Methanol → Ketorolac

HRID 1531414Notes

Reaction equation

HRID 1531414 reaction equation
[C:1]([C:9]1[N:10]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17](N(C)C1C=CC=CC=1)=[O:18])[CH2:12][CH2:11]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:27].[Na+].CO>O>[CH:5]1[CH:6]=[CH:7][C:2]([C:1]([C:9]2[N:10]3[CH2:11][CH2:12][CH:13]([C:17]([OH:18])=[O:27])[C:14]3=[CH:15][CH:16]=2)=[O:8])=[CH:3][CH:4]=1

Participants

5

Reactant 3

HCID 887MethanolHCID 14798Sodium HydroxideHCID 98410725-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide

Product 1

HCID 3826KetorolacYield 83.4%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Procedure

A mixture of 34.4 g (100 mmol) 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide, 25 g sodium hydroxide in 25 mL water, and 80 mL methanol was refluxed for 5 hours. The mixture was cooled to room temperature, stirred under nitrogen for sixteen hours, and then diluted with 80 mL of water. The mixture was extracted with toluene (2×50 mL), and the aqueous and organic phases were separated. The aqueous phase was acidified with 6 N hydrochloric acid (110 mL). The resulting precipitate was extracted several times with dichloromethane (1×150 mL), (1×75 mL), (1×50 mL). The combined extract was treated with FILTROL® (activated clay decolorizing agent) (4.5 g) for 30 minutes, filtered, and concentrated by atmospheric distillation. Hexane (190 mL) was added and the entire mixture allowed to cool to room temperature and then further cooled to 0° C. to −5° C. The product, 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (ketorolac) was collected by filtration, washed with 100 mL of hexane/dichloromethane (7:3 v/v), and dried at 60° C. to 70° C. under vacuum, to yield ketorolac (21.3 g, 83.4% yield), mp 152° C. to 162° C.

Workup

  1. temperaturewas refluxed for 5 hours
  2. extractionThe mixture was extracted with toluene (2×50 mL)
  3. customthe aqueous and organic phases were separated
  4. extractionThe resulting precipitate was extracted several times with dichloromethane (1×150 mL), (1×75 mL), (1×50 mL)
  5. extractionThe combined extract
  6. additionwas treated with FILTROL® (activated clay decolorizing agent) (4.5 g) for 30 minutes
  7. filtrationfiltered
  8. concentrationconcentrated by atmospheric distillation
  9. additionHexane (190 mL) was added
  10. temperatureto cool to room temperature
  11. temperaturefurther cooled to 0° C. to −5° C
  12. filtrationThe product, 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (ketorolac) was collected by filtration
  13. washwashed with 100 mL of hexane/dichloromethane (7:3 v/v)
  14. customdried at 60° C. to 70° C. under vacuum

Sources & evidence

ORD record
ord-8a51275b0f31424f8d1bd910847c0c4d
Source dataset
uspto-grants-2001_03
Patent number
US06197976B1

Reaction notes

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