Abstract:

In this study the synthesis of cyclo(His-Pro) was investigated under high pressure/temperature condition. Using
dipeptide methyl ester hydrochloride as starting material, cyclo(His-Pro) was synthesized in water by high pressure/
temperature assisted cyclization. Influences of different reaction variables including pressure, time, solution pH and substrate
concentration on the yield of cyclo(His-Pro) were investigated by single-factor experiments, and then an orthogonal array
design was used to optimize the cyclization conditions. Quantification and identification of cyclo(His-Pro) in the product
were carried out by ultra performance liquid chromatography (UPLC) and electro spray ionization mass spectrometry
(ESI-MS). The optimum cyclization conditions were determined as follows: reaction pressure, 0.20 MPa; reaction time,
3.5 h; solution pH, 6.0; and substrate concentration, 15 mg/mL. Under such conditions, cyclo(His-Pro) was obtained in
excellent yield (91.35%) and no racemization was observed in the reaction process. In contrast to the classic methanol-reflux
cyclization, this method is rapid, environmentally friendly and highly efficient.

Key words: cyclo(His-Pro), high pressure/temperature technology, cyclization, cyclic dipeptides preparation