2-(Trifluoromethyl)aniline → N-(2-trifluoromethyl-phenyl)-malonamic acid benzyl ester

A solution of mono-benzyl malonate (890 mg, 4.6 mmol) in 3:1 CH2Cl2/DMF (24 mL) was treated sequentially with N,N-diisopropylethylamine (2.0 mL, 11.5 mmol), 2-trifluoromethyl-phenylamine (0.6 mL, 4.6 mmol), and HATU (2.1 g, 5.5 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide N-(2-trifluoromethyl-phenyl)-malonamic acid benzyl ester as an oil (894 mg, 57% yield). This material was dissolved in EtOAc (35 mL). The resultant solution was charged with 10% Pd/C (178 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo to provide N-(2-trifluoromethyl-phenyl)-malonamic acid (621 mg, 95% yield). A portion of this material (100 mg, 0.4 mmol) was combined with [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (150 mg, 0.4 mmol, prepared as described in WO PCT 0250019) and dissolved in 6 mL of 3:1 CH2Cl2/DMF. The resultant solution was charged sequentially with N,N-diisopropylethylamine (0.35 mL, 1.5 mmol) and HATU (182 mg, 0.48 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide {(2S,3S)-3-hydroxy-2-[2-(2-trifluoromethyl-phenylcarbamoyl)-acetylamino]-hex-4-ynyl}-carbamic acid benzyl ester (54 mg, 28% yield). MS found: (M+Na)+=514.5. (1b) A solution of {(2S,3S)-3-hydroxy-2-[2-(2-trifluoromethyl-phenylcarbamoyl)-acetylamino]-hex-4-ynyl}-carbamic acid benzyl ester (54 mg, 0.11 mmol) in MeOH (2 mL) was charged with 5% Pd/C, Degussa style (10 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (2 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde and sodium cyanoborohydride, stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=480.6.

1. concentrationconcentrated in vacuo
2. custompartitioned between EtOAc and sat. NH4Cl
3. extractionThe aqueous phase was extracted with EtOAc (1×)
4. washThe combined organic extracts were washed with sat. NaHCO3 and brine
5. dry with materialdried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customThe residue was purified by flash chromatography

ORD record

ord-27357daf6856462fad764f70ba1a5e75

Source dataset

uspto-grants-2008_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07468440B2