Cyclohexylamine → (E)-2(R)-[1(R)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid

HRID 1978053Notes

Reaction equation

HRID 1978053 reaction equation
[CH2:1]([C@H:5]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].[CH2:25](Br)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(N)CCCCC1>O1CCCC1.CCCCCC>[C:13]([O:12][C:10]([C@@H:9]([C@@H:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]([OH:8])=[O:7])[CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:11])([CH3:14])([CH3:16])[CH3:15]

Participants

7

Reactant 4

HCID 7965CyclohexylamineHCID 98116BromomethylstyreneHCID 2724682Lithium diisopropylamideHCID 11085587(R)-2-(2-(tert-Butoxy)-2-oxoethyl)-4-methylpentanoic acid

Product 1

HCID 15380768(E)-2(R)-[1(R)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acidYield 82.1%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent4×HCID 8058HexaneSolvent

Procedure

A solution of 5.19 g of 4-tert-butyl hydrogen 2(R)-isobutylsuccinate in 50 ml of dry tetrahydrofuran was cooled to −78° C. while stirring under nitrogen. 25 ml of a 2M solution of lithium diisopropylamide in tetrahydrofuran was added dropwise and the mixture was stirred at −78° C. for 15 minutes. A solution of 5.55 g of cinnamyl bromide in 25 ml of dry tetrahydrofuran was then added dropwise and the mixture was left to come to room temperature gradually. After stirring overnight the tetrahydrofuran was evaporated and the residue was partitioned between ethyl acetate and 5% citric acid solution. The ethyl acetate layer was washed with two further portions of 5% citric acid solution, water and saturated sodium chloride solution and then dried over anhydrous magnesium sulphate. The solvent was evaporated to give an orange oil. This was dissolved in 100 ml of hexane to which 2.35 g of cyclohexylamine were added. The mixture was left to stand for 2 hours and the solid formed was collected by filtration. The solid was suspended in ethyl acetate and shaken with two portions of 2M sulphuric acid to give a clear solution. The ethyl acetate solution was washed twice with water and then with saturated sodium chloride solution and subsequently dried over anhydrous magnesium sulphate. After evaporation of the solvent there were obtained 6.41 g of (E)-2(R)-[1(R)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in the form of a pale cream coloured solid.

Workup

  1. stirringthe mixture was stirred at −78° C. for 15 minutes
  2. waitthe mixture was left
  3. customto come to room temperature
  4. customwas evaporated
  5. customthe residue was partitioned between ethyl acetate and 5% citric acid solution
  6. washThe ethyl acetate layer was washed with two further portions of 5% citric acid solution, water and saturated sodium chloride solution
  7. dry with materialdried over anhydrous magnesium sulphate
  8. customThe solvent was evaporated
  9. customto give an orange oil
  10. additionwere added
  11. waitThe mixture was left
  12. customthe solid formed
  13. filtrationwas collected by filtration
  14. stirringshaken with two portions of 2M sulphuric acid
  15. customto give a clear solution
  16. washThe ethyl acetate solution was washed twice with water
  17. dry with materialwith saturated sodium chloride solution and subsequently dried over anhydrous magnesium sulphate
  18. customAfter evaporation of the solvent there

Sources & evidence

ORD record
ord-8a1905b6a8e4464b944a4b8c4e7e2c3e
Source dataset
uspto-grants-2001_05
Patent number
US06235787B1

Reaction notes

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