Synthetic method of plecanatide

Abstract

The invention discloses a synthetic method of plecanatide. The method comprises the following steps: in the presence of an activating agent, coupling a resin solid-phase carrier and Fmoc-Leu-OH to obtain Fmoc-Leu-resin, sequentially coupling amino acids with N-terminal Fmoc protection and side chain protection according to a plecanatide main chain peptide sequence through a solid-phase synthesis method, and splitting after coupling, so that plecanatide is removed from the resin and all side chain protection groups are removed, lyophilizing after cracking to obtain a plecanatide linear crude peptide; the obtained plecanatide linear crude peptide is dissolved in a solvent to obtain a dissolving solution, the mass volume ratio of solute to solvent in the dissolving solution is 0.1-1.0 mg / mL, then cyclization, separation and purification are performed to obtain cyclized plecanatide, and freeze-drying is performed to obtain fine peptide. The method is simple, high in yield and low in mismatch rate.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a synthesis method of plecanatide. Background technique [0002] At present, there are two general methods for the synthesis of Puka: firstly, the hexapeptide fragments are synthesized by the liquid phase synthesis method, and the hexapeptide fragments are coupled to the solid-phase resin by enzymatic method; The selective synthesis of two disulfide rings was achieved by protecting groups at different positions of Cys, and then they were cleaved from the resin for purification. However, the enzymatic reaction is used to couple the fragment to the solid phase resin, the yield is low, and it is not suitable for industrial production; it is difficult to selectively remove the special protecting group on Cys, and the conditions are harsh; The sulfur bond cyclization method is complicated and the yield is low. Second, in the presence of an activator system, the Fmoc-Leu-resin is ob...

AI Technical Summary

Problems solved by technology

However, the enzymatic reaction is used to couple the fragment to the solid phase resin, the yield is low, and it is not suitable for industrial production; it is difficult to selectively remove the special protecting group on Cys, and the conditions are harsh; The sulfur bond cyclization method is complicated and the yield is low

Second, in the presence of an activator system, the Fmoc-Leu-resin is obtained by coupling the resin solid-phase carrier and Fmoc-Leu-OH, and through the solid-phase synthesis method, according to the sequence of the main chain peptide of plecanatide, the coupling with N For amino acids protected by terminal Fmoc and protected by side chains, amino acid coupling is carried out in sequence according to the peptide sequence of the main chain of plecanatide. After the synthesis is completed, cleavage is carried out, and liquid-phase cyclization is carried out in aqueous solution or DMSO solution, and finally purified and lyophilized. Plecanatide was obtained; however, at high oxidation capacity, the degree of disulfide bond mismatch is high, resulting in difficulties in final purification

Images