oxane-2-carbonyl chloride

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (9.31 g, 52.56 mmol) in anhydrous THF (150 mL) is added n-butyllithium (2.5 M in hexanes, 21.05 mL, 52.56 mmol) over 25 min at −78° C. Then a solution of tetrahydro-pyran-2-carbonyl chloride (7.1 g, 47.78 mmol) in anhydrous THF (12 mL) is added dropwise. The reaction is stirred at −70° C. for 0.5 h, then allowed to warm to room temperature and stirred for 2 h. Saturated aqueous NH4Cl solution (20 mL) is added and the reaction mixture is concentrated under reduced pressure. The residue is partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer is separated, washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (50 mL), dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the mixture of diastereoisomers is separated by multiple column chromatography (silica, eluent: toluene, 0-20% TBME) to afford 3.81 g of (4S)-4-benzyl-3-{[(2S)-oxan-2-yl]carbonyl}-1,3-oxazolidin-2-one (78%, yield: 22%; ES-MS: m/z 290 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.46-1.72 (4H, m), 1.81-1.90 (2H, m), 2.71 (1H, dd, J=13.43, 9.77 Hz), 3.30 (1H, dd, J=13.43, 3.05 Hz), 3.54 (1H, td, J=11.52, 2.14 Hz), 4.06-4.19 (3H, m), 4.60 (1H, m, J=9.88, 6.75, 3.28, 3.28 Hz), 4.97 (1H, dd, J=10.60, 1.91 Hz), 7.12-7.30 (5H, m)) and 1.65 g of (4S)-4-benzyl-3-{[(2R)-oxan-2-yl]carbonyl}-1,3-oxazolidin-2-one (93%, yield: 11%; ES-MS: m/z 290 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.54-1.80 (4H, m), 1.90-2.06 (2H, m), 2.83 (1H, dd, J=13.58, 9.16 Hz), 3.24 (1H, dd, J=13.50, 3.28 Hz), 3.53-3.61 (1H, m), 4.11-4.17 (1H, m), 4.19-4.24 (1H, m), 4.25-4.31 (1H, m), 4.71-4.78 (1H, m), 4.96 (1H, dd, J=10.60, 2.06 Hz), 7.16-7.37 (5H, m)) to warm to room temperature stirred for 2 h the reaction mixture is concentrated under reduced pressure The residue is partitioned between ethyl acetate (200 mL) and water (50 mL) The organic layer is separated washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (50 mL) dried (MgSO4) filtered The filtrate is concentrated under reduced pressure the mixture of diastereoisomers is separated by multiple column chromatography (silica, eluent: toluene, 0-20% TBME)

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (9.31 g, 52.56 mmol) in anhydrous THF (150 mL) is added n-butyllithium (2.5 M in hexanes, 21.05 mL, 52.56 mmol) over 25 min at −78° C. Then a solution of tetrahydro-pyran-2-carbonyl chloride (7.1 g, 47.78 mmol) in anhydrous THF (12 mL) is added dropwise. The reaction is stirred at −70° C. for 0.5 h, then allowed to warm to room temperature and stirred for 2 h. Saturated aqueous NH4Cl solution (20 mL) is added and the reaction mixture is concentrated under reduced pressure. The residue is partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer is separated, washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (50 mL), dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the mixture of diastereoisomers is separated by multiple column chromatography (silica, eluent: toluene, 0-20% TBME) to afford 3.81 g of (4S)-4-benzyl-3-{[(2S)-oxan-2-yl]carbonyl}-1,3-oxazolidin-2-one (78%, yield: 22%; ES-MS: m/z 290 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.46-1.72 (4H, m), 1.81-1.90 (2H, m), 2.71 (1H, dd, J=13.43, 9.77 Hz), 3.30 (1H, dd, J=13.43, 3.05 Hz), 3.54 (1H, td, J=11.52, 2.14 Hz), 4.06-4.19 (3H, m), 4.60 (1H, m, J=9.88, 6.75, 3.28, 3.28 Hz), 4.97 (1H, dd, J=10.60, 1.91 Hz), 7.12-7.30 (5H, m)) and 1.65 g of (4S)-4-benzyl-3-{[(2R)-oxan-2-yl]carbonyl}-1,3-oxazolidin-2-one (93%, yield: 11%; ES-MS: m/z 290 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.54-1.80 (4H, m), 1.90-2.06 (2H, m), 2.83 (1H, dd, J=13.58, 9.16 Hz), 3.24 (1H, dd, J=13.50, 3.28 Hz), 3.53-3.61 (1H, m), 4.11-4.17 (1H, m), 4.19-4.24 (1H, m), 4.25-4.31 (1H, m), 4.71-4.78 (1H, m), 4.96 (1H, dd, J=10.60, 2.06 Hz), 7.16-7.37 (5H, m)) to warm to room temperature stirred for 2 h the reaction mixture is concentrated under reduced pressure The residue is partitioned between ethyl acetate (200 mL) and water (50 mL) The organic layer is separated washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (50 mL) dried (MgSO4) filtered The filtrate is concentrated under reduced pressure the mixture of diastereoisomers is separated by multiple column chromatography (silica, eluent: toluene, 0-20% TBME)

