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

HRID 2075181Notes

Reaction equation

HRID 2075181 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), was added to DCM (700 mL) at rt under N2 atm. The mixture was stirred for 15 min, at which point sodium triacetoxyborohydride (127 g, 601 mmol) was added portionwise (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 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 portionwise (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-30e6fd728c0243abba027cb246f12ae6
Source dataset
uspto-grants-2011_04
Patent number
US07919519B2

Reaction notes

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