3-(Trifluoromethyl)aniline → Benzyl 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate

mono-Benzyl malonate (10 g) was dissolved in THF (100 ml), 4-methylmorpholine and cooled to −22° C. prior to the slow addition of diphenyl chlorophosphate (14 ml) and 3-trifluoromethyl-phenylamine (19 ml). After the reaction was warmed to rt overnight, it was heated to gently reflux for 0.5 h. After the reaction was cooled to rt, the solid was filtered off. The filtrate was concentrated. EtOAc was added along with 1N HCl solution. The organic layer was washed with NaHCO3 solution (aq) and brine, dried (MgSO4), filtered, and concentrated. Flash chromatography of the resulting residue gave N-(3-trifluoromethyl-phenyl)-malonamic acid benzyl ester (8.0 g): 1H NMR (CDCl3, δ ppm, 300 mHz) 3.56 (s, 2H),5.26 (s, 2H), 7.40 (m, 7H), 7.75 (d, 1H), 7.83 (s, 1H), 9.43 (s, br, 1H). (21b) A portion (6 g) of the above derivative (21a) was dissolved in MeOH (50 ml) prior to the addition of 10% Pd/C (4 g). A hydrogen balloon was added and the solution was stirred overnight. The palladium was filtered off and the solution was concentrated. Flash chromatography of the resulting residue gave N-(3-trifluoromethyl-phenyl)-malonamic acid (1.75 g). MS found: (2M−H)−=493.3. (21c) Derivative (21b)(65 mg) was incorporated into example (1e), to give the title compound (80 mg). MS found: (M+H)+=494.3.

1. temperatureit was heated
2. temperatureto gently reflux for 0.5 h
3. temperatureAfter the reaction was cooled to rt
4. filtrationthe solid was filtered off
5. concentrationThe filtrate was concentrated
6. additionEtOAc was added along with 1N HCl solution
7. washThe organic layer was washed with NaHCO3 solution (aq) and brine
8. dry with materialdried (MgSO4)
9. filtrationfiltered
10. concentrationconcentrated

ORD record

ord-a31a2780d4744bda96bd38917c820f70

Source dataset

uspto-grants-2007_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07291615B2