Imidazole → 5(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoic acid

HRID 1585324Notes

Reaction equation

HRID 1585324 reaction equation
N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[C:14]([NH:21][C@@H:22]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C@@H:23]([OH:38])[CH2:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:26]([OH:28])=[O:27])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CN(C=O)C>[C:14]([NH:21][C@@H:22]([CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[C@@H:23]([O:38][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12])[CH2:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:26]([OH:28])=[O:27])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]

Participants

5

Reactant 3

HCID 795ImidazoleHCID 28928tert-Butyldimethylsilyl chlorideHCID 228763985(S)-(Boc-Amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoic acid

Product 1

HCID 228764125(S)-(Boc-Amino)-4(S)-(tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoic acid

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

133 g (1.95 mol) of imidazole and 164 g (1.09 mol) of tert-butyldimethylchlorosilane are added, under an argon atmosphere, to an ice-cold solution of 124 g (238 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(p-methoxyphenyl)methyl]hexanoic acid in 800 ml of DMF. After 17 h at RT, the reaction mixture is poured onto 1.9 l of ice-water and extracted 3× with 0.8 l of ethyl acetate on each occasion. The organic phases are washed with water, sat. NaHCO3 solution, water, 10% citric acid solution, water and, finally, saline, dried with Na2SO4 and evaporated. The residue is dissolved in 700 ml of methanol and 175 ml of THF, and 175 g of K2CO3 in 820 ml of water are added to this solution, which is then stirred at RT for 1 h. The resulting emulsion is partially evaporated on an RE, and the residue is diluted with ice-water, and this mixture is acidified to pH 4 with 10% citric acid solution while stirring vigorously. The mixture is extracted 3× with ethyl acetate, and the organic phases are washed with water and saline, dried with Na2SO4 and evaporated. Column chromatography (SiO2, hexane→hexane/ethyl acetate 95:5→9:1→2:1→1:1) results in the title compound: TLC Rf (E)=0.15; tRet (II)=22.7 min.

Workup

  1. extractionextracted 3× with 0.8 l of ethyl acetate on each occasion
  2. washThe organic phases are washed with water, sat. NaHCO3 solution, water, 10% citric acid solution, water
  3. dry with materialfinally, saline, dried with Na2SO4
  4. customevaporated
  5. dissolutionThe residue is dissolved in 700 ml of methanol
  6. addition175 ml of THF, and 175 g of K2CO3 in 820 ml of water are added to this solution, which
  7. customThe resulting emulsion is partially evaporated on an RE, and the residue
  8. additionis diluted with ice-water
  9. stirringwhile stirring vigorously
  10. extractionThe mixture is extracted 3× with ethyl acetate
  11. washthe organic phases are washed with water and saline
  12. dry with materialdried with Na2SO4
  13. customevaporated

Sources & evidence

ORD record
ord-88328dea5a1446caa5d7bff8a444782d
Source dataset
uspto-grants-1999_08
Patent number
US05935976

Reaction notes

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