Sodium Iodide → 5-fluoro-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)aminopyridin-2-ol

HRID 1623322Notes

Reaction equation

HRID 1623322 reaction equation
[F:1][C:2]1[C:3]([NH:10][CH2:11][C:12]2([CH3:18])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:4][C:5]([O:8]C)=[CH:6][CH:7]=1.[I-].[Na+].[Si](Cl)(C)(C)C.OS([O-])(=O)=O.[Na+]>C(#N)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[N:4][C:3]=1[NH:10][CH2:11][C:12]1([CH3:18])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1

Participants

8

Reactant 4

HCID 5238Sodium IodideHCID 6397ChlorotrimethylsilaneHCID 516919Sodium BisulfateHCID 669370553-fluoro-6-methoxy-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine

Product 1

HCID 1784301505-fluoro-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)aminopyridin-2-ol

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent2×

Conditions

Temperature
83 °C

Procedure

To 3-fluoro-6-methoxy-N-((4-methyltetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine in acetonitrile (12 mL) was added sodium iodide (4.24 g, 28.3 mmol) and slowly TMS-Cl (3.62 mL, 28.3 mmol). The mixture was heated to reflux (oil bath: 83° C.) for 4 hr. The mixture was allowed to cool to ambient temperature and was diluted with EtOAc and saturated aqueous NaHCO3 solution. The mixture was vigorously stirred for 15 min and acidified with 0.5N aqueous NaHSO4 solution and stirring was continued for 5 min. The mixture was neutralized with saturated aqueous NaHCO3 solution. The separated aqueous phase was extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, 25 min, EtOAc/heptane=5/95 for 2 min, 5/95 to 50/50 over 18 min, then 50/50] providing 5-fluoro-6-((4-methyltetrahydro-2H-pyran-4-yl)methyl)aminopyridin-2-ol as colorless highly viscous oil. Yield: 420 mg. LCMS (m/z): 241.1 [M+H]+; Retention time=0.55 min.

Workup

  1. temperatureThe mixture was heated
  2. temperatureto cool to ambient temperature
  3. stirringstirring
  4. waitwas continued for 5 min
  5. extractionThe separated aqueous phase was extracted with EtOAc (3×)
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered off
  8. concentrationconcentrated in vacuo
  9. customThe resulting residue was purified by column chromatography [SiO2, 40 g, 25 min, EtOAc/heptane=5/95 for 2 min
  10. wait5/95 to 50/50 over 18 min

Sources & evidence

ORD record
ord-66f50f90adf544b887fdd9201dfb7759
Source dataset
uspto-grants-2014_07
Patent number
US08778951B2

Reaction notes

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