3-CYANO-4-FLUOROPHENYLACETIC ACID synthesis

Yield:519059-11-1 4.5 g

Reaction Conditions:

Stage #1: 2-fluoro-4-methylbenzonitrilewith N,N,N,N,N,N-hexamethylphosphoric triamide;lithium diisopropyl amide in tetrahydrofuran;n-heptane;ethylbenzene at -78; for 2 h;
Stage #2: carbon dioxide in tetrahydrofuran;n-heptane;ethylbenzene at -78; for 1 h;

Steps:

Intermediate I: Synthesis of (3-Cyano-4-fluoro-phenyl)-acetic acid

Lithium diisopropylamide solution 2.0 M in THF/heptane/ethylbenzene (20 mL, 40 mmol) is cooled to -78 °C. Hexamethylphosphoramide (7.1 mL, 40 mmol) is added followed by a solution of 2-fluoro-4-methyl-benzonitrile (5.0 g, 37 mmol) in 20 mL of THF. This is kept at -78 °C for two hours. CO2 is bubbled through the reaction for 1 hour. The -78 °C bath is removed. The reaction is slowly quenched with water. The reaction is diluted with EtOAc and the layers are separated. The basic water layer is made acidic with iN HC1. This is extracted with fresh EtOAc. The second EtOAc layer is concentrated to dryness to provide 4.5 g of I.

References:

WO2016/123275,2016,A1 Location in patent:Page/Page column 34