Piperazine → N-methyl-4-(piperazin-1-yl)benzamide

Temperature

120 °C

To a solution of 4-fluoro-N-methylbenzamide (6 g, 39.2 mmol) in DMSO (Volume: 24.0 mL) was added piperazine (16.87 g, 196 mmol) at 23° C. The reaction was stirred at 120° C. for 68 hr. The reaction mixture was poured into ice (261 g) and the reaction vessel was rinsed with H2O (50 mL). Next, celite (30 g) was added to aid the filtration. The resulting suspension was warmed to 100° C., cooled to 40° C., filtered, and rinsed with warm H2O (4×50 mL). The resulting solid was dried in vacuo. The filtrate was stirred at room temperature overnight affording a suspension. The suspension was filtered, rinsed with H2O (3×25 mL), and the resulting solid was dried in vacuo. The cloudy filtrate was filtered once again through a medium fritted funnel and rinsed with H2O (3×10 mL). Added NaCl (200.1 g) to the filtrate, cooled on ice, filtered, rinsed with cold H2O (3×25 mL), and dried the resulting solid in vacuo. Re-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C., filtered, rinsed with H2O (3×5 mL), and dried the resulting solid in vacuo. The purified product was re-suspended in ACN (25 mL), agitated for 10 min, and dried in vacuo. This procedure was repeated three times to provide N-methyl-4-(piperazin-1-yl)benzamide (5.64 g, 25.7 mmol, 65.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (br. s., 1 H) 2.74 (d, J=4.55 Hz, 3 H) 2.77-2.86 (m, 4 H) 3.08-3.18 (m, 4 H) 6.91 (m, 2 H) 7.69 (m, 2 H) 8.13 (q, J=4.04 Hz, 1 H). ESI-MS: m/z 220.2 (M+H)+. mp=153.9-156.5° C.

1. washthe reaction vessel was rinsed with H2O (50 mL)
2. additionNext, celite (30 g) was added
3. filtrationthe filtration
4. temperatureThe resulting suspension was warmed to 100° C.
5. temperaturecooled to 40° C.
6. filtrationfiltered
7. washrinsed with warm H2O (4×50 mL)
8. customThe resulting solid was dried in vacuo
9. stirringThe filtrate was stirred at room temperature overnight
10. customaffording a suspension
11. filtrationThe suspension was filtered
12. washrinsed with H2O (3×25 mL)
13. customthe resulting solid was dried in vacuo
14. filtrationThe cloudy filtrate was filtered once again through a medium fritted funnel
15. washrinsed with H2O (3×10 mL)
16. temperatureAdded NaCl (200.1 g) to the filtrate, cooled on ice
17. filtrationfiltered
18. washrinsed with cold H2O (3×25 mL)
19. customdried the resulting solid in vacuo
20. stirringRe-suspended the purified product in H2O (30 mL), stirred for 30 min at 23° C.
21. filtrationfiltered
22. washrinsed with H2O (3×5 mL)
23. customdried the resulting solid in vacuo
24. stirringagitated for 10 min
25. customdried in vacuo

ORD record

ord-d149261cfeaa46d1bdcf28168925ad47

Source dataset

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08541417B2