(3S)-3-methylmorpholine

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

実験手順: An ethanol (5 ml) solution of 2,6-dichloro-9H-purine (187 mg, 0.99 mmol), (S)-3-methyl-morpholine (100 mg, 0.99 mmol), and N,N-diisopropylethylamine (252 μl, 1.48 mmol) was heated to reflux for 15 hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (methylene chloride:methanol=98:2 to 97:3) to give the title compound (132 mg, 53%) as a solid. to reflux for 15 hours was returned to room temperature concentrated under reduced pressure The residue was purified by flash silica gel column chromatography (methylene chloride:methanol=98:2 to 97:3)

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

実験手順: To a solution of (S)-3-methylmorpholine (1.5 g, 15.0 mmol) in ethanol (20 mL) was added EDCI (3.33 g, 17.4 mmol), HOBt (2.35 g, 17.4 mmol), and 6-aminonicotinic acid (2.07 g, 15.0 mmol) at room temperature. After stirring for 18 h, the resulting suspension was filtered. The solid was purified by silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to straight ethyl acetate to afford 136a (1.0 g, 30%) as a white solid. MS-ESI: 222.3 (M+H)+. the resulting suspension was filtered The solid was purified by silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to straight ethyl acetate

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

実験手順: Reductive Amination Method B: 6-Bromopyridine-2-carbaldehyde (1.3 g, 7.0 mmol) was added to a 200 ml, round bottom under argon. Dichloroethane (28.0 ml) was added followed by (3S)-3-methylmorpholine (HCl salt) (1 g, 7.3 mmol) and triethylamine (1.0 ml, 7.3 mmol). The mixture was stirred for 0.5 hours at room temperature followed by the addition of sodium triacetoxyborohydride (2.07 g, 9.8 mmol) and the resulting slurry was maintained at room temperature overnight. The reaction was quenched by the careful addition of saturated aqueous sodium bicarbonate and was extracted once with DCM and once with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oily residue was purified via flash chromatography (silica, 0-10% methanol/ethyl acetate) to afford the title compound as a colorless oil. the resulting slurry was maintained at room temperature overnight The reaction was quenched by the careful addition of saturated aqueous sodium bicarbonate was extracted once with DCM and once with ethyl acetate The combined organics were dried over magnesium sulfate filtered concentrated in vacuo The resulting oily residue was purified via flash chromatography (silica, 0-10% methanol/ethyl acetate)

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

実験手順: To a solution of (S)-3-methylmorpholine (1.5 g, 15.0 mmol) in ethanol (20 mL) was added EDCI (3.33 g, 17.4 mmol), HOBt (2.35 g, 17.4 mmol), and 6-aminonicotinic acid (2.07 g, 15.0 mmol) at room temperature. After stirring for 18 h, the resulting suspension was filtered. The solid was purified by silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to straight ethyl acetate to afford 256a (1.0 g, 30%) as white solid. MS-ESI: 222.3 (M+H)+. the resulting suspension was filtered The solid was purified by silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to straight ethyl acetate

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

実験手順: To a solution of (S)-3-methylmorpholine (1.5 g, 15.0 mmol) in ethanol (20 mL) was added EDCI (3.33 g, 17.4 mmol), HOBt (2.35 g, 17.4 mmol), and 6-aminonicotinic acid (2.07 g, 15.0 mmol) at room temperature. After stirring for 18 h, the resulting suspension was filtered. The solid was purified by silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to straight ethyl acetate to afford 256a (1.0 g, 30%) as white solid. MS-ESI: 222.3 (M+H)+. the resulting suspension was filtered The solid was purified by silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to straight ethyl acetate

