Reaction #595330

Reaction equation

cyclopropanesulfonyl chloride

cyclopropanesulfonyl chloride

NaH

NaOH

HCl

NaH

1-(2-fluoro-4-iodophenyl)-5,7-dimethyl-1H-imidazo[4,5-c]pyridine-2,6(3H,5H)-dione

→

N-(4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)cyclopropanesulfonamide

Yield 35.0%

Solvents

THF

DMF

Conditions

Workup

1. 1
   Temperaturecooled to below 0° C. under an ice-bath
2. 2
   OtherThe cooling bath was removed
3. 3
   workup.ADDITIONafter addition
4. 4
   TemperatureThe same solution was re-cooled to −5° C. in a dry-ice/acetone bath
5. 5
   Temperatureto warm to room temperature
6. 6
   workup.STIRRINGstirred
7. 7
   workup.WAITwas and additional 16 hours
8. 8
   TemperatureThe reaction mixture was cooled to 0° C.
9. 9
   workup.ADDITIONwere added
10. 10
    workup.STIRRINGThe solution was stirred at room temperature for additional 5 hours
11. 11
    TemperatureThe mixture was heated to 65° C. for 40 minutes
12. 12
    TemperatureAfter cooled to room temperature
13. 13
    Extractionwas extracted with EtOAc (15 mL×3)
14. 14
    WashThe combined organic layers was washed with brine
15. 15
    Dryingdried (MgSO4)
16. 16
    Concentrationconcentrated under the reduced pressure
17. 17
    Otherto give a residue, which
18. 18
    Otherpurified

Procedure

To the solution of 1-(2-fluoro-4-iodophenyl)-5,7-dimethyl-1H-imidazo[4,5-c]pyridine-2,6(3H,5H)-dione (23 mg, 0.0576) dissolved in dry DMF (2 mL) cooled to below 0° C. under an ice-bath, was added NaH (60% in mineral oil) (5.0 mg, 0.125 mmol). The cooling bath was removed after addition and the solution was allowed to stir at room temperature for 1 hour. The same solution was re-cooled to −5° C. in a dry-ice/acetone bath, and added cyclopropanesulfonyl chloride (28 mg, 0.20 mmol) dissolved in dry THF (0.5 mL) slowly. The mixture was allowed to warm to room temperature and stirred was and additional 16 hours. The reaction mixture was cooled to 0° C., additional NaH (60% in oil) (5.0 mg, 0.125 mmol), followed by cyclopropanesulfonyl chloride (15 mg, 0.11 mmol) were added. The solution was stirred at room temperature for additional 5 hours. To the same reaction mixture was added aqueous NaOH (1N) (5 mL). The mixture was heated to 65° C. for 40 minutes. After cooled to room temperature, aqueous HCl (1N) (25 mL) was added to acidify the solution, which was extracted with EtOAc (15 mL×3). The combined organic layers was washed with brine, dried (MgSO4), and concentrated under the reduced pressure to give a residue, which was HPLC purified. (9.6 mg, 35% yield). MW m/z: 478.08 (MW+1), 476.10 (MW−1). 1H NMR (DMSO-d6, 300 Hz): δ ppm 8.89 (s, 7.65 (s, 1H), 7.56 (dd, J=10.8, 1.5 Hz, 1H), 7.42 (s, 1H), 7.0 (d, J=8.7 Hz, 1H), 6.34 (t, J=8.7 Hz, 1H), 3.43 (s, 3H), 2.43 (m, 2H), 1.65 (s, 3H), 0.69-0.79 (m, 4H)

Source