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

実験手順: To a solution of tetrahydro-pyran-2-carboxylic acid (6.94 g, 47.96 mmol) in DCM (200 mL) are added oxalyl chloride (4.81 mL, 56.83 mmol) as a solution in DCM (50 mL) and DMF (3 drops). The reaction is stirred at room temperature for 18 h, then concentrated under reduced pressure to afford 7.1 g of tetrahydro-pyran-2-carbonyl chloride, which is used in the next step. Yield: 99%; by 58° C., 1 mm Hg; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.49-1.98 (5H, m), 2.02-2.19 (1H, m), 3.46-3.66 (1H, m), 3.96-4.12 (1H, m), 4.24 (1H, dd, J=9.14, 3.20 Hz) concentrated under reduced pressure

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (9.31 g, 52.56 mmol) in anhydrous THF (150 mL) is added n-butyllithium (2.5 M in hexanes, 21.05 mL, 52.56 mmol) over 25 min at −78° C. Then a solution of tetrahydro-pyran-2-carbonyl chloride (7.1 g, 47.78 mmol) in anhydrous THF (12 mL) is added dropwise. The reaction is stirred at −70° C. for 0.5 h, then allowed to warm to room temperature and stirred for 2 h. Saturated aqueous NH4Cl solution (20 mL) is added and the reaction mixture is concentrated under reduced pressure. The residue is partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer is separated, washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (50 mL), dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the mixture of diastereoisomers is separated by multiple column chromatography (silica, eluent: toluene, 0-20% TBME) to afford 3.81 g of (4S)-4-benzyl-3-{[(2S)-oxan-2-yl]carbonyl}-1,3-oxazolidin-2-one (78%, yield: 22%; ES-MS: m/z 290 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.46-1.72 (4 H, m), 1.81-1.90 (2 H, m), 2.71 (1 H, dd, J=13.43, 9.77 Hz), 3.30 (1 H, dd, J=13.43, 3.05 Hz), 3.54 (1 H, td, J=11.52, 2.14 Hz), 4.06-4.19 (3 H, m), 4.60 (1 H, m, J=9.88, 6.75, 3.28, 3.28 Hz), 4.97 (1 H, dd, J=10.60, 1.91 Hz), 7.12-7.30 (5 H, m)) and 1.65 g of (4S)-4-benzyl-3-{[(2R)-oxan-2-yl]carbonyl}-1,3-oxazolidin-2-one (93%, yield: 11%; ES-MS: m/z 290 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.54-1.80 (4 H, m), 1.90-2.06 (2 H, m), 2.83 (1 H, dd, J=13.58, 9.16 Hz), 3.24 (1 H, dd, J=13.50, 3.28 Hz), 3.53-3.61 (1 H, m), 4.11-4.17 (1 H, m), 4.19-4.24 (1 H, m), 4.25-4.31 (1 H, m), 4.71-4.78 (1 H, m), 4.96 (1 H, dd, J=10.60, 2.06 Hz), 7.16-7.37 (5 H, m)) to warm to room temperature stirred for 2 h the reaction mixture is concentrated under reduced pressure The residue is partitioned between ethyl acetate (200 mL) and water (50 mL) The organic layer is separated washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (50 mL) dried (MgSO4) filtered The filtrate is concentrated under reduced pressure the mixture of diastereoisomers is separated by multiple column chromatography (silica, eluent: toluene, 0-20% TBME)

