Acetone → HCID 15378772, compound

Participants

Reaction Steps

To a slurry of crude (R)-(4-phenylphenoxy)methyl-3-(2-phenylethyl)-3-[(4-phenylphenoxy)methoxy]hexanoate (X, EXAMPLE 7, 56.5 wt %, 49.32 g, 46.38 mmol) in toluene (500 ml) is added a solution of diisobutylaluminum hydride in toluene (1.52 M, 85 ml, 129.2 mmol, 2.79 equiv) while maintaining −20°. The mixture is slowly warmed to 1° over 2.5 hrs, then stirred ½ hr. Acetone (8.0 ml, 108.5 mmol, 2.34 equiv) is added and the mixture cannulated into an 18° solution of citric acid monohydrate (136 g, 647.2 mmol, 14.0 equiv) in water (433 ml) with controlled exotherm to 28°, rinsing with toluene (100 ml). The mixture is stirred at 20-25° for 1.5 hrs and the insolubles removed by vacuum filtration, washing with toluene. The phases are separated in the filtrate and the aqueous phase is washed with toluene (2×300 ml). The organic phases are dried over magnesium sulfate, then washed with aqueous sodium hydroxide (0.5 M, 2×500 ml). The organic phases are concentrated to 137 g net weight and methanol (250 ml) is added. The resultant slurry is is concentrated and methanol (250 ml) is added. The mixture is again concentrated and methanol (250 ml) added. The slurry is cooled to −60° and the insolubles removed by filtration. The filtrate is concentrated 60 g net weight, hexane (500 ml) is added, and the mixture concentrated to 22 g net weight. Hexane (500 ml) is added and the mixture again concentrated to 40 g net weight. Methylene chloride (25 ml) is added followed by a slow addition of hexane (500 ml) and pentane (250 ml) with cooling to −55°. The product is collected by vacuum filtration, washed with pentane (200 ml) and dried in a nitrogen stream to give the desired product. An analytical sample is obtained by chromatography (ethyl acetate/hexane) followed by crystallization (methylene chloride/hexane) to give the title compound, mp=49-53°; TLC Rf=0.14 (15% ethyl acetate/hexane); HPLC rt=9.18 min; NMR (CDCl3) 7.56-7.07, 5.36, 3.76-3.74, 2.63-2.58, 1.94-1.88, 1.70-1.65, 1.38-1.30, 0.93 δ; CMR (CDCl3) 157.05, 142.25, 140.73, 134.68, 128.70, 128.42, 128.29, 128.21, 126.76, 125.85, 116.07, 87.05, 81.85, 58.89, 38.77, 38.60, 38.23, 29.90, 17.04, 14.62 δ; MS (CI, NH3) m/z (relative intensity) 423 (2.3), 422 (9.9), 252 (100); [α]25D=6 (C=1.0, methylene chloride).

Provenance & Evidence