(4-bromo-3-methylphenyl)methanamine

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

Procedure: 4-Bromo-3-methylbenzylamine (EP 532266) (7.36 g, 0.037 mol) was dissolved in 1,2-dimethoxyethane (DME) (180 ml), with stirring, and was treated with 4-carboxyphenyl boronic acid (6.14 g, 0.037 mol), followed by a solution of sodium carbonate (17.65 g, 0.167 mol) in water (180 ml). The reaction mixture was then flushed with argon and tetrakistriphenylphosphinepalladium (O) (1.00 g) was added. The reaction mixture was then heated to reflux under argon. After 16 h, the reaction mixture was allowed to cool and the DME was removed by evaporation under reduced pressure. The aqueous residue was then diluted with water (~200 ml) and extracted with EtOAc (2×150 ml). The aqueous layer was then treated with acetic anhydride (6.98 ml, 0.074 mol) and stirred for 1 h at room temperature. The resulting pale brown solution was then filtered through kieselguhr to give a pale yellow solution which was acidified to pH5 using conc. HCl to give an off white precipitate which was filtered off, washed with water and dried in vacuo to give the title compound as an off white solid (5.85 g, 56%). The reaction mixture was then flushed with argon and tetrakistriphenylphosphinepalladium (O) (1.00 g) was added The reaction mixture was then heated to reflux under argon to cool the DME was removed by evaporation under reduced pressure The aqueous residue was then diluted with water (~200 ml) extracted with EtOAc (2×150 ml) stirred for 1 h at room temperature The resulting pale brown solution was then filtered through kieselguhr to give a pale yellow solution which to give an off white precipitate which was filtered off washed with water dried in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: LiAlH4 (0.68 g) in diethyl ether (30 mL) was treated with 4-bromo-3-methylbenzonitrile (15 mmol) and refluxed for 2 hours. The mixture was cooled to 0° C. and treated in succession with water (0.7 mL), 20% NaOH (0.5 mL), and water (2.5 mL). The mixture was filtered through a celite pad and the filter cake was washed several times with diethyl ether. The filtrate was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 194 (M+H)+; MS (ESI−) m/z 192 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 3.97 (s, 2H), 7.30 (m, 1H), 7.46 m, 2H). refluxed for 2 hours The mixture was filtered through a celite pad the filter cake was washed several times with diethyl ether The filtrate was dried over Na2SO4 filtered the filtrate was concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: LiAlH4 (0.68 g) in diethyl ether (30 mL) was treated with 4-bromo-3-methylbenzonitrile (15 mmol) and refluxed for 2 hours. The mixture was cooled to 0° C. and treated in succession with water (0.7 mL), 20% NaOH (0.5 mL), and water (2.5 mL). The mixture was filtered through a celite pad and the filter cake was washed several times with diethyl ether. The filtrate was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 194 (M+H)+; MS (ESI−) m/z 192 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 3.97 (s, 2H), 7.30 (m, 1H), 7.46 (m, 2H). refluxed for 2 hours The mixture was filtered through a celite pad the filter cake was washed several times with diethyl ether The filtrate was dried over Na2SO4 filtered the filtrate was concentrated under reduced pressure

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

Procedure: 4-Bromo-3-methylbenzylamine (EP 532266) (7.36 g, 0.037 mol) was dissolved in 1,2-dimethoxyethane (DME) (180 ml), with stirring, and was treated with 4-carboxyphenyl boronic acid (6.14 g, 0.037 mol), followed by a solution of sodium carbonate (17.65 g, 0.167 mol) in water (180 ml). The reaction mixture was then flushed with argon and tetrakistriphenylphosphinepalladium (O) (1.00 g) was added. The reaction mixture was then heated to reflux under argon. After 16 h, the reaction mixture was allowed to cool and the DME was removed by evaporation under reduced pressure. The aqueous residue was then diluted with water (~200 ml) and extracted with EtOAc (2×150 ml). The aqueous layer was then treated with acetic anhydride (6.98 ml, 0.074 mol) and stirred for 1 h at room temperature. The resulting pale brown solution was then filtered through kieselguhr to give a pale yellow solution which was acidified to pH5 using conc. HCl to give an off white precipitate which was filtered off, washed with water and dried in vacuo to give the title compound as an off white solid (5.85 g, 56%). The reaction mixture was then flushed with argon and tetrakistriphenylphosphinepalladium (O) (1.00 g) was added The reaction mixture was then heated to reflux under argon to cool the DME was removed by evaporation under reduced pressure The aqueous residue was then diluted with water (~200 ml) extracted with EtOAc (2×150 ml) stirred for 1 h at room temperature The resulting pale brown solution was then filtered through kieselguhr to give a pale yellow solution which to give an off white precipitate which was filtered off washed with water dried in vacuo

