4-Fluorobenzoylacetonitrile

Chemical Properties

Uses

Synthesis

403-33-8

75-05-8

4640-67-9

The general procedure for the synthesis of 4-fluorobenzoylacetonitrile from methyl 4-fluorobenzoate and acetonitrile was as follows: methyl 4-fluorobenzoate (29.44 kg), toluene (177 L), and acetonitrile (59 L; 5.9 mole equivalents relative to methyl 4-fluorobenzoate) were added to a reactor. The reaction mixture was cooled to -5 to 0°C. A solution of sodium bis(trimethylmethylsilyl)amide (NaHMDS, 40% in THF) (192 L; 2 molar equivalents relative to methyl 4-fluorobenzoate) was slowly added while maintaining the temperature between -5 and +5 °C. The addition line was flushed with toluene (9 L) to ensure complete transfer. The reaction mixture was quenched by the addition of dilute hydrochloric acid while maintaining a temperature between -5 and +25°C. Continue to add acid until the pH falls below 5. Separate the layers and discard the lower aqueous layer. A small amount of solvent was removed by vacuum distillation. Toluene (59 L) was added and the mixture was heated to 85 to 90 °C to obtain a homogeneous solution. The mixture was cooled to 50 to 55 °C and n-heptane (29 L) was added to induce precipitation. The mixture was further cooled to 20 to 25 °C and the solid product was isolated by filtration and washed with n-heptane (59L). The wet product was dried under vacuum at 40 to 45°C to give 4-fluorobenzoylacetonitrile (26 kg, 83% yield) with 98.7% GC purity. The main impurity, 4-methoxybenzoylacetonitrile, was present in 0.03% (% GC area).

References