N,N'-Dimethylethylenediamine → (S)-5-(4-fluoro-phenyl)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one

HRID 2046192Notes

Reaction equation

HRID 2046192 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[O:9]([CH2:16][C:17]1[CH:32]=[C:20]2[C:21](=[O:31])[NH:22][C@H:23]([CH2:25][O:26][Si](C)(C)C)[CH2:24][N:19]2[N:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu]I>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:22]2[C@H:23]([CH2:25][OH:26])[CH2:24][N:19]3[N:18]=[C:17]([CH2:16][O:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:32]=[C:20]3[C:21]2=[O:31])=[CH:3][CH:4]=1

Participants

8

Reactant 4

HCID 8070N,N'-DimethylethylenediamineHCID 99931-Bromo-4-fluorobenzeneHCID 11430Potassium CarbonateHCID 67976039HCID 67976039, compound

Product 1

HCID 67974066(S)-5-(4-fluoro-phenyl)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-oneYield 71.8%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
140 °C

Procedure

Copper (I) iodide (41 mg, 0.22 mmol) was added to a stirred suspension of 4-bromofluorobenzene (0.24 mL, 2.17 mmol), (S)-2-phenoxymethyl-6-trimethylsilanyloxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.37 g, 1.08 mmol), K2CO3 (0.3 g, 2.17 mmol) and N,N′-dimethylethylenediamine (0.070 mL, 0.65 mmol) in toluene (8 mL) in a sealed tube and under nitrogen. The mixture was stirred at 140° C. for 24 hours. The mixture was diluted with AcOEt and washed with a 16% aqueous solution of NH4OH. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The residue was dissolved in MeOH (4 mL) and stirred at 100° C. for 10 minutes under microwave irradiation. The solvent was evaporated in vacuo and the residue purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). Desired fractions were collected and the solvents evaporated in vacuo to yield (S)-5-(4-fluoro-phenyl)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (285 mg, 71% yield) as an off-white foam. 1H NMR (400 MHz, CDCl3) δ ppm 2.21 (br. s., 1H), 3.57-3.68 (m, 1H), 3.81 (dt, J=10.9, 4.4 Hz, 1H), 4.13-4.20 (m, 1H), 4.61 (dd, J=13.4, 4.9 Hz, 1H), 4.81 (dd, J=13.4, 2.1 Hz, 1H), 5.10 (s, 2H), 6.95-7.03 (m, 4H), 7.09-7.18 (m, 2H), 7.27-7.35 (m, 4H).

Workup

  1. washwashed with a 16% aqueous solution of NH4OH
  2. customThe organic layer was separated
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. customthe solvents evaporated in vacuo
  6. dissolutionThe residue was dissolved in MeOH (4 mL)
  7. stirringstirred at 100° C. for 10 minutes under microwave irradiation
  8. customThe solvent was evaporated in vacuo
  9. customthe residue purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50)
  10. customDesired fractions were collected
  11. customthe solvents evaporated in vacuo

Sources & evidence

ORD record
ord-c00831e292cd4cad8610f0788aad389b
Source dataset
uspto-grants-2013_11
Patent number
US08592422B2

Reaction notes

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