Imidazole → HCID 67006780, compound

HRID 2388459Notes

Reaction equation

HRID 2388459 reaction equation
[CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:9]([NH:12][NH:13][C:14](=[O:30])[C@H:15]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[C:21]=1[CH3:29])[C@@H:16]([OH:18])[CH3:17])(=O)[CH3:10].N1C=CN=C1.II.CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCOC(C)=O.C(Cl)Cl.O>[Si:5]([O:18][C@@H:16]([CH3:17])[C@@H:15]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([Cl:28])[C:21]=1[CH3:29])[C:14]1[O:30][C:9]([CH3:10])=[N:12][N:13]=1)([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]

Participants

11

Reactant 6

HCID 795ImidazoleHCID 807IodineHCID 8471TriethylamineHCID 11776TriphenylphosphineHCID 28928tert-Butyldimethylsilyl chlorideHCID 67006525HCID 67006525, compound

Product 1

HCID 67006780HCID 67006780, compoundYield 97.3%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

TBDMS-Cl (3.20 g, 21.25 mmol) was added to a pre-cooled (0° C.) solution of (2R,3S)—N′-acetyl-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutane hydrazide (2.30 g, 7.08 mmol) and imidazole (2.41 g, 35.41 mmol) in DMF (47 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight, whereupon it was poured into H2O (300 mL) and diluted with EtOAc (50 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to provide crude title compound. Step 2: In a separate flask, I2 (2.70 g, 10.63 mmol) and Et3N (3.98 mL, 28.34 mmol) were added sequentially to a solution of PS-Ph3P (3.54 g, 3.0 mmol/g loading) in CH2Cl2 (25 mL) at 0° C. To this solution was added crude hydrazide in CH2Cl2 (51 mL). After 30 min, the reaction mixture was filtered and the mother liquid washed with 10% Na2S2O3 (200 mL), separated and the aqueous layer extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to provide a yellow oil, which was purified by flash chromatography over SiO2 (30% EtOAc in hexanes) yielding the title compound (2.9 g, 97%): 1H NMR (400 MHz, DMSO-d6, δ in ppm) 7.49 (d, J=8.8 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 5.66-5.63 (m, 1H), 4.98 (dd, J=6.8, 8.8 Hz, 1H), 4.58-4.52 (m, 1H), 2.46 (s, 3H), 2.32 (s, 3H), 1.38 (d, J=6.0 Hz, 3H), 0.83 (s, 9H), 0.09 (s, 3H), 0.01 (s, 3H).

Workup

  1. customThe organic layer was separated
  2. extractionthe aqueous layer extracted with EtOAc (3×50 mL)
  3. dry with materialThe combined organic layers were dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customto provide crude title compound
  7. waitAfter 30 min
  8. filtrationthe reaction mixture was filtered
  9. washthe mother liquid washed with 10% Na2S2O3 (200 mL)
  10. customseparated
  11. extractionthe aqueous layer extracted with CH2Cl2 (3×50 mL)
  12. dry with materialThe combined organic extracts were dried (Na2SO4)
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customto provide a yellow oil, which
  16. customwas purified by flash chromatography over SiO2 (30% EtOAc in hexanes)

Sources & evidence

ORD record
ord-387acdb57136442d9a6ac8d25f1a9cbd
Source dataset
uspto-grants-2012_09
Patent number
US08268872B2

Reaction notes

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