(2R)-2-methylmorpholine;hydrochloride

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

実験手順: The title compound was prepared as described in Example 283, Step 1 using (2R)-2-methylmorpholine hydrochloride (124 mg, 0.90 mmol) and 6-bromopyridine-2-carboxylic acid (150 mg, 0.74 mmol) as starting materials.

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under N2 atmosphere, to a mixture of (R)-2-methylmorpholine HCl salt (1.1 g, 8 mmol), N-(4-bromo-3-methylphenyl)acetamide (1.7 g, 7.45 mmol), Pd2 dba3 (92 mg, 0.1 mmol) and 2-(di-t-butylphosphino)biphenyl (72 mg, 0.24 mmol) was added LiHMDS (28 mmol, 28 mL, 1 M in THF). The resulting mixture was stirred at 65° C. overnight. THF was removed under reduced pressure. The residue was treated with HCl (1N), basified with NaHCO3, and then extracted with EtOAc. The combined organics was washed with brine and dried over Na2SO4. The crude was purified by flash chromatography on silica gel (40-100% EtOAc in hexanes) to afford the product as a yellow solid. THF was removed under reduced pressure The residue was treated with HCl (1N) extracted with EtOAc The combined organics was washed with brine dried over Na2SO4 The crude was purified by flash chromatography on silica gel (40-100% EtOAc in hexanes)

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

実験手順: A mixture of (R)-2-methylmorpholine hydrochloride (0.436 g, 3.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.184 mL, 6.80 mmol) in DCM (5 mL) was added dropwise to a stirred solution of methyl 8-bromo-2-(ethylsulfonyl)-4-oxo-4H-chromene-6-carboxylate (0.85 g, 2.27 mmol) in DCM (10 mL) at 10° C. under argon. The resulting solution was stirred at RT for 3 hrs. The reaction mixture was quenched with 1M HCl, the phases were separated, the organic phase was washed with brine dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford after a trituration with ether, methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (0.760 g, 88%) as a pale yellow foam. Mass Spectrum: M+H+ 382. The reaction was repeated on a similar scale before proceeding to the next step. The reaction mixture was quenched with 1M HCl the phases were separated the organic phase was washed with brine dried over magnesium sulfate concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM The solvent was evaporated to dryness

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

実験手順: A mixture of (R)-2-methylmorpholine hydrochloride (0.436 g, 3.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.184 mL, 6.80 mmol) in DCM (5 mL) was added dropwise to a stirred solution of methyl 8-bromo-2-(ethylsulfonyl)-4-oxo-4H-chromene-6-carboxylate (0.85 g, 2.27 mmol) in DCM (10 mL) at 10° C. under argon. The resulting solution was stirred at RT for 3 hrs. The reaction mixture was quenched with 1M HCl, the phases were separated, the organic phase was washed with brine dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford after a trituration with ether, methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (0.760 g, 88%) as a pale yellow foam. Mass Spectrum: M+H+ 382. The reaction was repeated on a similar scale before proceeding to the next step. The reaction mixture was quenched with 1M HCl the phases were separated the organic phase was washed with brine dried over magnesium sulfate concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM The solvent was evaporated to dryness

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

実験手順: The title compound was prepared as described in Example 283, Step 1 using (2R)-2-methylmorpholine hydrochloride (124 mg, 0.90 mmol) and 6-bromopyridine-2-carboxylic acid (150 mg, 0.74 mmol) as starting materials.

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

実験手順: DIPEA (51.7 mL, 296.91 mmol) was added dropwise to a stirred solution of methyl 8-bromo-2-(ethylsulfonyl)-4-oxo-4H-chromene-6-carboxylate (44.56 g, 118.77 mmol) and (R)-2-methylmorpholine hydrochloride (22.88 g, 166.27 mmol) in DCM (430 mL) at 5° C. under nitrogen. The resulting suspension was stirred at room temperature for 1 h. The reaction mixture was diluted with water and quenched slowly with HCl 1M (119 mL, 118.77 mmol) (pH 7). The phases were separated and the organic phase was washed with water, brine, dried over MgSO4 and concentrated. The crude product was triturated in EtAc for 1 h, the solid was collected by filtration and dried to afford methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (32.6 g, 67%) as a white solid. Mass Spectrum: m/z [M+H]+=384. The phases were separated the organic phase was washed with water, brine dried over MgSO4 concentrated The crude product was triturated in EtAc for 1 h the solid was collected by filtration dried