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

実験手順: To a solution of tetrahydro-pyran-2-carboxylic acid (6.94 g, 47.96 mmol) in DCM (200 mL) are added oxalyl chloride (4.81 mL, 56.83 mmol) as a solution in DCM (50 mL) and DMF (3 drops). The reaction is stirred at room temperature for 18 h, then concentrated under reduced pressure to afford 7.1 g of tetrahydro-pyran-2-carbonyl chloride, which is used in the next step. Yield: 99%; by 58° C., 1 mm Hg; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.49-1.98 (5 H, m), 2.02-2.19 (1 H, m), 3.46-3.66 (1 H, m), 3.96-4.12 (1 H, m), 4.24 (1 H, dd, J=9.14, 3.20 Hz) concentrated under reduced pressure

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: To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in 1,2-Dimethoxyethane (DME) (1000 ul) was added tetrahydro-2H-pyran-2-carbonyl chloride (81 mg, 0.545 mmol) in 1,2-Dimethoxyethane (DME) (400 ul). The mixture was stirred at room temperature for 3 h, then irradiated (uwave) for 20 min at 90° C. The mixture was quenched with methanol, concentrated, and purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-(tetrahydro-2H-pyran-2-yl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (17 mg, 14%); LC/MS: MS (ES*) m/e 461 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (br. s., 3H), 1.62-1.72 (m, 1H), 1.78-1.98 (m, 2H), 2.45 (s, 3H), 3.45-3.57 (m, 5H), 3.66 (t, J=4.8 Hz, 4H), 3.81 (d, J=11.6 Hz, 1H), 4.28 (m, 1H), 5.51-5.66 (m, 2H), 6.49 (d, J=7.8 Hz, 1H), 7.13 (m, 1H), 7.36 (d, J=7.8 Hz, 1H). irradiated (uwave) for 20 min at 90° C The mixture was quenched with methanol concentrated purified by reversed-phase HPLC

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (9.31 g, 52.56 mmol) in anhydrous THF (150 mL) is added n-butyllithium (2.5 M in hexanes, 21.05 mL, 52.56 mmol) over 25 min at −78° C. Then a solution of tetrahydro-pyran-2-carbonyl chloride (7.1 g, 47.78 mmol) in anhydrous THF (12 mL) is added dropwise. The reaction is stirred at −70° C. for 0.5 h, then allowed to warm to room temperature and stirred for 2 h. Saturated aqueous NH4Cl solution (20 mL) is added and the reaction mixture is concentrated under reduced pressure. The residue is partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer is separated, washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (50 mL), dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the mixture of diastereoisomers is separated by multiple column chromatography (silica, eluent: toluene, 0-20% TBME) to afford 3.81 g of (4S)-4-benzyl-3-{[(2S)-oxan-2-yl]carbonyl}-1,3-oxazolidin-2-one (78%, yield: 22%; ES-MS: m/z 290 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.46-1.72 (4H, m), 1.81-1.90 (2H, m), 2.71 (1H, dd, J=13.43, 9.77 Hz), 3.30 (1H, dd, J=13.43, 3.05 Hz), 3.54 (1H, td, J=11.52, 2.14 Hz), 4.06-4.19 (3H, m), 4.60 (1H, m, J=9.88, 6.75, 3.28, 3.28 Hz), 4.97 (1H, dd, J=10.60, 1.91 Hz), 7.12-7.30 (5H, m)) and 1.65 g of (4S)-4-benzyl-3-{[(2R)-oxan-2-yl]carbonyl}-1,3-oxazolidin-2-one (93%, yield: 11%; ES-MS: m/z 290 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.54-1.80 (4H, m), 1.90-2.06 (2H, m), 2.83 (1H, dd, J=13.58, 9.16 Hz), 3.24 (1H, dd, J=13.50, 3.28 Hz), 3.53-3.61 (1H, m), 4.11-4.17 (1H, m), 4.19-4.24 (1H, m), 4.25-4.31 (1H, m), 4.71-4.78 (1H, m), 4.96 (1H, dd, J=10.60, 2.06 Hz), 7.16-7.37 (5H, m)) to warm to room temperature stirred for 2 h the reaction mixture is concentrated under reduced pressure The residue is partitioned between ethyl acetate (200 mL) and water (50 mL) The organic layer is separated washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (50 mL) dried (MgSO4) filtered The filtrate is concentrated under reduced pressure the mixture of diastereoisomers is separated by multiple column chromatography (silica, eluent: toluene, 0-20% TBME)

