1-[4-bromo-2-(methoxymethyl)phenyl]-2-methylpiperidine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To anhydrous Et2O (130 mL) at −78° C. was added tert-butyllithium (63.79 mL; 1.50 M; 95.68 mmol) (solution in pentane) which was followed by the slow addition of a solution of 1-[4-bromo-2-(methoxymethyl)phenyl]-2-methylpiperidine obtained in step 3 (12.97 g; 43.49 mmol) in anhydrous Et2O (20 mL). After 40 min, the reaction mixture was poured on an excess of freshly crushed dry ice and stirred for 30 min after which time it was diluted with Et2O/EtOAc (1:1), water (pH 4-5). The organic layers were combined, dried over MgSO4 and the solvents were removed under reduced pressure to give a yellow oil that was triturated in iPr2O and pentane, filtered off and washed with pentane to give the title compound as a beige powder. 1H NMR (CDCl3, 300 MHz) δ 8.22 (d, J=2.1 Hz, 1H), 8.00 (dd, J=8.3, 2.1 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.60 (d, J=12.3 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 3.46 (s, 3H), 3.17 (m, 1H), 3.02 (m, 1H), 2.63 (m, 1H), 1.88-1.65 (m, 4H), 1.55-1.40 (m, 2H), 0.88 (d, J=6.2 Hz, 3H). LC/MS (Method B): 264.1 (M+H)+. dried over MgSO4 the solvents were removed under reduced pressure to give a yellow oil that was triturated in iPr2O pentane, filtered off washed with pentane

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To anhydrous Et2O (130 mL) at −78° C. was added tert-butyllithium (63.79 mL; 1.50 M; 95.68 mmol) (solution in pentane) which was followed by the slow addition of a solution of 1-[4-bromo-2-(methoxymethyl)phenyl]-2-methylpiperidine obtained in step 3 (12.97 g; 43.49 mmol) in anhydrous Et2O (20 mL). After 40 min, the reaction mixture was poured on an excess of freshly crushed dry ice and stirred for 30 min after which time it was diluted with Et2O/EtOAc (1:1), water (pH 4-5). The organic layers were combined, dried over MgSO4 and the solvents were removed under reduced pressure to give a yellow oil that was triturated in iPr2O and pentane, filtered off and washed with pentane to give the title compound as a beige powder. 1H NMR (CDCl3, 300 MHz) δ 8.22 (d, J=2.1 Hz, 1H), 8.00 (dd, J=8.3, 2.1 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.60 (d, J=12.3 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 3.46 (s, 3H), 3.17 (m, 1H), 3.02 (m, 1H), 2.63 (m, 1H), 1.88-1.65 (m, 4H), 1.55-1.40 (m, 2H), 0.88 (d, J=6.2 Hz, 3H). LC/MS (Method B): 264.1 (M+H)+. dried over MgSO4 the solvents were removed under reduced pressure to give a yellow oil that was triturated in iPr2O pentane, filtered off washed with pentane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To anhydrous Et2O (130 mL) at −78° C. was added tert-butyllithium (63.79 mL; 1.50 M; 95.68 mmol) (solution in pentane) which was followed by the slow addition of a solution of 1-[4-bromo-2-(methoxymethyl)phenyl]-2-methylpiperidine (12.97 g; 43.49 mmol) in anhydrous Et2O (20 mL). After 40 min, the reaction mixture was poured on an excess of freshly crushed dry ice and stirred for 30 min after which time it was diluted with Et2O/EtOAc (1:1, 800 mL), water (200 mL, pH 4-5). The organic layers were combined, dried over MgSO4 and the solvents were removed under reduced pressure to give a yellow oil that was triturated in iPr2O (˜20 mL) and pentane (˜20 mL), filtered off and washed with pentane to give the title compound as a beige powder. LC/MS (Method B): 264.1 (M+H)+. dried over MgSO4 the solvents were removed under reduced pressure to give a yellow oil that was triturated in iPr2O (˜20 mL) pentane (˜20 mL), filtered off washed with pentane

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To anhydrous Et2O (130 mL) at −78° C. was added tert-butyllithium (63.79 mL; 1.50 M; 95.68 mmol) (solution in pentane) which was followed by the slow addition of a solution of 1-[4-bromo-2-(methoxymethyl)phenyl]-2-methylpiperidine (12.97 g; 43.49 mmol) in anhydrous Et2O (20 mL). After 40 min, the reaction mixture was poured on an excess of freshly crushed dry ice and stirred for 30 min after which time it was diluted with Et2O/EtOAc (1:1, 800 mL), water (200 mL, pH 4-5). The organic layers were combined, dried over MgSO4 and the solvents were removed under reduced pressure to give a yellow oil that was triturated in iPr2O (˜20 mL) and pentane (˜20 mL), filtered off and washed with pentane to give the title compound as a beige powder. LC/MS (Method B): 264.1 (M+H)+. dried over MgSO4 the solvents were removed under reduced pressure to give a yellow oil that was triturated in iPr2O (˜20 mL) pentane (˜20 mL), filtered off washed with pentane

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1.5M solution of tert-butyllithium in pentane (64 mL, 95 mmol) was added into anhydrous Et2O (130 mL) cooled at −78° C. A solution of 1-[4-bromo-2-(methoxymethyl)phenyl]-2-methylpiperidine (13.0 g, 43.5 mmol) in anhydrous Et2O (20 mL) was added slowly. After 40 minutes, the reaction mixture was poured on an excess of freshly crushed dry ice and stirred for 30 min. The mixture was diluted with Et2O/EtOAc (1:1, 800 mL) and washed with water (200 mL, pH=4-5 adjusted with a 5N aqueous solution of HCl). The aqueous layer was extracted with EtOAc (400 mL). The organic layers were combined, dried (MgSO4) and the solvents were removed under reduced pressure to give a yellow oil, which was triturated in iPr2O (˜20 mL) and pentane (˜20 mL). The precipitate was filtered off, washed with pentane and dried under reduced pressure to give the title compound as a beige powder. HPLC (Method A), Rt: 1.6 min (purity: 93.5%). HPLC/MS, M+(ESI): 264.2, M−(ESI): 262.2. 1H NMR (CDCl3, 300 MHz) δ 8.22 (d, J=2.1 Hz, 1H), 8.00 (dd, J=8.3, 2.1 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.60 (d, J=12.3 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 3.46 (s, 3H), 3.17 (m, 1H), 3.02 (m, 1H), 2.63 (m, 1H), 1.88-1.65 (m, 4H), 1.55-1.40 (m, 2H), 0.88 (d, J=6.2 Hz, 3H). washed with water (200 mL, pH=4-5 The aqueous layer was extracted with EtOAc (400 mL) dried (MgSO4) the solvents were removed under reduced pressure to give a yellow oil, which was triturated in iPr2O (˜20 mL) The precipitate was filtered off washed with pentane dried under reduced pressure

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 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