4-(2-methylsulfonylethyl)piperidine;hydrochloride

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 1-(ethyloxy)-5-fluoro-4-methyl-2-nitrobenzene (Example 215, step A) (13.1 g, 65.9 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine hydrochloride (15.0 g, 65.9 mmol) and K2CO3 (31.9 g, 231 mmol) was added DMSO (300 mL). The reaction mixture was heated at 100° C. overnight. The reaction was cooled to rt and diluted with EtOAc and DCM. The organic layer was washed with H2O and the aqueous layer was backextracted with DCM. The combined organic layers were dried (MgSO4), filtered and rotovapped down. Purification by flash chromatography provided the title compound of Step F (16.2 g, 43.6 mmol, 66% yield). This reaction was carried out in duplicate to provide an overall amount of 33.2 g, 89.4 mmol of the title compound of Step F. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 6.56-6.73 (m, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.30 (d, J=12.2 Hz, 2H), 3.04-3.15 (m, 2H), 2.95 (s, 3H), 2.74 (t, J=11.5 Hz, 2H), 2.26 (s, 3H), 1.81-1.97 (m, 4H), 1.42-1.74 (m, 6H). The reaction was cooled to rt The organic layer was washed with H2O The combined organic layers were dried (MgSO4) filtered Purification by flash chromatography

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

実験手順: To 1,1-dimethylethyl 4-[2-(methylsulfonyl)ethyl]-1-piperidinecarboxylate (240 g, 824 mmol) in MeOH at 0° C. was added saturated HCl in MeOH slowly. The suspension was stirred at rt overnight. The mixture was washed with MeOH then dried by vacuum to provide the title compound of Step E (135 g, 593 mmol, 72%). 1H NMR (400 MHz, DMSO-d6) δ 1.25-1.40 (m, 2H), 1.52-1.65 (m, 3H), 1.70-1.80 (m, 2H), 2.68-2.83 (m, 2H), 2.79 (s, 3H), 3.07-3.20 (m, 4H). The mixture was washed with MeOH then dried by vacuum

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 1-(ethyloxy)-5-fluoro-4-methyl-2-nitrobenzene (Example 215, step A) (13.1 g, 65.9 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine hydrochloride (15.0 g, 65.9 mmol) and K2CO3 (31.9 g, 231 mmol) was added DMSO (300 mL). The reaction mixture was heated at 100° C. overnight. The reaction was cooled to rt and diluted with EtOAc and DCM. The organic layer was washed with H2O and the aqueous layer was backextracted with DCM. The combined organic layers were dried (MgSO4), filtered and rotovapped down. Purification by flash chromatography provided the title compound of Step F (16.2 g, 43.6 mmol, 66% yield). This reaction was carried out in duplicate to provide an overall amount of 33.2 g, 89.4 mmol of the title compound of Step F. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 6.56-6.73 (m, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.30 (d, J=12.2 Hz, 2H), 3.04-3.15 (m, 2H), 2.95 (s, 3H), 2.74 (t, J=11.5 Hz, 2H), 2.26 (s, 3H), 1.81-1.97 (m, 4H), 1.42-1.74 (m, 6H). The reaction was cooled to rt The organic layer was washed with H2O The combined organic layers were dried (MgSO4) filtered Purification by flash chromatography

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

実験手順: To 1,1-dimethylethyl 4-[2-(methylsulfonyl)ethyl]-1-piperidinecarboxylate (240 g, 824 mmol) in MeOH at 0° C. was added saturated HCl in MeOH slowly. The suspension was stirred at rt overnight. The mixture was washed with MeOH then dried by vacuum to provide the title compound of Step E (135 g, 593 mmol, 72%). 1H NMR (400 MHz, DMSO-d6) δ 1.25-1.40 (m, 2H), 1.52-1.65 (m, 3H), 1.70-1.80 (m, 2H), 2.68-2.83 (m, 2H), 2.79 (s, 3H), 3.07-3.20 (m, 4H). The mixture was washed with MeOH then dried by vacuum

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

実験手順: To 1,1-dimethylethyl 4-[2-(methylsulfonyl)ethyl]-1-piperidinecarboxylate (240 g, 824 mmol) in MeOH at 0° C. was added saturated HCl in MeOH slowly. The suspension was stirred at rt overnight. The mixture was washed with MeOH then dried by vacuum to provide the title compound of Step E (135 g, 593 mmol, 72%). 1H NMR (400 MHz, DMSO-d6) δ 1.25-1.40 (m, 2H), 1.52-1.65 (m, 3H), 1.70-1.80 (m, 2H), 2.68-2.83 (m, 2H), 2.79 (s, 3H), 3.07-3.20 (m, 4H). The mixture was washed with MeOH then dried by vacuum

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

実験手順: In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-(2-methanesulfonyl-ethyl)-piperidine hydrochloride to give the title compound. HR-MS (ES, m/z) calculated for C37H47N4O4SCl2 [(M+H)+] 713.2690, observed 713.2689.

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 1-(ethyloxy)-5-fluoro-4-methyl-2-nitrobenzene (Example 215, step A) (13.1 g, 65.9 mmol), 4-[2-(methylsulfonyl)ethyl]piperidine hydrochloride (15.0 g, 65.9 mmol) and K2CO3 (31.9 g, 231 mmol) was added DMSO (300 mL). The reaction mixture was heated at 100° C. overnight. The reaction was cooled to rt and diluted with EtOAc and DCM. The organic layer was washed with H2O and the aqueous layer was backextracted with DCM. The combined organic layers were dried (MgSO4), filtered and rotovapped down. Purification by flash chromatography provided the title compound of Step F (16.2 g, 43.6 mmol, 66% yield). This reaction was carried out in duplicate to provide an overall amount of 33.2 g, 89.4 mmol of the title compound of Step F. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 6.56-6.73 (m, 1H), 4.16 (q, J=7.0 Hz, 2H), 3.30 (d, J=12.2 Hz, 2H), 3.04-3.15 (m, 2H), 2.95 (s, 3H), 2.74 (t, J=11.5 Hz, 2H), 2.26 (s, 3H), 1.81-1.97 (m, 4H), 1.42-1.74 (m, 6H). The reaction was cooled to rt The organic layer was washed with H2O The combined organic layers were dried (MgSO4) filtered Purification by flash chromatography

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

実験手順: To 1,1-dimethylethyl 4-[2-(methylsulfonyl)ethyl]-1-piperidinecarboxylate (240 g, 824 mmol) in MeOH at 0° C. was added saturated HCl in MeOH slowly. The suspension was stirred at rt overnight. The mixture was washed with MeOH then dried by vacuum to provide the title compound of Step E (135 g, 593 mmol, 72%). 1H NMR (400 MHz, DMSO-d6) δ 1.25-1.40 (m, 2H), 1.52-1.65 (m, 3H), 1.70-1.80 (m, 2H), 2.68-2.83 (m, 2H), 2.79 (s, 3H), 3.07-3.20 (m, 4H). The mixture was washed with MeOH then dried by vacuum