Water → methyl 4-(1-(3,4-dichlorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamido)tetrahydro-2H-pyran-4-carboxylate

Participants

Reaction Steps

To a suspension of 4-amino-tetrahydro-pyran-4-carboxylic acid hydrochloride (53.5 mg, 0.294 mmol) in Et2O (1 mL) was added TMS-diazomethane (0.392 mL, 0.785 mmol) and water (200 μL). Upon addition of water, a vigorous evolution of gas occurred. The reaction was allowed to stir for 10 min at which time the reaction turned clear. The excess TMS-diazomethane was quenched by addition of AcOH until the solution turned colorless. The reaction mixture was concentrated in vacuo to provide an aqueous solution. The aqueous solution was added to a biphasic mixture of 1-(3,4-dichloro-phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonyl chloride (80 mg, 0.196 mmol, prepared from Intermediate O by analogy with Example 1) in DCM (4 mL) and saturated aqueous NaHCO3 (4 mL). The reaction was allowed to stir for 16 h. The biphasic mixture was extracted with DCM (3×5 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution of hexanes with 10-70% EtOAc to provide methyl 4-(1-(3,4-dichlorophenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamido)tetrahydro-2H-pyran-4-carboxylate (36.5 mg, 0.065 mmol, 33.3% yield) as a white solid. LCMS (+ESI) m/z=530.0 [M+H]+; 1H-NMR (CDCl3) δ 8.53 (s, 1H), 8.50 (br s, 1H), 7.83, (d, 1H), 7.59 (d, 1H), 7.49 (dd, 1H), 6.34 (br s, 1H), 4.10 (m, 2H), 3.89 (m, 4H), 3.80 (s, 3H), 3.75 (m, 2H), 2.35 (m, 2H), 2.10 (m, 1H), 2.07 (m 1H).

Provenance & Evidence