Methyl iodide → (S)-5-(4-fluoro-phenyl)-6-methoxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one

HRID 2046193Notes

Reaction equation

HRID 2046193 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@H:13]([CH2:14][OH:15])[CH2:12][N:11]3[N:16]=[C:17]([CH2:19][O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=[C:10]3[C:9]2=[O:27])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:31]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@H:13]([CH2:14][O:15][CH3:31])[CH2:12][N:11]3[N:16]=[C:17]([CH2:19][O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:18]=[C:10]3[C:9]2=[O:27])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 67974066(S)-5-(4-fluoro-phenyl)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one

Product 1

HCID 67974416(S)-5-(4-fluoro-phenyl)-6-methoxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-oneYield 65.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of (S)-5-(4-fluoro-phenyl)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.135 g, 0.36 mmol) in THF (0.5 mL) was added to a suspension of a 60% dispersion of sodium hydride in mineral oils (17 mg, 0.44 mmol) in THF (0.5 mL) at 0° C. The mixture was stirred for 10 minutes at 0° C., then iodomethane (0.046 mL, 0.73 mmol) was added. The reaction was heated at 120° C. for 10 minutes under microwave irradiation. Then the mixture was quenched with a saturated solution of NH4Cl and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). Desired fractions were collected and the solvents evaporated in vacuo. The residue was triturated with DIPE to yield (S)-5-(4-fluoro-phenyl)-6-methoxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (90 mg, 64% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.26 (s, 3H), 3.36 (t, J=9.2 Hz, 1H), 3.51 (dd, J=9.5, 3.9 Hz, 1H), 4.21 (dtd, J=9.0, 4.5, 4.5, 2.3 Hz, 1H), 4.59 (dd, J=13.3, 4.7 Hz, 1H), 4.74 (dd, J=13.3, 2.2 Hz, 1H), 5.13 (s, 2H), 6.94-7.00 (m, 1H), 7.00-7.04 (m, 3H), 7.10-7.19 (m, 2H), 7.27-7.36 (m, 4H).

Workup

  1. temperatureThe reaction was heated at 120° C. for 10 minutes under microwave irradiation
  2. customThen the mixture was quenched with a saturated solution of NH4Cl
  3. extractionextracted with AcOEt
  4. customThe organic layer was separated
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. customthe solvents evaporated in vacuo
  8. customThe residue was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80)
  9. customDesired fractions were collected
  10. customthe solvents evaporated in vacuo
  11. customThe residue was triturated with DIPE

Sources & evidence

ORD record
ord-c73544a53b1648849241ac4a1c012be3
Source dataset
uspto-grants-2013_11
Patent number
US08592422B2

Reaction notes

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