反应详情

2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.146 g, 0.38 mmol) was added portionwise to a stirred solution of 2-fluorobenzoic acid (0.063 g, 0.45 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred for 5 minutes and then DIPEA (0.09 mL, 0.52 mmol) and 4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.08 g, 0.35 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours, diluted with a saturated solution of NH4Cl and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 30/70). The desired fractions were collected, the solvents evaporated in vacuo and the product repurified by flash column chromatography (silica; AcOEt in DCM 0/100 to 70/30). The desired fractions were collected and the solvents evaporated in vacuo. The residue was suspended in a saturated solution of NH4Cl, stirred for 1 hour and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The product was repurified by reverse phase HPLC (gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% CH3CN) to yield 5-(2-fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine (0.050 g, 41% yield) as a clear oil. C20H18FN3O21H NMR (400 MHz, CDCl3) δ ppm 3.80 (br. s., 1.1H), 4.22 (br. s., 1.5H), 4.31 (br. s., 1.4H), 4.61 (s, 0.9H), 4.99 (s, 1.1H), 5.03 (s, 0.9H), 5.07 (s, 1.1H), 6.07 (s, 0.45H), 6.27 (s, 0.55H), 6.90-7.09 (m, 3H), 7.15 (td, J=8.8, 3.6 Hz, 1H), 7.21-7.35 (m, 3H), 7.38-7.53 (m, 2H).

1. stirringThe reaction mixture was stirred at room temperature for 15 hours
2. extractionextracted with DCM
3. customThe organic layer was separated
4. dry with materialdried (Na2SO4)
5. filtrationfiltered
6. customthe solvents evaporated in vacuo
7. customThe crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 30/70)
8. customThe desired fractions were collected
9. customthe solvents evaporated in vacuo
10. customthe product repurified by flash column chromatography (silica; AcOEt in DCM 0/100 to 70/30)
11. customThe desired fractions were collected
12. customthe solvents evaporated in vacuo
13. stirringstirred for 1 hour
14. extractionextracted with DCM
15. customThe organic layer was separated
16. dry with materialdried (Na2SO4)
17. filtrationfiltered
18. customthe solvents evaporated in vacuo
19. customThe product was repurified by reverse phase HPLC (gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% CH3CN)