4-(Bromoacetyl)benzonitrile → Isavuconazole

HRID 379652Notes

Reaction equation

HRID 379652 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@@H:10]([CH3:14])[C:11]([NH2:13])=[S:12].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1)=O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@H:10]([C:11]1[S:12][CH:23]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[N:13]=1)[CH3:14]

Participants

4

Reactant 2

HCID 986544-(Bromoacetyl)benzonitrileHCID 20692784(alphaR,betaR)-beta-(2,5-Difluorophenyl)-beta-hydroxy-alpha-methyl-1H-1,2,4-triazole-1-butanethioamide

Product 1

HCID 6918485IsavuconazoleYield 86%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A mixture of (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[1,2,4]triazol-1-ylthiobutyramide (26.7 g, 85.4 mmol) and a-bromo-4′-cyano-acetophenone (24.0 g, 0.107 mol) in EtOH (500 ml) was refluxed for 1 hr. The reaction mixture was cooled down to r.t. And the solvent was removed under reduced pressure down to 150 ml. The residue was poured into in to cold (0° C.) saturated NaHCO3 aq. (400 ml). The resulting mixture was extracted with EtOAc (300 ml+150 ml×2). The combined organic layer was washed with brine (200 ml), dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel (Wako-gel C-300, Hexane:EtOAc=1:2) to give 4-{2-[(1R,2R)-2-(2,5-Difluoro-phenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]-thiazol-4-yl }-benzonitrile (32.0 g, 86%).

Workup

  1. temperaturewas refluxed for 1 hr
  2. customAnd the solvent was removed under reduced pressure down to 150 ml
  3. additionThe residue was poured into in to cold (0° C.) saturated NaHCO3 aq. (400 ml)
  4. extractionThe resulting mixture was extracted with EtOAc (300 ml+150 ml×2)
  5. washThe combined organic layer was washed with brine (200 ml)
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customThe residue was chromatographed on silica gel (Wako-gel C-300, Hexane:EtOAc=1:2)

Sources & evidence

ORD record
ord-6694cdb912424263bf38aaabe8f2dbfe
Source dataset
uspto-grants-2001_10
Patent number
US06300353B1

Reaction notes

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