Citric Acid → 9-Benzyl-3-oxa-9-azabicyclo(3.3.1)nonan-7-one

HRID 2382581Notes

Reaction equation

HRID 2382581 reaction equation
C(O)(=O)C[C:3]([CH2:8][C:9]([OH:11])=O)([C:5]([OH:7])=O)O.OP([O-])([O-])=O.[K+].[K+].Cl.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.[CH2:31]([C:38](O)=O)[C:32](CC(O)=O)=O>O.C(O)(=O)C>[CH2:22]([N:29]1[CH:31]2[CH2:38][C:9](=[O:11])[CH2:8][CH:3]1[CH2:5][O:7][CH2:32]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1

Participants

8

Reactant 5

HCID 311Citric Acid2×HCID 313Hydrochloric Acid2×HCID 24450Potassium Phosphate, Dibasic2×HCID 68328Acetonedicarboxylic acidHCID 2724127Benzylammonium chloride

Product 1

HCID 156391149-Benzyl-3-oxa-9-azabicyclo(3.3.1)nonan-7-one

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 962WaterSolvent2×

Procedure

A solution of C-1 (18 g, 81 mmol) in 40 mL of water and 14 mL acetic acid was heated to 120° C. for 2 h, cooled to room temperature and diluted with 400 mL of pH 4 buffer (160 mL 0.1 M citric acid and 240 mL 0.1 M K2HPO4). After cooling to 0° C., a preformed solution of 9.54 g (66.4 mmol) benzylamine hydrochloride, 100 mL water, and 31 mL concentrated HCl was added dropwise over 10 minutes, keeping the internal temperature below 5° C. Acetonedicarboxylic acid (23.3 g, 160 mmol) was then added in four equal portions, five minutes apart. The pH of the solution was increased to 4 by adding K2HPO4, and the reaction was allowed to warm to room temperature and stir overnight. Solid citric acid was added to return the pH to 4, and the reaction was stirred at room temperature 48 h more, at which time it was cooled to 0° C. and acidified to pH 2 with HCl, and extracted twice with Et2O. The aqueous layer was again cooled to 0° C. and basified to pH 11 with NaOH, and extracted three times with CH2Cl2. The combined organic extracts were washed with 0.1 M citric acid, then with saturated NaHCO3, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc in hexanes) to provide C-2 as a yellowish solid. Data for C-2: 1H NMR (CDCl3, 500 MHz) δ 7.45-7.2 (m, 5H), 3.9 (s, 2H), 3.8 (m, 2H), 3.7 (m, 2H), 3.2 (m, 2H), 2.7 (m, 2H), 2.3 (m, 2H) ppm.

Workup

  1. temperatureAfter cooling to 0° C.
  2. customthe internal temperature below 5° C
  3. temperatureThe pH of the solution was increased to 4
  4. temperatureto warm to room temperature
  5. stirringthe reaction was stirred at room temperature 48 h more
  6. temperatureat which time it was cooled to 0° C.
  7. extractionextracted twice with Et2O
  8. temperatureThe aqueous layer was again cooled to 0° C. and basified to pH 11 with NaOH
  9. extractionextracted three times with CH2Cl2
  10. washThe combined organic extracts were washed with 0.1 M citric acid
  11. dry with materialwith saturated NaHCO3, brine, dried over Na2SO4
  12. concentrationconcentrated
  13. customThe residue was purified by column chromatography on silica gel (0 to 100% EtOAc in hexanes)
  14. customto provide C-2 as a yellowish solid

Sources & evidence

ORD record
ord-8ca6c61f0664446bbf7a285346ed5752
Source dataset
uspto-grants-2012_09
Patent number
US08263586B2

Reaction notes

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