Acetic Acid → Methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate

HRID 658980Notes

Reaction equation

HRID 658980 reaction equation
[NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[F:17].[CH:18]([O-])([O-])OC.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO.S(=O)(=O)(O)O>C(Cl)Cl>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:1]2[CH2:4][CH:3]([C:5]([O:7][CH3:18])=[O:6])[CH2:2]2)=[CH:11][C:10]=1[F:17]

Participants

9

Reactant 7

HCID 176Acetic AcidHCID 887MethanolHCID 1118Sulfuric AcidHCID 931923-azetidinecarboxylic AcidHCID 27834114-Bromo-3-fluorobenzaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 53629101Methylorthoformate

Product 1

HCID 59651823Methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Azetidine-3-carboxylic acid (43 g, 421 mmol), 4-bromo-3-fluorobenzaldehyde (81.4 g, 401 mmol), methyl orthoformate (219 mL, 2005 mmol), and AcOH (34 mL, 601 mmol) were added to DCM (700 mL) at rt under an N2 atmosphere. The mixture was stirred for 15 min, at which point sodium triacetoxyborohydride (127 g, 601 mmol) was added portion-wise (exothermic). After 2 h, solvent swap with MeOH (257 g, 8019 mmol), and sulfuric acid (79 g, 802 mmol) was added slowly (exothermic). The mixture was heated at reflux for 18 h. Solvent was removed and the mixture was extracted using DCM and water. The organic layer was purified using a Biotage column (isopropanol/heptane), affording methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate as a clear oil. MS (ESI) m/z: Calculated: 301.0; Observed: 302.0 (M++1).

Workup

  1. additionwas added portion-wise (exothermic)
  2. temperatureThe mixture was heated
  3. temperatureat reflux for 18 h
  4. customSolvent was removed
  5. extractionthe mixture was extracted
  6. customThe organic layer was purified

Sources & evidence

ORD record
ord-492108abe60e4a2989430bf04cfb827b
Source dataset
uspto-grants-2011_12
Patent number
US08080542B2

Reaction notes

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