2,4-Difluorobenzaldehyde → 3-(5-Fluoro-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

HRID 1479020Notes

Reaction equation

HRID 1479020 reaction equation
C(O[K])(C)(C)C.[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>O1CCOCC1.O>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([O:18][C:20]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=2[CH:22]=[O:23])[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]

Participants

6

Reactant 3

HCID 737702,4-DifluorobenzaldehydeHCID 2756801Tert-butyl 3-hydroxyazetidine-1-carboxylateHCID 178418922HCID 178418922, compound

Product 1

HCID 896501743-(5-Fluoro-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl esterYield 34%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent2×

Procedure

tBuOK (948 mg; 8.44 mmol; 1.2 eq.) was added to a solution of 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.46 g; 8.44 mmol; 1.2 eq.) in 1,4-dioxane (5 mL) and the solution was stirred at room temperature for 15 minutes whereupon a solution of 2,4-difluoro-benzaldehyde (1 g; 7.04 mmol; 1 eq.) in 1,4-dioxane (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 5 minutes then diluted with water. The solution was extracted with DCM (2×) and the combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (heptanes/EA) afforded the title compound (705 mg, 34%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.41 (d, J=0.8 Hz, 1H), 7.93 (dd, J=8.7, 6.8 Hz, 1H), 6.99-6.72 (m, 1H), 6.33 (dd, J=10.2, 2.2 Hz, 1H), 5.07-4.85 (m, 1H), 4.40 (ddd, J=9.9, 6.4, 1.1 Hz, 2H), 4.10 (ddd, J=9.9, 4.0, 1.1 Hz, 2H), 1.48 (s, 9H). HPLC (max plot) 96.4%; Rt 4.22 min.

Workup

  1. additionwas added dropwise
  2. extractionThe solution was extracted with DCM (2×)
  3. dry with materialthe combined organic phase was dried over magnesium sulfate
  4. concentrationconcentrated in vacuo
  5. customPurification by column chromatography (heptanes/EA)

Sources & evidence

ORD record
ord-73ad553d460944c8b211a4c2ef53df5f
Source dataset
uspto-grants-2016_08
Patent number
US09403835B2

Reaction notes

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