反应详情

Thiocarbonyl diimidazole (179 mg, 1.00 mmol) was added in one portion to a solution of 5-amino-1-methylpyrazole (98 mg, 1.00 mmol) in DMA (5 mL) and the solution was stirred at room temperature for 6 h. Methyl [trans-4-(4-{[hydrazino(oxo)acetyl]amino}phenyl)-cyclohexyl]acetate (Intermediate 43, 267 mg, 0.80 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 20 h and then heated at 80° C. for 10 minutes in the microwave. The solution was cooled to room temperature and EDCI (192 mg, 1.00 mmol) was added in one portion and the reaction mixture was heated to 90° C. for 15 minutes in the microwave. The reaction mixture was cooled to room temperature and poured into water (200 mL). The mixture was concentrated in vacuo to leave a gum, which was recrystallised (CH3CN) to leave a gummy solid. Filtration followed by concentration in vacuo of the filtrate gave the crude oxadiazole methyl ester intermediate that was used with no further purification; MS m/e MH+ 439. Lithium hydroxide (420 mg, 10.0 mmol) was added in one portion to a solution of the crude oxadiazole methyl ester intermediate in a mixture of THF (4 mL), MeOH (8 mL) and water (4 mL) and the reaction mixture was stirred at 35° C. for 4 h. Citric acid (30 mL) was added and the mixture was filtered to leave a solid that was recrystallised (MeOH) to give the title compound (87 mg, 26%) as a solid; 1H NMR δ 1.07-1.17 (2H, m), 1.41-1.51 (2H, m), 1.70-1.84 (5H, m), 2.14-2.16 (2H, d), 3.75 (3H, s), 6.70 (1H, s), 7.21-7.24 (2H, m), 7.40 (1H, s), 7.67-7.74 (2H, m); MS m/e MH+ 425.

1. stirringthe reaction mixture was stirred at room temperature for 20 h
2. temperatureheated at 80° C. for 10 minutes in the microwave
3. temperatureThe solution was cooled to room temperature
4. temperaturethe reaction mixture was heated to 90° C. for 15 minutes in the microwave
5. temperatureThe reaction mixture was cooled to room temperature
6. concentrationThe mixture was concentrated in vacuo
7. customto leave a gum, which
8. customwas recrystallised (CH3CN)
9. customto leave a gummy solid
10. filtrationFiltration
11. concentrationfollowed by concentration in vacuo of the filtrate
12. customgave the crude oxadiazole methyl ester intermediate that
13. customwas used with no further purification
14. stirringthe reaction mixture was stirred at 35° C. for 4 h
15. filtrationthe mixture was filtered
16. customto leave a solid
17. customthat was recrystallised (MeOH)