oxan-4-ylmethanamine;hydrochloride

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-bromo-6-fluoropyridine (750 mg, 4.26 mmol) in DMSO (3 mL) was mixed with (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride (775 mg, 5.11 mmol) and NEt3 (1.426 mL, 10.23 mmol). The resulting mixture was heated at about 110° C. for 18 hr. The mixture was cooled to ambient temperature and diluted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield a resulting residue. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane=0/100 to 30/70]. Pure fractions were combined and concentrated in vacuo providing 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (B1, 940 mg) as a white solid. LCMS (m/z): 271.0/272.9 [M+H]+; Retention time=0.81 min. The mixture was cooled to ambient temperature The organic layer was separated washed with saturated aqueous sodium bicarbonate solution, water, and brine dried over sodium sulfate filtered concentrated in vacuo to yield a resulting residue The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane=0/100 to 30/70] concentrated in vacuo

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

実験手順: Under a nitrogen atmosphere THF (90 mL) and triethylamine (17.5 mL, 125.6 mmol) were added sequentially to a mixture of crude 4-chloro-3-nitroquinoline (13.10 g, 62.81 mmol) and 1-tetrahydro-2H-pyran-4-ylmethylamine hydrochloride (10.0 g, 65.95 mmol). The reaction mixture was placed in an oil bath at 45° C. for 1 hour and then concentrated under reduced pressure. The residue was diluted with THF (30 mL) and water (200 mL). The THF was removed under reduced pressure. A solid was isolated by filtration and dried to provide 16.10 g of 3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine as a light yellow solid. concentrated under reduced pressure The residue was diluted with THF (30 mL) and water (200 mL) The THF was removed under reduced pressure A solid was isolated by filtration dried

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

実験手順: Under a nitrogen atmosphere THF (90 mL) and triethylamine (17.5 mL, 125.6 mmol) were added sequentially to a mixture of crude 4-chloro-3-nitroquinoline (13.10 g, 62.81 mmol) and 1-tetrahydro-2H-pyran-4-ylmethylamine hydrochloride (10.0 g, 65.95 mmol). The reaction mixture was placed in an oil bath at 45° C. for 1 hour and then concentrated under reduced pressure. The residue was diluted with THF (30 mL) and water (200 mL). The THF was removed under reduced pressure. A solid was isolated by filtration and dried to provide 16.10 g of 3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)quinolin-4-amine as a light yellow solid. concentrated under reduced pressure The residue was diluted with THF (30 mL) and water (200 mL) The THF was removed under reduced pressure A solid was isolated by filtration dried

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

実験手順: To a solution of compound prepared in example 8 (250 mg, 0.454 mmoles) in DMF (2 mL), (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride (83 mg, 0.545 mmoles), HOBT (Catalyst), EDC.HCl (130 mg, 0.681 mmoles) and N-ethyl morpholine (0.173 ml, 1.362 mmoles) were added and the reaction mixture was srirred at 25° C. for 5 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography to yield 200 mg (68%) of product as white solid. The reaction mixture was poured into ice cold water extracted with ethyl acetate The combined ethyl acetate extract was washed with water & brine dried over sodium sulphate evaporated under reduced pressure The crude product was purified by column chromatography

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

実験手順: To a solution of the product of step 4 (6.5 g, 0.0171 moles) in DMF (40 mL), (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride (2.6 gm, 0.0171 moles), HOBT (2.31 gm, 0.0171 moles), EDC.HCl (4.24 gm, 0.0222 moles) and N-ethyl morpholine (5.9 gm, 0.0513 moles) were added and reaction mixture was srirred at 25° C. for 5 hours under nitrogen atmosphere. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure. The crude product was purified by coloumn chromatography using 1% MeOH in chloroform as eluent to yield 1.22 g (15%) of product as white solid. reaction mixture The reaction mixture was poured into ice cold water extracted with ethyl acetate The combined ethyl acetate extract was washed with water & brine dried over sodium sulphate The crude product was purified by coloumn chromatography

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-bromo-6-fluoropyridine (750 mg, 4.26 mmol) in DMSO (3 mL) was mixed with (tetrahydro-2H-pyran-4-yl)methanamine hydrochloride (775 mg, 5.11 mmol) and NEt3 (1.426 mL, 10.23 mmol). The resulting mixture was heated at about 110° C. for 18 hr. The mixture was cooled to ambient temperature and diluted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield a resulting residue. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane=0/100 to 30/70]. Pure fractions were combined and concentrated in vacuo providing 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (B1, 940 mg) as a white solid. LCMS (m/z): 271.0/272.9 [M+H]+; Retention time=0.81 min. The mixture was cooled to ambient temperature The organic layer was separated washed with saturated aqueous sodium bicarbonate solution, water, and brine dried over sodium sulfate filtered concentrated in vacuo to yield a resulting residue The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane=0/100 to 30/70] concentrated in vacuo