4-Isothiocyanato-2-(trifluoromethyl)benzonitrile → HCID 86683694, compound

Participants

Reaction Steps

A solution of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (320 mg, 1.51 mmol) 3.2 and ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-β-alaninate (404 mg, 1.51 mmol) 5 (R1=CH3) in DMF (8 ml) was heated at 60° C. in microwave stove for 8 h. The reaction mixture was evaporated in vacuo, and by means of colomn chromatography on SiO2 (eluent—n-hexane:AcOEt=1:2) ethyl N-[4-(methylcarbamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]thiocarbamoyl}-β-alaninate 6(2) (R1=CH3, X═S) was isolated. LCMS (M+H)+ 497. A solution of NaOH (32 mg, 0.8 mmol) in water (0.25 ml) was added to a solution of ester (200 mg, 0.4 mmol) 6(2) in alcohol (1 ml), and the resultant mixture was stirred at 80° C. for 2 h (LCMS control), cooled and neutralized with HCl (69 mkl, 0.8 mmol), evaporated in vacuo, the residue was extracted with hot isopropanol and evaporated in vacuo again. It gave N-[4-(methylcarbamoyl)-3-fluorophenyl]-N-{[3-(trifluoromethyl)-4-cyanophenyl]thiocarbamoyl}-β-alanine 6(3) (R1=CH3, X═S). LCMS (M+H)+ 469. TBTU (86 mg, 0.36 mmol) and diisopropylethylamine (110 mg, 0.84 mmol) were added to the solution of the prepared acid (114 mg, 0.24 mmol) 6(3) in DMF (1.5 ml). The reaction mixture was stirred at 45° C. for 15 h. When the reaction was completed (LCMS control) the solution was poured into water and extracted with EtOAc. The organic layer was dried over Na2SO4, evaporated in vacuo and by HPLC method N-methyl-4-{[3-(trifluoromethyl)-4-cyanophenyl]-4-oxo-2-thioxo-tetrahydropyrimidin-1(2H)-yl}-2-fluorobenzamide 1.3.2(2) (R1=CH3, X═S) was isolated; Ki1.3.2(2)=95.2 nM. LCMS (M+H)+ 451. 1H NMR (DMSO-d6, 400 MHz): 8.35 (q, J=4.4 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H), 7.83 (dd, J1=8.0 Hz, J2=1.6 Hz, 1H), 7.71 (t, J=8.2 Hz, 1H), 7.42 (dd, J1=11.0 Hz, J2=1.8 Hz, 1H), 7.33 (dd, J1=8.2 Hz, J2=1.8 Hz, 1H), 4.13 (t, J=6.8 Hz, 2H), 3.17 (t, J=6.8 Hz, 2H), 2.78 (d, J=4.4 Hz, 3H).

Provenance & Evidence