N,2,2,6,6-pentamethylpiperidin-4-amine

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 3,6-dichloropyridazine (4 g, 26.8 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (7.32 g, 43.0 mmol) in a 300 mL round bottom flask was added butan-1-ol (67 mL) to give a colorless solution. The mixture was heated to 120° C. for 72 h. Butan-1-ol was removed using a rotary evaporator. The residue was partitioned between water and DCM, and the water layer was further extracted with DCM. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated in vacuo. The black crude material was stirred in small amount of EtOAc overnight, and the resulting off-white solid was collected to provide 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-1 (4.18 g, 14.78 mmol, 55.0% yield). LCMS Rt=0.8 min (condition B), MS (M+1)=283.5. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.40 (d, J=9.60 Hz, 1H), 7.14 (d, J=9.60 Hz, 1H), 4.96-5.13 (m, 1H), 2.93 (s, 3H), 1.59-1.68 (m, 2H), 1.51 (t, J=12.38 Hz, 2H), 1.20 (s, 6H), 1.33 (s, 6H). to give a colorless solution Butan-1-ol was removed a rotary evaporator The residue was partitioned between water and DCM the water layer was further extracted with DCM The combined organic layers were washed with water and brine dried over MgSO4 concentrated in vacuo the resulting off-white solid was collected

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 3,6-dichloropyridazine (4 g, 26.8 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (7.32 g, 43.0 mmol) in a 300 mL round bottom flask was added butan-1-ol (67 mL) to give a colorless solution. The mixture was heated to 120° C. for 72 h. Butan-1-ol was removed using a rotary evaporator. The residue was partitioned between water and DCM, and the water layer was further extracted with DCM. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated in vacuo. The black crude material was stirred in small amount of EtOAc overnight, and the resulting off-white solid was collected to provide 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-1 (4.18 g, 14.78 mmol, 55.0% yield). LCMS Rt=0.8 min (condition B), MS (M+1)=283.5. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.40 (d, J=9.60 Hz, 1H), 7.14 (d, J=9.60 Hz, 1H), 4.96-5.13 (m, 1H), 2.93 (s, 3H), 1.59-1.68 (m, 2H), 1.51 (t, J=12.38 Hz, 2H), 1.20 (s, 6H), 1.33 (s, 6H). to give a colorless solution Butan-1-ol was removed a rotary evaporator The residue was partitioned between water and DCM the water layer was further extracted with DCM The combined organic layers were washed with water and brine dried over MgSO4 concentrated in vacuo the resulting off-white solid was collected

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

実験手順: A stirred solution of 2-bromo-5-(2-fluoro-6-methoxyphenyl)-1,3,4-thiadiazole (335 mg, 1.159 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (197 mg, 1.159 mmol) in NMP (2.5 mL) was heated at 120° C. for ˜18 hours. The reaction mixture was diluted with saturated NaHCO3(aq) (30 mL), water (20 mL), and extracted with DCM (75 mL). The organic phase was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the crude product as a brown oil/liquid. The crude material was purified by UV directed preparative HPLC under acidic conditions (0.1% TFA), collecting at 298 nm. The product containing fractions were combined and loaded onto a 5 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (30 mL) then flushed with 7M NH3 in MeOH (20 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as an orange oil (121 mg, 28% yield). LC-MS: Rt 0.88 min; MS m/z 379.4 [M+H]+; [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (td, J=8.34, 6.57 Hz, 1H), 7.03 (d, J=8.59 Hz, 1H), 6.97 (t, J=9.09 Hz, 1H), 4.26-4.36 (m, 1H), 3.86 (s, 3H), 2.98 (s, 3H), 1.62 (dd, J=11.62, 2.53 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.27 (br. s., 1H), 1.20 (s, 6H), 1.09 (s, 6H). extracted with DCM (75 mL) The organic phase was separated dried over MgSO4 filtered The filtrate was concentrated in vacuo to afford the crude product as a brown oil/liquid The crude material was purified by UV collecting at 298 nm The product containing fractions The cartridge was washed with MeOH (30 mL) then flushed with 7M NH3 in MeOH (20 mL) The MeOH/NH3 was removed in vacuo

