(4-bromo-2-fluorophenyl)methanamine;hydrochloride

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(2-trichloroacetylpyrrol-1-yl)malonic acid ethyl (-)-menthyl ester (87.0 g), 4-bromo-2-fluorobenzylamine hydrochloride (53.0 g) and triethylamine (66.4 g, 91.0 ml) in anhydrous dimethylformamide (200 ml) was stirred under the stream of nitrogen at 75° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with 5% cold hydrochloric acid and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from methanol to give the title compound (74.0 g, 78.7%) as colorless crystals, mp 98°-99° C. The reaction mixture was concentrated under reduced pressure the residue was dissolved in ethyl acetate The solution was washed with 5% cold hydrochloric acid with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate evaporated under reduced pressure The residue was recrystallized from methanol

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(2-trichloroacetylpyrrol-1-yl)malonic acid ethyl (-)-menthyl ester (87.0 g), 4-bromo-2-fluorobenzylamine hydrochloride (53.0 g) and triethylamine (66.4 g, 91.0 ml) in anhydrous dimethylformamide (200 ml) was stirred under the stream of nitrogen at 75° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with 5% cold hydrochloric acid and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from methanol to give the title compound (74.0 g, 78.7%) as colorless crystals, mp 98°-99° C. The reaction mixture was concentrated under reduced pressure the residue was dissolved in ethyl acetate The solution was washed with 5% cold hydrochloric acid with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate evaporated under reduced pressure The residue was recrystallized from methanol

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(2-trichloroacetylpyrrol-1-yl)malonic acid diethyl ester (40.0 g), 4-bromo-2-fluorobenzylamine hydrochloride (29.0 g) and triethylamine (54.8 g, 75.0 ml) in anhydrous dimethylformamide (100 ml) was stirred under the stream of nitrogen at 70° C. for 1 hour. After cooling, the reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (38.0 g, 86.0%) as colorless crystals, mp 114°-115° C. After cooling extracted with ethyl acetate The extracts were dried over anhydrous sodium sulfate evaporated under reduced pressure The residue was recrystallized from ethyl acetate/n-hexane

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-(2-trichloroacetylpyrrol-1-yl)malonic acid diethyl ester (40.0 g), 4-bromo-2-fluorobenzylamine hydrochloride (29.0 g) and triethylamine (54.8 g, 75.0 ml) in anhydrous dimethylformamide (100 ml) was stirred under the stream of nitrogen at 70° C. for 1 hour. After cooling, the reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (38.0 g, 86.0%) as colorless crystals, mp 114°-115° C. After cooling extracted with ethyl acetate The extracts were dried over anhydrous sodium sulfate evaporated under reduced pressure The residue was recrystallized from ethyl acetate/n-hexane

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

Procedure: Acetyl chloride (0.7 mL, 9.9 mmol) followed by triethylamine (2.8 mL, 19.9 mmol) were added to a suspension of 4-bromo-2-fluorobenzylamine hydrochloride (2 g, 8.3 mmol) in CH2Cl2 (20 mL). The mixture was stirred for 90 mins and then partitioned between 1 N HCl and EtOAc. The organic layers were brine, dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 60% EtOAc in hexanes) gave the product as a clear oil (1.5 g, 74%). MS (ESI): 246.10, 248.10 (M+H)+ partitioned between 1 N HCl and EtOAc dried over Na2SO4 concentrated Purification by flash column chromatography (0% to 60% EtOAc in hexanes)

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

Procedure: Acetyl chloride (0.7 mL, 9.9 mmol) followed by triethylamine (2.8 mL, 19.9 mmol) were added to a suspension of 4-bromo-2-fluorobenzylamine hydrochloride (2 g, 8.3 mmol) in CH2Cl2 (20 mL). The mixture was stirred for 90 mins and then partitioned between 1 N HCl and EtOAc. The organic layers were brine, dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 60% EtOAc in hexanes) gave the product as a clear oil (1.5 g, 74%). MS (ESI): 246.10, 248.10 (M+H)+ partitioned between 1 N HCl and EtOAc dried over Na2SO4 concentrated Purification by flash column chromatography (0% to 60% EtOAc in hexanes)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-bromo-2-fluorobenzylamine (20.4 g, 0.10 mol) in toluene (300 ml) is saturated with gaseous hydrochloric acid at 25° C. The resulting suspension of the 4-bromo-2-fluorobenzylamine hydrochloride is heated at 100° C. Phosgene is passed in at this temperature. Stirring of the solution, which has eventually become clear, is continued at 100° C. for 1 hour, and the mixture is then refluxed to remove the gases phosgene and hydrogen chloride. The batch is worked up by distillation. 21.2 g of 4-bromo-2-fluorobenzyl isocyanate (boiling point 109° C. at 4 mbar) are obtained. Yield: 92.1% of theory. the mixture is then refluxed to remove the gases phosgene and hydrogen chloride The batch is worked up by distillation

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

Procedure: 2-chloroethyl chloridocarbonate (114 μL, 1.1 mmol) was added to a mixture of 1-(4-bromo-2-fluorophenyl)methanamine hydrochloride (0.240 g, 1.0 mmol) and triethylamine (293 μL, 2.1 mmol). The mixture was stirred at RT for 3 h, and then 1M of potassium tert-butoxide in THF (1.2 mL) was added. The mixture was stirred overnight at RT, diluted with methylene chloride, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product which was directly used in next step without further purification. LCMS: (M+H)=275.9/273.9. The mixture was stirred overnight at RT washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure

