Reaction #69375

Reaction equation

methylamine

3,5-difluoro-4-formylbenzoic acid

oxalyl chloride

HCl

→

title compound

Yield 80.2%

3,5-difluoro-4-formyl-N-methylbenzamide

Yield 80.2%

Solvents

dichloromethane

Conditions

Workup

1. 1
   Otheran internal temperature of 10° C
2. 2
   workup.STIRRINGstirred for an additional 1.5 hr
3. 3
   TemperatureThe solution was then cooled to 0° C.
4. 4
   Otheran internal temperature of 7° C
5. 5
   Temperaturewarmed to room temperature
6. 6
   OtherThe organic layer was separated
7. 7
   Washwashed with brine (500 mL)
8. 8
   Dryingdried over MgSO4
9. 9
   Filtrationfiltered
10. 10
    Concentrationconcentrated under vacuum
11. 11
    Temperaturethe resulting mixture was heated
12. 12
    Temperatureto reflux for 0.5 hr
13. 13
    Temperaturecooled to room temperature
14. 14
    workup.STIRRINGstirred for 18 hr
15. 15
    TemperatureAfterward, the mixture was cooled to 0° C.
16. 16
    Filtrationfiltered
17. 17
    Washrinsed with pentane
18. 18
    Otherdried under vacuum

Procedure

To an ice-cold solution of 3,5-difluoro-4-formylbenzoic acid (120 g, 645 mmol) in dichloromethane (1.5 L) and N,N-dimethylformamide (2.0 g, 27 mmol) was added oxalyl chloride (90 g, 709 mmol) drop-wise at a rate that allowed the mixture to not exceed an internal temperature of 10° C. The resulting mixture was stirred at the same temperature for 0.5 hr, warmed to room temperature, and stirred for an additional 1.5 hr. The solution was then cooled to 0° C., and aqueous methylamine (40%, 168 mL, 1.94 mol) was added drop-wise at a rate that allowed the mixture to not exceed an internal temperature of 7° C. Afterward, the mixture was quenched with aqueous HCl (2M, 335 mL, 670 mmol) and warmed to room temperature. The organic layer was separated, washed with brine (500 mL), dried over MgSO4, filtered, and concentrated under vacuum. The resulting residual solid was taken in MTBE (500 mL), and the resulting mixture was heated to reflux for 0.5 hr, cooled to room temperature, and stirred for 18 hr. Afterward, the mixture was cooled to 0° C., filtered, rinsed with pentane, and dried under vacuum to form the title compound (103 g, 80%) as a solid. 1H NMR (300 MHz, CDCl3) δ ppm 3.03 (d, J=4.86 Hz, 3H), 6.37 (br s, 1H), 7.36-7.42 (m, 2H), 10.36 (s, 1H); MS m/z 200.06 [M+H]+ (ESI).

Source