Ethyl Acetate → (rac.)-(1R*,5S*)-3-{4-[2-(2,6-Dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-8-methyl-8-aza-bicyclo[3.2.1]oct-2-ene-2-carboxylic Acid Methyl Ester

Participants

Reaction Conditions

Reaction Steps

1-[2-(4-Bromo-phenoxy)-ethoxy]-2,6-dichloro-4-methyl-benzene (10.5 g, 28.0 mmol) was dissolved in THF (90 mL), and the sol. was cooled to −78° C. BuLi (1.6M in hexane, 18.2 mL, 29.1 mmol) was added, and the sol. was stirred at −78° C. for 1 h. ZnCl2 (1M in THF, 30.8 mL, 30.8 mmol) was added, and the mixture was allowed to warm to rt. A sol. of (rac.)-(1R*,5S*)-8-methyl-3-trifluoromethanesulfonyloxy-8-aza-bicyclo[3.2.1]oct-2-ene-2-carboxylic acid methyl ester (WO 2004/096799; 4.60 g, 14.0 mmol) in THF (10 mL), and then Pd(PPh3)4 (324 mg, 0.280 mmol) were added. The mixture was heated rapidly to 55° C., and stirred at this temperature for 30 min. The mixture was cooled to 0° C., and EtOAc (250 mL) was added. This mixture was washed with cold aq. 1M NaOH (1×), and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 5:95) yielded the title compound (5.77 g, 87%). LC-MS: tR=0.86 min; ES+: 476.26.

Provenance & Evidence