Dimethylformamide → 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide

温度

80 °C

DMF (2.55 mL, 33.0 mmol) and SOCl2 (24.08 ml, 330 mmol) were added to a suspension of 5-bromo-6-chloro-nicotinic acid (26 g, 110 mmol) in toluene (220 mL) and the RM was stirred at 80° C. for 1 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in THF (220 mL) and cooled to −16° C. DIPEA (38.4 mL, 220 mmol) was added, followed by dropwise addition of a solution of 4-(chlorodifluoromethoxy)aniline (22.35 g, 115 mmol) in THF (220 mL) over 15 min. The suspension was stirred for 1 h at RT. The solvent was evaporated off under reduced pressure and the residue was dissolved in TBME (700 mL), washed with 1N HCl (2×200 mL), sat. NaHCO3 (200 mL) and brine (2×200 mL), dried over Na2SO4, and the solvent was evaporated off under reduced pressure to give the product which was crystallized from EtOAc—n-heptane to afford the title compound as a white crystalline solid. HPLC (Condition 5) tR=7.77 min, UPLC-MS (Condition 3) tR=1.24 min, m/z=409.1/411.1/413.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.38 (d, =8.99 Hz, 2H) 7.85 (d, =8.99 Hz, 2H) 8.72 (br. s, 1H) 8.92 (br. s, 1H) 10.68 (s, 1H).

1. customThe solvent was evaporated off under reduced pressure
2. dissolutionthe residue was dissolved in THF (220 mL)
3. temperaturecooled to −16° C
4. stirringThe suspension was stirred for 1 h at RT
5. customThe solvent was evaporated off under reduced pressure
6. dissolutionthe residue was dissolved in TBME (700 mL)
7. washwashed with 1N HCl (2×200 mL), sat. NaHCO3 (200 mL) and brine (2×200 mL)
8. dry with materialdried over Na2SO4
9. customthe solvent was evaporated off under reduced pressure
10. customto give the product which
11. customwas crystallized from EtOAc—n-heptane

ORDレコード

ord-20b29f4d4865480ba21beca489ef35de

出典データセット

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08829195B2