3-Fluorobenzoic Acid → 2-(Benzyloxy)-5-[(3-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

HRID 571731Notes

Reaction equation

HRID 571731 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:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=O.CCN(C(C)C)C(C)C.[CH2:44]([O: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-]>[CH2:44]([O:51][C:52]1[CH:60]=[C:55]2[CH2:56][N:57]([C:29]([C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([F:25])[CH:27]=3)=[O:31])[CH2:58][CH2:59][N:54]2[N:53]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1

Participants

7

Reactant 4

HCID 99683-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 867064922-(Benzyloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

Product 1

HCID 727032132-(Benzyloxy)-5-[(3-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazineYield 45%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 25517Ammonium ChlorideSolvent

Procedure

2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.159 g, 0.42 mmol) was added to a stirred solution of 3-fluorobenzoic acid (0.059 g, 0.42 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred for 5 minutes and then DIPEA (0.08 mL, 0.45 mmol) and 2-(benzyloxy)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.08 g, 0.35 mmol) were added. The mixture was stirred at room temperature for 16 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 20/80). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-(benzyloxy)-5-[(3-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.055 g, 45% yield) as a white solid. C20H18FN3O2. 1H NMR (mixture of conformers 1/1; 500 MHz, CDCl3) δ ppm 3.87 (br. s., 1 H), 4.09 (br. s., 2 H), 4.20 (br. s., 1 H), 4.62 (br. s., 1 H), 4.84 (br. s., 1 H), 5.18 (s, 2 H), 5.44 (br. s., 0.5 H), 5.56 (br. s., 0.5 H), 7.14-7.21 (m, 2 H), 7.23 (dt, J=7.8, 1.2 Hz, 1 H), 7.29-7.34 (m, 1 H), 7.37 (t, J=7.4 Hz, 2 H), 7.40-7.47 (m, 3 H).

Workup

  1. stirringThe mixture was stirred at room temperature for 16 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 20/80)
  8. customThe desired fractions were collected
  9. customthe solvents evaporated in vacuo

Sources & evidence

ORD record
ord-4d624231f0894511a27222240cace855
Source dataset
uspto-grants-2015_05
Patent number
US09029366B2

Reaction notes

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