反应详情

温度

90 °C

4-Fluorobenzonitrile (12 g, 99 mmol, 1 eq.) and 100 mL of DMF are placed in a 250 mL round-bottomed flask. N-Methylpiperazine (16 mL, 1.6 eq., 123 mmol) is added to this solution. The orange solution is heated at a temperature in the region of 90° C. for 15 hours. The solvent is then evaporated to dryness and the residue is diluted with 500 mL of diethyl ether. The solution is washed with sodium hydrogen carbonate solution (2×100 mL) and then with saturated sodium chloride solution (100 mL). After evaporation, the 4-(4-methylpiperazin-1-yl)benzonitrile (orange solid, 10 g, 77%) is used without further purification in the following hydrolysis step. It is added at a temperature in the region of 0° C. to a solution of 98% sulfuric acid (25 mL) and 5 mL of water. The purple solution is then heated at a temperature in the region of 100° C. for 8 hours. The solution is cooled and then hydrolyzed by pouring onto ice. The pH is adjusted to 9-10 with sodium hydroxide pellets. The precipitate obtained is filtered off and washed thoroughly with water and then with tetrahydrofuran, which partially dissolves the product. The water is separated out by settling. After evaporating the organic phase to dryness, a solid is obtained, which is purified by chromatography on silica gel, eluting with a methanol/dichloromethane mixture (15/85 by volume). 4-(4-Methylpiperazin-1-yl)benzamide (8.7 g, 80%) is thus obtained in the form of a white solid, which is used directly in the following step.

1. customThe solvent is then evaporated to dryness
2. additionthe residue is diluted with 500 mL of diethyl ether
3. washThe solution is washed with sodium hydrogen carbonate solution (2×100 mL)
4. customAfter evaporation
5. customthe 4-(4-methylpiperazin-1-yl)benzonitrile (orange solid, 10 g, 77%) is used without further purification in the following hydrolysis step
6. additionIt is added at a temperature in the region of 0° C. to a solution of 98% sulfuric acid (25 mL) and 5 mL of water
7. temperatureThe purple solution is then heated at a temperature in the region of 100° C. for 8 hours
8. temperatureThe solution is cooled
9. additionhydrolyzed by pouring onto ice
10. customThe precipitate obtained
11. filtrationis filtered off
12. washwashed thoroughly with water
13. dissolutionwith tetrahydrofuran, which partially dissolves the product
14. customThe water is separated out
15. customAfter evaporating the organic phase to dryness
16. customa solid is obtained
17. customwhich is purified by chromatography on silica gel
18. washeluting with a methanol/dichloromethane mixture (15/85 by volume)