2-Fluoro-4-iodoaniline → 3-((2-Fluoro-4-iodophenyl)amino)isonicotinic acid

A mixture of 2-fluoro-4-iodoaniline (20.0 g, 84.38 mmol) in dry THF (80 mL) was cooled to −67° C. (dry ice/IPA bath) under nitrogen, prior to slow addition of 1.0 M lithium bis(trimethylsilyl)amide (255 mL, 255 mmol) via addition funnel, at a rate that kept the internal temp below −59° C. (˜2 h). After final addition, the yellow-green slurry was stirred for 30 min and then treated with 2-fluoroisonicotinic acid (8.0 g, 56.69 mmol). The bath was not removed, but the contents were allowed to slowly warm to room temp. After 4 days, the dark slurry was poured into a biphasic mixture of aqueous 2.0 N sodium hydroxide (1000 mL) and ethyl acetate (150 mL). The aqueous layer was separated and the organics were again extracted with base (1000 mL). The pH of the two aqueous layers was adjusted to −2 with concentrated hydrochloric acid. A yellow solid precipitated, which was filtered. The resultant yellow cake was washed with water (2×400 mL) and dried under high vacuum at 40° C. (17-19 g). LC/MS [(5.2 min; 359 (M+1)].

1. additionvia addition funnel
2. customthe internal temp below −59° C. (˜2 h)
3. additionAfter final addition
4. customThe bath was not removed
5. waitAfter 4 days
6. additionthe dark slurry was poured into a biphasic mixture of aqueous 2.0 N sodium hydroxide (1000 mL) and ethyl acetate (150 mL)
7. customThe aqueous layer was separated
8. extractionthe organics were again extracted with base (1000 mL)
9. customA yellow solid precipitated
10. filtrationwhich was filtered
11. washThe resultant yellow cake was washed with water (2×400 mL)
12. customdried under high vacuum at 40° C. (17-19 g)
13. custom5.2 min

ORDレコード

ord-b751755c3074471abb9f0f3d049827a0

出典データセット

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08841459B2