4-Fluorobenzylamine → Rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester

Temperature

25 °C

Diisobutylaluminum hydride (35.2 mL of a 1.0 M solution in toluene, 35.2 mmol) was added over 5 min to a solution of 2-tert-butyl-malonic acid diethyl ester (3.81 g, 17.6 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (30 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (2.34 g, 13.6 mmol, 77%). This material was dissolved in ethanol (40 mL) at 25° C. and 4-fluorobenzylamine (1.55 mL, 13.6 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.71 g, 27.2 mmol) were added sequentially. The mixture was stirred at 25° C. for 36 h, and then was concentrated in vacuo. The residue was 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; 10-70% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester (1.25 g, 4.44 mmol, 33%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.96 (9H, s), 1.28 (3H, t, J=7.0 Hz), 2.39 (1H, dd, J1=3.5 Hz, J2=11.4 Hz), 2.46 (1H, dd, J1=3.9 Hz, J2=9.5 Hz), 2.73 (1H, dd, J1=3.7 Hz, J2=11.7 Hz), 3.71 (2H, d, J=13.2 Hz), 3.78 (1H, d, J=13.4 Hz), 4.14-4.20 (2H, m), 6.95-7.00 (2H, m), 7.22-7.26 (2H, m).

1. customwas quenched with saturated aqueous ammonium chloride (30 mL)
2. customThe cold bath was removed
3. addition1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially
4. customThe biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL)
5. dry with materialThe organic layer was dried over sodium sulfate
6. concentrationwas concentrated in vacuo
7. customto afford crude product (2.34 g, 13.6 mmol, 77%)
8. stirringThe mixture was stirred at 25° C. for 36 h
9. concentrationwas concentrated in vacuo
10. customThe residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL)
11. dry with materialThe combined organic layers were dried over sodium sulfate
12. concentrationwere concentrated in vacuo
13. customThe residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes)

ORD record

ord-75ee18e806404b08bb3cf5941a6e7a2f

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08222404B2