Reaction Steps
A mixture of 5-bromo-2-(hydroxymethyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (Intermediate 30-3(a), 50 mg, 0.155 mmol), 5-tert-butyl-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoindoline-1,3-dione (Intermediate 50-11, 97 mg, 0.232 mmol), 2 M aqueous tripotassium phosphate (0.232 mL, 0.464 mmol), and tetrakis(triphenylphosphine)palladium (8.9 mg, 7.7 μmol) in toluene (3 mL) and ethanol (1 mL) was heated at 100° C. in a sealed tube overnight. The mixture was cooled to rt, treated with 1 M hydrochloric acid, extracted with EtOAc, and the organic phase was dried and concentrated to provide 5-tert-butyl-2-(3-(8-carbamoyl-2-(hydroxymethyl)-2,3,4,9-tetrahydro-1H-carbazol-5-yl)-2-methylphenylcarbamoyl)benzoic acid (Mass spectrum m/z 554.4 (M+H)+). Without purification, this material was dissolved in acetic acid (4 mL) and heated at 100° C. for 2 h, then was concentrated. The residue was purified by column chromatography (eluting with a gradient from DCM to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide), followed by purification by preparative HPLC. The appropriate effluent fractions were made basic with NaHCO3 (aq) and extracted with DCM, dried and concentrated to provide 5-(3-(5-tert-butyl-1,3-dioxoisoindolin-2-yl)-2-methylphenyl)-2-(hydroxymethyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (Example 31-2) as a light yellow solid (18 mg, 18%). 1H NMR (400 MHz, chloroform-d) δ 10.05 (1 H, s), 7.98-8.02 (1 H, m), 7.86-7.91 (1 H, m), 7.79-7.84 (1 H, m), 7.33-7.45 (4 H, m), 7.24-7.28 (2 H, m), 6.89-6.94 (1 H, m), 3.56-3.71 (2 H, m), 2.91 (1 H, dd, J=16.70, 4.83 Hz), 2.48-2.61 (1 H, m), 1.99-2.10 (2 H, m), 1.88-1.99 (2 H, m), 1.86 (3 H, s), 1.43-1.55 (2 H, m), 1.41 (9 H, s). Mass spectrum m/z 536.3 (M+H)+. Also obtained was (5-(3-(5-tert-butyl-1,3-dioxoisoindolin-2-yl)-2-methylphenyl)-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazol-2-yl)mEtOAc (Example 31-3) as a light yellow solid (15 mg, 14%). 1H NMR (400 MHz, chloroform-d) δ 10.05 (1 H, s), 7.97-8.05 (1 H, m), 7.86-7.91 (1 H, m), 7.79-7.84 (1 H, m), 7.33-7.41 (3 H, m), 7.26-7.28 (1 H, m), 4.00-4.13 (2 H, m), 2.90 (2 H, td, J=10.88, 5.05 Hz), 2.46-2.71 (2 H, m), 2.12-2.34 (2 H, m), 2.08 (4 H, s), 1.87 (3 H, d, J=7.03 Hz), 1.45-1.54 (1 H, m), 1.41 (9 H, s). Mass spectrum m/z 578.3 (M+H)+.
