Novel methods for the synthesis of 2-[(4R)-2-oxo-4-phenylpyrrolidin-1-yl]-acetamide ((R)-phenotropil)

Two novel methods have been developed for the preparation of 2-[(4R)-2-oxo-4-phenylpyrrolidin-1-yl]acetamide ((R)-Phenotropil). In the first, n-butyl (3R)-4-amino-3-phenylbutyrate is alkylated with haloacetamide in DMF in the presence of potassium phosphate monohydrate, and the intermediate 4-carbamoylmethylamino-3-phenylbutyrate is subsequently cyclized by refluxing in toluene in the presence of potassium phosphate monohydrate and tetrabutylammonium bromide. In the second, chloroacetonitrile is used under similar conditions in place of the haloacetamide. Both methods lead to (R)-Phenotropil in 40-60% yields calculated on the starting n-butyl (3R)-4-amino-3-phenylbutyrate.