Imidazole → (4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-6-phenyl-2-(4-pyridin-2-ylbenzyl)hexanoic acid

HRID 1174100Notes

Reaction equation

HRID 1174100 reaction equation
[O:1]=[C:2]1[O:6][C@H:5]([C@@H:7]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH:3]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][CH:25]=1.[OH-:36].[Na+].N1C=CN=C1.[Si:43](Cl)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>O1CCOCC1.CN(C)C=O>[C:18]([O:17][C:16]([NH:15][C@@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C@@H:5]([O:6][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:4][CH:3]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][CH:25]=1)[C:2]([OH:36])=[O:1])=[O:22])([CH3:20])([CH3:21])[CH3:19]

Participants

7

Reactant 4

HCID 795ImidazoleHCID 14798Sodium HydroxideHCID 28928tert-Butyldimethylsilyl chlorideHCID 86598802tert-butyl (1S)-1-{(2S)-5-oxo-4-[4-(2-pyridinyl)benzyl]tetrahydro-2-furanyl}-2-phenylethylcarbamate

Product 1

HCID 67406695(4S,5S)-5-[(tert-butoxycarbonyl)amino]-4-{[tert-butyl(dimethyl)silyl]oxy}-6-phenyl-2-(4-pyridin-2-ylbenzyl)hexanoic acidYield 49%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
25 °C

Procedure

A solution of the product from Example 1A (21.4 g) in dioxane (100 mL) was treated with sodium hydroxide solution (57 mL, 1N), stirred at 25° C. for 30 minutes and concentrated. The concentrate was cooled to 0° C., and acidified to pH 5 with 4N HCl. The mixture was partitioned between dichloromethane and water, and the organic phase layer was washed with brine, dried over MgSO4, filtered and concentrated. A solution of the residue in N,N-dimethylformamide (100 mL) was treated with imidazole (21 g, 308.5 mmol) and t-butyldimethylsilyl chloride (23 g, 152.6 mmol), stirred at 25° C. for 16 hours and concentrated. The residue was combined with ice and acidified with 4N HCl to pH 3. Ethyl acetate (50 mL) was added to permit stirring during the acidification. The mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel eluting with a gradient of 200%-100% ethyl acetate in chloroform, followed by elution with 5% methanol in ethyl acetate to give the title product (11.3 g, 49% yield).

Workup

  1. concentrationconcentrated
  2. temperatureThe concentrate was cooled to 0° C.
  3. customThe mixture was partitioned between dichloromethane and water
  4. washthe organic phase layer was washed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. stirringstirred at 25° C. for 16 hours
  9. concentrationconcentrated
  10. additionEthyl acetate (50 mL) was added
  11. stirringto permit stirring during the acidification
  12. extractionThe mixture was extracted with ethyl acetate
  13. washwashed with brine
  14. dry with materialdried over MgSO4
  15. filtrationfiltered
  16. concentrationconcentrated
  17. customThe residue was chromatographed on silica gel eluting with a gradient of 200%-100% ethyl acetate in chloroform
  18. washfollowed by elution with 5% methanol in ethyl acetate

Sources & evidence

ORD record
ord-e8868c5129bf4b6fac43ddb73a22972f
Source dataset
uspto-grants-2010_11
Patent number
US07834043B2

Reaction notes

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