Synthetic method of desmopressin

Abstract

The invention discloses a synthetic method of desmopressin. The synthetic method comprises the following steps: 1) selecting solid phase carrier resin; 2) synthesizing main chain peptide resin; 3) conducting cracking to remove resin and protective groups; and 4) conducting liquid phase electrochemical oxidation and coupling disulfide bonds to obtain the desmopressin. According to the method, the problem of specific selectivity of reaction can be avoided, the utilization rate of fragment peptide resin, the utilization rate of main chain fragments and the atom utilization rate can be increased,so that the production cost is reduced, the use of chemical oxidants iodine and hydrogen peroxide is avoided, and the method is more environment-friendly and more conforms to the concept of green chemistry.

Description

technical field [0001] The invention belongs to the technical field of polypeptide drug production and relates to a synthesis method of desmopressin. Background technique [0002] Desmopressin is a structural analogue of natural arginine vasopressin, which is obtained by making two changes to the chemical structure of the natural hormone, namely deamination of 1-cysteine ​​and substitution of 8-D-arginine Substitution of 8-L-arginine. The peptide sequence of desmopressin is shown in formula I, wherein Mpa and Cys form a ring through a disulfide bond. [0003] [0004] Desmopressin is mainly used for the treatment of central diabetes insipidus, nocturnal enuresis and hemophilia, etc. It is also used for the test of renal urine concentration function, and it can also be used for postoperative hemostasis. [0005] With the increasing development of the Fmoc solid-phase peptide synthesis method and the maturity of the preparation process, at present, in the peptide synthesi...

AI Technical Summary

Problems solved by technology

Among them, solid-phase oxidants include iodine and hydrogen peroxide; liquid-phase oxidation methods include air oxidation, iodine / acetic acid system oxidation and hydrogen peroxide oxidation. These methods cannot guarantee the specific selectivity of the reaction, and inevitably produce mismatched impurities. , the product purity is low, which increases the difficulty of purification

Patent CN101372505A introduces a pseudo-dilution reaction to avoid the problem of disulphide bond mismatch between polypeptide chains in the liquid phase reaction. Solid phase oxidation synthesizes disulfide bonds, but the solid phase disulfide bond formation reaction is a heterogeneous reaction, and the reaction transformation The yield is low, resulting in a low yield of the product desmopressin

At the same time, iodine is used for oxidation, which pollutes the environment, is not conducive to environmental protection, and is not conducive to the sustainable development of the industry.

[0006] The development of atom-economical reactions and environmental protection has become the core content of green chemistry research. From the perspective of atom economy, the conventional sequential coupling method cannot avoid the specific selectivity of the disulfide bond construction of this linear peptide. problem, resulting in the construction of L-cysteine ​​and mercaptopropionic acid disulfide bonds, the effective utilization of the main chain fragments is low, that is, the atom utilization is low

In the general solid-phase synthesis operation, the amount of amino acid is generally 3-5eqv, when the effective utilization rate of the main chain fragment is low, it will cause a lot of waste of the corresponding amino acid

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