Acetic Acid → 4-Ethyl-2-(2-hydroxy-1-phenyl-ethylamino)-2-methyl-hexanoic acid

Participants

Reaction Conditions

Reaction Steps

To a solution of (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-[1,4]oxazin-2-one (5 g, 26.4 mmol, see WO-A-02/051983) in anhydrous 2-methyltetrahydrofuran (50 ml) was added boron trifluoride tetrahydrofuran complex (5.8 ml, 52.8 mmol) with stirring under nitrogen at −78° C. The resultant solution was then stirred at −78° C. for 1 hour. (2-Ethylbutyl)magnesium bromide as a solution in tetrahydrofuran (170 ml, 0.16 M, 27.7 mmol) was then added maintaining the temperature below −60° C. during the addition. The resultant solution was stirred at −78° C. for a further 2 hours. Acetic acid (0.6 ml 10.6 mmol) was then added and the solution warmed to 22° C. Saturated aqueous ammonium chloride (50 ml) was then added followed by water (100 ml). The phases were separated and the organic phase retained. The resultant solution was then distilled to dryness under vacuum. Toluene (75 ml) was then added and the organic solution was washed with water (25 ml) then saturated aqueous sodium chloride solution (25 ml) and the phases separated and the organic phase retained. Aqueous hydrochloric acid (100 ml, 1.5 M) was then added and the resultant biphasic mixture warmed to 30° C. and stirred for 2 hours. The phases were separated and the aqueous phase retained. Aqueous sodium hydroxide (47% w/w, 6 ml then 2M, 16 ml) was then added to give a pH of 5 by pH paper. The resultant slurry was stirred at 22° C. for 30 minutes and the solid was then isolated by filtration. The filter cake was washed with water (25 ml) and dried at 60° C. overnight under vacuum to give the title compound (4.1 g crude weight, 95% purity, 14.0 mmol, 53% yield): mp 149° C.; 1H-NMR (CD3OD, 300 MHz), δ: 0.83 (3H, t), 0.90 (3H, t), 1.06 (3H, s), 1.31-1.54 (5H, m) 1.73 (2H, d), 4.40 (1H, t), 7.46-7.50 (5H, m); LRMS (ES): m/z 293 [M]+.

Provenance & Evidence