反应详情

温度

-5 °C

1,8-Diazabicyclo[5.4.0]undec-7-ene (19.87 mL, 132.90 mmol) was added to a suspension of tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (48 g, 102.23 mmol) in 2-methylTHF (300 mL). A dark solution was obtained after 5 minutes which was treated with charcoal and filtered through a celite pad, washing the charcoal and charcoal with additional 2-methylTHF (100 mL). The filtrate was stirred with an air stirrer at −5° C. in a 3 L jacketed fixed vessel under an atmosphere of nitrogen. 2-methylTHF (100 mL) was added to help stir the yellow suspension. Iodomethane (7.96 mL, 127.78 mmol) was added dropwise over 15 minutes. The mixture was stirred for 2 hours and the reaction mixture was warmed to room temperature. After 16 hours, additional iodomethane (6 mL) and DBU (20 mL) was added and stirring was continued for 16 hours. The mixture was poured into water and stirred for 5 minutes. The insoluble material was isolated as a beige solid and dried in vacuo to afford tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (24.77 g, 50.1%). The mother liquors were concentrated under reduced pressure and the residue was purified by flash column chromatography on silica using MTBE as the eluant. A second crop of the desired product (13.04 g, 26%), was thus obtained as a yellow solid: 1H NMR Spectrum: (DMSO-d6) 1.47 (9H, s), 1.51 (9H, s), 1.57-1.76 (2H, m), 1.94-2.1 (2H, m), 2.87-3.09 (3H, m), 3.9-4.08 (2H, m), 4.26 (3H, s), 7.97 (2H, br, s), 8.92 (1H, s); Mass Spectrum [M+H]+=484

1. customA dark solution was obtained after 5 minutes which
2. filtrationfiltered through a celite pad
3. washwashing the charcoal and charcoal with additional 2-methylTHF (100 mL)
4. addition2-methylTHF (100 mL) was added
5. stirringto help stir the yellow suspension
6. stirringThe mixture was stirred for 2 hours
7. temperaturethe reaction mixture was warmed to room temperature
8. stirringstirring
9. waitwas continued for 16 hours
10. stirringstirred for 5 minutes
11. customThe insoluble material was isolated as a beige solid
12. customdried in vacuo