2-Fluoro-4-iodoaniline → 4-(2-Fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

Temperature

-78 °C

To the stirred solution of 2-fluoro-4-iodoaniline (470 mg, 1.94 mmol) in dry THF (4 mL) cooled to −78° C., was added LDA (2M in THF) (1.35 mL, 2.70 mmol). After vigorous stirring for 10 minutes at this temperature, a solution of 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (160 mg, 0.792 mmol) dissolved in dry THF (8 mL) was added dropwise through a syringe. The dry-ice bath was removed after 1 hour, and the reaction was stirred for 16 hours at room temperature At this time, LC/MS indicated 23% of the title product and 33% of unreacted chloride in the reaction mixture. The same reaction mixture was continued to stir at room temperature for additional 24 hours. The mixture was then re-cooled to −78° C. under a dry-ice/acetone bath. Additional LDA (1.35 mL, 2.70 mmol) (2M in THF) was added to the reaction mixture and slowly warmed to room temperature in 16 hours until LC/MS showed the consumption of chloride material. The mixture was cooled to −5° C., and aqueous HCl (1N) (15 mL) was added. The solution was extracted with EtOAc (15 mL×3). The combined organic layers was dried (MgSO4) and concentrated to give a residue which was triturated with DCM to give a solid. The title compound was used for the next reaction without further purification. (165 mg, 52% yield).

1. additionwas added dropwise through a syringe
2. customThe dry-ice bath was removed after 1 hour
3. stirringthe reaction was stirred for 16 hours at room temperature At this time, LC/MS
4. stirringto stir at room temperature for additional 24 hours
5. temperatureslowly warmed to room temperature in 16 hours until LC/MS
6. customthe consumption of chloride material
7. temperatureThe mixture was cooled to −5° C.
8. additionaqueous HCl (1N) (15 mL) was added
9. extractionThe solution was extracted with EtOAc (15 mL×3)
10. dry with materialThe combined organic layers was dried (MgSO4)
11. concentrationconcentrated
12. customto give a residue which
13. customwas triturated with DCM
14. customto give a solid

ORD record

ord-deb2c90c71ca428994164fa0e1806517

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07897624B2