Triethylamine → 4-(4-fluoro-3-(4-hydroxy-4-methylpiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

온도

25 °C

O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (572 mg, 1.51 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (300 mg, 1.01 mmol) and triethylamine (0.308 mL, 2.21 mmol) in N,N-dimethylformamide (3 mL) at 25° C. under an air atmosphere. The resulting solution was stirred at 25° C. for 10 minutes. A solution of 4-methylpiperidin-4-ol hydrochloride (154 mg, 1.02 mmol) and triethylamine (0.308 mL, 2.21 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the resulting solution stirred at 25° C. for 2 hours. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (3×50 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, which 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 compound were evaporated to dryness to afford the desired material as a gum (94 mg, 23.63% yield); 1H NMR (400.132 MHz, DMSO) δ 1.13 (3H, s), 1.29-1.47 (4H, m), 3.20-3.28 (4H, m), 4.32 (2H, s), 4.41 (1H, s), 7.19 (1H, d), 7.31 (1H, dd), 7.38-7.42 (1H, m), 7.83 (1H, td), 7.88 (1H, td), 7.96 (1H, d), 8.27 (1H, dd), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.45 (M+H 396.4).

1. stirringthe resulting solution stirred at 25° C. for 2 hours
2. washwashed sequentially with water (3×50 mL) and saturated brine (20 mL)
3. dry with materialThe organic layer was dried over MgSO4
4. filtrationfiltered
5. customevaporated
6. customto afford crude product, which
7. customwas purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length)
8. additionFractions containing the desired compound
9. customwere evaporated to dryness

ORD 기록

ord-3aba7beadd7f4730aa53bedce98b448e

출처 데이터셋

uspto-grants-2012_03

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08129380B2