[5-bromo-2-(2-methylpiperidin-1-yl)phenyl]methanol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of solution of [5-bromo-2-(2-methylpiperidin-1-yl)phenyl]methanol (7.9 g; 27.8 mmol) and n-ethyldiisopropylamine (10.40 mL; 61.15 mmol) in anhydrous DCM (150 mL) cooled to 0° C., was added methanesulfonyl chloride (2.36 mL; 30.57 mmol). The reaction mixture was diluted with MeOH (150 mL) and heated to 50° C. for 3 h after which time solvents were removed under vacuum to give a brown oil. Residue was taken up with Et2O (450 mL), washed with water (150 mL, pH 8 adjusted with aqueous NaOH), saturated aqueous solution of NH4Cl (2×150 mL) and brine (150 mL). The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure to give the title compound as a brown yellow oil (12.97 g, 92%). LC/MS (Method B): 298.1 (M+H)+. were removed under vacuum to give a brown oil washed with water (150 mL, pH 8 adjusted with aqueous NaOH), saturated aqueous solution of NH4Cl (2×150 mL) and brine (150 mL) The combined organic layers were dried over MgSO4 filtered the solvent was removed under reduced pressure

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

Procedure: To a solution of 5-bromo-2-(2-methylpiperidin-1-yl)benzaldehyde (16.30 g; 57.76 mmol) in MeOH (300 mL) was added sodium borohydride (2.19 g; 57.76 mmol) at 5° C. in a portion-wise fashion and stirred for 30 min. After this time, reaction mixture was diluted with a saturated aqueous solution of NH4Cl (300 mL), extracted with EtOAc. The org layers were washed with aqueous solution of NH4Cl (150 mL), brine (300 mL), dried over MgSO4 and evaporated under vacuum to give the title compound as a yellow oil (15.9 g, 97%). LC/MS (Method A): 285.6 (M+H)+. HPLC (Method A): Rt 2.13 min (Purity: 94.9%). After this time, reaction mixture extracted with EtOAc The org layers were washed with aqueous solution of NH4Cl (150 mL), brine (300 mL) dried over MgSO4 evaporated under vacuum

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of solution of [5-bromo-2-(2-methylpiperidin-1-yl)phenyl]methanol (7.9 g; 27.8 mmol) and n-ethyldiisopropylamine (10.40 mL; 61.15 mmol) in anhydrous DCM (150 mL) cooled to 0° C., was added methanesulfonyl chloride (2.36 mL; 30.57 mmol). The reaction mixture was diluted with MeOH (150 mL) and heated to 50° C. for 3 h after which time solvents were removed under vacuum to give a brown oil. Residue was taken up with Et2O (450 mL), washed with water (150 mL, pH 8 adjusted with aqueous NaOH), saturated aqueous solution of NH4Cl (2×150 mL) and brine (150 mL). The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure to give the title compound as a brown yellow oil (12.97 g, 92%). LC/MS (Method B): 298.1 (M+H)+. were removed under vacuum to give a brown oil washed with water (150 mL, pH 8 adjusted with aqueous NaOH), saturated aqueous solution of NH4Cl (2×150 mL) and brine (150 mL) The combined organic layers were dried over MgSO4 filtered the solvent was removed under reduced pressure

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

Procedure: To a solution of 5-bromo-2-(2-methylpiperidin-1-yl)benzaldehyde (16.30 g; 57.76 mmol) in MeOH (300 mL) was added sodium borohydride (2.19 g; 57.76 mmol) at 5° C. in a portion-wise fashion and stirred for 30 min. After this time, reaction mixture was diluted with a saturated aqueous solution of NH4Cl (300 mL), extracted with EtOAc. The org layers were washed with aqueous solution of NH4Cl (150 mL), brine (300 mL), dried over MgSO4 and evaporated under vacuum to give the title compound as a yellow oil (15.9 g, 97%). LC/MS (Method A): 285.6 (M+H)+. HPLC (Method A): Rt 2.13 min (Purity: 94.9%). After this time, reaction mixture extracted with EtOAc The org layers were washed with aqueous solution of NH4Cl (150 mL), brine (300 mL) dried over MgSO4 evaporated under vacuum

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Methanesulfonyl chloride (4.0 mL, 51.6 mmol) was added into a solution of [5-bromo-2-(2-methylpiperidin-1-yl)phenyl]methanol (13.43 g, 47.3 mmol) and DIEA (17.7 mL, 104 mmol) in anhydrous DCM (130 mL) cooled at 0° C. After 1 hour, the reaction mixture was diluted with MeOH (150 mL) and heated at 50° C. for 3 hours. The solvents were removed under reduced pressure to give a brown oil. The residue was taken up with Et2O (450 mL), and then washed with water (150 mL, pH 8 adjusted with a 5N aqueous solution of NaOH), saturated aqueous solution of NH4Cl (2×150 mL) and brine (150 mL). The aqueous layers were extracted with Et2O (150 mL). The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure to give the title compound as a brown yellow oil (13.0 g, 92%) used without further purification in the next step. HPLC (Method A), Rt 2.9 min (Purity: 97.1%). HPLC/MS, M+(ESI): 298.1, 300.1. 1H NMR (CDCl3, 300 MHz) δ 7.59 (d, J=2.5 Hz, 1H), 7.36 (dd, J=8.5, 2.5 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 4.60 (d, J=12.8 Hz, 1H), 4.52 (d, J=12.8 Hz, 1H), 3.44 (s, 3H), 2.96-2.81 (m, 2H), 2.51 (m, 1H), 1.77 (m, 2H), 1.64 (m, 2H), 1.50-1.30 (m, 2H), 0.79 (d, J=6.1 Hz, 3H). heated at 50° C. for 3 hours The solvents were removed under reduced pressure to give a brown oil washed with water (150 mL, pH 8 The aqueous layers were extracted with Et2O (150 mL) The combined organic layers were dried (MgSO4) the solvent was removed under reduced pressure

