4-(aminomethyl)-3-fluorophenol;hydrochloride

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

Procedure: A solution of 4-aminomethyl-3-fluoro-phenol hydrochloride (4.75 g, 27 mmol) in N,N-dimethylformamide (20 ml) was added to a stirred solution of 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid (14 g, 54 mmol), 1-hydroxybenzotriazole hydrate (7.29 g, 54 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (10.37 g, 54 mmol), and triethylamine (3.76 ml, 27 mmol) in N,N-dimethylformamide (130 ml) at room temperature and stirred over night. The reaction was quenched into dilute aqueous hydrochloric acid and extracted with diethyl ether, then ethyl acetate. The pooled organic layers were washed successively with dilute aqueous sodium hydroxide, water, and brine. The solvents were stripped in vacuo to afford 12.2 g crude. The residue was dissolved in methanol (100 ml) and stirred with lithium hydroxide (10 ml, 1M) for 1 h to hydrolyze the ester of the bis-acylated product. Solvents were stripped in vacuo, the residue was diluted with water (200 ml) and saponified to pH 12 with sodium hydroxide. The precipitate was filtered off, and the filtrate was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (2×200 ml). The pooled organics were washed with 2N sodium carbonate, then brine and dried (MgSO4). The solvents were stripped in vacuo to afford pure product (5.7 g, 14.9 mmol) in 55% yield. The reaction was quenched into dilute aqueous hydrochloric acid extracted with diethyl ether The pooled organic layers were washed successively with dilute aqueous sodium hydroxide, water, and brine to afford 12.2 g crude The precipitate was filtered off extracted with ethyl acetate (2×200 ml) The pooled organics were washed with 2N sodium carbonate brine and dried (MgSO4)

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

Procedure: A mixture of 2-fluoro-4-hydroxy-benzonitrile (6 g, 43.8 mmol), palladium hydroxide (600 mg), ethanol (60 ml) and 2N hydrochloric acid (6 ml) was hydrogenated (60 psi) for 18 hours. The mixture was filtered through Arbocel® and the filter cake was washed with methanol and the filtrates were evaporated in-vacuo. The residue was triturated with diethylether to give 4-aminomethyl-3-fluoro phenol hydrochloride (4.71 g). for 18 hours The mixture was filtered through Arbocel® the filter cake was washed with methanol the filtrates were evaporated in-vacuo The residue was triturated with diethylether

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

Procedure: A mixture of 2-fluoro-4-hydroxy-benzonitrile (6 g, 43.8 mmol), palladium hydroxide (600 mg), ethanol (60 ml) and 2N hydrochloric acid (6 ml) was hydrogenated (60 psi) for 18 hours. The mixture was filtered through Arbocel® and the filter cake was washed with methanol and the filtrates were evaporated in-vacuo. The residue was triturated with diethylether to give 4-aminomethyl-3-fluoro phenol hydrochloride (4.71 g). for 18 hours The mixture was filtered through Arbocel® the filter cake was washed with methanol the filtrates were evaporated in-vacuo The residue was triturated with diethylether

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

Procedure: A solution of 4-aminomethyl-3-fluoro-phenol hydrochloride (4.75 g, 27 mmol) in N,N-dimethylformamide (20 ml) was added to a stirred solution of 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid (14 g, 54 mmol), 1-hydroxybenzotriazole hydrate (7.29 g, 54 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (10.37 g, 54 mmol), and triethylamine (3.76 ml, 27 mmol) in N,N-dimethylformamide (130 ml) at room temperature and stirred over night. The reaction was quenched into dilute aqueous hydrochloric acid and extracted with diethyl ether, then ethyl acetate. The pooled organic layers were washed successively with dilute aqueous sodium hydroxide, water, and brine. The solvents were stripped in vacuo to afford 12.2 g crude. The residue was dissolved in methanol (100 ml) and stirred with lithium hydroxide (10 ml, 1M) for 1 h to hydrolyze the ester of the bis-acylated product. Solvents were stripped in vacuo, the residue was diluted with water (200 ml) and saponified to pH 12 with sodium hydroxide. The precipitate was filtered off, and the filtrate was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (2×200 ml). The pooled organics were washed with 2N sodium carbonate, then brine and dried (MgSO4). The solvents were stripped in vacuo to afford pure product (5.7 g, 14.9 mmol) in 55% yield. The reaction was quenched into dilute aqueous hydrochloric acid extracted with diethyl ether The pooled organic layers were washed successively with dilute aqueous sodium hydroxide, water, and brine to afford 12.2 g crude The precipitate was filtered off extracted with ethyl acetate (2×200 ml) The pooled organics were washed with 2N sodium carbonate brine and dried (MgSO4)

