Trifluoroacetic acid → HCID 178448286, compound

HRID 2367964Notes

Reaction equation

HRID 2367964 reaction equation
Br[C:2]1[N:3](C2CCCCO2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][C@@H:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[N:5]=2.C[O-].[Na+].[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28].[CH3:34][O:35]C1CCCC1>CC1CCCO1.CO>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[CH3:17][C@H:13]([O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:35][CH3:34])[NH:3]2)=[C:8]([NH2:11])[N:7]=1)[CH2:14][CH2:15][CH3:16]

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 138539Cyclopentyl methyl etherHCID 10942334Sodium MethoxideHCID 576998418-bromo-2-(((S)-pentan-2-yl)oxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

Product 1

HCID 178448286HCID 178448286, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 73012-MethyltetrahydrofuranSolvent

Procedure

8-Bromo-2-{[(1S)-1-methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.26 kg, corrected for residual solvent) was dissolved in anhydrous methyl tetrahydrofuran (MeTHF) (11.4 L) and 25% sodium methoxide in methanol (2.65 L, 3.5 eq) was added. The resultant reaction mixture was heated to 65+/−5° C. for 3 hrs. The complete reaction was cooled to room temperature and washed with 20% w/v aqueous ammonium chloride solution (2×6.3 L) and brine (6.3 L). The organic phase was dried with MgSO4 (1.8 kg) and filtered, washing through with MeTHF (6.3 L). The combined organic phases were evaporated to 6.3 L by vacuum distillation. MeOH (2.5 L) and TFA (1.26 L, 5 eq) were added and the mixture heated to 60° C. for 1.5 hours. Cyclopentyl methyl ether (CPME) (6.3 L) was added and the mixture reduced to 6.3 L by vacuum distillation. CPME (6.3 L) was again added and the reaction further concentrated to 6.3 L, when solids precipitated. The slurry was cooled to 10° C. then aged for 30 min. The product was filtered and washed with TBME (2×3.8 L) and dried in vacuo at 40° C. to afford a white solid (886 g, 74% theoretical yield).

Workup

  1. customThe resultant reaction mixture
  2. temperaturewas heated to 65+/−5° C. for 3 hrs
  3. customThe complete reaction
  4. washwashed with 20% w/v aqueous ammonium chloride solution (2×6.3 L) and brine (6.3 L)
  5. dry with materialThe organic phase was dried with MgSO4 (1.8 kg)
  6. filtrationfiltered
  7. washwashing through with MeTHF (6.3 L)
  8. customThe combined organic phases were evaporated to 6.3 L by vacuum distillation
  9. temperaturethe mixture heated to 60° C. for 1.5 hours
  10. distillationthe mixture reduced to 6.3 L by vacuum distillation
  11. additionCPME (6.3 L) was again added
  12. customthe reaction
  13. concentrationfurther concentrated to 6.3 L, when solids
  14. customprecipitated
  15. temperatureThe slurry was cooled to 10° C.
  16. filtrationThe product was filtered
  17. washwashed with TBME (2×3.8 L)
  18. customdried in vacuo at 40° C.
  19. customto afford
  20. customa white solid (886 g, 74% theoretical yield)

Sources & evidence

ORD record
ord-12197ba6c29d46a48b44dce473901365
Source dataset
uspto-grants-2014_04
Patent number
US08703754B2

Reaction notes

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