Ethyl Acetate → Tert-butyl 4-amino-3-chloro-2-fluorobenzoate

HRID 2406313Notes

Reaction equation

HRID 2406313 reaction equation
[Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([F:23])[CH:11]=1.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[NH2:9][C:10]1[C:22]([Cl:1])=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])=[C:12]([F:23])[CH:11]=1.[NH2:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])=[C:12]([F:23])[C:11]=1[Cl:1]

Participants

7

Reactant 3

HCID 8857Ethyl AcetateHCID 31398ChlorosuccinimideHCID 10058989Tert-butyl 4-amino-2-fluorobenzoate

Product 2

HCID 68684306Tert-butyl 4-amino-5-chloro-2-fluorobenzoateYield 23%HCID 86687946Tert-butyl 4-amino-3-chloro-2-fluorobenzoateYield 28%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 57417360Sodium chloride; waterSolvent

Procedure

To a solution of N-chlorosuccinimide (950 mg, 7.1 mmol) in N,N-dimethylformamide (25 mL) was added dropwise a solution of tert-butyl 4-amino-2-fluorobenzoate (1.5 g, 7.1 mmol) in N,N-dimethylformamide (22 mL). The resulting mixture was stirred at room temperature for 3 hours and then brine solution (80 mL) and ethyl acetate (100 mL) were added. The organic phase was collected and washed three times with brine (50 mL). Combined organic phases were dried on magnesium sulphate and evaporated under reduced pressure. Purification of the residue via silica gel column chromatography (4% EtOAc in iso-hexane) gave tert-butyl 4-amino-5-chloro-2-fluorobenzoate (400 mg, 23%, 1H NMR (400 MHz, DMSO-d6): δ 7.63 (d, J=7.6 Hz, 1H), 6.55 (d, J=13.2 Hz, 1H), 6.46 (brs, 2H), 1.52 (s, 9H)) and tert-butyl 4-amino-3-chloro-2-fluorobenzoate (490 mg, 28%, 1H NMR (400 MHz, DMSO-d6): δ 7.52 (t, J=8.4 Hz, 1H), 6.64 (dd, J=1.2 Hz and J=8.4 Hz, 1H), 6.50 (brs, 2H), 1.53 (s, 9H)) both as a white solid.

Workup

  1. customThe organic phase was collected
  2. washwashed three times with brine (50 mL)
  3. customCombined organic phases were dried on magnesium sulphate
  4. customevaporated under reduced pressure
  5. customPurification of the residue via silica gel column chromatography (4% EtOAc in iso-hexane)

Sources & evidence

ORD record
ord-a75468e349ef425598185566ee38c42d
Source dataset
uspto-grants-2014_08
Patent number
US08809331B2

Reaction notes

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