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

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Reaction Steps

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). MS found: (M+H)+=248.02. (34b) A solution of (1R*,3R*,4S*)—N1-isopropyl-N1-methyl-3-(phenylsulfonylmethyl)cyclohexane-1,4-diamine (47.4 mg, 0.11 mmol, see example 25b) in DMF (2 mL) was charged sequentially with N-(2-trifluoromethyl-phenyl)-malonamic acid (29.5 mg, 0.12 mmol), BOP (72 mg, 0.16 mmol), and N-methyl morpholine (60 uL, 0.54 mmol). The solution was stirred for 14 h and the reaction was partitioned between water and EtOAc. The organic phase was washed with sat. NH4Cl, water, and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by RP-HPLC to afford the desired product as a white powder (presumed mono-TFA salt). MS found: (M+H)+=554.32.

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