Water → (R)-5-Bromo-3-(1-methyl-2-pyrrolidinyl methyl)-1H-indole

HRID 1441071Notes

Reaction equation

HRID 1441071 reaction equation
C(O[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([Br:27])[CH:25]=2)[NH:20][CH:19]=1)=O)=O)C1C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:16][C@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH3:9]

Participants

7

Reactant 4

HCID 962Water2×HCID 14798Sodium HydroxideHCID 11224090Phenylmethyl (2R)-2-((5-bromo-1H-indol-3-yl)carbonyl)-1-pyrrolidinecarboxylateHCID 21226445Aluminium lithium hydride3×

Product 1

HCID 11185464(R)-5-Bromo-3-(1-methyl-2-pyrrolidinyl methyl)-1H-indole

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of 3-(1-benzyloxycarbonylpyrrolidin-2(R)-ylcarbonyl)-5-bromo-1H-indole (1.04 g) (see Preparation 35) in dry tetrahydrofuran (20 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.27 g) in dry tetrahydrofuran (15 ml) at room temperature under an atmosphere of dry nitrogen. The mixture was heated under reflux with stirring for 18 hours and then cooled. Additional lithium aluminium hydride (50 mg) was added and the mixture heated under reflux for an additional 3 hours. The mixture was again cooled, lithium aluminium hydride (40 mg) was added and the mixture heated under reflux for a further 18 hours. The mixture was cooled, water (0.44 ml) was carefully added with stirring followed by 20% aqueous sodium hydroxide (0.44 ml) and then more water (1.33 ml). The mixture was diluted with ethyl acetate and filtered through a cellulose-based filter aid. The filtrate was washed with water then brine and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:0.5) gave, after combination and evaporation of the appropriate fractions, the title compound as a solid, (0.51 g). A small sample was crystallised from dichloromethane/hexane, m.p. 137°-140° C. Found: C, 56.65; H,5.69; N,9.23; C14H17N2Br.0.25 H2O requires: C,56,48; H,5,93; N,9.41%.

Workup

  1. temperatureThe mixture was heated
  2. temperatureunder reflux
  3. temperaturecooled
  4. temperaturethe mixture heated
  5. temperatureunder reflux for an additional 3 hours
  6. temperatureThe mixture was again cooled
  7. temperaturethe mixture heated
  8. temperatureunder reflux for a further 18 hours
  9. temperatureThe mixture was cooled
  10. stirringwith stirring
  11. filtrationfiltered through a cellulose-
  12. filtrationbased filter aid
  13. washThe filtrate was washed with water
  14. dry with materialbrine and dried (Na2SO4)
  15. customEvaporation of the solvent
  16. customgave an oil which
  17. customwas chromatographed on silica gel
  18. washElution with dichloromethane/ethanol/concentrated aqueous ammonia (90:10:0.5)
  19. customgave
  20. customafter combination and evaporation of the appropriate fractions
  21. customA small sample was crystallised from dichloromethane/hexane, m.p. 137°-140° C

Sources & evidence

ORD record
ord-b0899d1a5cac4ef892e735f6f216d5ec
Source dataset
uspto-grants-1996_03
Patent number
US05502065

Reaction notes

Loading…