N-甲基-1-(四氢-2H-吡喃-4-基)甲胺盐酸

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

实验步骤: To a stirred solution of 4.70 g (20.0 mmol) 4-bromo-2-nitro-anisole in 100 ml dioxane were added 4.03 g (24.3 mmol) methyl-(tetrahydro-pyran-4-ylmethyl)-amine hydrochloride (1:1), 0.710 g (20.0 mmol) 2-(dicyclohexylphosphino)biphenyl, 16.5 g (50.65 mmol) cesium carbonate, and 227 mg (1.0 mmol) palladium (II) acetate. The mixture was heated at reflux for 24 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/1 hexane/ethyl acetate) afforded 3.5 g (62%) (4-methoxy-3-nitro-phenyl)-methyl-(tetrahydro-pyran-4-ylmethyl)-amine as a red oil. ES-MS m/e (%): 281 (M+H+, 100). The mixture was heated at reflux for 24 h poured onto water extracted three times with ethyl acetate The combined organic phases were dried over sodium sulfate concentrated in vacuo

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

实验步骤: To a stirred solution of 4.70 g (20.0 mmol) 4-bromo-2-nitro-anisole in 100 ml dioxane were added 4.03 g (24.3 mmol) methyl-(tetrahydro-pyran-4-ylmethyl)-amine hydrochloride (1:1), 0.710 g (20.0 mmol) 2-(dicyclohexylphosphino)biphenyl, 16.5 g (50.65 mmol) cesium carbonate, and 227 mg (1.0 mmol) palladium (II) acetate. The mixture was heated at reflux for 24 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/1 hexane/ethyl acetate) afforded 3.5 g (62%) (4-methoxy-3-nitro-phenyl)-methyl-(tetrahydro-pyran-4-ylmethyl)-amine as a red oil. ES-MS m/e (%): 281 (M+H+, 100). The mixture was heated at reflux for 24 h poured onto water extracted three times with ethyl acetate The combined organic phases were dried over sodium sulfate concentrated in vacuo

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

实验步骤: To a solution of tert-butyl N-methyl-N-(4-tetrahydropyranylmethyl)carbamate (600 mg, 2.6 mmol) in 4.0 mL of ethyl acetate was added 4 M HCl-ethyl acetate (4 mL). After being stirred at room temperature for 1.5 h, the reaction mixture was concentrated in vacuo, and the residue was rinsed with hexane to obtain the title compound (356 mg, 82%). the reaction mixture was concentrated in vacuo the residue was rinsed with hexane

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

实验步骤: To a solution of tert-butyl N-methyl-N-(4-tetrahydropyranylmethyl)carbamate (600 mg, 2.6 mmol) in 4.0 mL of ethyl acetate was added 4 M HCl-ethyl acetate (4 mL). After being stirred at room temperature for 1.5 h, the reaction mixture was concentrated in vacuo, and the residue was rinsed with hexane to obtain the title compound (356 mg, 82%). the reaction mixture was concentrated in vacuo the residue was rinsed with hexane

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

实验步骤: To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added methyl-(tetrahydro-pyran-4-ylmethyl)-amine hydrochloride (200 mg, 1.21 mmol), triethylamine (0.108 ml, 0.78 mmol) and T3P (50% solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at rt for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (87 mg, 32% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C23H33Cl N2 O, 420.9, found, 421.3 (M+1) APCI; 400 MHz 1H NMR (CDCl3) mixture of rotomers, diagnostic peaks, δ 3.98-3.88 (m, 2H), 3.73 (s, 2H), 2.95 (s, 3H), 2.62-2.54 (m, 6H), 1.70-1.46 (m, 2H), 1.38-1.17 (m, 2H). The resulting reaction mixture the layers were separated The aqueous layer was subjected to EtOAc extraction (2×60 ml) again the combined organic layers were dried over MgSO4 evaporated The residue was purified by flash column chromatography eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH The product containing fractions were collected concentrated under reduced pressure

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

实验步骤: In a manner similar to Reference Example 1 (c) 2-(3-chlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (50 mg) and N-methyl-N-(tetrahydro-pyran-4-yl methyl)amine hydrochloride (39 mg) afforded, after Biotage chromatography over silica gel, eluting with 1% MeOH/CH2Cl2, the title compound (33 mg). after Biotage chromatography over silica gel, eluting with 1% MeOH/CH2Cl2

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

实验步骤: A solution of N-methyl-N-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (740 mg) in 4N hydrochloric acid in 1,4-dioxan (10 ml, ex Aldrich) was stirred at room temperature for 1 h. The dioxan was removed under reduced pressure and the residue triturated with ether. The solid was filtered onto a sinter, washed with ether and dried, to afford N-methyl-N-(tetrahydro-pyran-4-ylmethyl)-amine hydrochloride (460 mg). The dioxan was removed under reduced pressure the residue triturated with ether The solid was filtered onto a sinter washed with ether dried

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

实验步骤: To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added methyl-(tetrahydro-pyran-4-ylmethyl)-amine hydrochloride (200 mg, 1.21 mmol), triethylamine (0.108 ml, 0.78 mmol) and T3P (50% solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at rt for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (87 mg, 32% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C23H33ClN2O, 420.9, found, 421.3 (M+1) APCI; 400 MHz 1H NMR (CDCl3) mixture of rotomers, diagnostic peaks, δ 3.98-3.88 (m, 2H), 3.73 (s, 2H), 2.95 (s, 3H), 2.62-2.54 (m, 6H), 1.70-1.46 (m, 2H), 1.38-1.17 (m, 2H). The resulting reaction mixture the layers were separated The aqueous layer was subjected to EtOAc extraction (2×60 ml) again the combined organic layers were dried over MgSO4 evaporated The residue was purified by flash column chromatography eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH The product containing fractions were collected concentrated under reduced pressure

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

实验步骤: To a stirred solution of 4.70 g (20.0 mmol) 4-bromo-2-nitro-anisole in 100 ml dioxane were added 4.03 g (24.3 mmol) methyl-(tetrahydro-pyran-4-ylmethyl)-amine hydrochloride (1:1), 0.710 g (20.0 mmol) 2-(dicyclohexylphosphino)biphenyl, 16.5 g (50.65 mmol) cesium carbonate, and 227 mg (1.0 mmol) palladium (II) acetate. The mixture was heated at reflux for 24 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/1 hexane/ethyl acetate) afforded 3.5 g (62%) (4-methoxy-3-nitro-phenyl)-methyl-(tetrahydro-pyran-4-ylmethyl)-amine as a red oil. ES-MS m/e (%): 281 (M+H+, 100). The mixture was heated at reflux for 24 h poured onto water extracted three times with ethyl acetate The combined organic phases were dried over sodium sulfate concentrated in vacuo