Diisopropylamine → 3,5-difluoro-4-[1-hydroxy-3-(1-trityl-1H-imidazol-4-yl)-propyl]benzonitrile

HRID 923260Notes

Reaction equation

HRID 923260 reaction equation
C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:17]#[N:18].[C:23]([N:42]1[CH:46]=[C:45]([CH2:47][CH2:48][CH:49]=[O:50])[N:44]=[CH:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCOC(C)=O>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([F:22])[C:21]=1[CH:49]([OH:50])[CH2:48][CH2:47][C:45]1[N:44]=[CH:43][N:42]([C:23]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:46]=1)[C:17]#[N:18]

Participants

7

Reactant 4

HCID 7912DiisopropylamineHCID 5872043,5-DifluorobenzonitrileHCID 114514283-(1-Tritylimidazol-4-YL) propionaldehydeHCID 178418339Butyllithium

Product 1

HCID 668855153,5-difluoro-4-[1-hydroxy-3-(1-trityl-1H-imidazol-4-yl)-propyl]benzonitrile

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

Diisopropylamine (0.53 mL, 3.75 mmol) is dissolved in 5 mL THF and cooled down to −78° C. To this is added n-BuLi (2.3 mL, 1.6M in hexanes). After 15 min, a solution of 3,5-difluorobenzonitrile (0.52 g, 3.75 mmol) and THF (5 mL) is added and the solution maintained at that temperature for 0.5 h before adding a solution of 3-(1-trityl-1H-imidazol-4-yl)propionaldehyde and THF (20 mL). After 2 h, the solution is diluted with EtOAc and quenched with saturated aqueous NH4Cl. The mixture is then partitioned between EtOAc and saturated aqueous NH4Cl. The organic is dried (Na2SO4) and evaporated. The residue is purified via flash column chromatography (EtOAc/hexanes 2:8→EtOAc) to give 3,5-difluoro-4-[1-hydroxy-3-(1-trityl-1H-imidazol-4-yl)-propyl]benzonitrile as a yellow powder. MS (ESI) m/z 506.2 (M+H).

Workup

  1. temperaturethe solution maintained at that temperature for 0.5 h
  2. waitAfter 2 h
  3. customquenched with saturated aqueous NH4Cl
  4. customThe mixture is then partitioned between EtOAc and saturated aqueous NH4Cl
  5. dry with materialThe organic is dried (Na2SO4)
  6. customevaporated
  7. customThe residue is purified via flash column chromatography (EtOAc/hexanes 2:8→EtOAc)

Sources & evidence

ORD record
ord-db831d6d9ae04ed8b4fadfc765d18a9a
Source dataset
uspto-grants-2016_03
Patent number
US09278969B2

Reaction notes

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