反应详情

A mixture of MTBE (990 mL) and water (10 mL) was stirred for 5 h until a clear solution was obtained. To this solution was added 2-methyl-1-methylthiocarbonyloxypropyl 2-methylpropanoate (2b) (50 g), prepared as described in Gallop et al., U.S. Pat. No. 7,227,028, and a non-covalent complex of porcine liver esterase (PLE), with methoxypolyethylene glycol (mPEG) (5 wt %, 75 g) prepared according to the method described by Heiss and Gais, Tetrahedron Lett., 1995, 36, 3833-3836; and Rupport and Gais, Tetrahedron Asymmetry, 1997, 8(21), 3657-3664. The resulting suspension was stirred at room temperature and the reaction periodically monitored by 1H-NMR using the chiral solvating agent (R)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol. After ca. 48 h, 1H-NMR indicated that only one enantiomer remained in the reaction mixture at which time the reaction was quenched by filtration through a pad of CELITE®. The supernatant was washed with water, aqueous sodium bicarbonate (NaHCO3) then brine, and dried over anhydrous sodium sulfate (Na2SO4). After removing the solvent in vacuo, the title compound (12) was isolated as a single S-enantiomer (as determined by HPLC using a chiral column) in 70% yield. The absolute configuration was established by: (i) conversion to compound (20b) (see Step B); (ii) reaction of (20b) with R-baclofen to afford 4-{[(1S)-isobutanoyloxyisobutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoic acid; and (iii) correlation with the product formed in Example 18 of Gallop et al., U.S. Pat. No. 7,227,028. 1H NMR (CDCl3, 400 MHz): δ 0.96 (d, J=6.8 Hz, 6H), 1.16 (d, J=6.8 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.98-2.07 (m, 1H), 2.32 (s, 3H), 2.56 (hept, J=7.2 Hz, 1H), 6.67 (d, J=5.6 Hz, 1H). 1H NMR with chiral solvating agent, (R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol: δ 0.98 (d, J=6.8Hz, 3H), 0.99 (d, J=6.8 Hz, 3H), 1.19 (d, J=7.2 Hz, 1.5H), 1.19 (d, J=6.8 Hz, 1.5H), 1.20 (d, J=6.8 Hz, 1.5H), 1.20 (d, J=7.2 Hz, 1.5H), 2.01-2.09 (m, 1H), 2.34 (s, 1.5H), 2.444 (s, 1.5H), 2.591 (hept, J=7.2 Hz, 0.5H), 2.59 (hept, J=6.8 Hz, 0.5H), 6.70 (d, J=5.6 Hz, 0.5H), 6.70 (d, J=5.2 Hz, 0.5H).

1. customwas obtained
2. customprepared
3. stirringThe resulting suspension was stirred at room temperature
4. customthe reaction
5. waitAfter ca. 48 h
6. customwas quenched by filtration through a pad of CELITE®
7. washThe supernatant was washed with water, aqueous sodium bicarbonate (NaHCO3)
8. dry with materialbrine, and dried over anhydrous sodium sulfate (Na2SO4)
9. customAfter removing the solvent in vacuo