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

Procedure: 2-chloroethyl chloridocarbonate (114 μL, 1.1 mmol) was added to a mixture of 1-(4-bromo-2-fluorophenyl)methanamine hydrochloride (0.240 g, 1.0 mmol) and triethylamine (293 μL, 2.1 mmol). The mixture was stirred at RT for 3 h, and then 1M of potassium tert-butoxide in THF (1.2 mL) was added. The mixture was stirred overnight at RT, diluted with methylene chloride, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product which was directly used in next step without further purification. LCMS: (M+H)=275.9/273.9. The mixture was stirred overnight at RT washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure

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

Procedure: Under a dry atmosphere of nitrogen, a solution of 4-fluoro-2-methoxy-5-methyl-benzoic acid (1.19 g, 6.47 mmol) in dichloromethane (16 mL, 0.5 M) was treated with oxalyl chloride (1.7 mL, 19.4 mmol) and a drop of DMF at 0° C. The mixture was allowed to gradually warm to room temperature and was then concentrated to afford a yellow powder. The powder was dissolved in dichloromethane (16 mL, 0.5 M). To the stirring solution at 0° C. was added diisopropylethylamine (2.8 mL, 16.2 mmol) followed by 4-bromo-2-fluorobenzylamine hydrochloride salt (2.34 g, 9.71 mmol). Stirring under nitrogen, the mixture was gradually allowed to warm to room temperature. After 21 hours, the reaction was washed successively with 1N HCl (3×50 mL) and saturated aq NaCl (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-methoxy-5-methyl-benzamide (2.33 g, 97%) as a brown oil which was used without further purification: Rf 0.40 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 8.17 (bd s, 1 H), 8.06 (d, J=9.3 Hz, 1 H), 7.33–7.22 (m, 3 H), 6.65 (d, J=11.1 Hz, 1 H), 4.63 (d, J=6.3 Hz, 2 H), 3.92 (s, 3 H), 2.23 (bd d, J=1.8 Hz, 3 H). at 0° C was then concentrated to afford a yellow powder to warm to room temperature the reaction was washed successively with 1N HCl (3×50 mL) and saturated aq NaCl (50 mL) The organic layer was dried over Na2SO4 filtered concentrated

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

Procedure: Under a dry atmosphere of nitrogen, a solution of 4-fluoro-2-methoxy-5-methyl-benzoic acid (1.19 g, 6.47 mmol) in dichloromethane (16 mL, 0.5 M) was treated with oxalyl chloride (1.7 mL, 19.4 mmol) and a drop of DMF at 0° C. The mixture was allowed to gradually warm to room temperature and was then concentrated to afford a yellow powder. The powder was dissolved in dichloromethane (16 mL, 0.5 M). To the stirring solution at 0° C. was added diisopropylethylamine (2.8 mL, 16.2 mmol) followed by 4-bromo-2-fluorobenzylamine hydrochloride salt (2.34 g, 9.71 mmol). Stirring under nitrogen, the mixture was gradually allowed to warm to room temperature. After 21 hours, the reaction was washed successively with 1N HCl (3×50 mL) and saturated aq NaCl (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-methoxy-5-methyl-benzamide (2.33 g, 97%) as a brown oil which was used without further purification: Rf 0.40 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 8.17 (bd s, 1 H), 8.06 (d, J=9.3 Hz, 1 H), 7.33–7.22 (m, 3 H), 6.65 (d, J=11.1 Hz, 1 H), 4.63 (d, J=6.3 Hz, 2 H), 3.92 (s, 3 H), 2.23 (bd d, J=1.8 Hz, 3 H). at 0° C was then concentrated to afford a yellow powder to warm to room temperature the reaction was washed successively with 1N HCl (3×50 mL) and saturated aq NaCl (50 mL) The organic layer was dried over Na2SO4 filtered concentrated

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

Procedure: A solution of 2-methoxy-4-(methylthio)benzoic acid (5.0 g, 25.2 mmol) in dichloromethane (50 mL) was cooled to 0° C. and treated with oxalyl chloride (6.6 mL, 75.6 mmol). A drop of N,N-dimethylformamide was added and the reaction was heated to a gentle reflux for 2 h. After cooling to room temperature, the solution was concentrated in vacuo to remove the excess oxalyl chloride, diluted with dichloromethane (53 mL) and cooled to 0° C. The resulting solution was treated with N,N-diisopropylethylamine (11.6 mL, 67 mmol) and 4-bromo-2-fluorobenzylamine hydrochloride (9.7 g, 40.2 mmol). The resulting solution was stirred at room temperature overnight, concentrated in vacuo, diluted with ethyl acetate and successively washed with 2 N HCl and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Rf 0.43 (40% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 8.63 (t, J=6 Hz, 1 H), 7.70 (d, J=8.1 Hz, 1 H), 7.50 (dd, J1=9.6 Hz, J2=2.1 Hz, 1 H), 7.38 (dd, J1=8.4 Hz, J2=2.0 Hz, 1 H), 7.28 (t, J=8.4 Hz, 1 H), 6.94 (br s, 1 H), 6.89 (dd, J1=5.7 Hz, J2=1.7 Hz, 1 H), 4.46 (d, J=6 Hz, 2 H), 3.91 (s, 3 H), 2.51 (s, 3 H). the reaction was heated to a gentle reflux for 2 h the solution was concentrated in vacuo to remove the excess oxalyl chloride diluted with dichloromethane (53 mL) cooled to 0° C concentrated in vacuo diluted with ethyl acetate successively washed with 2 N HCl and saturated NaCl The organic layer was dried over MgSO4 filtered concentrated