反应详情

Di-tert-butyl azodicarboxylate (0.027 g, 1.2 mmol) was added portionwise to a stirred solution of 5-(4-fluoro-phenyl)-2-hydroxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (104 mg, 0.4 mmol), p-cresol (0.13 mL, 1.2 mmol) and triphenylphosphine (0.31 g, 1.2 mmol) in THF (2 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. More di-tert-butyl azodicarboxylate (0.027 g, 1.2 mmol), p-cresol (0.13 mL, 1.2 mmol) and triphenylphosphine (0.31 g, 1.2 mmol) were added at 0° C. and the mixture was stirred at 130° C. for 20 minutes. The mixture was diluted with AcOEt and washed with a 10% solution of NaOH. The organic layer was separated, dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The crude product was purified by open column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo. The crude product was dissolved in a mixture of TFA (2.5 mL) and DCM (2.5 mL) and stirred at room temperature for 2 days. The mixture was basified with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with DIPE to yield 5-(4-fluorophenyl)-2-(p-tolyloxymethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (54 mg, 38% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 2.29 (s, 3H), 4.16 (dd, J=6.8, 5.3 Hz, 2H), 4.53 (dd, J=6.9, 5.2 Hz, 2H), 5.09 (s, 2H), 6.90 (d, J=8.7 Hz, 2H), 7.01 (s, 1H), 7.09 (d, J=8.4 Hz, 2H), 7.13 (t, J=8.7 Hz, 2H), 7.28-7.35 (m, 2H).

1. stirringthe mixture was stirred at 130° C. for 20 minutes
2. washwashed with a 10% solution of NaOH
3. customThe organic layer was separated
4. dry with materialdried (Na2SO4)
5. filtrationfiltered
6. customthe solvent was evaporated in vacuo
7. customThe crude product was purified by open column chromatography (silica; AcOEt in DCM 0/100 to 20/80)
8. customThe desired fractions were collected
9. customthe solvents evaporated in vacuo
10. dissolutionThe crude product was dissolved in a mixture of TFA (2.5 mL) and DCM (2.5 mL)
11. stirringstirred at room temperature for 2 days
12. extractionextracted with DCM
13. customThe organic layer was separated
14. dry with materialdried (MgSO4)
15. filtrationfiltered
16. customthe solvents evaporated in vacuo
17. customThe crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0)
18. customThe desired fractions were collected
19. customthe solvents evaporated in vacuo
20. customThe product was triturated with DIPE