2,6-Dichlorobenzamide → EL 494

Temperature

-72 °C

A solution of 304 mg. of 2,6-dichlorobenzamide and 25 ml. of dry tetrahydrofuran was placed in a 3-necked, 50 ml. round bottomed flask. With mechanical stirring and under nitrogen the solution was cooled to about -72° C. in a dry ice/acetone bath. To this solution was added 0.6 ml. of n-butyllithium reagent over a period of 5 minutes. After the addition was complete, the mixture was stirred for 30 minutes at about -72° C. A solution of 268 ml. of 4-nitrophenyl chloroformate in 8 ml. of dry tetrahydrofuran was added dropwise over a period of 15 to 20 minutes. A pale yellow solution formed. After the addition was complete, the mixture was stirred for 30 minutes at about -72° C. giving a colorless solution. The cooling bath was adjusted so that the temperature was raised to between -40° C. and -30° C. and stirring was continued for 3 hours. The mixture was recooled to approximately -72° C. and a solution of 351 mg. of 2-amino-5-(4-bromophenyl)-6-methylpyrazine in 6 ml. of dry tetrahydrofuran was added dropwise over a period of 10 minutes. The cooling bath was removed allowing the mixture to warm to room temperature. The mixture was then heated at 50° C. for 16 hours to complete the reaction. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The ethyl acetate solution was washed 5 times with aqueous sodium carbonate solution and twice with salt water. The solvent was again evaporated and the residue dissolved in 2 ml. of tetrahydrofuran and chromatographed over silica gel using 4:1 benzene/tetrahydrofuran. The product from chromatography was dissolved in tetrahydrofuran and the solution concentrated in vacuo to an oil. Ether was added and the solution was cooled to precipitate in 2 crops 240 mg. of product. Recrystallization from tetrahydrofuran/ether yielded 132 mg. of product, m.p. 225°-227° C. An additional 69 mg. of product was obtained from the filtrate by preparative thin-layer chromatography.

1. additionTo this solution was added 0.6 ml
2. additionAfter the addition
3. stirringthe mixture was stirred for 30 minutes at about -72° C
4. customA pale yellow solution formed
5. additionAfter the addition
6. stirringthe mixture was stirred for 30 minutes at about -72° C.
7. customgiving a colorless solution
8. temperaturewas raised to between -40° C. and -30° C.
9. stirringstirring
10. customwas recooled to approximately -72° C.
11. customThe cooling bath was removed
12. temperatureto warm to room temperature
13. temperatureThe mixture was then heated at 50° C. for 16 hours
14. customthe reaction
15. customThe solvent was removed in vacuo
16. washThe ethyl acetate solution was washed 5 times with aqueous sodium carbonate solution
17. customThe solvent was again evaporated
18. dissolutionthe residue dissolved in 2 ml
19. customof tetrahydrofuran and chromatographed over silica gel using 4:1 benzene/tetrahydrofuran
20. dissolutionThe product from chromatography was dissolved in tetrahydrofuran
21. concentrationthe solution concentrated in vacuo to an oil
22. additionEther was added
23. temperaturethe solution was cooled
24. customto precipitate in 2 crops 240 mg
25. customRecrystallization from tetrahydrofuran/ether
26. customyielded 132 mg
27. customof product was obtained from the filtrate by preparative thin-layer chromatography

ORD record

ord-d04bbd84595d48b3bb19c20c8260d05d

Source dataset

uspto-grants-1981_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

USRE030563