Compound QG3.0

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

In an argon-flushed flask fitted with a septum cap, tert-butyl 4-bromo-3-methylbenzoate 17 (Martin, S. W.et al. The synthesis and evaluation of a novel class of (E)-3-(1-cyclohexyl-1H-pyrazol-3-yl)-2-methylacrylic acid Hepatitis C virus polymerase NS5B inhibitors. Bioorg. Med. Chem. Lett. 21, 2869-2872 (2011)) (150 mg, 0.550 mmol, 12 eq.) was dissolved in dry THF (5ml) and the solution was cooled to –78°C. tert-BuLi (1.6 M in pentane, 300 μl, 0.472 mmol, 10 eq.) was slowly added dropwise, and stirring was continued at the same temperature for 10 minutes. Compound 13a (3-(allyl(methyl)amino)-7-(diallylamino)-5,5-dimethyldibenzo[b,e]silin-10(5H)-one) (19 mg, 0.047 mmol, 1 eq.) in dry THF (5 ml) was added dropwise via a syringe at –78 °C. The reaction mixture was stirred for 10 minutes, warmed to room temperature, further stirred for 2 hours, quenched with 1N HCl aq., and then basified with sat. aq. NaHCO₃. The aqueous solution was extracted with dichloromethane (x2), and the combined organic phase was washed with brine, dried over Na₂SO₄, filtered and evaporated. The resultant crude product was dissolved in MeOH (2 ml), and NaBH₄ was added to the solution at room temperature until the intense blue color disappeared (< 1 min). The reaction mixture was quenched with water, and the aqueous solution was extracted with ethyl acetate. The organic solution washed with water and brine, dried over Na₂SO₄, filtered and evaporated. The resultant crude product was dissolved in degassed dichloromethane (2 ml), then 1,3-dimethylbarbituric acid (145 mg, 0.922 mmol, 20 eq.) and Pd(PPh₃)₄ (6.0 mg, 5 µmol, 0.1 eq.) were added. The reaction mixture was stirred at 40 ^oC for 1 hour, and then cooled to room temperature. p-Chloranil (15.1 mg, 0.061 mmol, 1.3 eq.) was added to it and stirring was continued for 10 minutes. Short silica gel column chromatography (eluent: dichloromethane/methanol = 100/0, 98/2 to 60/40, 0.5% TFA) gave a blue fraction, which was evaporated. The resultant crude product was dissolved in TFA (1 ml) and water (200 µl) and the solution was stirred at room temperature for 30 minutes, and then evaporated. The residue was purified by HPLC (1st eluent; A/B = 90/10 to 10/90, 25 min: 2nd eluent; 70/30 to 30/70, 25 min) to afford 4’COOH 2’Me SiR610 (16.2 mg, 67%) as a blue solid. ¹H NMR (CD₃OD): δ 8.06 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 2.5 Hz, 1H), 7.02 (br s, 1H), 6.94 (d, J = 9.3 Hz, 1H), 6.62 (dd, J = 9.4 Hz, 1.8 Hz, 1H), 6.58 (dd, J = 9.3 Hz, 2.5 Hz, 1H), 3.07 (s, 3H), 2.11 (s, 3H), 0.562 (s, 3H), 0.549 (s, 3H); ¹³C NMR^* (CD₃OD): δ 169.8 (C), 169.2 (C), 158.4 (C), 157.5 (C), 150.0 (C), 144.9 (C), 143.1 (CH), 137.6 (C), 132.57 (C), 132.47 (CH), 130.5 (C), 128.08 (CH), 128.04 (C), 127.97 (C), 124.5 (CH), 117.0 (CH), 30.1 (CH₃), 19.4 (CH₃), –1.4 (CH₃), –1.6 (CH₃); HRMS-ESI (m/z): [M]⁺ calcd for C₂₄H₂₅N₂O₂Si: 401.16798; found: 401.16723 (0.8 mDa, 1.9ppm). ^*Some peaks corresponding to xanthene carbons were not recorded.

Compound 16 (as synthesized in the production of QG0.6) (2.9 mg, 3.8 µmol, 1 eq.), 4’COOH 2’Me SiR610 (2.4 mg, 4.5 µmol, 1.2 eq.), PyBOP (4.0 mg, 7.6 µmol, 2.0 eq.) were dissolved in DMF (200 µl). DIEA (10 µl, 56 µmol, 15 eq.) was added. The reaction mixture was stirred at room temperature for 1.5 hours, and purified by HPLC (1st; A/B = 90/10 to 10/90, 25 min: 2nd; C/B = 90/10 to 10/90, 25 min) to afford QG3.0 (2.3 mg, 53%) as a dark purple solid. ¹H NMR (CD₃OD): δ 8.79 –8.77 (m, 1H, NH), 8.77 (d, J = 1.5 Hz, 1H), 8.50 (d, J = 7.9 Hz, 1H, NH), 8.31 (dd, J = 7.9 Hz, 1.5 Hz, 1H), 7.89 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.22 (br s, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.13 (d, J = 9.4 Hz, 2H), 7.07 (dd, J = 9.5 Hz, 2.3 Hz, 2H), 7.03 (d, J = 2.3 Hz, 2H), 7.09 –7.02 (m, 1H), 6.97 (d, J = 9.3 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.57 (dd, J = 9.3 Hz, 2.4 Hz), 4.03 (m, 2H), 3.66 (s, 3H), 3.33 (s, 12H), 3.08 (s, 3H), 2.18 –2.16 (m, 4H), 2.13 (s, 3H), 1.72 –1.61 (m, 4H), 0.571 (s, 3H), 0.558 (s, 3H); ¹³C NMR^* (CD₃OD): δ 170.0 (C), 169.0 (C), 167.5 (C), 166.4 (C), 165.5 (C), 159.9 (C), 159.09 (C), 159.06 (C), 158.4 (C), 150.2 (C), 143.4 (C), 143.2 (CH), 138.01 (C), 137.93 (C), 137.6 (C), 136.5 (C), 132.7 (CH), 132.08 (CH), 131.94 (CH), 131.84 (CH), 131.1 (CH), 130.5 (CH), 130.2 (CH), 128.19 (C), 128.12 (C), 125.8 (CH), 124.4 (CH), 116.9 (CH), 115.7 (CH), 114.7 (C), 97.6 (CH), 53.1 (CH₃), 50.2 (CH), 49.9 (CH), 41.0 (CH₃), 32.35 (CH₂), 32.32 (CH₂), 30.1 (CH₃), 19.5(CH₃), –1.44 (CH₃), –1.63 (CH₃); HRMS-ESI (m/z): [M]^2+/2 calcd for C₅₆H₆₀N₆O₅Si: 462.21917; found: 462.21878 (0.4mDa, 0.9ppm). ^*Some peaks corresponding to xanthene carbons were not recorded.

PubChemID:

318172225

MDL Molfile:

41557_2017_BFnchem2648_MOESM39_ESM.mol

ChemDraw:

41557_2017_BFnchem2648_MOESM40_ESM.cdx