1-isocyanato-2-methoxyethane

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: 70 mg (0.19 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 2.5 ml of THF, and 19 mg (0.19 mmol) of 1-isocyanato-2-methoxyethane and 29 μl (0.21 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 32 mg (35% of theory) The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient)

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

実験手順: 70 mg (0.19 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 2.5 ml of THF, and 19 mg (0.19 mmol) of 1-isocyanato-2-methoxyethane and 29 μl (0.21 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 32 mg (35% of theory) The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient)

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

実験手順: To a solution of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (42.8 mg, 0.070 mmol) and triethylamine (0.029 mL, 0.211 mmol) in DCM (0.75 mL) was added 1-isocyanato-2-methoxyethane (11.0 μL, 0.105 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (26.3 mg, 60.5%) as a hygroscopic, yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (d, J=6.3 Hz, 6H), 1.83-1.93 (m, 2H), 2.02-2.11 (m, 2H), 2.61 (t, J=5.6 Hz, 2H), 2.82-2.93 (m, 2H), 3.14-3.21 (m, 2H), 3.23 (s, 3H), 3.24-3.31 (m, 2H), 3.31-3.37 (m, 2H), 3.60 (t, J=5.8 Hz, 2H), 4.08-4.17 (m, 1H), 4.29 (s, 2H), 4.49-4.56 (m, 1H), 5.61-5.70 (m, 1H), 6.66-6.73 (m, 1H), 6.99-7.05 (m, 1H), 7.26-7.34 (m, 2H); ESI-MS m/z [M+H]+ 505.0. concentrated via rotary evaporation The crude material was diluted with DMSO filtered rinsed with DMSO purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm

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

実験手順: To a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (39.0 mg, 0.075 mmol) in DCM (754 μL) at 0° C. was added triethylamine (31.5 μL, 0.226 mmol) and 1-isocyanato-2-methoxyethane (11.8 μL, 0.113 mmol). The reaction mixture was stirred for 1 h at 0° C. The reaction mixture was concentrated under reduced pressure and purified by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 45% to 70% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (24.5 mg, 52.6%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.32 (d, J=6.6 Hz, 6H), 1.97 (m, 2H), 2.14 (m, 2H), 2.77 (t, J=5.8 Hz, 2H), 3.12 (m, 2H), 3.37 (m, 5H), 3.46 (m, 4H), 3.71 (t, J=5.8 Hz, 2H), 4.13 (m, 1H), 4.50 (m, 3H), 6.88 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 505.6. The reaction mixture was concentrated under reduced pressure purified by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column

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

実験手順: At 50° C., 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide were substantially suspended in 30 ml of dry THF. 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane dissolved in 30 ml of THF were then added dropwise. The mixture was stirred at 50° C. for 2.5 h. After cooling to RT, the solvent was removed on a rotary evaporator and the residue was triturated with diethyl ether. The crystals were filtered off with suction, washed with diethyl ether and dried under high vacuum. This gave 4.87 g (100% of theory) of the title compound. At 50° C. were then added dropwise After cooling to RT the solvent was removed on a rotary evaporator the residue was triturated with diethyl ether The crystals were filtered off with suction washed with diethyl ether dried under high vacuum

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

実験手順: At 50° C., 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide were finely suspended in 30 ml of dry THF. 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane dissolved in 30 ml of THF were then added dropwise. The mixture was stirred at 50° C. for 2.5 h. After cooling to RT, the solvent was removed on a rotary evaporator, and diethyl ether was added to the residue. The crystals were filtered off with suction, washed with diethyl ether and dried under high vacuum. This gave 4.87 g (100% of theory) of the title compound. At 50° C. were then added dropwise After cooling to RT the solvent was removed on a rotary evaporator, and diethyl ether was added to the residue The crystals were filtered off with suction washed with diethyl ether dried under high vacuum

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

実験手順: A quantity of 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide was suspended largely finely in 30 ml of dry THF at 50° C. Then 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane in solution in 30 ml of THF were added dropwise. The mixture was stirred at 50° C. for 2.5 h. After cooling to RT, the solvent was removed on a rotary evaporator and the residue was admixed with diethyl ether. The crystals were filtered off with suction, washed with diethyl ether and dried in an HV. This gave 4.87 g (100% of theory) of the title compound. After cooling to RT the solvent was removed on a rotary evaporator The crystals were filtered off with suction washed with diethyl ether dried in an HV

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

実験手順: A quantity of 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide was suspended largely finely in 30 ml of dry THF at 50° C. Then 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane in solution in 30 ml of THF were added dropwise. The mixture was stirred at 50° C. for 2.5 h. After cooling to RT, the solvent was removed on a rotary evaporator and the residue was admixed with diethyl ether. The crystals were filtered off with suction, washed with diethyl ether and dried in an HV. This gave 4.87 g (100% of theory) of the title compound. After cooling to RT the solvent was removed on a rotary evaporator The crystals were filtered off with suction washed with diethyl ether dried in an HV

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

実験手順: A quantity of 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide was suspended largely finely in 30 ml of dry THF at 50° C. Then 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane in solution in 30 ml of THF were added dropwise. The mixture was stirred at 50° C. for 2.5 h. After cooling to RT, the solvent was removed on a rotary evaporator and the residue was admixed with diethyl ether. The crystals were filtered off with suction, washed with diethyl ether and dried in an HV. This gave 4.87 g (100% of theory) of the title compound. After cooling to RT the solvent was removed on a rotary evaporator The crystals were filtered off with suction washed with diethyl ether dried in an HV

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

実験手順: A quantity of 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide was suspended largely finely in 30 ml of dry THF at 50° C. Then 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane in solution in 30 ml of THF were added dropwise. The mixture was stirred at 50° C. for 2.5 h. After cooling to RT, the solvent was removed on a rotary evaporator and the residue was admixed with diethyl ether. The crystals were filtered off with suction, washed with diethyl ether and dried in an HV. This gave 4.87 g (100% of theory) of the title compound. After cooling to RT the solvent was removed on a rotary evaporator The crystals were filtered off with suction washed with diethyl ether dried in an HV

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

実験手順: A quantity of 3.1 g (17.55 mmol) of 5-chlorothiophene-2-carbohydrazide was suspended largely finely in 30 ml of dry THF at 50° C. Then 1.81 g (17.90 mmol) of 1-isocyanato-2-methoxyethane in solution in 30 ml of THF were added dropwise. The mixture was stirred at 50° C. for 2.5 h. After cooling to RT, the solvent was removed on a rotary evaporator and the residue was admixed with diethyl ether. The crystals were filtered off with suction, washed with diethyl ether and dried in an HV. This gave 4.87 g (100% of theory) of the title compound. After cooling to RT the solvent was removed on a rotary evaporator The crystals were filtered off with suction washed with diethyl ether dried in an HV