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

Procedure: Methanesulfonyl chloride (4.0 mL, 51.6 mmol) was added into a solution of [5-bromo-2-(2-methylpiperidin-1-yl)phenyl]methanol (13.43 g, 47.3 mmol) and DIEA (17.7 mL, 104 mmol) in anhydrous DCM (130 mL) cooled at 0° C. After 1 hour, the reaction mixture was diluted with MeOH (150 mL) and heated at 50° C. for 3 hours. The solvents were removed under reduced pressure to give a brown oil. The residue was taken up with Et2O (450 mL), and then washed with water (150 mL, pH 8 adjusted with a 5N aqueous solution of NaOH), saturated aqueous solution of NH4Cl (2×150 mL) and brine (150 mL). The aqueous layers were extracted with Et2O (150 mL). The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure to give the title compound as a brown yellow oil (13.0 g, 92%) used without further purification in the next step. HPLC (Method A), Rt 2.9 min (Purity: 97.1%). HPLC/MS, M+(ESI): 298.1, 300.1. 1H NMR (CDCl3, 300 MHz) δ 7.59 (d, J=2.5 Hz, 1H), 7.36 (dd, J=8.5, 2.5 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 4.60 (d, J=12.8 Hz, 1H), 4.52 (d, J=12.8 Hz, 1H), 3.44 (s, 3H), 2.96-2.81 (m, 2H), 2.51 (m, 1H), 1.77 (m, 2H), 1.64 (m, 2H), 1.50-1.30 (m, 2H), 0.79 (d, J=6.1 Hz, 3H). heated at 50° C. for 3 hours The solvents were removed under reduced pressure to give a brown oil washed with water (150 mL, pH 8 The aqueous layers were extracted with Et2O (150 mL) The combined organic layers were dried (MgSO4) the solvent was removed under reduced pressure

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

Procedure: Methanesulfonyl chloride (4.0 mL, 51.6 mmol) was added into a solution of [5-bromo-2-(2-methylpiperidin-1-yl)phenyl]methanol (13.43 g, 47.3 mmol) and DIEA (17.7 mL, 104 mmol) in anhydrous DCM (130 mL) cooled at 0° C. After 1 hour, the reaction mixture was diluted with MeOH (150 mL) and heated at 50° C. for 3 hours. The solvents were removed under reduced pressure to give a brown oil. The residue was taken up with Et2O (450 mL), and then washed with water (150 mL, pH 8 adjusted with a 5N aqueous solution of NaOH), saturated aqueous solution of NH4Cl (2×150 mL) and brine (150 mL). The aqueous layers were extracted with Et2O (150 mL). The combined organic layers were dried (MgSO4) and the solvent was removed under reduced pressure to give the title compound as a brown yellow oil (13.0 g, 92%) used without further purification in the next step. HPLC (Method A), Rt 2.9 min (Purity: 97.1%). HPLC/MS, M+(ESI): 298.1, 300.1. 1H NMR (CDCl3, 300 MHz) δ 7.59 (d, J=2.5 Hz, 1H), 7.36 (dd, J=8.5, 2.5 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 4.60 (d, J=12.8 Hz, 1H), 4.52 (d, J=12.8 Hz, 1H), 3.44 (s, 3H), 2.96-2.81 (m, 2H), 2.51 (m, 1H), 1.77 (m, 2H), 1.64 (m, 2H), 1.50-1.30 (m, 2H), 0.79 (d, J=6.1 Hz, 3H). heated at 50° C. for 3 hours The solvents were removed under reduced pressure to give a brown oil washed with water (150 mL, pH 8 The aqueous layers were extracted with Et2O (150 mL) The combined organic layers were dried (MgSO4) the solvent was removed under reduced pressure

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium borohydride (2.2 g, 57.8 mmol) was added portion-wise into a solution of 5-bromo-2-(2-methylpiperidin-1-yl)benzaldehyde (16.3 g, 57.8 mmol) in MeOH (300 mL) cooled at 5° C. After 30 min, the reaction mixture was diluted with a saturated aqueous solution of NH4Cl (300 mL) and extracted with EtOAc (600 mL+300 mL). The organic layers were washed with a saturated aqueous solution of NH4Cl (150 mL) and brine (300 mL). The organic layers were combined, dried (MgSO4) and the solvents were removed under reduced pressure to give the title compound as a yellow oil (15.9 g, 97%) used without further purification in the next step. HPLC (Method A), Rt 2.1 min (Purity: 94.9%). HPLC/MS, M+(ESI): 284.1, 286.0. 1H NMR (CDCl3, 300 MHz) δ 7.38 (dd, J=8.5, 2.4 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.40 (brs, 1H), 4.86 (d, J=13.9 Hz, 1H), 4.67 (d, J=13.9 Hz, 1H), 3.06-2.88 (m, 2H), 2.61 (td, J=11.4, 3.2 Hz, 1H), 1.88-1.58 (m, 4H), 1.53-1.32 (m, 2H), 0.90 (d, J=6.2 Hz, 3H). extracted with EtOAc (600 mL+300 mL) The organic layers were washed with a saturated aqueous solution of NH4Cl (150 mL) and brine (300 mL) dried (MgSO4) the solvents were removed under reduced pressure