2-Fluorobenzoic acid → 5-(2-Fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine

HRID 1773782Notes

Reaction equation

HRID 1773782 reaction equation
F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=O.CCN(C(C)C)C(C)C.[O:44]([CH2:51][C:52]1[CH:60]=[C:55]2[CH2:56][NH:57][CH2:58][CH2:59][N:54]2[N:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C.[NH4+].[Cl-]>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([N:57]1[CH2:58][CH2:59][N:54]2[N:53]=[C:52]([CH2:51][O:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:60]=[C:55]2[CH2:56]1)=[O:30]

Participants

7

Reactant 4

HCID 99352-Fluorobenzoic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 679582494,5,6,7-Tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazine

Product 1

HCID 573876305-(2-Fluorobenzoyl)-4,5,6,7-tetrahydro-2-(phenoxymethyl)-pyrazolo[1,5-a]pyrazineYield 41%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 25517Ammonium ChlorideSolvent

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-7a24b6b404da4ee8b2e6f1f3519a631b
Source dataset
uspto-grants-2016_02
Patent number
US09255103B2

Reaction notes

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