Hydrochloric Acid → Methyl 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate

Temperature

-13 °C

To a stirred solution of 2-fluoro-4-iodoaniline (182 g, 0.77 mol) in THF (5.25 L) at −45° C. under nitrogen was added 1M lithium bis(trimethylsilyl)amide solution in hexanes (1260 g), over 28 minutes at −43 to −41.6° C. After 1 hour, 2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (155 g, 0.72 mol) in THF (1.05 L) was added over 43 minutes. The mixture was held for 1 hour 55 minutes at −46° C., then allowed to warm to −13° C. and quenched with water (186 mL, 10.3 mol) over 5 minutes, maintaining the temperature between −13° C. and −11° C. The mixture was then allowed to warm to 0° C. over 30 minutes. 2M HCl was then added over 1 hour until pH 7-8 was achieved (1855 mL added). After standing overnight the mixture was allowed to warm to ambient temperature, and sodium chloride solution (1 L, 15% w/v) was added. The lower (aqueous layer) was discarded and the THF layer was concentrated by distillation to approx 1.4 L. Iso-hexane (4.65 L) was added to the mixture at approximately 52° C. over 1 hour 15 minutes, and then the mixture was cooled to 20° C. over 3 hours. After 1 hour at 20° C., the mixture was cooled to 0° C. and held at this temperature overnight. The reaction mixture was then filtered, and the solid was washed with chilled iso-hexane (5° C.) (2×1.25 L). The solid was dried in a vacuum oven at 45° C. to provide 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (248 g, 0.60 mol, 83% yield). 1H NMR (D6-DMSO): δ 7.75 (d, 1H, J 1 Hz, ArH), 7.68 (dd, 1H, J 11, 2 Hz, ArH), 7.42 (d, 1H, J 8.5 Hz, ArH), 6.62 (˜t, 1H, J 8.5 Hz, ArH), 3.69 (s, 3H, OCH3), 3.22 (s, 3H, NCH3), 2.03 (s, 3H, ArCH3).

1. waitAfter 1 hour
2. waitThe mixture was held for 1 hour 55 minutes at −46° C.
3. temperaturemaintaining the temperature between −13° C. and −11° C
4. temperatureto warm to 0° C. over 30 minutes
5. addition(1855 mL added)
6. waitAfter standing overnight
7. temperatureto warm to ambient temperature
8. concentrationthe THF layer was concentrated by distillation to approx 1.4 L
9. additionIso-hexane (4.65 L) was added to the mixture at approximately 52° C. over 1 hour 15 minutes
10. temperaturethe mixture was cooled to 20° C. over 3 hours
11. waitAfter 1 hour at 20° C.
12. temperaturethe mixture was cooled to 0° C.
13. customheld at this temperature overnight
14. filtrationThe reaction mixture was then filtered
15. washthe solid was washed with chilled iso-hexane (5° C.) (2×1.25 L)
16. customThe solid was dried in a vacuum oven at 45° C.

ORD record

ord-559c31c673f240f58856ec0e94039c4e

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08299076B2