4-Fluorobenzaldehyde → Rac-3-(4-fluoro-benzylamino)-5-methyl-hexanoic acid ethyl ester

Temperature

25 °C

4-Fluorobenzaldehyde (0.500 mL, 4.66 mmol), sodium acetate (0.766 g, 9.34 mmol), powdered/activated 4 Å molecular sieves (1.0 g) and sodium cyanoborohydride (0.587 g, 9.34 mmol) were added sequentially to a solution of racemic 3-amino-5-methyl-hexanoic acid ethyl ester hydrochloride (0.979 g, 4.67 mmol) in methanol (25 mL) at 25° C. The mixture was stirred at 25° C. for 22 h, and then was filtered through Celite. The Celite was washed with ethyl acetate (2×30 mL) and the combined filtrate and washings were partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes) to afford rac-3-(4-fluoro-benzylamino)-5-methyl-hexanoic acid ethyl ester (0.616 g, 2.19 mmol, 47%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.88 (3H, d, J=3.8 Hz), 0.90 (3H, d, J=3.4 Hz), 1.26 (3H, t, J=7.0 Hz), 1.43-1.49 (1H, m), 1.66-1.76 (1H, m), 2.48 (2H, d, J=6.3 Hz), 3.04-3.11 (1H, m), 3.76 (1H, d, J=13.6 Hz), 3.80 (1H, d, J=12.2 Hz), 4.10-4.18 (2H, m), 6.97-7.01 (2H, m), 7.29-7.32 (2H, m).

1. filtrationwas filtered through Celite
2. washThe Celite was washed with ethyl acetate (2×30 mL)
3. customthe combined filtrate and washings were partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL)
4. dry with materialThe combined organic layers were dried over sodium sulfate
5. concentrationwere concentrated in vacuo
6. customThe residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes)

ORD record

ord-a5266ffd1fbb45ed981924af7892c35a

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08097613B2