2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), 1-(3,3-difluoroazetidin-1-yl)-2-(piperidin-4-yloxy)ethanone (88) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compounds were evaporated to dryness to afford 4-(3-(4-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethoxy)piperidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (89) as a white solid (0.061 g, 17.7% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.67-1.48 (2H, m), 1.86-1.75 (1H, m), 2.01-1.89 (1H, m), 3.19-3.06 (1H, m), 3.56-3.39 (2H, m), 3.66-3.57 (1H, m), 4.17-3.95 (3H, m), 4.28 (2H, s), 4.39-4.33 (2H, m), 4.62-4.57 (2H, m), 7.02 (1H, t), 7.31-7.26 (2H, m), 7.79-7.70 (3H, m), 8.48-8.46 (1H, m), 10.53 (1H, s) m/z (LC-MS, ESI+), RT=1.83 (M+H 515). and 2-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidin-4-yloxy)acetic acid (90) as a white solid (0.016 g, 5.50%); 1H NMR (400.132 MHz, CDCl3) δ 1.68-1.60 (1H, m), 1.84-1.71 (2H, m), 2.05-1.96 (1H, m), 3.16-3.04 (1H, m), 3.53-3.45 (2H, m), 3.78-3.68 (1H, m), 4.23-4.04 (3H, m), 4.32-4.28 (2H, m), 7.07-7.02 (1H, m), 7.30-7.24 (2H, m), 7.86-7.74 (3H, m), 8.47-8.42 (1H, m), 11.12 (1H, s) COOH missing; m/z (LC-MS, ESI+), RT=0.91 (M+H 440).
