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

Temperature

80 °C

6-Chloro-5-iodo-3-pyridinecarboxylic acid (18 g, 62.2 mmol) was suspended in toluene (125 mL). DMF (1.446 mL, 18.67 mmol) and SOCl2 (13.63 mL, 187 mmol) were added at RT. The RM was stirred at 80° C. for 1 h, cooled to RT then the solvent was evaporated off under reduced pressure to give a residue that was dissolved in THF (125 mL) and cooled to −15° C. DIPEA (21.74 mL, 124 mmol) was added at −15° C., and the cold mixture was treated dropwise with a solution of 4-(chlorodifluoromethoxy)aniline in THF (125 mL) over 12 min. The resulting fine orange suspension was stirred for 1 h at RT. The solvent was evaporated off under reduced pressure and the residue was dissolved in TBME (500 mL), and sequentially washed with 1N HCl (2×150 mL), sat. aq. NaHCO3 solution (2×150 mL) and brine (2×150 mL). The aq. phases were extracted with TBME (400 mL). Combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure until crystallization began (around 100 mL). n-Heptane (800 mL) was then added with stirring and the light yellow suspension was stirred at RT for 30 min. The crystalline product was filtrated, washed with n-heptane (200 mL) and dried to afford the title product as a beige solid. LC-MS (Condition 3) tR 1.25 min, 459.0/460.7/462.1 [M+H]+.

1. temperaturecooled to RT
2. customthe solvent was evaporated off under reduced pressure
3. customto give a residue that
4. temperaturecooled to −15° C
5. stirringThe resulting fine orange suspension was stirred for 1 h at RT
6. customThe solvent was evaporated off under reduced pressure
7. dissolutionthe residue was dissolved in TBME (500 mL)
8. washsequentially washed with 1N HCl (2×150 mL), sat. aq. NaHCO3 solution (2×150 mL) and brine (2×150 mL)
9. extractionThe aq. phases were extracted with TBME (400 mL)
10. dry with materialCombined organic phases were dried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated under reduced pressure until crystallization
13. additionn-Heptane (800 mL) was then added
14. stirringwith stirring
15. stirringthe light yellow suspension was stirred at RT for 30 min
16. filtrationThe crystalline product was filtrated
17. washwashed with n-heptane (200 mL)
18. customdried

ORD record

ord-bba9dc094cf94c0eac014078e74aa978

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09278981B2