4-[2-(trifluoromethyl)phenyl]piperidine;hydrochloride

反応条件: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), 4-(2-trifluoromethyl-phenyl)-piperidine hydrochloride (0.266 g, 1 mmol), and cesium carbonate (0.684 g, 2.1 mmol) were dissolved in a mixture of 1,4-dioxane (5 ml) and H2O (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210° C. for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in 5% methanol in CH2Cl2 (20 ml), dried over Na2SO4 and concentrated to get the crude intermediate, 4-chloro-6-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-pyrimidin-2-ylamine (0.42 g) which was directly used in the following step. Solvent was removed the residue was dissolved in 5% methanol in CH2Cl2 (20 ml) dried over Na2SO4 concentrated

反応条件: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), 4-(2-trifluoromethyl-phenyl)-piperidine hydrochloride (0.266 g, 1 mmol), and cesium carbonate (0.684 g, 2.1 mmol) were dissolved in a mixture of 1,4-dioxane (5 ml) and H2O (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210° C. for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in 5% methanol in CH2Cl2 (20 ml), dried over Na2SO4 and concentrated to get the crude intermediate, 4-chloro-6-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-pyrimidin-2-ylamine (0.42 g) which was directly used in the following step. Solvent was removed the residue was dissolved in 5% methanol in CH2Cl2 (20 ml) dried over Na2SO4 concentrated

反応条件: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), 4-(2-trifluoromethyl-phenyl)-piperidine hydrochloride (0.266 g, 1 mmol), and cesium carbonate (0.684 g, 2.1 mmol) were dissolved in a mixture of 1,4-dioxane (5 ml) and H2O (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210° C. for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in 5% methanol in CH2Cl2 (20 ml), dried over Na2SO4 and concentrated to get the crude intermediate, 4-chloro-6-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-pyrimidin-2-ylamine (0.42 g) which was directly used in the following step. Solvent was removed the residue was dissolved in 5% methanol in CH2Cl2 (20 ml) dried over Na2SO4 concentrated

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

実験手順: A solution of methyl 2-isocyanatobenzoate (10.00 g, 56.4 mmol) in tetrahydrofuran (30 ml) was slowly added to a solution of 4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (14.3 g, 53.8 mmol, Sigma) and triethylamine 99% (8.99 ml, 64.5 mmol) in tetrahydrofuran (120 ml) at 0° C. The mixture was removed from the cooling bath and stirred at room temperature for 15 min, at which time LC/MS analysis indicated that the reaction was complete. EtOH (75 ml) and aqueous LiOH (2N, 95 ml) were then added, and the solution was stirred for 6 h at room temperature. Subsequently, aqueous HCl (2N, 150 ml) was added, and the resulting mixture was extracted with EtOAc (2×600 ml). The EtOAc extract was dried over MgSO4 and concentrated to an off-white solid. Recrystallization from EtOAc yielded 14.0 g (66%) of 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxamido) benzoic acid as a white solid, which was homogeneous by analytical high-performance liquid chromatography (>99%). The mixture was removed from the cooling bath EtOH (75 ml) and aqueous LiOH (2N, 95 ml) were then added the solution was stirred for 6 h at room temperature Subsequently, aqueous HCl (2N, 150 ml) was added the resulting mixture was extracted with EtOAc (2×600 ml) The EtOAc extract was dried over MgSO4 concentrated to an off-white solid Recrystallization from EtOAc

反応条件: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), 4-(2-trifluoromethyl-phenyl)-piperidine hydrochloride (0.266 g, 1 mmol), and cesium carbonate (0.684 g, 2.1 mmol) were dissolved in a mixture of 1,4-dioxane (5 ml) and H2O (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210° C. for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in 5% methanol in CH2Cl2 (20 ml), dried over Na2SO4 and concentrated to get the crude intermediate, 4-chloro-6-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-pyrimidin-2-ylamine (0.42 g) which was directly used in the following step. Solvent was removed the residue was dissolved in 5% methanol in CH2Cl2 (20 ml) dried over Na2SO4 concentrated

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

実験手順: The title compound was prepared according to the procedure described in Example 1 (Step f) from 4-[2-(trifluoromethyl)phenyl]piperidine hydrochloride (Step c) (0.792 g, 3.0 mmol), DIEA (0.54 mL, 3.0 mmol), Boc-p-Cl-D-PheOH (PepTech Corporation) (1.36 g, 4.5 mmol), HOAT (Aldrich) (0.615 g, 4.5 mmol) and EDC (Aldrich) (0.864 g, 4.5 mmol) in DMF (5 mL). Purification by silica gel chromatography (5:2 hexane:EtOAc) provided the title compound as a white foam (1.06 g). MS (ESI, pos. ion) m/z: 511 (M+1); MS (ESI, neg. ion) m/z: 509 (M−1). Calc'd for C26H30ClF3N2O3: 510.98. The title compound was prepared Purification by silica gel chromatography (5:2 hexane:EtOAc)

