Developing the Optimal Synthetic Schem for the Potential Nootropic Drug GZK-111, N-Phenylacetylglycyl-L-Proline Ethyl Ester

• DOI: 10.1007/s11094-020-02251-6
• Publication Date: 2020-09-28T10:03:20Z
• Authors: E. A. Kuznetsova; K. N. Kolyasnikova; A. K. Golubyatnikova; A. G. Rebeko; T. A. Gudasheva
• Keywords: Succinimides; Benzotriazole; Peptide bond; Ethyl ester; Oxalyl chloride; Nootropic

The optimal synthetic scheme for the potential nootropic drug GZK-111 (N-phenylacetylglycyl-L-proline ethyl ester) was developed. Three synthetic schemes were tested, each of which included the following steps: 1) esterification of L-proline; 2) preparation of N-phenylacetylglycine; 3) formation of the peptide bond. Esterification of proline per Brenner and preparation of N-phenylacetylglycine via acylation of glycine with phenylacetyl chloride under Schotten—Baumann conditions were used in all synthetic schemes. Three methods for forming the peptide bond between N-phenylacetylglycine and the proline ester were tried (mixed anhydride under Anderson conditions, activated benzotriazole ester, and activated succinimide ester methods) and showed that the mixed anhydride method was optimal, giving a total yield of 42%.