Oxalyl chloride → 2,3-Dichloroaniline

A room temperature solution of 2-fluoronicotinic acid (1 g) in DCM (20 mL) was sequentially treated with DMF (0.2 mL) and oxalyl chloride (0.62 mL, 1 eq). The resulting solution was stirred at RT for 1 hour and monitored by HPLC (analyte quenced with methanol) until the consumption of starting material was complete. The reaction mixture was cooled to 0° C. and sequentially treated with 2,3-difluoroaniline (1.4 g, 1.5 eq) and 2 mL of triethylamine. The reaction was warmed to RT and maintained for 3 additional hours, followed by washing the mixture with 2N HCl, saturated NaCl, and saturated NaHCO3 solution. The organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude 2-fluoro-N-(2,3-difluorophenyl)pyridine-3-carboxamide was dissolved in NMP (20 mL) and reacted with excess t-butylamine at 80° C. for 14 hours. After cooling to RT, the solution was poured into sat NaHCO3 solution. The resulting precipitate was collected by filtration and washed with water. The crude product, 2-(tert-butylamino)-N-(2,3-difluorophenyl)pyridine-3-carboxamide, was dried in vacuo and used directly in the next reaction without further purification. Using the same procedure, 2-(tert-butylamino)-N-(2,3-dichlorophenyl)pyridine-3-carboxamide and 2-(tert-butylamino)-N-(3-chloro-2-fluorophenyl)pyridine-3-carboxamide can be produced from the reaction of 2-fluoronicotinic acid with 2,3-dichloroaniline and 3-chloro-2-fluoroaniline, respectively.

1. custommonitored by HPLC (analyte quenced with methanol) until the consumption of starting material
2. temperatureThe reaction mixture was cooled to 0° C.
3. temperatureThe reaction was warmed to RT
4. temperaturemaintained for 3 additional hours
5. washby washing the mixture with 2N HCl, saturated NaCl, and saturated NaHCO3 solution
6. dry with materialThe organic extracts were dried over MgSO4
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. dissolutionThe resulting crude 2-fluoro-N-(2,3-difluorophenyl)pyridine-3-carboxamide was dissolved in NMP (20 mL)
10. customreacted with excess t-butylamine at 80° C. for 14 hours
11. temperatureAfter cooling to RT
12. additionthe solution was poured
13. filtrationThe resulting precipitate was collected by filtration
14. washwashed with water
15. dry with materialThe crude product, 2-(tert-butylamino)-N-(2,3-difluorophenyl)pyridine-3-carboxamide, was dried in vacuo
16. customused directly in the next reaction without further purification

ORD record

ord-2945f749b62946f08d1ec5096eaa4ea7

Source dataset

uspto-grants-2011_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07872031B2