Diisopropylamine → HCID 58016960, compound

HRID 2189065Notes

Reaction equation

HRID 2189065 reaction equation
C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([O:24][Si](C)(C)C)C#N)=[CH:17][CH:16]=1)[CH3:14].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=[O:33]>CCCCCC.COCCOC>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH:32]([C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[F:29])[OH:33])=[CH:17][CH:16]=1)[CH3:14]

Participants

7

Reactant 4

HCID 7912DiisopropylamineHCID 67970o-FluorobenzaldehydeHCID 23540703HCID 23540703, compoundHCID 178418339Butyllithium

Product 1

HCID 58016960HCID 58016960, compound

Reagents, catalysts & solvents 2

HCID 8058HexaneSolventHCID 80711,2-DimethoxyethaneSolvent3×

Procedure

Add 217 ml (0.54 mol) of a 2.5 M n-butyllithium solution in hexane dropwise at −78° C. to a solution of 77 ml (56 g, 0.55 mol) N,N-diisopropylamine in 960 ml 1,2-dimethoxyethane in such a way that the temperature does not exceed −60° C. After stirring for 15 min at this temperature, add a solution of 116 g (0.50 mol) (4-ethylphenyl)[(trimethylsilyl)oxy]acetonitrile [D. S. Dhanoa, J. Med. Chem. 1993, 36 (23), 3738-3742] in 373 ml 1,2-dimethoxyethane dropwise in the space of 30 min. Next, after stirring for 30 min at this temperature, add a solution of 64 g (0.50 mol) 2-fluorobenzaldehyde in 373 ml 1,2-dimethoxyethane dropwise in the space of 20 min. Leave the reaction mixture to warm to room temperature in 4 h. After adding 1900 ml satd. aqueous ammonium chloride solution, extract with ethyl acetate. Wash the organic phase with satd. ammonium chloride solution, dry over sodium sulphate and filter. Concentrate the filtrate by vacuum evaporation. Add 1900 ml dioxan, 1350 ml methanol and 1560 ml 1 M hydrochloric acid to the residue and stir for 16 h at room temperature. After adding 4000 ml satd. aqueous sodium chloride solution, extract with 2000 ml ethyl acetate. Wash the organic phase with 1000 ml water and 1000 ml satd. sodium chloride solution, dry over sodium sulphate and filter. Concentrate the filtrate by vacuum evaporation. Purify the residue by flash chromatography on silica gel (solvent: cyclohexane/ethyl acetate 5:1). Mix the product fraction thus obtained in 80 ml diisopropyl ether and 240 ml petroleum ether, filter, wash with petroleum ether and dry under vacuum. 50 g (85% purity, 33% of theor.) of the title compound is obtained.

Workup

  1. customdoes not exceed −60° C
  2. stirringNext, after stirring for 30 min at this temperature
  3. customLeave the reaction mixture
  4. additionAfter adding 1900 ml
  5. extractionaqueous ammonium chloride solution, extract with ethyl acetate
  6. washWash the organic phase with satd
  7. dry with materialammonium chloride solution, dry over sodium sulphate
  8. filtrationfilter
  9. concentrationConcentrate the filtrate
  10. customby vacuum evaporation
  11. additionAdd 1900 ml dioxan, 1350 ml methanol and 1560 ml 1 M hydrochloric acid to the residue
  12. stirringstir for 16 h at room temperature
  13. additionAfter adding 4000 ml
  14. extractionaqueous sodium chloride solution, extract with 2000 ml ethyl acetate
  15. washWash the organic phase with 1000 ml water and 1000 ml
  16. dry with materialsodium chloride solution, dry over sodium sulphate
  17. filtrationfilter
  18. concentrationConcentrate the filtrate
  19. customby vacuum evaporation
  20. customPurify the residue by flash chromatography on silica gel (solvent: cyclohexane/ethyl acetate 5:1)
  21. additionMix the product fraction
  22. customthus obtained in 80 ml diisopropyl ether
  23. filtration240 ml petroleum ether, filter
  24. washwash with petroleum ether
  25. customdry under vacuum

Sources & evidence

ORD record
ord-9373f3b90f3b43ce9fd8b8014c0a4069
Source dataset
uspto-grants-2012_12
Patent number
US08324222B2

Reaction notes

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