Potassium bisulfate → tert-butyl (2S)-2-(hydroxymethyl)azetidine-1-carboxylate

HRID 969265Notes

Reaction equation

HRID 969265 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

4

Reactant 2

HCID 516920Potassium bisulfateHCID 2734495(2S)-1-((tert-butoxy)carbonyl)azetidine-2-carboxylic acid

Product 1

HCID 10511797tert-butyl (2S)-2-(hydroxymethyl)azetidine-1-carboxylateYield 74%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

N-Methylmorpholine (1.35 ml, 12 mmol) was added to a stirred solution of (S)-azetidine-2-carboxylic acid (1.08 g; 10 mmol) and di-tert-butyl-dicarbonate (3.03 g; 14 mmol) in 1,4-dioxane: water (1:1, 30 ml) cooled to 0° C. The system was allowed to stir for 18 h with the temperature being allowed to rise slowly to room temperature. Saturated sodium bicarbonate solution (15 ml), cooled to 5° C. was added and the system was washed with ethyl acetate (3×75 ml). The aqueous phase was then acidified to pH 3 by the addition of potassium hydrogen sulfate. The aqueous phase was then extracted with ethyl acetate (3×100 ml), these organic layers were combined, dried (MgSO4), filtered and solvent removed in vacuo to give the product (S)-N-tert-butoxycarbonyl-azetidine-2-carboxylic acid (2.15 g) as a viscous oil. EIMS: m/z=201 (M+H)+. Borane-THF complex (1M sol, 35 ml, 35 mmol) was added slowly to a stirred solution of the above carboxylic acid in dry tetrahydrofuran cooled to <5° C. under nitrogen. The reaction was allowed to stir for 18 h, with the temperature being allowed to slowly rise to room temperature. 10% Aqueous potassium hydrogen sulfate (10 ml) was then added dropwise. Volatile components were evaporated in vacuo and the remaining slurry was extracted with ethyl acetate (3×75 ml). The combined organic phase was dried (MgSO4), filtered and solvent removed in vacuo to give the product (S)-N-tert-Butoxycarbonyl-2-hydroxymethylazetidine as a viscous oil (1.48 g, 74%), m/z [M+Na]+ 210.

Workup

  1. temperaturecooled to <5° C. under nitrogen
  2. customto slowly rise to room temperature
  3. customVolatile components were evaporated in vacuo
  4. extractionthe remaining slurry was extracted with ethyl acetate (3×75 ml)
  5. dry with materialThe combined organic phase was dried (MgSO4)
  6. filtrationfiltered
  7. customsolvent removed in vacuo

Sources & evidence

ORD record
ord-7c96ebe8c2254322bf9a5be64173c15b
Source dataset
uspto-grants-2007_12
Patent number
US07307073B2

Reaction notes

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