Hydrogen Peroxide → (2R)-2-[(S)-hydroxy(phenyl)methyl]hex-5-ynoic acid

Temperature

0 °C

To a stirred solution of 65.0 g (179 mmol) of (4S)-3-{(2R)-2-[(S)-hydroxy(phenyl)methyl]hex-5-ynoyl}-4-phenyl-1,3-oxazolidin-2-one from Step B above in 1050 mL of a 20 to 1 mixture of anhydrous tetrahydrofuran to water at 0° C. under an atmosphere of nitrogen was added 77.0 mL (894 mmol) of a 35% aqueous hydrogen peroxide solution at a rate slow enough to keep the internal temperature below 3° C. Next, 395 mL (395 mmol) of a 1.0 M aqueous lithium hydroxide solution was added at a rate slow enough to keep the internal temperature of the reaction below 5° C. and the resulting mixture was stirred for 3 h at 0° C. The reaction was quenched with 755 mL (984 mmol) of a 1.3 M aqueous sodium sulfite solution at a rate slow enough to keep the internal temperature of the mixture below 5° C. All volatiles were removed in vacuo and the remaining aqueous phase was extracted with ethyl acetate (3×200 mL). The aqueous phase was then cooled to 0° C. and acidified with a 6 M aqueous hydrogen chloride solution until a pH of 3 was achieved. The aqueous phase was then extracted with ethyl acetate (3×300 mL) and the combined organics were washed with brine (100 ml), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a 5-10% ethyl acetate and 3% acetic acid in hexanes gradient to afford the title compound as a colorless gum (32.0 g, 82.0%). 1H NMR (500 MHz, CDCl3): δ 7.39-7.28 (m, 5H), 4.85 (d, J=8.2, 1H), 3.03-2.97 (m, 1H), 2.29-2.15 (m, 2H), 1.97 (t, J=2.5 Hz, 1H), 1.93-1.82 (m, 1H), 1.62-1.55 (m, 1H). LC-MS: m/z (ES) 201.0 (MH-H2O)+.

1. customthe internal temperature below 3° C
2. customthe internal temperature of the reaction below 5° C.
3. customThe reaction was quenched with 755 mL (984 mmol) of a 1.3 M aqueous sodium sulfite solution at a rate slow enough
4. customthe internal temperature of the mixture below 5° C
5. customAll volatiles were removed in vacuo
6. extractionthe remaining aqueous phase was extracted with ethyl acetate (3×200 mL)
7. temperatureThe aqueous phase was then cooled to 0° C.
8. extractionThe aqueous phase was then extracted with ethyl acetate (3×300 mL)
9. washthe combined organics were washed with brine (100 ml)
10. dry with materialdried over magnesium sulfate
11. filtrationfiltered
12. customevaporated in vacuo
13. customThe residue was purified by silica gel chromatography
14. washeluting with a 5-10% ethyl acetate and 3% acetic acid in hexanes gradient

ORD record

ord-72966cd76d384a33bb48d18dcca05ba5

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08653260B2