反应详情

To a solution of 0.23 g 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one from Step A Example 1 in 10 mL anhydrous THF at −78° C. under nitrogen was added 0.93 mL 2 M LDA in heptane, THF, and ethylbenzene. After 15 minutes, 0.160 g trimethylacetaldehyde was added. Remove the cooling bath and let the reaction mixture warm up to room temperature. After 30 minutes, evaporate the reaction mixture under reduced pressure to remove solvents. Dilute the residue with ether, wash with 1 M HCl (2×) and saturated brine, dry over anhydrous Na2SO4, and evaporate to give a crude product. It was purified on RP-HPLC using 75˜100% MeCN in water without TFA to give the title compound as colorless solid after lyophilization. 1H NMR (CDCl3, 500 MHz) 7.44 (d, J=9.2 Hz, 1H), 7.12 (dd, J=2.7 & 9.1 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H), 3.89 (s, 3H), 3.48˜3.52 (br m, 1H), 3.40 (br d, J=7.0 Hz, 1OH), 3.10˜3.16 (m, 2H), 1.43 (s, 9H), 1.10 (s, 9H). LC-MS: 4.23 min. (m/Z=245.2, 315.2, 355.2=M+Na, 259.1). A faster-eluting isomeric side-product was also isolated during purification: 1-[2-(1-hydroxy-2,2-dimethylpropyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylbutan-2-one. 1H NMR (CDCl3, 500 MHz) 7.34 (d, J=8.9 Hz, 1H), 6.87 (dd, J=2.5 & 9.0 Hz, 1H), 6.79 (d, J=2.5 Hz, 1H), 4.53 (s, 1H), 3.99 (d, J=17.6 Hz, 1H), 3.92 (d, J=17.4 Hz, 1H), 3.84 (s, 3H), 1.32 (s, 9H), 1.06 (s, 9H). LC-MS: 3.77 min. (m/Z=355.2=M+Na, 315.2). The structures of the isomers were further confirmed by COSY and NOESY spectroscopy.

1. customRemove the cooling bath
2. waitAfter 30 minutes
3. customevaporate the reaction mixture under reduced pressure
4. customto remove solvents
5. additionDilute the residue with ether
6. washwash with 1 M HCl (2×) and saturated brine
7. dry with materialdry over anhydrous Na2SO4
8. customevaporate
9. customto give a crude product
10. customIt was purified on RP-HPLC