The invention relates to the field of pharmaceutical synthesis, and discloses a synthetic method for
linaclotide. The method uses a
solid phase one-step cyclization method to prepare
linaclotide, andthe
linaclotide linear
peptide resin is directly cyclized by a N-X-substituted
succinimide solution oxidation
system without cleavage to obtain linaclotide resin, the resin is cleaved, purified and lyophilized to give linaclotide. The N-X-substitured
succinimide is one of N-chlorosuccinimide, N-
bromosuccinimide, N-iodosuccinimide, and N-hydroxy thiosuccinimide. The method has the following advantages that: 1)
solid phase cyclization is adopted, firstly, the pseudo-
dilution effect is achieved, repeated folding of the
peptide chain is avoided, and the cyclization reaction can be carried out at ahigher concentration, which can greatly improve the production efficiency; secondly, the linear
peptide resin is not cleaved before cyclization, avoiding the production of a large amount of impurities and improving the efficiency of linaclotide cyclization; 2) one-step cyclization using N-X-substituted
succinimide can avoid multi-step purification of the intermediates, reduce the composition of the intermediate purification step, and improve the total yield of linaclotide; and 3) a specific
amino acid side chain protecting group is adopted, thus positioning a pair of disulfide bonds in the cyclization process, reducing the formation of mismatch by-products, improving the purity of linaclotide, greatly improving production efficiency, and reducing the manufacturing cost.