Hydrochloric Acid → 7-Methyl-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid

HRID 275709Notes

Reaction equation

HRID 275709 reaction equation
[C:1]1(C)[C:2]([CH:7]=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:10]([CH2:12][C:13]([O:15]CC)=[O:14])#N.N1CCCC[CH2:19]1.[C-]#N.[Na+].Cl>O.S(Cl)(Cl)=O.CN(C=O)C.O.C(O)C.C(O)C>[CH3:19][C:6]1[C:1]2[CH:12]([C:13]([OH:15])=[O:14])[CH2:10][C:7](=[O:8])[C:2]=2[CH:3]=[CH:4][CH:5]=1

Participants

11

Reactant 5

HCID 313Hydrochloric AcidHCID 7764Ethyl cyanoacetateHCID 8082PiperidineHCID 8929Sodium CyanideHCID 107222-Methylbenzaldehyde

Product 1

HCID 2895327-Methyl-3-oxo-2,3-dihydro-1H-indene-1-carboxylic acid

Reagents, catalysts & solvents 5

HCID 702EthanolSolvent2×HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 24386Thionyl ChlorideSolventHCID 19096565Water ethanolSolvent

Conditions

Temperature
40 °C

Procedure

To a mixture of o-tolualdehyde (500 g), ethyl cyanoacetate (445 g) and ethanol (500 ml) was added piperidine (16 ml). After azeotrope destillation (200 ml) more ethanol (200 ml) was added, and the mixture was refluxed for 2 hours. The solution was cooled to 40° C., and a solution of NaCN (225 g) in water (300 ml) was added over 20 minutes. The mixture was stirred for one hour and was then left for 16 hours at room temperature. Concentrated HCl (5 l) was added slowly and then water/ethanol was destilled off until the temperature reached 100° C. The mixture was then refluxed for 4 hours and then stirred at room temperature for 16 hours. The mixture was filtered, and the crystals were washed with water. The crystals were dissolved in 4 M NaOH (3 l) and filtrated. Then pH was adjusted to 1 with concentrated hydrochloric acid, and the crystals were filtered off and dried yielding 610 g which was dissolved in thionyl chloride (2 l). DMF (10 ml) was added and the solution was refluxed for 2.5 hours and evaporated in vacuo. The residue was dissolved in CH2Cl2 (1.2 l) and was added during 1 hour to a cooled mixture of AlCl3 (600 g) in CH2Cl2 (4 l) at 0-5° C. The mixture was stirred at room temperature for 16 hours and was then poured on ice/water (5 l) and concentrated hydrochloric acid (500 ml). Conventional work up gave the crude title product (605 g), which was purified by column chromatography on silica gel eluted with CH2Cl2-ether-acetic acid (50:50:2) giving 236 g of the title product.

Workup

  1. temperaturethe mixture was refluxed for 2 hours
  2. waitwas then left for 16 hours at room temperature
  3. customreached 100° C
  4. temperatureThe mixture was then refluxed for 4 hours
  5. stirringstirred at room temperature for 16 hours
  6. filtrationThe mixture was filtered
  7. washthe crystals were washed with water
  8. dissolutionThe crystals were dissolved in 4 M NaOH (3 l)
  9. filtrationfiltrated
  10. filtrationthe crystals were filtered off
  11. customdried
  12. customyielding 610 g which
  13. temperaturethe solution was refluxed for 2.5 hours
  14. customevaporated in vacuo
  15. dissolutionThe residue was dissolved in CH2Cl2 (1.2 l)
  16. additionwas added during 1 hour to a cooled mixture of AlCl3 (600 g) in CH2Cl2 (4 l) at 0-5° C
  17. stirringThe mixture was stirred at room temperature for 16 hours
  18. additionwas then poured on ice/water (5 l) and concentrated hydrochloric acid (500 ml)
  19. customConventional work up gave the crude title product (605 g), which
  20. customwas purified by column chromatography on silica gel
  21. washeluted with CH2Cl2-ether-acetic acid (50:50:2)

Sources & evidence

ORD record
ord-af27f08745a548c99906101db57306fa
Source dataset
uspto-grants-2002_03
Patent number
US06352988B2

Reaction notes

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