (1H, m), 7.83 (1H, t), 7.88 (1H, t), 7.97 (1H, d), 8.27 (1H, d), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.98 (M+H 432). before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.266 g, 92%) m/z (LC-MS, ESI+), RT=1.98 (M+H 432)

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

Procedure: 4-(difluoromethoxy)piperidine-1-carbaldehyde (17) (2.7 g, 15.07 mmol) and potassium hydroxide (2.96 g, 52.74 mmol) were dissolved in water (40 mL) and stirred vigorously for 3 hours. The reaction was extracted with diethyl ether (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange liquid. The crude product was purified by distillation at 0.70 mBar, collecting fractions that distilled at 25° C. to afford the desired material as a colourless oil (1.100 g, 48.3%); 1H NMR (400.132 MHz, CDCl3) δ 1.50 (1H, s), 1.66-1.57 (2H, m), 1.95-1.89 (2H, m), 2.70-2.64 (2H, m), 3.09 (2H, dt), 4.25-4.19 (1H, m), 6.24 (1H, t). The reaction was extracted with diethyl ether (3×75 mL) the organic layer was dried over MgSO4 filtered evaporated to afford an orange liquid The crude product was purified by distillation at 0.70 mBar collecting fractions that distilled at 25° C.

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

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

Procedure: 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), 4-(difluoromethoxy)piperidine (18) (0.101 g, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (0.381 g, 1.01 mmol) were added to N,N-dimethylformamide (30 mL). To this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and the reaction was stirred for 2 hours before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.266 g, 92%); 1H NMR (400.132 MHz, DMSO) δ 1.53-1.45 (1H, m), 1.65-1.56 (1H, m), 1.83-1.74 (1H, m), 1.98-1.92 (1H, m), 3.15-3.09 (1H, m), 3.40-3.26 (2H, m), 4.01-3.91 (1H, m), 4.33 (2H, s), 4.41-4.35 (1H, m), 6.75 (1H, t), 7.22 (1H, t), 7.38-7.36 (1H, m), 7.44-7.40 (1H, m), 7.83 (1H, t), 7.88 (1H, t), 7.97 (1H, d), 8.27 (1H, d), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.98 (M+H 432). before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.266 g, 92%) m/z (LC-MS, ESI+), RT=1.98 (M+H 432)

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

Procedure: 4-(difluoromethoxy)piperidine-1-carbaldehyde (17) (2.7 g, 15.07 mmol) and potassium hydroxide (2.96 g, 52.74 mmol) were dissolved in water (40 mL) and stirred vigorously for 3 hours. The reaction was extracted with diethyl ether (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange liquid. The crude product was purified by distillation at 0.70 mBar, collecting fractions that distilled at 25° C. to afford the desired material as a colourless oil (1.100 g, 48.3%); 1H NMR (400.132 MHz, CDCl3) δ 1.50 (1H, s), 1.66-1.57 (2H, m), 1.95-1.89 (2H, m), 2.70-2.64 (2H, m), 3.09 (2H, dt), 4.25-4.19 (1H, m), 6.24 (1H, t). The reaction was extracted with diethyl ether (3×75 mL) the organic layer was dried over MgSO4 filtered evaporated to afford an orange liquid The crude product was purified by distillation at 0.70 mBar collecting fractions that distilled at 25° C.