(R)-camphorsulfonic acid → Isavuconazole

HRID 222809Notes

Reaction equation

HRID 222809 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]=[C:27]([F:29])[CH:26]=[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>CC(C)=O.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]=[C:27]([F:29])[CH:26]=[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 2

HCID 131278(R)-camphorsulfonic acidHCID 21937662Isavuconazole(BAL-4815; RO-0094815)

Product 1

HCID 6918485IsavuconazoleYield 39%

Reagents, catalysts & solvents 2

HCID 180AcetoneSolventHCID 887MethanolSolvent

Procedure

To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (100 g) in acetone (1000 ml) a solution of (1R)-10-camphorsulfonic acid (47 g) in methanol (500 ml) was added at rt, then slurry was heated under stirring to almost reflux for ca. 30 min, then cooled slowly to rt, seeded with the pure enantiomeric salt and stirred over night. The solid was collected by filtration, washed with methanol/acetone mixture, dried under reduced pressure. The residue was taken up with a solvent mixture of methylenechloride/water and after addition of saturated aqueous sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated, the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 39 g (39% yield, 92% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.

Workup

  1. temperatureslurry was heated
  2. temperatureto almost reflux for ca. 30 min
  3. stirringstirred over night
  4. filtrationThe solid was collected by filtration
  5. washwashed with methanol/acetone mixture
  6. customdried under reduced pressure
  7. additionThe residue was taken up with a solvent mixture of methylenechloride/water
  8. additionafter addition of saturated aqueous sodium bicarbonate solution the organic phase
  9. customwas separated
  10. washaqueous phase washed twice with methylenechloride
  11. filtrationThe combined organic phases were filtrated
  12. customthe solvent removed under reduced pressure
  13. customRecrystallization of the crude product from aqueous ethanol

Sources & evidence

ORD record
ord-9faf534ec0c044f1a300c37ed31320e5
Source dataset
uspto-grants-2012_06
Patent number
US08207352B2

Reaction notes

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