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

Procedure: A mixture of 2-fluoro-4-hydroxy-benzonitrile (6 g, 43.8 mmol), palladium hydroxide (600 mg), ethanol (60 ml) and 2N hydrochloric acid (6 ml) was hydrogenated (60 psi) for 18 hours. The mixture was filtered through Arbocel® and the filter cake was washed with methanol and the filtrates were evaporated in-vacuo. The residue was triturated with diethylether to give 4-aminomethyl-3-fluoro phenol hydrochloride (4.71 g). for 18 hours The mixture was filtered through Arbocel® the filter cake was washed with methanol the filtrates were evaporated in-vacuo The residue was triturated with diethylether

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

Procedure: To 2-(4-fluoro-phenoxy)-nicotinic acid (20.47 g) were added anhydrous dichloromethane (200 mL), dimethylformamide (2 mL), and oxalyl chloride (2.0 M in dichloromethane, 46.10 mL) were then added. The solution was cooled in a dry ice/acetone bath. Triethylamine (24.5 mL) and 2-fluoro-4-hydroxy-benzylamine hydrochloride (7.81 g) were then added. The solution was allowed to warm to ambient temperature and stir overnight. The reaction was then diluted with 200 mL dichloromethane and washed with 100 mL water. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude product was then taken up in a solution of tetrahydrofuran (50 mL) and methanol (25 mL). Lithium hydroxide (5.26 g) in water (25 mL) were then added to the mixture, and the reaction was allowed to stir overnight at ambient temperature. The solution was then concentrated in vacuo. The resulting residue was taken up in 100 mL water, and acidified with conc. aq. HCl to pH 4. The aqueous layer was then extracted with ethyl acetate (3×300 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo. Recrystallization from methanol yielded pure title compound (9.75 g) were then added The solution was cooled in a dry ice/acetone bath washed with 100 mL water The organic phase was dried over magnesium sulfate concentrated in vacuo Lithium hydroxide (5.26 g) in water (25 mL) were then added to the mixture to stir overnight at ambient temperature The solution was then concentrated in vacuo The aqueous layer was then extracted with ethyl acetate (3×300 mL) The combined organics were dried over magnesium sulfate concentrated in vacuo Recrystallization from methanol yielded pure title compound (9.75 g)

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

Procedure: 2-Fluoro-4-hydroxybenzonitrile (10 g, Allied Signal) was added to a 500 mL Parr flask, followed by palladium hydroxide (5 g). Anhydrous ethanol (200 mL) was then added under nitrogen atmosphere, followed by aq. concentrated hydrochloric acid (7.55 mL). The mixture was shaken under 50 psi of hydrogen for 1.5 h, then filtered through nylon. The filtrate was concentrated, washed with ethyl acetate, then dried in vacuo to yield the crude title compound (9.8 g). filtered through nylon The filtrate was concentrated washed with ethyl acetate dried in vacuo

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

Procedure: A mixture of 2-fluoro-4-hydroxy-benzonitrile (6 g, 43.8 mmol), palladium hydroxide (600 mg), ethanol (60 ml) and 2N hydrochloric acid (6 ml) was hydrogenated (60 psi) for 18 hours. The mixture was filtered through Arbocel® and the filter cake was washed with methanol and the filtrates were evaporated in-vacuo. The residue was triturated with diethylether to give 4-aminomethyl-3-fluoro phenol hydrochloride (4.71 g). for 18 hours The mixture was filtered through Arbocel® the filter cake was washed with methanol the filtrates were evaporated in-vacuo The residue was triturated with diethylether

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

Procedure: A solution of 4-aminomethyl-3-fluoro-phenol hydrochloride (4.75 g, 27 mmol) in N,N-dimethylformamide (20 ml) was added to a stirred solution of 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid (14 g, 54 mmol), 1-hydroxybenzotriazole hydrate (7.29 g, 54 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (10.37 g, 54 mmol), and triethylamine (3.76 ml, 27 mmol) in N,N-dimethylformamide (130 ml) at room temperature and stirred over night. The reaction was quenched into dilute aqueous hydrochloric acid and extracted with diethyl ether, then ethyl acetate. The pooled organic layers were washed successively with dilute aqueous sodium hydroxide, water, and brine. The solvents were stripped in vacuo to afford 12.2 g crude. The residue was dissolved in methanol (100 ml) and stirred with lithium hydroxide (10 ml, 1M) for 1 h to hydrolyze the ester of the bis-acylated product. Solvents were stripped in vacuo, the residue was diluted with water (200 ml) and saponified to pH 12 with sodium hydroxide. The precipitate was filtered off, and the filtrate was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate (2×200 ml). The pooled organics were washed with 2N sodium carbonate, then brine and dried (MgSO4). The solvents were stripped in vacuo to afford pure product (5.7 g, 14.9 mmol) in 55% yield. The reaction was quenched into dilute aqueous hydrochloric acid extracted with diethyl ether The pooled organic layers were washed successively with dilute aqueous sodium hydroxide, water, and brine to afford 12.2 g crude The precipitate was filtered off extracted with ethyl acetate (2×200 ml) The pooled organics were washed with 2N sodium carbonate brine and dried (MgSO4)