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

実験手順: A stirred solution of 2-bromo-5-(2-fluoro-6-methoxyphenyl)-1,3,4-thiadiazole (335 mg, 1.159 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (197 mg, 1.159 mmol) in NMP (2.5 mL) was heated at 120° C. for ˜18 hours. The reaction mixture was diluted with saturated NaHCO3(aq) (30 mL), water (20 mL), and extracted with DCM (75 mL). The organic phase was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the crude product as a brown oil/liquid. The crude material was purified by UV directed preparative HPLC under acidic conditions (0.1% TFA), collecting at 298 nm. The product containing fractions were combined and loaded onto a 5 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (30 mL) then flushed with 7M NH3 in MeOH (20 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as an orange oil (121 mg, 28% yield). LC-MS: Rt 0.88 min; MS m/z 379.4 [M+H]+; [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (td, J=8.34, 6.57 Hz, 1H), 7.03 (d, J=8.59 Hz, 1H), 6.97 (t, J=9.09 Hz, 1H), 4.26-4.36 (m, 1H), 3.86 (s, 3H), 2.98 (s, 3H), 1.62 (dd, J=11.62, 2.53 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.27 (br. s., 1H), 1.20 (s, 6H), 1.09 (s, 6H). extracted with DCM (75 mL) The organic phase was separated dried over MgSO4 filtered The filtrate was concentrated in vacuo to afford the crude product as a brown oil/liquid The crude material was purified by UV collecting at 298 nm The product containing fractions The cartridge was washed with MeOH (30 mL) then flushed with 7M NH3 in MeOH (20 mL) The MeOH/NH3 was removed in vacuo

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of 2,5-dibromo-1,3,4-thiadiazole (2.975 g, 12.2 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (2.493 g, 14.64 mmol) in dioxane (40 mL) was added DIPEA (10.65 mL, 61 mmol) and the resulting mixture refluxed at 120° C. for 16 hours. The reaction mixture was cooled to room temperature then filtered under vacuum, rinsed with dioxane, and the filtrate concentrated in vacuo to afford the crude product as a pink/red oil. The crude material was purified by flash chromatography using 3% [7M NH3 in MeOH]/DCM as the eluent to afford the title compound as a pink/red solid (2.924 g, 72% yield). LC-MS: Rt 0.70 min; MS m/z 335.2 [M+2H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.13-4.03 (m, 1H), 2.92 (s, 3H), 1.57 (dd, J=12.13, 3.54 Hz, 2H), 1.39 (t, J=12.13 Hz, 2H), 1.26 (br. s., 1H), 1.16 (s, 6H), 1.06 (s, 6H). LC-MS: Rt 1.12 min; MS m/z 335.2 [M+H]+ [Method B]. The reaction mixture was cooled to room temperature then filtered under vacuum rinsed with dioxane the filtrate concentrated in vacuo to afford the crude product as a pink/red oil The crude material was purified by flash chromatography

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

実験手順: 18.4 g of cyanuric chloride and 34.0 g of 2,2,6,6-tetramethyl-4-(methylamino)piperidine were dissolved in 250 ml of xylene, and the solution was stirred at a temperature of 90°-110° C. for 3 hours. 30 ml of a saturated aqueous solution of potassium carbonate were then added and the resulting mixture was heated under reflux for 5 hours. At the end of this time, the reaction mixture was poured into water and extracted with benzene. The extract was dried over anhydrous potassium carbonate and then the benzene was distilled off. The residue was recrystallized from ethyl acetate, giving the title compound in the form of crystals melting at 179°-180° C. the resulting mixture was heated under reflux for 5 hours extracted with benzene The extract was dried over anhydrous potassium carbonate the benzene was distilled off The residue was recrystallized from ethyl acetate

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

実験手順: 3.58 g (0.03 mol) chloroform; 14.42 g (0.20 mol) 2-butanone; and, 4.0 g (0.1 mol) 4-methylamino-2,2,6,6-tetramethylpiperidine are reacted in a manner analogous to that described in Example 1 hereinabove and the product worked up and recovered. The structure of the compound obtained is represented as follows: ##STR5## wherein n is in the range from 2 to about 5. recovered The structure of the compound obtained

