methyl 4-(aminomethyl)-2-fluorobenzoate

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

Procedure: Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.24 g, 2.91 mmol) with methyl 4-aminomethyl-2-fluoro-benzoate (1.065 g, 5.821 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (0.533 g, 0.582 mmol), BINAP (0.725 g, 1.16 mmol) and cesium carbonate (3.32 g, 10.2 mmol) under nitrogen in anhydrous toluene (20 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 1:1 gradient over 71 min; 50 mL/min) to afford the desired intermediate as a yellow oil (1.3 g, 100%). Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 1:1 gradient over 71 min; 50 mL/min)

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

Procedure: Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.24 g, 2.91 mmol) with methyl 4-aminomethyl-2-fluoro-benzoate (1.065 g, 5.821 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (0.533 g, 0.582 mmol), BINAP (0.725 g, 1.16 mmol) and cesium carbonate (3.32 g, 10.2 mmol) under nitrogen in anhydrous toluene (20 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 1:1 gradient over 71 min; 50 mL/min) to afford the desired intermediate as a yellow oil (1.3 g, 100%). Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 1:1 gradient over 71 min; 50 mL/min)

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

Procedure: Combine a solution of methyl 4-cyano-2-fluoro-benzoate (1 g, 5.58 mmol) in absolute ethanol (42 mL) and acetic acid (1.9 mL) with a mixture of 10% Pd/C (Degussa type E101, 0.17 g, 0.078 mmol) in water (15.6 mL) at room temperature under nitrogen. Purge with nitrogen and then with hydrogen at 55 psi and stir for 1 h. Purge the reaction with nitrogen, filter through Celite® and wash the filter cake with ethanol (100 mL), THF (100 mL) and isopropanol (100 mL). Concentrate in vacuo and purify by SCX chromatography and then chromatography on silica gel (40 g RediSep® column) eluting with dichloromethane/2M ammonia in methanol (99:1 to 9:1 gradient over 30 min; 35 mL/min) to afford the desired intermediate as a white solid (0.602 g, 59%). Purge with nitrogen Purge the reaction with nitrogen filter through Celite® wash the filter cake with ethanol (100 mL), THF (100 mL) and isopropanol (100 mL) Concentrate in vacuo purify by SCX chromatography chromatography on silica gel (40 g RediSep® column) eluting with dichloromethane/2M ammonia in methanol (99:1 to 9:1 gradient over 30 min; 35 mL/min)

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

Procedure: To a mixture of methyl 4-(aminomethyl)-2-fluorobenzoate (106.9 mg, 0.584 mmol) in N,N-dimethyl formamide (4.0 mL) was added 1,1′-carbonyldiimidazole (Aldrich, 98.9 mg, 0.592 mmol). After it was stirred at rt overnight under an argon atmosphere, the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 2-Fluoro-4-{[(imidazole-1-carbonyl)-amino]-methyl}-benzoic acid methyl ester (187.0 mg) which was used without further purification. the reaction mixture was extracted with EtOAc washed with water (2×), and saturated NaCl The organic phase was separated dried over Na2SO4 filtered concentrated

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

Procedure: To a mixture of methyl 4-(aminomethyl)-2-fluorobenzoate (106.9 mg, 0.584 mmol) in N,N-dimethyl formamide (4.0 mL) was added 1,1′-carbonyldiimidazole (Aldrich, 98.9 mg, 0.592 mmol). After it was stirred at rt overnight under an argon atmosphere, the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 2-Fluoro-4-{[(imidazole-1-carbonyl)-amino]-methyl}-benzoic acid methyl ester (187.0 mg) which was used without further purification. the reaction mixture was extracted with EtOAc washed with water (2×), and saturated NaCl The organic phase was separated dried over Na2SO4 filtered concentrated

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

Procedure: Using methyl 4-aminomethyl-2-fluorobenzoate (181 mg) described in Preparation Example 199 and 3-chloropropane-1-sulfonyl chloride (0.14 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (233 mg) was obtained.

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

Procedure: Using methyl 4-aminomethyl-2-fluorobenzoate (181 mg) described in Preparation Example 199 and 3-chloropropane-1-sulfonyl chloride (0.14 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (233 mg) was obtained.

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

Procedure: 4-Aminomethyl-2-fluorobenzoic acid hydrochloride (500 mg) was dissolved in methanol (10 mL), concentrated sulfuric acid (6 μL) was added, and the mixture was stirred with heating under reflux for 9 hr. After completion of the reaction, the solvent was evaporated, saturated aqueous potassium carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated to give the title compound (181 mg). with heating under reflux for 9 hr After completion of the reaction the solvent was evaporated saturated aqueous potassium carbonate solution was added the mixture was extracted with chloroform The organic layer was dried over sodium sulfate the solvent was evaporated

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

Procedure: 4-Aminomethyl-2-fluorobenzoic acid hydrochloride (500 mg) was dissolved in methanol (10 mL), concentrated sulfuric acid (6 μL) was added, and the mixture was stirred with heating under reflux for 9 hr. After completion of the reaction, the solvent was evaporated, saturated aqueous potassium carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and the solvent was evaporated to give the title compound (181 mg). with heating under reflux for 9 hr After completion of the reaction the solvent was evaporated saturated aqueous potassium carbonate solution was added the mixture was extracted with chloroform The organic layer was dried over sodium sulfate the solvent was evaporated

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

Procedure: Add a slurry of Raney nickel in ethanol (1.2 g, 1.2 ml) to 4-cyano-2-fluoro-benzoic acid methyl ester (5.8 g, 30.0 mmol) in 2N ammonia in methanol (580 mL). Purge with nitrogen gas (3×), purge with hydrogen gas (3×), and pressurize with hydrogen gas to 419 KPa. Heat the reaction at 40° C. for 18 hrs. Allow to cool to room temperature and filter the reaction mixture. Concentrate the filtrate to the crude title compound (6.9 g, 99%). MS (m/z): 184 (M+1). Purge with nitrogen gas (3×) purge with hydrogen gas (3×) Heat the reaction at 40° C. for 18 hrs filter the reaction mixture Concentrate the filtrate to the crude title compound (6.9 g, 99%)

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

Procedure: Add a slurry of Raney nickel in ethanol (1.2 g, 1.2 ml) to 4-cyano-2-fluoro-benzoic acid methyl ester (5.8 g, 30.0 mmol) in 2N ammonia in methanol (580 mL). Purge with nitrogen gas (3×), purge with hydrogen gas (3×), and pressurize with hydrogen gas to 419 KPa. Heat the reaction at 40° C. for 18 hrs. Allow to cool to room temperature and filter the reaction mixture. Concentrate the filtrate to the crude title compound (6.9 g, 99%). MS (m/z): 184 (M+1). Purge with nitrogen gas (3×) purge with hydrogen gas (3×) Heat the reaction at 40° C. for 18 hrs filter the reaction mixture Concentrate the filtrate to the crude title compound (6.9 g, 99%)

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

Procedure: Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.24 g, 2.91 mmol) with methyl 4-aminomethyl-2-fluoro-benzoate (1.065 g, 5.821 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (0.533 g, 0.582 mmol), BINAP (0.725 g, 1.16 mmol) and cesium carbonate (3.32 g, 10.2 mmol) under nitrogen in anhydrous toluene (20 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 1:1 gradient over 71 min; 50 mL/min) to afford the desired intermediate as a yellow oil (1.3 g, 100%). Purify by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 1:1 gradient over 71 min; 50 mL/min)