Bromoacetonitrile → Methyl 3-(cyanomethylamino)-5-fluoro-4-methylbenzoate

HRID 869822Notes

Reaction equation

HRID 869822 reaction equation
[CH:1]([N:4](CC)C(C)C)(C)[CH3:2].S(=O)(=O)(O)O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([F:27])[C:25]=1[CH3:26])[C:19]([O:21][CH3:22])=[O:20].BrCC#N>C1COCC1>[C:1]([CH2:2][NH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([F:27])[C:25]=1[CH3:26])[C:19]([O:21][CH3:22])=[O:20])#[N:4]

Participants

5

Reactant 3

HCID 11534BromoacetonitrileHCID 81531DiisopropylethylamineHCID 66713590Methyl 3-amino-5-fluoro-4-methylbenzoate sulfuric acid salt

Product 1

HCID 86661587Methyl 3-(cyanomethylamino)-5-fluoro-4-methylbenzoateYield 91.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
55 °C

Procedure

To a solution of N,N-diisopropylethylamine (187 mL, 1073.6 mmol) in THF (240 mL) at 60-65° C. was added a solution of methyl 3-amino-5-fluoro-4-methylbenzoate sulfuric acid salt (80.0 g, 268.8 mmol) in THF (720 mL), maintaining the temperature in the range 45-65° C. Bromoacetonitrile (56.2 mL, 806.8 mmol) was charged and the solution heated to reflux for 3 d before concentration to 8 rel. vols. by distillation at atmospheric pressure. The solution was cooled to ambient temperature and water (1000 mL) added, maintaining the temperature in the range 18-23° C. The pH was adjusted to 1.2-1.5 with aq. hydrochloric acid (4 M, ˜80 mL) and the resulting slurry stirred at ambient temperature for 2 h before being filtered through 100 μm filter cloth under nitrogen. The filter cake was washed with mixed heptanes (2×320 mL) and dried under nitrogen at up to 45° C. to afford methyl 3-(cyanomethylamino)-5-fluoro-4-methylbenzoate (54.9 g, 99.1% w/w).

Workup

  1. temperaturethe solution heated
  2. temperatureto reflux for 3 d before concentration to 8 rel
  3. distillationby distillation at atmospheric pressure
  4. temperatureThe solution was cooled to ambient temperature
  5. additionwater (1000 mL) added
  6. temperaturemaintaining the temperature in the range 18-23° C
  7. filtrationbefore being filtered through 100 μm
  8. filtrationfilter cloth under nitrogen
  9. washThe filter cake was washed with mixed heptanes (2×320 mL)
  10. customdried under nitrogen at up to 45° C.

Sources & evidence

ORD record
ord-13830941ea0442ff803f0614f8ce3a58
Source dataset
uspto-grants-2015_03
Patent number
US08969350B2

Reaction notes

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