Thionyl Chloride → 3-Chloro-4-(2-fluoro-4-(1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide

To 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid (3.7 g, 10 mmol) in 6 mL of toluene was added thionyl chloride (10 mL, Aldrich ReagentPlus 99.5%). After stirring at rt for 2.5 h, the mixture became homogenous and was then concentrated in vacuo. Toluene (3 mL) was added to the residue and the mixture was concentrated in vacuo to remove excess thionyl chloride (performed twice). The crude acid chloride was then dried under high vacuum for 15 minutes. While the acid chloride was drying, 4-(4-amino-2-fluorophenoxy)-3-chloropicolinamide (2.5 g, 8.9 mmol) was dissolved in THF (50 mL) and DMF (3 mL). The solution was cooled to 0° C. and then N,N-diisopropylethylamine (3.1 mL, 18 mmol, Aldrich 99.5% redistilled) was added. The acid chloride was then added over 30 min as a solid. Upon completion of the addition, the cooling bath was removed and the reaction mixture was stirred at rt for 15 min before being quenched with saturated aqueous sodium bicarbonate solution (30 mL). Water was added (˜30 mL) to dissolve the salts and the mixture was extracted with ethyl acetate (1×100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (2% methanol/ethyl acetate) to give 4.9 g of the desired product along with a minor amount of 3-chloro-4-(4-(4-chloro-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide together as an off-white solid (89% based on iodide). 1H NMR (CD3OD) δ 8.34 (d, 1H, J=5.6 Hz), 7.92 (dd, 1H, J=12.4, 2.4 Hz), 7.51-7.47 (m, 4H), 7.37-7.29 (m, 3H), 6.99 (d, 1H, J=7.2 Hz), 6.86 (d, 1H, J=5.6 Hz); MS(ESI+) m/z 623.08 (M+H)+.

1. concentrationwas then concentrated in vacuo
2. additionToluene (3 mL) was added to the residue
3. concentrationthe mixture was concentrated in vacuo
4. customto remove excess thionyl chloride (
5. dry with materialThe crude acid chloride was then dried under high vacuum for 15 minutes
6. dry with materialWhile the acid chloride was drying
7. temperatureThe solution was cooled to 0° C.
8. additionUpon completion of the addition
9. customthe cooling bath was removed
10. stirringthe reaction mixture was stirred at rt for 15 min
11. custombefore being quenched with saturated aqueous sodium bicarbonate solution (30 mL)
12. additionWater was added (˜30 mL)
13. dissolutionto dissolve the salts
14. extractionthe mixture was extracted with ethyl acetate (1×100 mL)
15. dry with materialThe organic phase was dried over anhydrous sodium sulfate
16. concentrationconcentrated in vacuo
17. customThe crude product was purified by flash chromatography on silica gel (2% methanol/ethyl acetate)

ORD record

ord-bc0e8cfd3eae42e98e28f1d74b1223d1

Source dataset

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08536200B2