反应详情

A solution of 4-hydroxybenzonitrile (48 mg, 0.40 mmol) and 4-(4-fluoro-3-(4-hydroxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (2a) (150 mg, 0.39 mmol) in dichloromethane (5 mL) was treated with polymer supported triphenylphosphine (ex-Biotage, 742 mg, 1.37 mmol) and di-tert-butyl azodicarboxylate (300 mg, 1.30 mmol). The reaction mixture was agitated at ambient temperature for 4-5 hours. Mixture was then filtered to remove resin, and filter cake washed through with methanol. Filtrate was evaporated to afford a waxy yellow solid, which was purified by repeated preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), firstly using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents, then using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents (Waters Sunfire Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length). Fractions containing the desired compound were evaporated to dryness and lyophilised to afford the desired product (17 mg, 8% yield); 1H NMR (400.132 MHz, DMSO) δ 1.49-1.69 (2H, m), 1.83-1.91 (1H, m), 1.99-2.06 (1H, m), 3.14-3.22 (1H, m), 3.32-3.51 (2H, m), 3.94-4.04 (1H, m), 4.33 (2H, s), 4.78-4.84 (1H, m), 7.15-7.18 (2H, m), 7.23 (1H, t), 7.36-7.44 (2H, m), 7.75-7.78 (2H, m), 7.80-7.90 (2H, m), 7.97 (1H, d), 8.26 (1H, d), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=2.20 (M+H 483.6).

1. filtrationMixture was then filtered
2. customto remove resin
3. filtrationfilter cake
4. washwashed through with methanol
5. customFiltrate was evaporated
6. customto afford a waxy yellow solid, which
7. customwas purified
8. additionFractions containing the desired compound
9. customwere evaporated to dryness