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

Procedure: 4-Bromo-3-methylbenzylamine (EP 532266) (7.36 g, 0.037 mol) was dissolved in 1,2-dimethoxyethane (DME) (180 ml), with stirring, and was treated with 4-carboxyphenyl boronic acid (6.14 g, 0.037 mol), followed by a solution of sodium carbonate (17.65 g, 0.167 mol) in water (180 ml). The reaction mixture was then flushed with argon and tetrakistriphenylphosphinepalladium (O) (1.00 g) was added. The reaction mixture was then heated to reflux under argon. After 16 h, the reaction mixture was allowed to cool and the DME was removed by evaporation under reduced pressure. The aqueous residue was then diluted with water (~200 ml) and extracted with EtOAc (2×150 ml). The aqueous layer was then treated with acetic anhydride (6.98 ml, 0.074 mol) and stirred for 1 h at room temperature. The resulting pale brown solution was then filtered through kieselguhr to give a pale yellow solution which was acidified to pH5 using conc. HCl to give an off white precipitate which was filtered off, washed with water and dried in vacuo to give the title compound as an off white solid (5.85 g, 56%). The reaction mixture was then flushed with argon and tetrakistriphenylphosphinepalladium (O) (1.00 g) was added The reaction mixture was then heated to reflux under argon to cool the DME was removed by evaporation under reduced pressure The aqueous residue was then diluted with water (~200 ml) extracted with EtOAc (2×150 ml) stirred for 1 h at room temperature The resulting pale brown solution was then filtered through kieselguhr to give a pale yellow solution which to give an off white precipitate which was filtered off washed with water dried in vacuo

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

Procedure: 4-Bromo-3-methylbenzylamine (EP 532266) (7.36 g, 0.037 mol) was dissolved in 1,2-dimethoxyethane (DME) (180 ml), with stirring, and was treated with 4-boronobenzoic acid (6.14 g, 0.037 mol), followed by a solution of sodium carbonate (17.65 g, 0.167 mol) in water (180 ml). The reaction mixture was then flushed with argon and tetrakis (triphenylphosphine)palladium (O) (1.00 g) was added. The reaction mixture was then heated to reflux under argon. After 16 h, the reaction mixture was allowed to cool and the DME was removed by evaporation under reduced pressure. The aqueous residue was then diluted with water (~200 ml) and washed with EtOAc (2×150 ml). The aqueous layer was then treated with acetic anhydride (6.98 ml, 0.074 mol) and stirred for 1 h at room temperature. The resulting pale brown solution was filtered through kieselguhr to give a pale yellow solution, which was acidified to pH 5 using conc. HCl to give an off white precipitate. This was filtered off, washed with water and dried in vacuo to give the title compound as on off white solid (5.85 g, 56%). The reaction mixture was then flushed with argon and tetrakis (triphenylphosphine)palladium (O) (1.00 g) was added The reaction mixture was then heated to reflux under argon to cool the DME was removed by evaporation under reduced pressure The aqueous residue was then diluted with water (~200 ml) washed with EtOAc (2×150 ml) stirred for 1 h at room temperature The resulting pale brown solution was filtered through kieselguhr to give a pale yellow solution, which to give an off white precipitate This was filtered off washed with water dried in vacuo

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

Procedure: Borane in THF (25.5 ml) was added dropwise, at 0° C., under nitrogen to a solution of 4-bromo-3-methylbenzonitrile (1.0 g) in THF (dry, 20 ml). The solution was left at 0° C. for 30 min and then stirred at room temperature overnight. Methanol was added carefully to quench the reaction. Hydrochloric acid (2N, 20 ml) was added and the solution stirred at room temperature for 4 h. Further 2N hydrochloric acid (20 ml) was added and the mixture heated to reflux for several hours. Sodium bicarbonate was added to the cooled mixture till basic and extracted with dichloromethane (4×50 ml), dried and slowly evaporated to give an orange/yellow oil. This was then applied in methanol to a flash column of silica gel which was eluted with hexane: ethyl acetate (1:1)→ethyl acetate:methanol:0.88 ammonia (790:200:10) to give the title compound as a yellow/orange oil (364 mg). to quench the reaction the solution stirred at room temperature for 4 h the mixture heated to reflux for several hours extracted with dichloromethane (4×50 ml) dried slowly evaporated to give an orange/yellow oil was eluted with hexane: ethyl acetate (1:1)→ethyl acetate