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

実験手順: 4-chloro-2-(methyloxy)-1-nitrobenzene (6.71 g, 29.7 mmol), (3S)-3-methylmorpholine (Synthetech Inc., 2.0 g, 19.8 mmol), cesium carbonate (13.0 g, 40 mmol), Pd2dba3 (1.83 g, 2.0 mmol), and XANTPHOS (1.73 g, 3.0 mmol) were added to degassed dioxane (200 mL) and heated to 100° C. under a water cooled reflux condenser for 12 hours. The dioxane was removed under reduced pressure and the solids were partitioned between methylene chloride (500 mL) and water (500 mL). The organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and purified by chromatography on SiO2to give 4-[(3S)-3-methyl-4-morpholinyl]-2-(methyloxy)aniline as a yellow solid (2.46 g, 8.45 mmol, 43% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (dd, J=6.41, 4.58 Hz, 3 H), 3.22-3.29 (m, J=12.11, 8.03, 4.03, 4.03 Hz, 1 H), 3.31-3.37 (m, 1 H), 3.59-3.69 (m, 1 H), 3.78 (d, J=2.93 Hz, 2H), 3.92 (d, J=4.21 Hz, 4 H), 4.02 (s, 1 H), 6.25 (s, 1 H), 6.32-6.39 (m, 1 H), 7.98 (dd, J=9.34, 4.21 Hz, 1 H). to degassed dioxane (200 mL) cooled reflux condenser for 12 hours The dioxane was removed under reduced pressure the solids were partitioned between methylene chloride (500 mL) and water (500 mL) The organic layer was dried over sodium sulfate purified by chromatography on SiO2to

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

実験手順: 4-chloro-2-(methyloxy)-1-nitrobenzene (6.71 g, 29.7 mmol), (3S)-3-methylmorpholine (Synthetech Inc., 2.0 g, 19.8 mmol), cesium carbonate (13.0 g, 40 mmol), Pd2dba3 (1.83 g, 2.0 mmol), and XANTPHOS (1.73 g, 3.0 mmol) were added to degassed dioxane (200 mL) and heated to 100° C. under a water cooled reflux condenser for 12 hours. The dioxane was removed under reduced pressure and the solids were partitioned between methylene chloride (500 mL) and water (500 mL). The organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and purified by chromatography on SiO2to give 4-[(3S)-3-methyl-4-morpholinyl]-2-(methyloxy)aniline as a yellow solid (2.46 g, 8.45 mmol, 43% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (dd, J=6.41, 4.58 Hz, 3 H), 3.22-3.29 (m, J=12.11, 8.03, 4.03, 4.03 Hz, 1 H), 3.31-3.37 (m, 1 H), 3.59-3.69 (m, 1 H), 3.78 (d, J=2.93 Hz, 2H), 3.92 (d, J=4.21 Hz, 4 H), 4.02 (s, 1 H), 6.25 (s, 1 H), 6.32-6.39 (m, 1 H), 7.98 (dd, J=9.34, 4.21 Hz, 1 H). to degassed dioxane (200 mL) cooled reflux condenser for 12 hours The dioxane was removed under reduced pressure the solids were partitioned between methylene chloride (500 mL) and water (500 mL) The organic layer was dried over sodium sulfate purified by chromatography on SiO2to

反応条件: temp:165.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-(7-chlorothieno[2,3-d]pyridazin-2-yl)-N-cyclopropyl-4-methylbenzamide (90 mg, 262 μmol) and (S)-3-methylmorpholine (79 mg, 785 μmol) in NMP (2 ml) was heated to 165° C. for 48 hrs. The mixture was cooled to RT, diluted with H2O and filtered. The solids were washed with H2O and air-dried. The residue was purified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 ml/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 min gradient) to afford the title compound. MS (ESI, pos. ion) m/z: 409 (M+1). The mixture was cooled to RT filtered The solids were washed with H2O air-dried The residue was purified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 ml/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 min gradient)

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

実験手順: Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-3-methylmorpholine (1.2 equiv) to give 138 (14.9 mg, M+1 397.1)

