2-Benzyl 1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol → (3S,4R)-3-benzyl-7-bromo-chroman-4-ol

Participants

Reaction Steps

To a solution of (1 R, 2S)-2-benzyl 1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (prepared from 33.5 kg (54.8 moles) of [4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2- fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one, 1-methyl-2-pyrrolidinone solvate without isolation) in 185 L of tetrahydrofuran was added 12.9 kg (115 mol) of potassium tert-butoxide. The reaction mixture was heated at reflux for 4 hours at which point the reaction was found to be complete by thin layer chromatography (hexanes/ethyl acetate, 3:1). The reaction mixture was cooled to ambient temperature, quenched with 170 L of water, diluted with 83 L of ethyl acetate, and acidified to pH 5.3 (aqueous layer) with 7.5 L of concentrated hydrochloric acid. The organic layer was concentrated under vacuum to approximately 38 L of a slurry, diluted with 76 L of isopropyl ether, warmed to dissolve the solids, slowly cooled to 0° C., and granulated at 0° C. for 12 hours. (3S, 4R)-3-Benzyl-7-bromo-chroman-4-ol, 5.1 kg of white solid, was isolated by filtration. The mother liquor was washed with 4 L of saturated aqueous sodium chloride, concentrated to a final volume of 57 L, and granulated at 0° C. for 12 hours affording a 4.3 kg second crop of (3S, 4R)-3-benzyl-7-bromo-chroman-4-ol.

Provenance & Evidence