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

実験手順: 3.58 g (0.03 mol) chloroform; 14.42 g (0.20 mol) 2-butanone; and, 4.0 g (0.1 mol) 4-methylamino-2,2,6,6-tetramethylpiperidine are reacted in a manner analogous to that described in Example 1 hereinabove and the product worked up and recovered. The structure of the compound obtained is represented as follows: ##STR5## wherein n is in the range from 2 to about 5. recovered The structure of the compound obtained

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

実験手順: A mixture of 2.2 g of 4-[N-(2,3-epoxypropyl)-N-methylamino]-2,2,6,6-tetramethylpiperidine and 1.7 g of 4-methylamino-2,2,6,6-tetramethylpiperidine in 20 ml of benzene was refluxed, with stirring, for 3 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure and then the resulting residue was distilled in vacuo, giving the desired compound in the form of a colourless, viscous oil boiling at 194°-196° C. at 0.2 mmHg. was refluxed At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure the resulting residue was distilled in vacuo

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

実験手順: To 50 ml of methanol were added 3.4 g of 2,2,6,6-tetramethyl-4-methylaminopiperidine and 3.4 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane; the mixture was then reacted in a manner similar to that described in Example 1, giving the desired compound in the form of a white powder. The compound had an Rf value of 0.50 on thin layer chromatography on silica gel developed with a 1:3:1 by volume mixture of methanol, ethyl acetate and triethylamine. the mixture was then reacted in a manner similar to

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 3,6-dichloropyridazine (4 g, 26.8 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (7.32 g, 43.0 mmol) in a 300 mL round bottom flask was added butan-1-ol (67 mL) to give a colorless solution. The mixture was heated to 120° C. for 72 h. Butan-1-ol was removed using a rotary evaporator. The residue was partitioned between water and DCM, and the water layer was further extracted with DCM. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated in vacuo. The black crude material was stirred in small amount of EtOAc overnight, and the resulting off-white solid was collected to provide 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine, Intermediate 1-1 (4.18 g, 14.78 mmol, 55.0% yield). LCMS Rt=0.8 min (condition B), MS (M+1)=283.5. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.40 (d, J=9.60 Hz, 1H), 7.14 (d, J=9.60 Hz, 1H), 4.96-5.13 (m, 1H), 2.93 (s, 3H), 1.59-1.68 (m, 2H), 1.51 (t, J=12.38 Hz, 2H), 1.20 (s, 6H), 1.33 (s, 6H). to give a colorless solution Butan-1-ol was removed a rotary evaporator The residue was partitioned between water and DCM the water layer was further extracted with DCM The combined organic layers were washed with water and brine dried over MgSO4 concentrated in vacuo the resulting off-white solid was collected

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

実験手順: A stirred solution of 2-bromo-5-(2-fluoro-6-methoxyphenyl)-1,3,4-thiadiazole (335 mg, 1.159 mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (197 mg, 1.159 mmol) in NMP (2.5 mL) was heated at 120° C. for ˜18 hours. The reaction mixture was diluted with saturated NaHCO3(aq) (30 mL), water (20 mL), and extracted with DCM (75 mL). The organic phase was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to afford the crude product as a brown oil/liquid. The crude material was purified by UV directed preparative HPLC under acidic conditions (0.1% TFA), collecting at 298 nm. The product containing fractions were combined and loaded onto a 5 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (30 mL) then flushed with 7M NH3 in MeOH (20 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as an orange oil (121 mg, 28% yield). LC-MS: Rt 0.88 min; MS m/z 379.4 [M+H]+; [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49 (td, J=8.34, 6.57 Hz, 1H), 7.03 (d, J=8.59 Hz, 1H), 6.97 (t, J=9.09 Hz, 1H), 4.26-4.36 (m, 1H), 3.86 (s, 3H), 2.98 (s, 3H), 1.62 (dd, J=11.62, 2.53 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.27 (br. s., 1H), 1.20 (s, 6H), 1.09 (s, 6H). extracted with DCM (75 mL) The organic phase was separated dried over MgSO4 filtered The filtrate was concentrated in vacuo to afford the crude product as a brown oil/liquid The crude material was purified by UV collecting at 298 nm The product containing fractions The cartridge was washed with MeOH (30 mL) then flushed with 7M NH3 in MeOH (20 mL) The MeOH/NH3 was removed in vacuo