Reaction Steps
(D,L)-, (D)- or (L)-Alanine (347 mg, 7.8 mmol) and Cs2CO3 (2.54 g, 7.8 mmol) were added to the solution of N-methyl-2,4-difluorobenzamide (667 mg, 3.9 mmol) in DMSO (3 ml). The reaction mixture was stirred in closed vial at 90° C. for 18 h. Cooled mixture was diluted with isopropanol, neutralized with HCl (1.36 ml, 15.6 mmol), filtered, evaporated in vacuo, and by HPLC method N-(4-methylcarbamoyl-3-fluorophenyl)alanine 4.2(2) (R1=CH3, R4=H, R5=CH3), (S)—N-(4-methylcarbamoyl-3-fluorophenyl)alanine (S)-4.2(2) or (R)—N-(4-methylcarbamoyl-3-fluorophenyl)alanine (R)-4.2(2) were isolated. LCMS (M+H)+ 241. 1H NMR (DMSO-d6, 400 MHz): 12.66 (br. s, 1H), 7.62 (m, 1H), 7.45 (t, J=8.8 Hz, 1H), 6.67 (br. d, J=7.2 Hz, 1H), 6.42 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H), 6.29 (dd, J1=14.8 Hz, J2=2.0 Hz, 1H), 4.03 (m, 1H), 2.73 (d, J=4.4 Hz, 3H), 1.37 (d, J=7.2 Hz, 3H). Solution of amine 4.2(2), (S)-4.2(2) or (R)-4.2(2) (110 mg, 0.46 mmol) and 4-isothiocyanato-2-(trifluoromethyl)-benzonitrile 3.2 (144 mg, 0.55 mmol) in DMF (2 ml) was stirred at 90° C. for 12 h in microwave oven, then additional portion of 4-isothiocyanato-2-(trifluoromethyl)-benzonitrile 3.2 (50 mg, 0.19 mmol) was added and stirring was continued for another 12 h. The reaction mixture was evaporated in vacuo, and by HPLC method N-methyl-4-{5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl}-2-fluorobenzamide 1.2(2), or N-methyl-4-{(S)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl}-2-fluorobenzamide (S)-1.2(2) or N-methyl-4-{(R)-5-methyl-4-oxo-2-thioxo-3-[3-(trifluoromethyl)-4-cyanophenyl]imidazolidin-1-yl}-2-fluorobenzamide (R)-1.2(2) were isolated, respectively. The apparent inhibition constant of androgen receptors (Ki) for these compounds are: Ki1.2(2)=140.2 nM, Ki(S)-1.2(2)=106.7 nM Ki(R)-1.2(2)=73.6 nM, respectively. LCMS (M+H)+ 451. 1H NMR (CDCl3, 400 MHz): 8.28 (t, J=8.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.94 (d, J=1.2 Hz, 1H), 7.81 (dd, J1=8.0 Hz, J2=1.2 Hz, 1H), 7.48 (dd, J1=12.4 Hz, J2=1.6 Hz, 1H), 7.36 (dd, J1=8.4 Hz, J2=1.6 Hz, 1H), 6.72 (br. m, 1H), 4.83 (q, J=7.2 Hz, 1H), 3.08 (d, J=4.8 Hz, 3H), 1.60 (d, J=7.2 Hz, 3H).
