Acetic Acid → 4-Hydroxybicyclo[2.2.1]heptane-1-carboxylic acid

HRID 2280793Notes

Reaction equation

HRID 2280793 reaction equation
N[C:2]12[CH2:8][C:5]([C:9]([OH:11])=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(O)(=[O:14])C.N([O-])=O.[Na+].[OH-].[K+]>O.CO.CO.C(OCC)(=O)C>[OH:14][C:2]12[CH2:8][C:5]([C:9]([OH:11])=[O:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2

Participants

8

Reactant 4

HCID 176Acetic AcidHCID 14797Potassium HydroxideHCID 23668193Sodium NitriteHCID 450848204-Aminobicyclo[2.2.1]heptane-1-carboxylic acid

Product 1

HCID 216343224-Hydroxybicyclo[2.2.1]heptane-1-carboxylic acidYield 94%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 21584119Ethylacetate methanolSolvent

Conditions

Temperature
10 °C

Procedure

A 2-L, 3-neck, round bottom flask was equipped with a mechanical stirrer, a reflux condenser, a J-KEM temperature controller, and a nitrogen inlet. The flask was charged with 4-aminobicyclo[2.2.1]heptane-1-carboxylic acid (56.3 g, 363 mmol) and 10% aqueous acetic acid (340 mL). The reaction mixture was cooled to 10° C. and was slowly treated over 45 min with sodium nitrite (75.0 g, 1.088 mol) in water (125 mL) via addition funnel. A significant amount of gas evolution was observed and the reaction mixture was stirred at 65° C. overnight. The reaction was cooled to 5° C. and slowly treated over 30 min with potassium hydroxide (183 g, 3.265 mol) in methanol (400 mL) via addition funnel. The reaction was stirred at 65° C. for 5 h when TLC analysis (10% methanol/ethyl acetate) indicated a complete reaction. The reaction mixture was concentrated to remove methanol and the remaining aqueous mixture was extracted with ethyl acetate (2×400 mL). The aqueous layer was acidified to pH 3 using concentrated hydrochloric acid (210 mL) while cooling in ice/water bath. The resulting solids (impurities) were filtered and washed with water (2×30 mL). The filtrate was extracted with ethyl acetate (10×400 mL), dried over sodium sulfate, and concentrated to dryness to provide 53 g (94%) of 4-hydroxybicyclo[2.2.1]heptane-1-carboxylic acid; MS (ESI) m/z 155.2 [M+1]−

Workup

  1. temperatureThe reaction was cooled to 5° C.
  2. customa complete reaction
  3. concentrationThe reaction mixture was concentrated
  4. customto remove methanol
  5. extractionthe remaining aqueous mixture was extracted with ethyl acetate (2×400 mL)
  6. temperaturewhile cooling in ice/water bath
  7. filtrationThe resulting solids (impurities) were filtered
  8. washwashed with water (2×30 mL)
  9. extractionThe filtrate was extracted with ethyl acetate (10×400 mL)
  10. dry with materialdried over sodium sulfate
  11. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-a99c6f8e81514ead845bac6c500f30c2
Source dataset
uspto-grants-2015_09
Patent number
US09139534B2

Reaction notes

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