Potassium Carbonate → (1S,4S)-1-[5-(6-Hydroxy-benzofuran-3-ylmethyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-ethanone

HRID 1947500Notes

Reaction equation

HRID 1947500 reaction equation
Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9](=[O:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]1[C:24]2[CH:25]=[CH:26][C:27]([O:29]C(=O)C)=[CH:28][C:23]=2[O:22][CH:21]=1>CC#N>[OH:29][C:27]1[CH:26]=[CH:25][C:24]2[C:20]([CH2:19][N:6]3[CH2:7][C@@H:2]4[CH2:8][C@H:5]3[CH2:4][N:3]4[C:9](=[O:11])[CH3:10])=[CH:21][O:22][C:23]=2[CH:28]=1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 574640501-((1S,4S)-2,5-diazabicyclo(2.2.1)heptan-2-yl)ethan-1-one hydrochlorideHCID 59577463Acetic acid 3-chloromethyl-benzofuran-6-yl ester

Product 1

HCID 59577593(1S,4S)-1-[5-(6-Hydroxy-benzofuran-3-ylmethyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-ethanoneYield 94.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of (1S,4S)-1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethanone hydrochloride (330 mg, 2.35 mmol) and K2CO3 (0.831 g, 6.01 mmol) in MeCN (20 mL) was added acetic acid 3-chloromethyl-benzofuran-6-yl ester (450 mg, 2.00 mmol) and the reaction mixture was heated (50° C., 20 h). The solvent was removed in vacuo and the remaining residue was dissolved in water (10 mL) and 2-3 mL of 4 M KOH was slowly added to reach pH 13-14. The dark green solution was stirred (10 min) and treated with concentrated acetic acid until the solution reached pH 10. The aqueous mixture was extracted with 20% IPA/DCM (4×30 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as a gummy yellow solid (540 mg, 94%). MS (ESI): mass calcd. for C16H18N2O3, 286.1; m/z found, 287.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.51 (m, 1H), 7.48 (dd, J=8.4, 2.5, 1H), 6.84 (t, J=1.8, 1H), 6.75 (ddd, J=8.4, 2.9, 2.2, 1H), 4.66 (s, 0.5H), 4.44 (s, 0.5H), 3.89-3.75 (m, 2H), 3.69-3.58 (m, 2H), 3.40 (dd, J=9.8, 2.3, 0.5H), 3.23 (dd, J=11.4, 2.0, 0.5H), 2.96 (dd, J=10.0, 2.2, 0.5H), 2.88 (dd, J=9.9, 2.2, 0.5H), 2.73 (dd, J=9.4, 7.0, 1H), 2.09 (s, 1.5H), 2.03-1.92 (m, 2.5H), 1.80 (d, J=10.1, 0.5H), 1.71 (d, J=10.1, 0.5H).

Workup

  1. customThe solvent was removed in vacuo
  2. dissolutionthe remaining residue was dissolved in water (10 mL)
  3. addition2-3 mL of 4 M KOH was slowly added
  4. additiontreated with concentrated acetic acid until the solution
  5. extractionThe aqueous mixture was extracted with 20% IPA/DCM (4×30 mL)
  6. customThe organic layer was dried
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-40dec259165546099cf7c6293d71c54a
Source dataset
uspto-grants-2013_03
Patent number
US08399465B2

Reaction notes

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