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

実験手順: DIPEA (51.7 mL, 296.91 mmol) was added dropwise to a stirred solution of methyl 8-bromo-2-(ethylsulfonyl)-4-oxo-4H-chromene-6-carboxylate (44.56 g, 118.77 mmol) and (R)-2-methylmorpholine hydrochloride (22.88 g, 166.27 mmol) in DCM (430 mL) at 5° C. under nitrogen. The resulting suspension was stirred at room temperature for 1 h. The reaction mixture was diluted with water and quenched slowly with HCl 1M (119 mL, 118.77 mmol) (pH 7). The phases were separated and the organic phase was washed with water, brine, dried over MgSO4 and concentrated. The crude product was triturated in EtAc for 1 h, the solid was collected by filtration and dried to afford methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (32.6 g, 67%) as a white solid. Mass Spectrum: m/z [M+H]+=384. The phases were separated the organic phase was washed with water, brine dried over MgSO4 concentrated The crude product was triturated in EtAc for 1 h the solid was collected by filtration dried

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

実験手順: A mixture of (R)-2-methylmorpholine hydrochloride (0.436 g, 3.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.184 mL, 6.80 mmol) in DCM (5 mL) was added dropwise to a stirred solution of methyl 8-bromo-2-(ethylsulfonyl)-4-oxo-4H-chromene-6-carboxylate (0.85 g, 2.27 mmol) in DCM (10 mL) at 10° C. under argon. The resulting solution was stirred at RT for 3 hrs. The reaction mixture was quenched with 1M HCl, the phases were separated, the organic phase was washed with brine dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford after a trituration with ether, methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (0.760 g, 88%) as a pale yellow foam. Mass Spectrum: M+H+ 382. The reaction was repeated on a similar scale before proceeding to the next step. The reaction mixture was quenched with 1M HCl the phases were separated the organic phase was washed with brine dried over magnesium sulfate concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM The solvent was evaporated to dryness

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

実験手順: A mixture of (R)-2-methylmorpholine hydrochloride (0.436 g, 3.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.184 mL, 6.80 mmol) in DCM (5 mL) was added dropwise to a stirred solution of methyl 8-bromo-2-(ethylsulfonyl)-4-oxo-4H-chromene-6-carboxylate (0.85 g, 2.27 mmol) in DCM (10 mL) at 10° C. under argon. The resulting solution was stirred at RT for 3 hrs. The reaction mixture was quenched with 1M HCl, the phases were separated, the organic phase was washed with brine dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford after a trituration with ether, methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (0.760 g, 88%) as a pale yellow foam. Mass Spectrum: M+H+ 382. The reaction was repeated on a similar scale before proceeding to the next step. The reaction mixture was quenched with 1M HCl the phases were separated the organic phase was washed with brine dried over magnesium sulfate concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM The solvent was evaporated to dryness

反応条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under N2 atmosphere, to a mixture of (R)-2-methylmorpholine HCl salt (1.1 g, 8 mmol), N-(4-bromo-3-methylphenyl)acetamide (1.7 g, 7.45 mmol), Pd2 dba3 (92 mg, 0.1 mmol) and 2-(di-t-butylphosphino)biphenyl (72 mg, 0.24 mmol) was added LiHMDS (28 mmol, 28 mL, 1 M in THF). The resulting mixture was stirred at 65° C. overnight. THF was removed under reduced pressure. The residue was treated with HCl (1N), basified with NaHCO3, and then extracted with EtOAc. The combined organics was washed with brine and dried over Na2SO4. The crude was purified by flash chromatography on silica gel (40-100% EtOAc in hexanes) to afford the product as a yellow solid. THF was removed under reduced pressure The residue was treated with HCl (1N) extracted with EtOAc The combined organics was washed with brine dried over Na2SO4 The crude was purified by flash chromatography on silica gel (40-100% EtOAc in hexanes)

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

実験手順: A mixture of (R)-2-methylmorpholine hydrochloride (0.436 g, 3.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.184 mL, 6.80 mmol) in DCM (5 mL) was added dropwise to a stirred solution of methyl 8-bromo-2-(ethylsulfonyl)-4-oxo-4H-chromene-6-carboxylate (0.85 g, 2.27 mmol) in DCM (10 mL) at 10° C. under argon. The resulting solution was stirred at RT for 3 hrs. The reaction mixture was quenched with 1M HCl, the phases were separated, the organic phase was washed with brine dried over magnesium sulfate and concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford after a trituration with ether, methyl 8-bromo-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (0.760 g, 88%) as a pale yellow foam. Mass Spectrum: M+H+ 382. The reaction was repeated on a similar scale before proceeding to the next step. The reaction mixture was quenched with 1M HCl the phases were separated the organic phase was washed with brine dried over magnesium sulfate concentrated to afford the crude product which was purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM The solvent was evaporated to dryness

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

実験手順: The title compound was prepared as described in Example 283, Step 1 using (2R)-2-methylmorpholine hydrochloride (124 mg, 0.90 mmol) and 6-bromopyridine-2-carboxylic acid (150 mg, 0.74 mmol) as starting materials.