4-(2-methoxyethoxy)piperidine;hydrochloride

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

Procedure: A solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (150 mg, 0.50 mmol) in N,N-dimethylacetamide (4 mL) was treated with 4-(2-methoxyethoxy)piperidine hydrochloride (103 mg, 0.53 mmol) and triethylamine (0.210 mL, 1.51 mmol). O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (253 mg, 0.67 mmol) was added and the resulting solution was stirred at ambient temperature for 4.5 hours. The crude reaction mixture was filtered before being 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 and lyophilised to afford a gum, which was taken up in a small amount of diethyl ether and dichloromethane and allowed to evaporate before drying under vacuum, at 55° C., for 2 hours to afford the desired compound as a white solid (151 mg, 68.3% yield); 1H NMR (400.132 MHz, DMSO) δ 1.28-1.36 (1H, m), 1.40-1.49 (1H, m), 1.68-1.75 (1H, m), 1.82-1.90 (1H, m), 2.99-3.06 (1H, m), 3.25 (3H, s), 3.26-3.32 (2H, m), 3.44 (2H, t), 3.53-3.58 (3H, m), 3.90-3.98 (1H, m), 4.33 (2H, s), 7.21 (1H, t), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.27 (1H, dd), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.65 (M+H 440.6). The crude reaction mixture was filtered before being 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 to afford a gum, which to evaporate before drying under vacuum, at 55° C., for 2 hours

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

Procedure: A solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (150 mg, 0.50 mmol) in N,N-dimethylacetamide (4 mL) was treated with 4-(2-methoxyethoxy)piperidine hydrochloride (103 mg, 0.53 mmol) and triethylamine (0.210 mL, 1.51 mmol). O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (253 mg, 0.67 mmol) was added and the resulting solution was stirred at ambient temperature for 4.5 hours. The crude reaction mixture was filtered before being 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 and lyophilised to afford a gum, which was taken up in a small amount of diethyl ether and dichloromethane and allowed to evaporate before drying under vacuum, at 55° C., for 2 hours to afford the desired compound as a white solid (151 mg, 68.3% yield); 1H NMR (400.132 MHz, DMSO) δ 1.28-1.36 (1H, m), 1.40-1.49 (1H, m), 1.68-1.75 (1H, m), 1.82-1.90 (1H, m), 2.99-3.06 (1H, m), 3.25 (3H, s), 3.26-3.32 (2H, m), 3.44 (2H, t), 3.53-3.58 (3H, m), 3.90-3.98 (1H, m), 4.33 (2H, s), 7.21 (1H, t), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.27 (1H, dd), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.65 (M+H 440.6). The crude reaction mixture was filtered before being 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 to afford a gum, which to evaporate before drying under vacuum, at 55° C., for 2 hours

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

Procedure: To a solution of 4-(2-methoxyethoxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 81, 114 mg, 0.44 mmol) in methanol (3 mL) was added 4M HCl in dioxane (550 μL, 2.20 mmol) and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the crude residue dissolved in water (10 mL). The aqueous solution was extracted with ethyl acetate (2×10 mL) then concentrated in vacuo. Purification by trituration in ethyl acetate gave the title compound as the hydrochloride salt. δH (CD3OD): 3.74–3.67 (1H, m), 3.64 (2H, m), 3.56 (2H, m), 3.40–2.39 (7H, m), 2.11–1.96 (2H, m), 1.93–1.83 (2H, m). Solvent was removed in vacuo the crude residue dissolved in water (10 mL) The aqueous solution was extracted with ethyl acetate (2×10 mL) then concentrated in vacuo Purification by trituration in ethyl acetate

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

Procedure: The title compound was prepared according to EXAMPLE 229 from 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228) and 4-(2-methoxyethoxy)piperidine hydrochloride (Preparation 82). Purification by chromatography using dichloromethane/methanol (95:5) as the eluent gave the title compound as an off-white powder. m/z (ES+) 503.26 [M+H]+; RT=3.3 min. The title compound was prepared Purification by chromatography

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

Procedure: To a solution of 4-(2-methoxyethoxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 81, 114 mg, 0.44 mmol) in methanol (3 mL) was added 4M HCl in dioxane (550 μL, 2.20 mmol) and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the crude residue dissolved in water (10 mL). The aqueous solution was extracted with ethyl acetate (2×10 mL) then concentrated in vacuo. Purification by trituration in ethyl acetate gave the title compound as the hydrochloride salt. δH (CD3OD): 3.74-3.67 (1H, m), 3.64 (2H, m), 3.56 (2H, m), 3.40-2.39 (7H, m), 2.11-1.96 (2H, m), 1.93-1.83 (2H, m). Solvent was removed in vacuo the crude residue dissolved in water (10 mL) The aqueous solution was extracted with ethyl acetate (2×10 mL) then concentrated in vacuo Purification by trituration in ethyl acetate

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

Procedure: A solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (150 mg, 0.50 mmol) in N,N-dimethylacetamide (4 mL) was treated with 4-(2-methoxyethoxy)piperidine hydrochloride (103 mg, 0.53 mmol) and triethylamine (0.210 mL, 1.51 mmol). O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (253 mg, 0.67 mmol) was added and the resulting solution was stirred at ambient temperature for 4.5 hours. The crude reaction mixture was filtered before being 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 and lyophilised to afford a gum, which was taken up in a small amount of diethyl ether and dichloromethane and allowed to evaporate before drying under vacuum, at 55° C., for 2 hours to afford the desired compound as a white solid (151 mg, 68.3% yield); 1H NMR (400.132 MHz, DMSO) δ 1.28-1.36 (1H, m), 1.40-1.49 (1H, m), 1.68-1.75 (1H, m), 1.82-1.90 (1H, m), 2.99-3.06 (1H, m), 3.25 (3H, s), 3.26-3.32 (2H, m), 3.44 (2H, t), 3.53-3.58 (3H, m), 3.90-3.98 (1H, m), 4.33 (2H, s), 7.21 (1H, t), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.27 (1H, dd), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.65 (M+H 440.6). The crude reaction mixture was filtered before being 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 to afford a gum, which to evaporate before drying under vacuum, at 55° C., for 2 hours

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

Procedure: To a solution of 4-(2-methoxyethoxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 81, 114 mg, 0.44 mmol) in methanol (3 mL) was added 4M HCl in dioxane (550 μL, 2.20 mmol) and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the crude residue dissolved in water (10 mL). The aqueous solution was extracted with ethyl acetate (2×10 mL) then concentrated in vacuo. Purification by trituration in ethyl acetate gave the title compound as the hydrochloride salt. δH (CD3OD): 3.74–3.67 (1H, m), 3.64 (2H, m), 3.56 (2H, m), 3.40–2.39 (7H, m), 2.11–1.96 (2H, m), 1.93–1.83 (2H, m). Solvent was removed in vacuo the crude residue dissolved in water (10 mL) The aqueous solution was extracted with ethyl acetate (2×10 mL) then concentrated in vacuo Purification by trituration in ethyl acetate