Trifluoroacetic acid → Rac-2-phenoxymethyl-4-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine

HRID 1773795Notes

Reaction equation

HRID 1773795 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3](O)=O.[O:8]([CH2:15][C:16]1[CH:24]=[C:19]2C=[N:21][CH2:22][CH2:23][N:18]2[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.F.[K].C[Si](C(F)(F)F)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CC#N.CN(C=O)C.O>[O:8]([CH2:15][C:16]1[CH:24]=[C:19]2[CH:3]([C:2]([F:7])([F:6])[F:1])[NH:21][CH2:22][CH2:23][N:18]2[N:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 10340Sodium CarbonateHCID 552549(Trifluoromethyl)trimethylsilaneHCID 53443437Potassium fluoride, 99%, spray-driedHCID 679583882-Phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine

Product 1

HCID 67960098Rac-2-phenoxymethyl-4-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazineYield 63%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
0 °C

Procedure

Trifluoroacetic acid (0.36 mL) was added to a stirred mixture of 2-phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine (0.43 g, 1.87 mmol) and potassium hydrogen fluoride (0.18 g, 2.34 mmol) in CH3CN (3.7 mL) and DMF (0.4 mL) at 0° C. The mixture was stirred at 0° C. for 5 minutes. Then Ruppert's reagent (0.83 mL, 5.61 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was treated with a saturated solution of Na2CO3, diluted with water 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; 7N solution of ammonia in methanol in DCM 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo to yield rac-2-phenoxymethyl-4-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (350 mg, 63% yield) as a yellow oil.

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; 7N solution of ammonia in methanol in DCM 0/100 to 30/70)
  8. customThe desired fractions were collected
  9. customthe solvents evaporated in vacuo

Sources & evidence

ORD record
ord-66d36fc6448a4a448226e3ecb7972b0f
Source dataset
uspto-grants-2016_02
Patent number
US09255103B2

Reaction notes

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