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

Procedure: To a solution of 4-bromo-3-methyl-benzylamine (Example 10.1) (15.11 g) in ethyl formate (150 ml) was added triethylamine (1.5 ml) at ambient temperature. The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was concentrated and the residue was triturated with diisopropyl ether/heptane (1:1) (100 ml) to give N-(4-bromo-3-methyl-benzyl)-formamide (14.04 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.49 (m, 1H), 7.16 (s, 1H), 6.97 (m, 1H), 5.85 (s, 1H), 4.42 (m, 2H), 2.39 (s, 3H) ppm. at reflux for 16 hours The reaction mixture was concentrated the residue was triturated with diisopropyl ether/heptane (1:1) (100 ml)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-3-methyl-benzonitrile (commercially available) (15 g) in diethyl ether (150 ml) under an argon atmosphere was added a solution of lithium aluminum hydride in diethyl ether (1M) (150 ml) at ambient temperature. The reaction mixture was stirred at 40° C. for 2 hours. Then the reaction mixture was cooled to 0° C. and quenched by successive addition of water (10.5 ml), aqueous sodium hydroxide (20% w/v) (7.5 ml) and water (37.5 ml). The phases were separated. The organic phase was filtered through a plug of silica gel and the filtrate concentrated to give 4-bromo-3-methyl-benzylamine (15.11 g) as a yellow oil. 1H-NMR (400 MHz, CDCl3): 7.47 (d, 1H), 7.19 (s, 1H), 6.98 (d, 1H), 3.80 (s, 2H), 2.39 (s, 3H) ppm. Then the reaction mixture was cooled to 0° C. quenched by successive addition of water (10.5 ml), aqueous sodium hydroxide (20% w/v) (7.5 ml) and water (37.5 ml) The phases were separated The organic phase was filtered through a plug of silica gel the filtrate concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: LiAlH4 (0.68 g) in diethyl ether (30 mL) was treated with 4-bromo-3-methylbenzonitrile (15 mmol) and refluxed for 2 hours. The mixture was cooled to 0° C. and treated in succession with water (0.7 mL), 20% NaOH (0.5 mL), and water (2.5 mL). The mixture was filtered through a celite pad and the filter cake was washed several times with diethyl ether. The filtrate was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 194 (M+H)+; MS (ESI−) m/z 192 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 3.97 (s, 2H), 7.30 (m, 1H), 7.46 (m, 2H). refluxed for 2 hours The mixture was filtered through a celite pad the filter cake was washed several times with diethyl ether The filtrate was dried over Na2SO4 filtered the filtrate was concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: LiAlH4 (0.68 g) in diethyl ether (30 mL) was treated with 4-bromo-3-methylbenzonitrile (15 mmol) and refluxed for 2 hours. The mixture was cooled to 0° C. and treated in succession with water (0.7 mL), 20% NaOH (0.5 mL), and water (2.5 mL). The mixture was filtered through a celite pad and the filter cake was washed several times with diethyl ether. The filtrate was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 194 (M+H)+; MS (ESI−) m/z 192 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 3.97 (s, 2H), 7.30 (m, 1H), 7.46 m, 2H). refluxed for 2 hours The mixture was filtered through a celite pad the filter cake was washed several times with diethyl ether The filtrate was dried over Na2SO4 filtered the filtrate was concentrated under reduced pressure

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

Procedure: To a solution of 4-bromo-3-methyl-benzylamine (15.11 g) (Example I1) in ethyl formate (150 ml) was added triethylamine (1.5 ml) at ambient temperature. The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was concentrated and the residue was triturated with diisopropyl ether/heptane (1:1) (100 ml) to give N-(4-bromo-3-methyl-benzyl)-formamide (14.04 g) as a white solid. 1H-NMR (400 MHz, CDCl3): 8.28 (s, 1H), 7.49 (m, 1H), 7.16 (s, 1H), 6.97 (m, 1H), 5.85 (s, 1H), 4.42 (m, 2H), 2.39 (s, 3H) ppm. at ambient temperature at reflux for 16 hours The reaction mixture was concentrated the residue was triturated with diisopropyl ether/heptane (1:1) (100 ml)