Solid phase synthesis of Argireline Acetate with difficult amino acid series Arg-Arg and its reaction kinetics

In order to obtain a best synthetic route of Argireline Acetate and the guidance of its industrial production, this paper focuses on the condensation reaction between sterically hindered amino acid Fmoc-Arg (Pbf)-OH and NH₂-Arg(Pbf)-Rink Amide-AM with self-designed reactor, and its kinetic experiments were carried out at the same time. In self-designed reactor, the four functions of filtration, stir, temperature control and bubbling were combined. By optimizing the reaction conditions in the condensation process, a best synthetic route of Argireline Acetate was established, and its optimum reaction conditions were found as follows: the molar ratio of amino acid to resin 3:1, reaction time 2.5 h, temperature 40°C, NMP/DCM (2:1, V/V) as the solvent and HBTU/HOBt/DIEA as coupling reagents. Under above conditions, the highest yield of Argireline Acetate is 90.2%, and its purity is 83.5% by RP-HPLC analysis. The macroscopic kinetics of condensation reaction of Fmoc-Arg-(Pbf)-OH and NH₂-Arg(Pbf)-Rink Amide-AM resin were studied by using the differential method. The effect of reaction temperature on reaction rate was determined, and the macroscopic kinetic parameters of condensation reaction under activated ester method were obtained. The results show that the reaction order is 1.67 and the activation energy is 37.4 kJ·mol^-1.