Reaction Steps
To a solution of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (10 mg, 0.023 mmol) in CH2Cl2 (5 mL) was added Et3N (0.020 mL, 0.140 mmol) and the resulting mixture cooled to 0° C. Added to this was 2-(1H-indol-3-yl)-2-oxoacetyl chloride (14.5 mg, 0.070 mmol) and the mixture stirred at room temperature (mixture became a clear colorless solution over time). After 1 h, 0.5 mL MeOH was added and the mixture was concentrated under a stream of air, taken up in MeOH and purified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm column). The product was repurified by preparative HPLC (10% AcCN/90% H2O/0.1% NH4OAc, Sunfire 19×100 mm, C18, 5 μm column). The product-containing fractions were combined, concentrated to remove the organic solvent and the resulting precipitate collected by filtration to give 2-(6-(2-(1H-indol-3-yl)-2-oxoacetyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-2-tert-butoxyacetic acid (2.4 mg, 16% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 8.24 (0.5H, d, J=5.80 Hz), 8.13 (0.5H, d, J=7.32 Hz), 8.05 (0.5H, s), 7.82 (0.5H, s), 7.48-7.68 (2H, m), 7.24-7.48 (4H, m), 7.09 (0.5H, t, J=5.80 Hz), 6.80-6.92 (0.5H, m), 6.71-6.80 (0.5H, m), 6.59-6.71 (0.5H, m), 4.72 (0.5H, s), 4.58 (0.5H, d, J=18.01 Hz), 4.37 (1H, dd, J=17.24, 8.09 Hz), 3.96 (0.5H, d, J=16.79 Hz), 3.77-3.93 (1H, m), 3.55-3.72 (2.5H, m), 1.49 (3H, d, J=7.02 Hz), 1.23-1.38 (6H, m), 1.17 (3H, t, J=5.80 Hz), 0.85-1.05 (9H, m). 19F NMR (500 MHz, CD3OD) δ ppm −115.51. LCMS (M+H) calcd for C35H39FN3O5: 600.28. found: 600.3.
