Yield:-

Reaction Conditions:

in toluene at 80; for 0.5 h;

Steps:

38

To a solution of triphosgene (609 mg, 2.14 mmol) in toluene (5 mL) was added dropwise a solution of 4-methyl-3-(trifluoromethyl)aniline (100 mg, 0.51 mmol) and refluxed at 80° C. for 0.5 h. Then the mixture was concentrated to give crude 4-isocyanato-1-methyl-2-(trifluoromethyl)benzene. To the solution of crude 4-isocyanato-1-methyl-2-(trifluoromethyl)benzene in THF (4 ml) was added (S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione 2,2,2-trifluoroacetic acid salt (52.2 mg, 0.18 mmol), followed by TEA (34 mg, 0.34 mmol). The mixture was stirred at RT for 2 h. The mixture was concentrated to give crude product, which was purified by prep-HPLC to give (S)-1-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(4-methyl-3-(trifluoromethyl)phenyl)urea (25.7 mg, 29.0%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (s, 1H), 8.94 (s, 1H), 7.89 (s, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.48 (dd, J=6.4, 8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.89 (t, J=6.0 Hz, 1H), 5.14 (dd, J=6.8, 12.0 Hz, 1H), 4.45 (d, J=6.0 Hz, 2H), 4.39 (d, J=4.8 Hz, 2H), 3.09-3.01 (m, 1H), 2.57-2.55 (m, 1H), 2.34 (s, 3H), 2.16-1.95 (m, 3H), 1.82-1.76 (m, 1H). MS (ESI) m/z 495.1 [M+H]⁺.

References:

US2018/170948,2018,A1 Location in patent:Paragraph 0522-0523