Solid-liquid phase synthesis method of polypeptide drug containing pair of disulfide bonds

Abstract

The invention discloses a solid-liquid phase synthesis method of a polypeptide drug containing a pair of disulfide bonds, which comprises the following steps: 1) preparing amino acid resin Fmoc-AA-NH2-Serb Resin by using Serb Resin resin, and synthesizing peptide resin by using a specific weak acid-sensitive protective group Fmoc amino acid; 2) cracking the resin, and forming disulfide bonds at the same time; and 3) conducting precipitating to obtain crude peptide. According to the synthesis method disclosed by the invention, high-concentration TFA cracking can be avoided, and meanwhile, sidechain protecting group deprotection, resin cracking and cyclization can be completed under the same condition; a strategy of adding 0.5-1.5% iodine-DCM solution in the later stage of cracking is adopted, so that oxidation can be completed while cracking is performed, the process is greatly simplified, and meanwhile, secondary preparation is avoided; after the reaction is finished, concentration isconducted to 1 / 2 of the reaction system, and then ether precipitation is conducted to obtain crude peptide with higher purity, and the separation degree of impurities and main peaks is better, so that preparation and purification are facilitated; and the process is simple to operate, operation steps are greatly simplified, the construction period is shortened, and aftertreatment is convenient.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis methods, and relates to a solid-liquid phase synthesis method of polypeptide drugs containing a pair of disulfide bonds. Background technique [0002] A disulfide bond is a type of cyclic compound structure formed by the oxidation of two sulfhydryl groups (SH), and is a common structural form in polypeptide compounds. For example, listed peptide drugs: oxytocin, desmopressin, arginine vasopressin, lysine vasopressin, terlipressin, lanreotide, etc. [0003] There are two main types of synthesis methods for this type of peptide products, one is liquid-phase synthesis; the other is solid-phase synthesis. Among them, the strategy of liquid phase synthesis mainly adopts fragment condensation method, that is, different fragments are synthesized, and then fragments are condensed; for example, the decapeptide compound arginine vasopressin adopts "4+6", "5+5", "3+7" and other strategies. Finally,...

AI Technical Summary

Problems solved by technology

This method is the synthesis scheme of conventional arginine vasopressin peptides (polypeptides containing a pair of disulfide bonds such as arginine vasopressin, oxytocin, terlipressin) at this stage; the scheme is obvious The disadvantages are: the whole experimental process is cumbersome, two preparations and purifications are required, and when the linear peptide is oxidized, a large volume of solvent is required to dissolve (to prevent dimer production, the reaction concentration is required to be extremely dilute), so when the purification work after oxidation , the separation of a large number of solvents brings a large workload to the purification work, and there are problems such as the troublesome treatment of the three wastes and the low overall yield of the two-step purification.

[0011] We tried to develop a new synthesis process to solve the above problems: cumbersome operation, low purity of crude peptide, low total yield, etc., while avoiding the use of strong acids such as trifluoroacetic acid to cause the three wastes, which has achieved the goal of environmental protection

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