Acetic Acid → 7-Benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-one

HRID 626949Notes

Reaction equation

HRID 626949 reaction equation
[O:1]1[CH2:6]C[C:4](=O)[CH2:3][CH2:2]1.[CH2:8]=O.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18]([OH:21])(=O)[CH3:19]>C(O)(C)C>[CH2:10]([N:17]1[CH2:4][CH:3]2[C:18](=[O:21])[CH:19]([CH2:6][O:1][CH2:2]2)[CH2:8]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 712FormaldehydeHCID 7504BenzylamineHCID 121599Tetrahydro-4H-pyran-4-one

Product 1

HCID 137229517-Benzyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-oneYield 43.2%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent2×

Conditions

Temperature
65 °C

Procedure

To a solution of tetrahydro-4H-pyran-4-one (6 g, 60 mmol) and powdered paraformaldehyde (4.50 g, 150 mmol) in isopropanol (150 mL) at 65° C. was added a solution of benzylamine (7.2 mL, 66 mmol) and acetic acid (3.77 mL, 66 mmol) in isopropanol (150 mL) dropwise over 1.5 h. The reaction mixture was stirred at 65° C. for 1.5 h. Upon cooling, the solvent was removed in vacuo. The residue was diluted with water (250 mL) and 1M hydrogen chloride solution (22.5 mL), and extracted with tert-butyl methyl ether (2×100 mL). The aqueous phase was basified to pH 13 with 1M aqueous sodium hydroxide solution and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (Biotage Isolera 4, SNAP 100 g), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound 6 g, 37%) as a yellow oil. δH (500 MHz, DMSO-d6) 7.40-7.18 (m, 5H), 4.09 (d, J 10.9 Hz, 2H), 3.73 (dd, J 11.2, 2.8 Hz, 2H), 3.52 (s, 2H), 2.97 (dd, J 11.1, 2.9 Hz, 2H), 2.89 (dd, J 11.1, 6.8 Hz, 2H), 2.49-2.44 (m, 2H). Method E HPLC-MS: MH+ m/z 232, RT 4.10 minutes.

Workup

  1. temperatureUpon cooling
  2. customthe solvent was removed in vacuo
  3. additionThe residue was diluted with water (250 mL) and 1M hydrogen chloride solution (22.5 mL)
  4. extractionextracted with tert-butyl methyl ether (2×100 mL)
  5. extractionextracted with ethyl acetate (3×100 mL)
  6. dry with materialThe combined organic extracts were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified by flash column chromatography (Biotage Isolera 4, SNAP 100 g)
  10. washeluting with 0 to 100% ethyl acetate in heptanes

Sources & evidence

ORD record
ord-7f9e61a7c54b4e0bb222978f813dab52
Source dataset
uspto-grants-2016_04
Patent number
US09309243B2

Reaction notes

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