4-ethoxypiperidine

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

Procedure: 3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-5-fluorobenzoic acid (128), 4-ethoxypiperidine and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate were dissolved in DMF (10 mL), to this was added DIPEA and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 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 afford the desired compound as a white foam (130 mg); 1H NMR (400.132 MHz, CDCl3) δ 1.20 (3H, t), 2.00-1.38 (4H, m), 3.29-3.05 (1H, m), 3.57-3.34 (5H, m), 4.08-3.91 (1H, m), 4.68 (2H, s), 6.90 (1H, d), 6.97-6.94 (2H, m), 7.67 (1H, t), 7.80 (1H, d), 8.50 (1H, dd); NH missing; m/z (LC-MS, ESI+), RT=2.06 (M+H 444). The solvent was evaporated to dryness the gum was dissolved in acetonitrile (4 mL) purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness

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

Procedure: 2-fluoro-5-((8-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (125) (200 mg, 0.61 mmol) and 4-ethoxypiperidine (79 mg, 0.61 mmol) were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.163 mL, 0.91 mmol) and then HBTU (347 mg, 0.91 mmol). The solvent was then removed to give a brown solid, which was dissolved in acetonitrile. A white solid precipitated, which was filtered and dried to afford the desired material as a white crystalline solid (200 mg, 74.7% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.20 (3H, t), 1.46-1.62 (1H, m), 1.63-1.82 (2H, m), 1.87-1.96 (1H, m), 3.07-3.18 (1H, m), 3.43-3.59 (5H, m), 3.77-3.82 (3H, m), 3.99-4.11 (1H, m), 4.45 (2H, s), 6.91-7.02 (1H, m), 7.11-7.28 (3H, m), 7.62-7.71 (1H, m), 8.03-8.08 (1H, m), 10.29 (1H, s); m/z (ES+) (M+H)+=440.41; HPLC RT=1.87 min. The solvent was then removed to give a brown solid, which A white solid precipitated which was filtered dried

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

Procedure: 3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (118) (200 mg, 0.64 mmol) and 4-ethoxypiperidine were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.170 mL, 0.95 mmol) and then HBTU (362 mg, 0.95 mmol). The solvent was removed and the crude product dissolved in acetonitrile and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 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 afford the desired material as a white solid (111 mg, 41.0% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.17-1.46 (2H, m), 1.58-1.92 (2H, m), 2.97-3.42 (4H, m), 3.42-3.55 (3H, m), 4.68 (2H, s), 7.13 (1H, s), 7.21 (2H, t), 7.35 (1H, t), 7.81 (1H, t), 7.94-7.99 (1H, m), 8.32-8.36 (1H, m), 12.91 (1H, s); m/z (LC-MS, ESI+), RT=1.96 (M+H 426.7) The solvent was removed the crude product dissolved in acetonitrile purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness

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

Procedure: 3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (118) (200 mg, 0.64 mmol) and 4-ethoxypiperidine were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.170 mL, 0.95 mmol) and then HBTU (362 mg, 0.95 mmol). The solvent was removed and the crude product dissolved in acetonitrile and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 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 afford the desired material as a white solid (111 mg, 41.0% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.17-1.46 (2H, m), 1.58-1.92 (2H, m), 2.97-3.42 (4H, m), 3.42-3.55 (3H, m), 4.68 (2H, s), 7.13 (1H, s), 7.21 (2H, t), 7.35 (1H, t), 7.81 (1H, t), 7.94-7.99 (1H, m), 8.32-8.36 (1H, m), 12.91 (1H, s); m/z (LC-MS, ESI+), RT=1.96 (M+H 426.7) The solvent was removed the crude product dissolved in acetonitrile purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness

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

Procedure: 5-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorobenzoic acid (103) (0.2 g, 0.60 mmol), 4-ethoxypiperidine (0.078 g, 0.60 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.251 g, 0.78 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.136 mL, 0.78 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL) and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 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 afford the desired compound as a white foam (0.052 g, 19.49%); 1H NMR (400.132 MHz, CDCl3) δ 1.20 (3H, t), 1.59-1.48 (1H, m), 1.81-1.63 (2H, m), 1.94-1.89 (1H, m), 3.16-3.07 (1H, m), 3.57-3.45 (4H, m), 4.09-4.00 (1H, m), 4.65 (2H, s), 6.99 (1H, t), 7.17-7.13 (2H, m), 7.26 (1H, s), 7.66 (1H, t), 7.80 (1H, dd), 8.49 (1H, dd); NH missing; m/z (LC-MS, ESI+), RT=2.08 (M+H 444). The solvent was evaporated to dryness the gum was dissolved in acetonitrile (4 mL) purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness

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

Procedure: 2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.163 g, 0.43 mmol) was added to 3-((5,7-dimethyl-1-oxo-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-4-yl)methyl)benzoic acid (51) (0.091 g, 0.31 mmol), 4-ethoxypiperidine (0.044 g, 0.34 mmol) and triethylamine (0.107 mL, 0.77 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 16 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 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 afford the desired material (0.028 g, 22.5% yield). 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.16-1.95 (4H, m), 2.24 (3H, s), 2.51 (3H, s), 2.99-3.26 (2H, m), 3.33-3.54 (4H, m), 3.85-4.01 (1H, m), 4.09 (2H, s), 7.14 (1H, s), 7.20 (1H, d), 7.27 (1H, d), 7.35 (1H, t), 11.08 (1H, s), 11.92 (1H, s); m/z (LC-MS, ESI+), RT=1.53 min (M+H=409.13). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness

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

Procedure: 2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.163 g, 0.43 mmol) was added to 3-((5,7-dimethyl-1-oxo-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-4-yl)methyl)benzoic acid (51) (0.091 g, 0.31 mmol), 4-ethoxypiperidine (0.044 g, 0.34 mmol) and triethylamine (0.107 mL, 0.77 mmol) in DMF (2 mL). The resulting solution was stirred at room temperature for 16 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 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 afford the desired material (0.028 g, 22.5% yield). 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.16-1.95 (4H, m), 2.24 (3H, s), 2.51 (3H, s), 2.99-3.26 (2H, m), 3.33-3.54 (4H, m), 3.85-4.01 (1H, m), 4.09 (2H, s), 7.14 (1H, s), 7.20 (1H, d), 7.27 (1H, d), 7.35 (1H, t), 11.08 (1H, s), 11.92 (1H, s); m/z (LC-MS, ESI+), RT=1.53 min (M+H=409.13). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness

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

Procedure: 2-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.379 g, 1.00 mmol) was added to 3-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1b) (0.200 g, 0.71 mmol), 4-ethoxypiperidine (0.101 g, 0.78 mmol) and triethylamine (0.249 mL, 1.78 mmol) in DMF (3 mL). The resulting solution was stirred at room temperature for 3 days. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 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 afford the desired compound (0.175 g, 62.6% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.20-1.93 (4H, m), 2.98-3.27 (2H, m), 3.33-3.41 (1H, m), 3.42-3.54 (3H, m), 3.93 (1H, s), 4.35 (2H, s), 7.21 (1H, m), 7.31 (1H, s), 7.33-7.42 (2H, m), 7.79-7.90 (2H, m), 7.95 (1H, m), 8.26 (1H, m), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.81 min (M+H=392.13). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length) Fractions containing the desired compound were evaporated to dryness