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

実験手順: Pyridine (1.60 mL, 19.8 mmol) was added dropwise to an ice cold suspension of triphosgene (2.94 g, 9.90 mmol) in DCM (20.0 mL). (S)-3-Methylmorpholine (1.00 mL, 9.90 mmol) was added and the reaction stirred for 3 hours, then quenched by dropwise addition of HCl (1M aqueous, 20 mL). The mixture was extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give (S)-3-methylmorpholine-carbamoylchloride (1.25 g, 77%). The product was used in the next reaction without purification. (S)-3-Methylmorpholine-carbamoylchloride (766 mg, 4.33 mmol) was dissolved in DCM (35.0 mL) and DIPEA (1.03 mL, 5390 mmol) was added followed by (5-fluoro-pyridin-2-yl)-hydrazine (WO2010022076, 500 mg, 3.94 mmol) and the reaction heated to 45° C. overnight. The reaction was cooled and quenched into water. The mixture was extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (574 mg, 57%). 1H NMR (300 MHz, CDCl3): 1.36 (3H, d, J=6.9 Hz), 3.30 (1H, td, J=12.5, 3.9 Hz), 3.47-3.74 (4H, m), 3.89-4.03 (2H, m), 6.41 (1H, br s), 6.45 (1H, br s), 6.73 (1H, dd, J=9.0, 3.5 Hz), 7.29 (1H, ddd, J=9.0, 7.9, 2.9 Hz), 8.04 (1H, d, J=2.9 Hz). quenched by dropwise addition of HCl (1M aqueous, 20 mL) The mixture was extracted into DCM (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo

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

実験手順: Pyridine (1.60 mL, 19.8 mmol) was added dropwise to an ice cold suspension of triphosgene (2.94 g, 9.90 mmol) in DCM (20.0 mL). (S)-3-Methylmorpholine (1.00 mL, 9.90 mmol) was added and the reaction stirred for 3 hours, then quenched by dropwise addition of HCl (1M aqueous, 20 mL). The mixture was extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give (S)-3-methylmorpholine-carbamoylchloride (1.25 g, 77%). The product was used in the next reaction without purification. (S)-3-Methylmorpholine-carbamoylchloride (766 mg, 4.33 mmol) was dissolved in DCM (35.0 mL) and DIPEA (1.03 mL, 5390 mmol) was added followed by (5-fluoro-pyridin-2-yl)-hydrazine (WO2010022076, 500 mg, 3.94 mmol) and the reaction heated to 45° C. overnight. The reaction was cooled and quenched into water. The mixture was extracted into DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (574 mg, 57%). 1H NMR (300 MHz, CDCl3): 1.36 (3H, d, J=6.9 Hz), 3.30 (1H, td, J=12.5, 3.9 Hz), 3.47-3.74 (4H, m), 3.89-4.03 (2H, m), 6.41 (1H, br s), 6.45 (1H, br s), 6.73 (1H, dd, J=9.0, 3.5 Hz), 7.29 (1H, ddd, J=9.0, 7.9, 2.9 Hz), 8.04 (1H, d, J=2.9 Hz). quenched by dropwise addition of HCl (1M aqueous, 20 mL) The mixture was extracted into DCM (3×) The combined organic layers were washed with brine dried (MgSO4) filtered evaporated in vacuo

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

実験手順: T3P (50 wt % solution in ethyl acetate, 179 μl, 0.304 mmol) was added to a solution of (S)-3-methylmorpholine (46 mg, 0.456 mmol) and 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid (60 mg, 0.152 mmol) in dichloromethane (3 mL) at room temperature and the mixture was stirred overnight. 1 M sodium carbonate solution (20 mL) was poured into the reaction mixture and stirring was continued for 1 h. The mixture was extracted with dichloromethane (3×) and the combined organic layers were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography [dichloromethane with 0-5% ethanol]. White foam. Yield: 68 mg (93% of theory). stirring was continued for 1 h The mixture was extracted with dichloromethane (3×) the combined organic layers were dried over magnesium sulfate concentrated The residue was purified by flash chromatography [dichloromethane with 0-5% ethanol]