| 73% |
Stage #1: With dihydrogen peroxide In tetrahydrofuran; water at 0℃; for 0.416667 h; Inert atmosphere
Stage #2: With lithium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 16 h; Inert atmosphere |
General procedure: The title compd was prepared as per Scheme 2 (steps a-d). Steps a-b:To a solution of 3-cyclopentylpropanoic acid 30 (46.6 g, 0.33mol) in freshly distilled anhydrous THF (0.9M) was added triethylamine (52mL, 0.38mol), the mixture was cooled to −78 °C and pivaloyl chloride (41mL, 0.33 mol) was added dropwise, stirred for 15min at −78 °C then allowed to warm to rt and stirred for 1 h (white suspension forms). To asolution of (S)-4-benzyloxazolidin-2-one (59.2mg, 0.33 mol) in freshly distilled THF was added nBuLi (2.5M in THF, 134mL, 0.33mol) and the mixture stirred for 20 min at −78 °C whereupon it was added to the precooled (−78 °C) pivalic anhydride prepared in situ above. The result antmixture was stirred for 30min at −78 °C whereupon the reaction was allowed to reach rt by removing the cooling bath. Saturated aq NH4Cl (500mL) was then added and the aq phase extracted with EtOAc (2×200 mL). Combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude thus obtained was subjected to flash chromatographic purification using 20percent EtOAc in petroleum etherto obtain 91 g (91percent) (S)-4-benzyl-3-(3-cyclopentylpropanoyl)oxazolidin-2-one (34) as white solid. 1H NMR (CDCl3) δ: 7.43 – 7.12 (m, 5H), 4.67(ddt, J=10.2, 7.0, 3.4 Hz, 1H), 4.27 – 4.10 (m, 2H), 3.30 (dd, J=13.4,3.3Hz, 1H), 3.08 – 2.83 (m, 2H), 2.76 (dd, J=13.3, 9.6 Hz, 1H), 1.93 –1.42 (m, 10H), 1.20 – 1.04 (m, 2H). Step c: To a stirred solution of 34(95 g, 0.315 mol) in THF (0.08M) at−78 °C was added NaHMDS (1M inTHF, 410mL, 0.41 mol) dropwise over 1 h, whereupon tert-butyl bromoacetate (70 mL, 0.41mol) was added dropwise over 30 min at −78 °C. The cooling bath was then removed to allow the reaction to warm to rtand stirred overnight. The mixture was then cooled using an ice-bath and saturated aq NH4Cl added slowly (300mL), followed by water (100mL); then the aq phase was extracted with EtOAc (200 mL) and the combined organic extracts dried (Na2SO4), filtered and evaporated to dryness. The thus obtained crude was purified by flash chromatography using 5–30percent EtOAc in petroleum ether gradient to obtain 73 g (56percent) of tert-butyl (R)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(cyclopentylmethyl)-4-oxobutanoate (38) as white solid. Step d: To a stirred solution of 38 (73 g, 0.18mol) in 750mL THF/water (4:1, v/v) at 0 °C was added H2O2 (35percent in water, 68mL, 0.7mol) dropwise over 15min. Stirring was continued for 10 min, then 1M aq LiOH (300mL, 0.35mol) was added dropwise over 15 min whereupon the mixture was allowed to warm to rt and stirred for 16 h till reaction deemed completed by LCMS. The reaction mixture was cooled using an ice-bath and a solution of sodium bisulfite (225 g, 1.8mol) in water (1 L) was added dropwise over 1 h. (Caution: slight exotherm during this addition) The bulk of THF was removed in vacuo and the thus obtained aq layer (pH∼12) was washed with Et2O (3×500 mL), cooled (ice-bath) and acidified to pH 1–2 with 6M HCl and extracted with EtOAc (5×500mL). The combined extracts dried (MgSO4), filtered and concentrated in vacuo to dryness to obtain the titlecompound, 42 (30 g, 65percent) as pale yellow oil. 1H NMR (CDCl3) δ: 2.80 (td,J=8.5, 7.6, 4.4Hz, 1H), 2.60 (dd, J=16.4, 9.3 Hz, 1H), 2.39 (dd,J=16.4, 5.1 Hz, 1H), 1.96 – 1.65 (m, 5H), 1.49 (m, 4H), 1.43 (s, 9H),1.07 (m, 2H). |
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