1,2-Dibromoethane → Methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-[4-{[(2-fluorophenyl)methyl]oxy}-3-(methyloxy)phenyl]-5-oxopentanoate

Participants

Reaction Conditions

Reaction Steps

1,2-Dibromoethane (1064, 232 mg, 1.233 mmol) was added to a suspension of magnesium (300 mg, 12.33 mmol) in dry THF (3 mL). Then a solution of 4-bromo-1-{[(2-fluorophenyl)methyl]oxy}-2-(methyloxy)benzene (D54, 2.40 g, 8.22 mmol) in dry THF (17 ml) was added dropwise. The mixture was heated under reflux for 1.5 h. The Grignard formation was followed via HPLC (Rt(HPLC, 1-fluoro-2-({[2-(methyloxy)phenyl]oxy}methyl)benzene): 5.59 min, Rt (HPLC, D54): 6.24 min). When the reaction stopped, additional 1,2-dibromoethane (0.1 eq) was added. After Grignard formation was complete, the mixture was added dropwise to a solution of 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D1, 1 g, 4.11 mmol) in dry THF (20 ml) at −65° C. Stirring at −65° C. was continued for 3.5 h. Then isopropanol and diethylether were added, the organic layer was washed with aqueous ammonium chloride solution, dried (Na2SO4) and evaporated. The residue was purified with flash chromatography using a cyclohexanes/ethyl acetate (40% to 100%) gradient to afford the title compound (900 mg, 46%). MS: (ES/+) m/z: 376 [M-BOC+], C25H30FNO7 requires 475; HPLC: 0.84 min, m/z: 476 [MH+], 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.6 (m, 2H), 7.4 (m, 2H), 7.3-7.2 (m, 4H), 5.2 (s, 2H), 4.1 (m, 1H), 3.8 (s, 3H), 3.6 (s, 3H), 3.2-3.0 (m, 2H), 2.1-2.0 (m, 1H), 1.9 (m, 1H), 1.4 (s, 9H).

Provenance & Evidence