Potassium Hydroxide → 3-(1-t-Butoxycarbonyl-2-(r)-azetidinylmethoxy)-5-chloropyridine

HRID 2185748Notes

Reaction equation

HRID 2185748 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].S(C1C=CC(C)=CC=1)(O[CH2:15][C@H:16]1[CH2:19][CH2:18][N:17]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)=O>CN(C=O)C>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:16]1[CH2:15][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:21])([CH3:26])([CH3:24])[CH3:25]

Participants

5

Reactant 3

HCID 14797Potassium HydroxideHCID 5823053-Hydroxy-5-chloropyridineHCID 11002347(R)-tert-butyl 2-(tosyloxymethyl)azetidine-1-carboxylate

Product 1

HCID 213451803-(1-t-Butoxycarbonyl-2-(r)-azetidinylmethoxy)-5-chloropyridineYield 87%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 5-chloro-3-hydroxypyridine (0.3 g, 2.6 mmol) in DMF was added KOH (0.2 g, 3.8 mmol) at room temperature. 1-t-Butoxycarbonyl-2-(R)-azetidinylmethyl tosylate (0.8 g, 2.4 mmol, from example 10d) was then added, and the reaction mixture was stirred at 80° C. for 16 hours. The DMF was removed by washing with H2O/brine (1:1) in EtOAc. The organic layer was dried, concentrated and chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (0.6 g, 87%): 1H NMR (CDCl3, 300 MHz) δ1.43 (s, 9H), 2.21-2.40 (m, 2H), 3.89 (t, 2H, J=8 Hz), 4.12 (m, 1H), 4.36 (m, 1H), 4.52 (m, 1H), 7.29 (m, 1H), 8.20 (d, 1H, J=2 Hz), 8.25 (d, 1H, J=3 Hz); MS (CI/NH3) m/z 299 (M+H)+.

Workup

  1. customThe DMF was removed
  2. washby washing with H2O/brine (1:1) in EtOAc
  3. customThe organic layer was dried
  4. concentrationconcentrated
  5. customchromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1)

Sources & evidence

ORD record
ord-c4566f57b2f64533a459653c341ffb7d
Source dataset
uspto-grants-2002_06
Patent number
US06403575B1

Reaction notes

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