3,3-二甲基哌啶-4-ol

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: General synthesis of amides: A 10 mL scintillation vial was charged with the 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (164 mg, 0.4 mmol), freshly prepared 3,3-dimethylpiperidin-4-ol (0.56 mmol) ((M+H+), 130.1), HATU (192 mg, 0.5 mmol), DIEA (260 mg, 2 mmol) and anhydrous DMF (1.5 mL). The resultant solution was heated to 70° C. and stirred for 2 h. After cooled to room temperature, the mixture was purified via preparative HPLC and dried (lyophilizer) to afford (S)-4-chloro-N-(5-chloro-2-(4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide (1:2 mixture of rotamers): 1H NMR (400 MHz, CDCl3) (major rotamer) δ 9.54 (s, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.00 (d, 1H), 7.88 (dd, 1H), 7.62 (d, 1H), 4.05 (m, 1H), 3.70 (d, 1H), 3.50 (m, 2H), 3.40 (m, 1H), 3.10 (d, 1H), 1.82 (m, 2H), 1.00 (s, 3H), 0.92 (s, 3H); MS (ES) (M+H)+ expected 526.0, found 526.0. the mixture was purified via preparative HPLC dried (lyophilizer)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1-benzyl-3,3-dimethyl-4-hydroxypiperidine (5.0 g, 22.0 mmole) and 20% palladium hydroxide (1.5 g) in methanol (100 ml) was stirred at 50-55° C. in hydrogen atmosphere (1 atm.) for 20 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,3-dimethyl-4-hydroxypiperidine as oil. Yield 2.9 g (94%), C7H15NO, m/z 130 (M+1), PMR (CDCl3): 0.83 (3H, s, CH3), 1.13 (3H, s, CH3), 1.29 (1H, m, H5), 1.45-1.9 (2H, m, H5& H6), 2.4 (1H, d, H2, j=12 Hz), 2.68 (1H, d, H2, j=12 Hz), 3.08 (1H, m, H6), 3.4 (1H, dd, H4, j=6 Hz & 12 Hz). Catalyst was filtered off washed with methanol, filtrate was concentrated to dryness

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: General synthesis of amides: A 10 mL scintillation vial was charged with the 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (164 mg, 0.4 mmol), freshly prepared 3,3-dimethylpiperidin-4-ol (0.56 mmol) ((M+H+), 130.1), HATU (192 mg, 0.5 mmol), DIEA (260 mg, 2 mmol) and anhydrous DMF (1.5 mL). The resultant solution was heated to 70° C. and stirred for 2 h. After cooled to room temperature, the mixture was purified via preparative HPLC and dried (lyophilizer) to afford (S)-4-chloro-N-(5-chloro-2-(4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide (1:2 mixture of rotamers): 1H NMR (400 MHz, CDCl3) (major rotamer) δ 9.54 (s, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.00 (d, 1H), 7.88 (dd, 1H), 7.62 (d, 1H), 4.05 (m, 1H), 3.70 (d, 1H), 3.50 (m, 2H), 3.40 (m, 1H), 3.10 (d, 1H), 1.82 (m, 2H), 1.00 (s, 3H), 0.92 (s, 3H); MS (ES) (M+H)+ expected 526.0, found 526.0. the mixture was purified via preparative HPLC dried (lyophilizer)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1-benzyl-3,3-dimethyl-4-hydroxypiperidine (5.0 g, 22.0 mmole) and 20% palladium hydroxide (1.5 g) in methanol (100 ml) was stirred at 50-55° C. in hydrogen atmosphere (1 atm.) for 20 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,3-dimethyl-4-hydroxypiperidine as oil. Yield 2.9 g (94%), C7H15NO, m/z 130 (M+1), PMR (CDCl3): 0.83 (3H, s, CH3), 1.13 (3H, s, CH3), 1.29 (1H, m, H5), 1.45-1.9 (2H, m, H5& H6), 2.4 (1H, d, H2, j=12 Hz), 2.68 (1H, d, H2, j=12 Hz), 3.08 (1H, m, H6), 3.4 (1H, dd, H4, j=6 Hz & 12 Hz). Catalyst was filtered off washed with methanol, filtrate was concentrated to dryness

