Compound 22

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

Crude 21 (4.4 g, 11.7 mmol, 1 equiv) was resuspended in CH₂Cl₂ (100 mL) and N,N-diisopropylethylamine (3.06 mL, 17.6 mmol, 1.5 equiv) and 3-(trifluoromethyl)phenyl isocyanate (1.61 mL, 11.7 mmol, 1 equiv) were added sequentially. The resulting mixture was stirred at room temperature overnight (ca. 16 h) and concentrated under reduced pressure. The crude product was purified by chromatography on SiO₂ (MeOH:CH₂Cl₂, 2:98 to 12:88) to give 2.5 g (38% yield) of the desired product tert-butyl (2-((1-(1-(pentan-2-yl)piperidin-4-yl)-3-(3-(trifluoromethyl)phenyl)ureido)methyl)phenyl)carbamate (22) as a colorless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.83 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.58 (bs, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.31 – 7.23 (m, 3H), 7.23 – 7.13 (m, 2H), 6.85 (s, 1H), 4.50 (s, 2H), 4.49 – 4.41 (m, 1H), 2.92 – 2.75 (m, 2H), 2.65 – 2.55 (m, 1H), 2.48 (t, J = 11.6 Hz, 1H), 2.34 (t, J = 11.6 Hz, 1H), 1.91 – 1.80 (m, 2H), 1.80 – 1.63 (m, 2H), 1.53 (s, 9H), 1.52 – 1.42 (m, 2H), 1.41 – 1.14 (m, 2H), 0.97 (d, J = 6.5 Hz, 3H), 0.89 (t, J = 7.0 Hz, 3H). ¹³C NMR (126 MHz, Chloroform-d) δ 155.5, 154.5, 140.4, 134.5, 132.9, 130.8 (q, J = 32.0 Hz), 128.9, 128.2, 127.1, 126.7, 125.5, 124.1 (q, J = 272.4 Hz), 122.7, 118.8 (q, J = 3.7 Hz), 116.5 (q, J = 4.0 Hz), 81.4, 59.1, 53.1, 49.7, 46.2, 42.6, 35.7, 30.4, 30.3, 28.3, 20.1, 14.2, 14.1. LRMS (ESI+) m/z calcd for C₃₀H₄₂F₃N₄O₃ [M+H]⁺ 563.3, found 563.5.

PubChemID:

336287090

MDL Molfile:

41589_2017_BFnchembio2386_MOESM61_ESM.mol

ChemDraw:

41589_2017_BFnchembio2386_MOESM62_ESM.cdx