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Acetic Acid → Isavuconazole

HRID 222810
Notes
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Reaction equation

HRID 222810 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.C(O)(=O)C>C1(C)C=CC=CC=1>[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]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 131278(R)-camphorsulfonic acidHCID 21937662Isavuconazole(BAL-4815; RO-0094815)

Product 1

HCID 6918485IsavuconazoleYield 45%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
70 °C

Procedure

A solution of the racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (4.4 g) and (1R)-10-camphorsulfonic acid (2 g) in toluene (40 ml) containing glacial acetic acid (0.6 ml) was warmed up to approximately 70° C., then allowed to cool slowly to 20° C., seeded with the pure enantiomeric salt whereupon the pure enantiomeric salt start to crystallize out. After ca. 2 hrs at this temperature the solid was collected, washed with cold toluene and dried. The crystals were taken with a solvent mixture of methylenechloride/water and after addition of aqueous saturated sodium bicarbonate solution the organic phase was separated and aqueous phase washed twice with methylenechloride. The combined organic phases were filtrated and the solvent removed under reduced pressure. Recrystallization of the crude product from aqueous ethanol provided enantiomerically pure title compound: 2 g (45% yield, 99% ee). The analytical data were identical with published: U.S. Pat. No. 6,300,353 and WO 99/45008.

Workup

  1. temperatureto cool slowly to 20° C.
  2. customto crystallize out
  3. customAfter ca. 2 hrs at this temperature the solid was collected
  4. washwashed with cold toluene
  5. customdried
  6. additionThe crystals were taken with a solvent mixture of methylenechloride/water
  7. additionafter addition of aqueous saturated sodium bicarbonate solution the organic phase
  8. customwas separated
  9. washaqueous phase washed twice with methylenechloride
  10. filtrationThe combined organic phases were filtrated
  11. customthe solvent removed under reduced pressure
  12. customRecrystallization of the crude product from aqueous ethanol

Sources & evidence

ORD record
ord-46c98376319b4a43a4412249b7eaf454
Source dataset
uspto-grants-2012_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08207352B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes