Reaction #595329

Reaction equation

LDA

LDA

2-fluoro-4-iodoaniline

4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

→

title compound

Yield 52.0%

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

Yield 52.0%

Solvents

THF

THF

Conditions

Workup

1. 1
   workup.ADDITIONwas added dropwise through a syringe
2. 2
   OtherThe dry-ice bath was removed after 1 hour
3. 3
   workup.STIRRINGthe reaction was stirred for 16 hours at room temperature At this time, LC/MS
4. 4
   workup.STIRRINGto stir at room temperature for additional 24 hours
5. 5
   Temperatureslowly warmed to room temperature in 16 hours until LC/MS
6. 6
   Otherthe consumption of chloride material
7. 7
   TemperatureThe mixture was cooled to −5° C.
8. 8
   workup.ADDITIONaqueous HCl (1N) (15 mL) was added
9. 9
   ExtractionThe solution was extracted with EtOAc (15 mL×3)
10. 10
    DryingThe combined organic layers was dried (MgSO4)
11. 11
    Concentrationconcentrated
12. 12
    Otherto give a residue which
13. 13
    Otherwas triturated with DCM
14. 14
    Otherto give a solid

Procedure

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). MW m/z: 403.13 (MW+1), 401.18 (MW−1). 1H NMR (DMSO-d6, 300 Hz): δ ppm 13.26 (s, br, 1H), 9.08 (s, 1H), 8.48 (s, 1H), 7.62 (d, J=10.8 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 6.49 (t, J=8.7 Hz, 1H), 3.48 (s, 3H), 1.58 (s, 3H)

Source