Method for preparing AMG416 by combination of solid and liquid phase

Abstract

The invention provides a method for preparing AMG416 by combination of solid and liquid phase, and belongs to the field of polypeptide synthesis. The method is characterized by comprising the following steps: firstly, preparing completely-protected main chain peptide resin by using acid-sensitive amino resin as a solid phase carrier; then, directly adding diluted acid lysate to the peptide resin,and simultaneously, adding Y-Cys(X)-OH to form a disulfide bond to obtain a completely-protected target peptide; and finally, performing cracking and purification to obtain the AMG416. By adopting themethod provided by the invention for preparing the AMG416 by combination of the solid and liquid phase, the reaction time is shortened, the increase of by-products caused by long-time reaction is reduced, the purity of the target peptide is improved, the cost is reduced, the pollution to the environment is reduced, and large-scale production is facilitated.

Description

technical field [0001] The invention belongs to the field of polypeptide synthesis, and in particular relates to a method for preparing AMG416 by solid-liquid phase combination. Background technique [0002] AMG416, also known as Velcalcetide, is a polypeptide compound consisting of 8 amino acids, the C-terminus ends with amide, and the N-terminus is modified by acetylation. The sequence is as follows: [0003] [0004] AMG416 was developed by Amgen Corporation of the United States. It has been declared to the FDA and approved in the European Union. It is mainly used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease undergoing dialysis. Phase III clinical research shows that AMG416 is superior to the currently marketed similar product cinacalcet in the treatment and safety of secondary hyperparathyroidism. The industry expects that after the product is launched, its annual sales will exceed US$1 billion , has broad market prospect...

AI Technical Summary

Problems solved by technology

However, this method forms disulfide bonds in a solid-phase manner, and the reaction time is too long, usually more than 24 hours, which is not conducive to large-scale production

[0008] The above-mentioned existing AMG416 preparation method mainly has the following deficiencies: 1. When the liquid-phase synthesis method is oxidized to form disulfide bonds, the amount of solvent used is large, which not only increases the cost but also pollutes the environment; post-processing is tedious, and the formed disulfide bonds are easily broken Generate impurities, require multiple purifications and reduce product purity and yield

2. The solid-phase synthesis method requires a long reaction time to form disulfide bonds by oxidation, which increases the cost and is not conducive to large-scale production

[0009] Based on the above technical application background, the inventor of the present invention intends to solve the shortcomings of the existing preparation method such as cumbersome disulfide bond formation process, long reaction time, and large amount of solvent used to pollute the environment, and provide a new method for preparing AMG416

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