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: General synthesis of amides: A 10 mL scintillation vial was charged with the 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (164 mg, 0.4 mmol), freshly prepared 3,3-dimethylpiperidin-4-ol (0.56 mmol) ((M+H+), 130.1), HATU (192 mg, 0.5 mmol), DIEA (260 mg, 2 mmol) and anhydrous DMF (1.5 mL). The resultant solution was heated to 70° C. and stirred for 2 h. After cooled to room temperature, the mixture was purified via preparative HPLC and dried (lyophilizer) to afford (S)-4-chloro-N-(5-chloro-2-(4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide (1:2 mixture of rotamers): 1H NMR (400 MHz, CDCl3) (major rotamer) δ 9.54 (s, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.00 (d, 1H), 7.88 (dd, 1H), 7.62 (d, 1H), 4.05 (m, 1H), 3.70 (d, 1H), 3.50 (m, 2H), 3.40 (m, 1H), 3.10 (d, 1H), 1.82 (m, 2H), 1.00 (s, 3H), 0.92 (s, 3H); MS (ES) (M+H)+ expected 526.0. found 526.0. the mixture was purified via preparative HPLC dried (lyophilizer)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: General synthesis of amides: A 10 mL scintillation vial was charged with the 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (164 mg, 0.4 mmol), freshly prepared 3,3-dimethylpiperidin-4-ol (0.56 mmol) ((M+H+), 130.1), HATU (192 mg, 0.5 mmol), DIEA (260 mg, 2 mmol) and anhydrous DMF (1.5 mL). The resultant solution was heated to 70° C. and stirred for 2 h. After cooled to room temperature, the mixture was purified via preparative HPLC and dried (lyophilizer) to afford (S)-4-chloro-N-(5-chloro-2-(4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)pyridine-3-yl)-3-(trifluoromethyl) benzenesulfonamide (1:2 mixture of rotamers): 1H NMR (400 MHz, CDCl3) (major rotamer) δ 9.54 (s, 1 H), 8.26 (d, 1 H), 8.12 (d, 1 H), 8.00 (d, 1 H), 7.88 (dd, 1 H), 7.62 (d, 1 H), 4.05 (m, 1 H), 3.70 (d, 1 H), 3.50 (m, 2H), 3.40 (m, 1 H), 3.10 (d, 1 H), 1.82 (m, 2H), 1.00 (s, 3H), 0.92 (s, 3H); MS (ES) (M+H)+ expected 526.0, found 526.0. the mixture was purified via preparative HPLC dried (lyophilizer)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: General synthesis of amides: A 10 mL scintillation vial was charged with the 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (164 mg, 0.4 mmol), freshly prepared 3,3-dimethylpiperidin-4-ol (0.56 mmol) ((M+H+), 130.1), HATU (192 mg, 0.5 mmol), DIEA (260 mg, 2 mmol) and anhydrous DMF (1.5 mL). The resultant solution was heated to 70° C. and stirred for 2 h. After cooled to room temperature, the mixture was purified via preparative HPLC and dried (lyophilizer) to afford (S)-4-chloro-N-(5-chloro-2-(4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide (1:2 mixture of rotamers): 1H NMR (400 MHz, CDCl3) (major rotamer) δ 9.54 (s, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.00 (d, 1H), 7.88 (dd, 1H), 7.62 (d, 1H), 4.05 (m, 1H), 3.70 (d, 1H), 3.50 (m, 2H), 3.40 (m, 1H), 3.10 (d, 1H), 1.82 (m, 2H), 1.00 (s, 3H), 0.92 (s, 3H); MS (ES) (M+H)+ expected 526.0, found 526.0. the mixture was purified via preparative HPLC dried (lyophilizer)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 1-benzyl-3,3-dimethyl-4-hydroxypiperidine (5.0 g, 22.0 mmole) and 20% palladium hydroxide (1.5 g) in methanol (100 ml) was stirred at 50-55° C. in hydrogen atmosphere (1 atm.) for 20 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,3-dimethyl-4-hydroxypiperidine as oil. Yield 2.9 g (94%), C7H15NO, m/z 130 (M+1), PMR (CDCl3): 0.83 (3H, s, CH3), 1.13 (3H, s, CH3), 1.29 (1H, m, H5), 1.45-1.9 (2H, m, H5& H6), 2.4 (1H, d, H2, j=12 Hz), 2.68 (1H, d, H2, j=12 Hz), 3.08 (1H, m, H6), 3.4 (1H, dd, H4, j=6 Hz & 12 Hz). Catalyst was filtered off washed with methanol, filtrate was concentrated to dryness