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

実験手順: The title compound was prepared according to the procedure described in Example 1 (Step f) from 4-[2-(trifluoromethyl)phenyl]piperidine hydrochloride (Step c) (0.792 g, 3.0 mmol), DIEA (0.54 mL, 3.0 mmol), Boc-p-Cl-D-PheOH (PepTech Corporation) (1.36 g, 4.5 mmol), HOAT (Aldrich) (0.615 g, 4.5 mmol) and EDC (Aldrich) (0.864 g, 4.5 mmol) in DMF (5 mL). Purification by silica gel chromatography (5:2 hexane:EtOAc) provided the title compound as a white foam (1.06 g). MS (ESI, pos. ion) m/z: 511 (M+1); MS (ESI, neg. ion) m/z: 509 (M−1). Calc'd for C26H30ClF3N2O3: 510.98. The title compound was prepared Purification by silica gel chromatography (5:2 hexane:EtOAc)

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

実験手順: The title compound was prepared according to the procedure described in Example 1 (Step e) from tert-butyl 4-[2-(trifluoromethyl)phenyl]piperidine carboxylate (Step b) (1.64 g, 5 mmol) and satd HCl in EtOAc (50 m[). The title compound was obtained as a white solid (1.32 g). MS (ESI, pos. ion) m/z: 230 (M+1); MS (ESI, neg. ion) m/z: 228 (M−1). Calc'd for C12H15CF3N: 265.70. The title compound was prepared

反応条件: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), 4-(2-trifluoromethyl-phenyl)-piperidine hydrochloride (0.266 g, 1 mmol), and cesium carbonate (0.684 g, 2.1 mmol) were dissolved in a mixture of 1,4-dioxane (5 ml) and H2O (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210° C. for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in 5% methanol in CH2Cl2 (20 ml), dried over Na2SO4 and concentrated to get the crude intermediate, 4-chloro-6-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-pyrimidin-2-ylamine (0.42 g) which was directly used in the following step. Solvent was removed the residue was dissolved in 5% methanol in CH2Cl2 (20 ml) dried over Na2SO4 concentrated

反応条件: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), 4-(2-trifluoromethyl-phenyl)-piperidine hydrochloride (0.266 g, 1 mmol), and cesium carbonate (0.684 g, 2.1 mmol) were dissolved in a mixture of 1,4-dioxane (5 ml) and H2O (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210° C. for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in 5% methanol in CH2Cl2 (20 ml), dried over Na2SO4 and concentrated to get the crude intermediate, 4-chloro-6-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-pyrimidin-2-ylamine (0.42 g) which was directly used in the following step. Solvent was removed the residue was dissolved in 5% methanol in CH2Cl2 (20 ml) dried over Na2SO4 concentrated

反応条件: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), 4-(2-trifluoromethyl-phenyl)-piperidine hydrochloride (0.266 g, 1 mmol), and cesium carbonate (0.684 g, 2.1 mmol) were dissolved in a mixture of 1,4-dioxane (5 ml) and H2O (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210° C. for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in 5% methanol in CH2Cl2 (20 ml), dried over Na2SO4 and concentrated to get the crude intermediate, 4-chloro-6-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-pyrimidin-2-ylamine (0.42 g) which was directly used in the following step. Solvent was removed the residue was dissolved in 5% methanol in CH2Cl2 (20 ml) dried over Na2SO4 concentrated

反応条件: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Amino 4,6-dichloro pyrimidine (0.164 g, 1 mmol), 4-(2-trifluoromethyl-phenyl)-piperidine hydrochloride (0.266 g, 1 mmol), and cesium carbonate (0.684 g, 2.1 mmol) were dissolved in a mixture of 1,4-dioxane (5 ml) and H2O (5 ml) in a 20 ml microwave vial. The mixture was stirred at 210° C. for 20 minutes in a microwave reactor. Solvent was removed and the residue was dissolved in 5% methanol in CH2Cl2 (20 ml), dried over Na2SO4 and concentrated to get the crude intermediate, 4-chloro-6-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-pyrimidin-2-ylamine (0.42 g) which was directly used in the following step. Solvent was removed the residue was dissolved in 5% methanol in CH2Cl2 (20 ml) dried over Na2SO4 concentrated