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

実験手順: To a solution of tetrahydro-pyran-2-carboxylic acid (6.94 g, 47.96 mmol) in DCM (200 mL) are added oxalyl chloride (4.81 mL, 56.83 mmol) as a solution in DCM (50 mL) and DMF (3 drops). The reaction is stirred at room temperature for 18 h, then concentrated under reduced pressure to afford 7.1 g of tetrahydro-pyran-2-carbonyl chloride, which is used in the next step. Yield: 99%; by 58° C., 1 mm Hg; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.49-1.98 (5H, m), 2.02-2.19 (1H, m), 3.46-3.66 (1H, m), 3.96-4.12 (1H, m), 4.24 (1H, dd, J=9.14, 3.20 Hz) concentrated under reduced pressure

反応条件: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (9.31 g, 52.56 mmol) in anhydrous THF (150 mL) is added n-butyllithium (2.5 M in hexanes, 21.05 mL, 52.56 mmol) over 25 min at −78° C. Then a solution of tetrahydro-pyran-2-carbonyl chloride (7.1 g, 47.78 mmol) in anhydrous THF (12 mL) is added dropwise. The reaction is stirred at −70° C. for 0.5 h, then allowed to warm to room temperature and stirred for 2 h. Saturated aqueous NH4Cl solution (20 mL) is added and the reaction mixture is concentrated under reduced pressure. The residue is partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer is separated, washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (50 mL), dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the mixture of diastereoisomers is separated by multiple column chromatography (silica, eluent: toluene, 0-20% TBME) to afford 3.81 g of (4S)-4-benzyl-3-{[(2S)-oxan-2-yl]carbonyl}-1,3-oxazolidin-2-one (78%, yield: 22%; ES-MS: m/z 290 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.46-1.72 (4H, m), 1.81-1.90 (2H, m), 2.71 (1H, dd, J=13.43, 9.77 Hz), 3.30 (1H, dd, J=13.43, 3.05 Hz), 3.54 (1H, td, J=11.52, 2.14 Hz), 4.06-4.19 (3H, m), 4.60 (1H, m, J=9.88, 6.75, 3.28, 3.28 Hz), 4.97 (1H, dd, J=10.60, 1.91 Hz), 7.12-7.30 (5H, m)) and 1.65 g of (4S)-4-benzyl-3-{[(2R)-oxan-2-yl]carbonyl}-1,3-oxazolidin-2-one (93%, yield: 11%; ES-MS: m/z 290 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.54-1.80 (4H, m), 1.90-2.06 (2H, m), 2.83 (1H, dd, J=13.58, 9.16 Hz), 3.24 (1H, dd, J=13.50, 3.28 Hz), 3.53-3.61 (1H, m), 4.11-4.17 (1H, m), 4.19-4.24 (1H, m), 4.25-4.31 (1H, m), 4.71-4.78 (1H, m), 4.96 (1H, dd, J=10.60, 2.06 Hz), 7.16-7.37 (5H, m)) to warm to room temperature stirred for 2 h the reaction mixture is concentrated under reduced pressure The residue is partitioned between ethyl acetate (200 mL) and water (50 mL) The organic layer is separated washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (50 mL) dried (MgSO4) filtered The filtrate is concentrated under reduced pressure the mixture of diastereoisomers is separated by multiple column chromatography (silica, eluent: toluene, 0-20% TBME)

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

実験手順: To a solution of tetrahydro-pyran-2-carboxylic acid (6.94 g, 47.96 mmol) in DCM (200 mL) are added oxalyl chloride (4.81 mL, 56.83 mmol) as a solution in DCM (50 mL) and DMF (3 drops). The reaction is stirred at room temperature for 18 h, then concentrated under reduced pressure to afford 7.1 g of tetrahydro-pyran-2-carbonyl chloride, which is used in the next step. Yield: 99%; by 58° C., 1 mm Hg; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.49-1.98 (5H, m), 2.02-2.19 (1H, m), 3.46-3.66 (1H, m), 3.96-4.12 (1H, m), 4.24 (1H, dd, J=9.14, 3.20 Hz) concentrated under reduced pressure