Hexane → 5-Isoxazolecarboxylic acid, 4-(dimethoxymethyl)-3-phenyl-, methyl ester

To a solution of (E)-methyl 4,4-dimethoxy-2-(phenylsulfinyl)but-2-enoate (0.284 g, 1 mmol) and (Z)-N-hydroxybenzimidoyl chloride (0.370 g, 2.378 mmol) in DCM (5 mL) at rt was added Et3N (0.488 mL, 3.50 mmol) dropwise over 30 minutes as a solution in 5 mL of DCM. After stirring 18 hr at rt, the reaction mixture was cooled to 0° C. and additional (Z)-N-hydroxybenzimidoyl chloride (0.370 g, 2.378 mmol) was added. The cooling bath was removed and the reaction mixture stirred for 2 hr during which the temperature of the reaction reached rt, Et3N (0.488 mL, 3.50 mmol) was added over ˜2 minutes. The reaction mixture was stirred an additional 18 hr at rt. The reaction mixture was poured into ˜100 ml of hexane. The resulting suspension was allowed to stand at rt for 30 minutes. After filtration, the filtrate was concentrated and the residue was chromatographed on a 5×12 cm silica gel column, eluting with a 0-6% EtOAc/Hex gradient. (Note: to load the column, the residue was slurried in 5% CH2Cl2/Hex. Not all of the material dissolved). The essentially pure fractions containing the product were concentrated to afford methyl 4-(dimethoxymethyl)-3-phenylisoxazole-5-carboxylate (125 mg, 0.451 mmol, 45.1% yield) as a colorless oil. (Note: The desired product is the third product to elute and began eluting at 6% EtOAc/Hex.). HPLC retention time=1.63 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+H)=278.12. 1H NMR (400 MHz, chloroform-d) δ ppm 3.41 (s, 6H), 4.03 (s, 3H), 5.95 (s, 1H), 7.45 (m, 3H), 7.96 (dd, J=7.8, 2.0 Hz, 2H).

1. temperaturethe reaction mixture was cooled to 0° C.
2. customThe cooling bath was removed
3. stirringthe reaction mixture stirred for 2 hr during which the temperature of the reaction
4. customreached rt
5. stirringThe reaction mixture was stirred an additional 18 hr at rt
6. waitto stand at rt for 30 minutes
7. filtrationAfter filtration
8. concentrationthe filtrate was concentrated
9. customthe residue was chromatographed on a 5×12 cm silica gel column
10. washeluting with a 0-6% EtOAc/Hex gradient
11. dissolutionNot all of the material dissolved)
12. additionThe essentially pure fractions containing the product
13. concentrationwere concentrated

ORD record

ord-20de3bd5474849c2aecc37b8471f6944

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08354398B2