Phosgene → (3S,4S)-4-ethyl-4-methyl-2-oxotetrahydro-3-furanyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate

To a solution of 120 mg (0.83 mmol) of (3S,4S)-4-ethyl-3-hydroxy-4-methyldihydro-2(3H)-furanone and 0.11 mL (0.92 mmol) of 2,6-lutidine in 3 mL of ether was added 180 mg of 4 Å molecular sieves. The mixture was stirred for 45 min and let settle for 30 min. The supernatant was transferred via cannula to a solution of phosgene (2.6 mL, 1.93 M in toluene, 5.0 mmol) in 10 mL of ether at 0° C. After 30 min, the reaction mixture was allowed to warm to room temperature. It was stirred for 2 h, and then filtered through a celite plug with ether. The filtrate was concentrated to 1 mL, and added to a solution of 220 mg (0.83 mmol) of (3S)-3-amino-2-hydroxy-N-[(1R)-1-phenylethyl]heptanamide and 0.13 mL (0.91 mmol) of triethylamine in 2 mL of tetrahydrofuran. The reaction mixture was stirred for 18 h at room temperature. It was then diluted with ethyl acetate, washed with 1N HCl, and dried over magnesium sulfate before being concentrated. The residue was purified by silica gel chromatography, eluting with 1:1 ethyl acetate:hexanes to afford 170 mg (47%) of (3S,4S)-4-ethyl-4-methyl-2-oxotetrahydro-3-furanyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate. 1H NMR (300 MHz, DMSO-d6) δ 7.99 (d, J=8 Hz, 1H), 7.23-7.29 (m, 5H), 7.16 (m, 1H), 6.85 (d, J=9 Hz, 1H), 5.53 (s, 1H), 4.87 (m, 1H), 4.10 (d, J=9 Hz, 1H), 3.98 (d, J=9 Hz, 1H), 3.83 (s, 1H), 3.73 (m, 1H), 1.15-1.55 (m, 11H), 0.97 (s, 3H), 0.76-0.81 (m, 6H). ES-LCMS m/z 435 (M+H).

1. waitlet settle for 30 min
2. waitAfter 30 min
3. stirringIt was stirred for 2 h
4. filtrationfiltered through a celite plug with ether
5. concentrationThe filtrate was concentrated to 1 mL
6. stirringThe reaction mixture was stirred for 18 h at room temperature
7. washwashed with 1N HCl
8. dry with materialdried over magnesium sulfate
9. concentrationbefore being concentrated
10. customThe residue was purified by silica gel chromatography
11. washeluting with 1:1 ethyl acetate

ORDレコード

ord-83204517ab67405e9706df279156d90f

出典データセット

uspto-grants-2008_07

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07402606B2