Sodium Carbonate → 3-(5-Bromo-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

HRID 237246Notes

Reaction equation

HRID 237246 reaction equation
[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=NC(C)(C)C)=[C:4](F)[CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([OH:26])[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[H-].[Na+].C([O-])([O-])=[O:30].[Na+].[Na+]>CC(O)=O.O.C1COCC1.CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:25][CH:24]([O:26][C:4]2[CH:3]=[C:2]([Br:1])[CH:13]=[CH:12][C:5]=2[CH:6]=[O:30])[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]

Participants

9

Reactant 4

HCID 10340Sodium CarbonateHCID 24758Sodium hydrideHCID 2756801Tert-butyl 3-hydroxyazetidine-1-carboxylateHCID 67343773(4-Bromo-2-fluoro-benzylidene)-tert-butyl-amine

Product 1

HCID 866570483-(5-Bromo-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl esterYield 82%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a 0° C. DMF (720 mL) solution of the title compound of Step A (37.2 g, 144 mmol) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (25.0 g, 144 mmol) was added NaH (60 wt % in mineral oil, 7.50 g, 188 mmol) portionwise over 2 h. The reaction was then allowed to warm to rt. After 18 h, H2O was added and the reaction mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine and concentrated to give a yellow liquid that was treated with THF (360 mL), H2O (360 mL) and AcOH (25 mL). After 5 h, this solution was made basic with 5% Na2CO3 (aq.) and extracted with EtOAc (2×). The combined organic layers were washed with brine and dried. The resulting solid was then triturated with 20% EtOAc in hexanes to give 41.9 g (82%) of the title compound as a white solid. 1H NMR (CDCl3): 10.43 (s, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.26-7.23 (m, 1H), 6.77 (d, J=1.6 Hz, 1H), 5.01-4.95 (m, 1H), 4.39 (ddd, J=9.9, 6.3, 0.8 Hz, 2H), 4.08 (dd, J=6.4, 0.8 Hz, 2H), 1.46 (s, 9H).

Workup

  1. customTo a 0° C
  2. extractionthe reaction mixture was extracted with EtOAc (2×)
  3. washThe combined organic layers were washed with brine
  4. concentrationconcentrated
  5. customto give a yellow liquid that
  6. waitAfter 5 h
  7. extractionextracted with EtOAc (2×)
  8. washThe combined organic layers were washed with brine
  9. customdried
  10. customThe resulting solid was then triturated with 20% EtOAc in hexanes

Sources & evidence

ORD record
ord-9d9b0052b05e41ad8c54c93a11952ca0
Source dataset
uspto-grants-2014_02
Patent number
US08642583B2

Reaction notes

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