Potassium Hydroxide → 5-fluoro-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine

HRID 2185718Notes

Reaction equation

HRID 2185718 reaction equation
[F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[OH-].[K+].[C:11]([O:15][C:16]([N:18]1[CH2:21][CH2:20][C@H:19]1[CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:22][C@@H:19]2[CH2:20][CH2:21][N:18]2[C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17])[CH:5]=[N:4][CH:3]=1

Participants

5

Reactant 3

HCID 14797Potassium HydroxideHCID 27629063-Fluoro-5-hydroxypyridineHCID 11602568(S)-tert-Butyl 2-((tosyloxy)methyl)azetidine-1-carboxylate

Product 1

HCID 108028345-fluoro-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridineYield 56%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
80 °C

Procedure

A solution of 3-fluoro-5-hydroxypyridine (500 mg, 4.43 mmol, as prepared in step 10f below) in dimethylformamide (20 mL) was treated with ground KOH (400 mg, 7.10 mmol) and stirred for 30 minutes at 80° C. To this mixture was rapidly added the 1-(t-butyloxycarbonyl)-(2S)-p-toluene-sulfonyloxymethylazetidine (1.05 g, 4.39 mmol, as prepared in Step 10b below) dissolved in dimethylformamide (5 mL) and the reaction mixture was subsequently stirred for 16 h at 80° C. The mixture was concentrated to remove the dimethylformamide and the resultant residue diluted with water and extracted with EtOAc (3×). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo. This material was purified by flash chromatography (silica gel; hexane/EtOAc, 10:1) to give 5-fluoro-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (692 mg, 56%): 1H NMR (CDCl3, 300 MHz) δ1.40 (s, 9H), 2.30 (m, 2H), 3.92 (m, 2H), 4.16 (m, 1H), 4.40 (m, 1H), 4.54 (m, 1H), 7.05 (m, 1H), 8.20 (m, 2H); MS (CI/NH3) m/z: 283 (M+H)+. To 5-fluoro-3-(1-Boc-(2S)-azetidinylmethoxy)pyridine from above (320 mg, 1.14 mmol) was added HCl/Et2O in methylene chloride at 0° C., and the solution was stirred for 2 h. The solvent was removed and the residue was recrystallized from EtOH/Et2O to afford the title compound (250 mg): mp 165-167° C.; [α]D25 27.8 (c 0.56, MeOH); 1H NMR (D2O, 300 MHz) δ2.70 (m, 2H), 4.10 (m, 2H), 4.50 (d, J=4.5 Hz, 2H), 5.01 (m, 1H), 7.80 (tt, J=3 Hz, 1H), 8.42 (dd, J=3, 6 Hz, 2H); MS (CI/NH3) m/z 183 (M+H)+, 200 (M+NH4)+.

Workup

  1. stirringthe reaction mixture was subsequently stirred for 16 h at 80° C
  2. concentrationThe mixture was concentrated
  3. customto remove the dimethylformamide
  4. additionthe resultant residue diluted with water
  5. extractionextracted with EtOAc (3×)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThis material was purified by flash chromatography (silica gel; hexane/EtOAc, 10:1)

Sources & evidence

ORD record
ord-8dbd3a62dbab4f16b1ea6372d389d0c4
Source dataset
uspto-grants-2002_06
Patent number
US06403575B1

Reaction notes

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