Acetic Acid → Ravuconazole

HRID 222807Notes

Reaction equation

HRID 222807 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH3:31])[C:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C@@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(=O)C>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C@H:14]([CH3:31])[C@:15]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])([OH:22])[CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 131278(R)-camphorsulfonic acidHCID 98459224-[2-[3-(2,4-Difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl]benzonitrile

Product 1

HCID 467825RavuconazoleYield 38.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
70 °C

Procedure

Racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-butan-2-ol (44 g) and (1R)-10-camphorsulfonic acid (20 g) were suspended in methanol (ca. 300 ml), the slurry was stirred intensively, warmed up to ca. 70° C. and a small addition of acetic acid was added to obtain a clear solution. After cooling of the solution to rt and then to 0° C., the mixture was seeded with enantiomerically pure salt and stirred for another 2 hrs. The crystalline solid was collected by filtration, washed with cooled methanol and dried under reduced pressure. The crystals were partitioned between methylenechloride (300 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was washed twice with water (50 ml), dried with magnesium sulphate, filtrated and evaporated under reduced pressure to give the title compound (16.9 g, 38% yield, 95% ee). The analytical data were identical with published (U.S. Pat. No. 5,648,372 or Chem. Pharm. Bull. 1998, 46, 623).

Workup

  1. additionwas added
  2. customto obtain a clear solution
  3. temperatureAfter cooling of the solution to rt
  4. customto 0° C.
  5. stirringstirred for another 2 hrs
  6. filtrationThe crystalline solid was collected by filtration
  7. washwashed with cooled methanol
  8. customdried under reduced pressure
  9. customThe crystals were partitioned between methylenechloride (300 ml) and saturated aqueous sodium bicarbonate solution (200 ml)
  10. washThe organic layer was washed twice with water (50 ml)
  11. dry with materialdried with magnesium sulphate
  12. filtrationfiltrated
  13. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-30cce2b0ac5e40679b012cd435abe240
Source dataset
uspto-grants-2012_06
Patent number
US08207352B2

Reaction notes

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