A synthetic method of semaglutide

Through natural chemical ligation/desulfurization method and glutamine main chain Allyl protection technology, the problem of poor resin shrinkage and solubility in somaglutide synthesis is solved, and the efficient and purification difficulty of somaglutide synthesis is achieved, which improves the overall yield and purity.

CN114685645BActive Publication Date: 2025-03-21HYBIO PHARMA
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Patent Information

Application Number
CN202011618277.2
Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
Filing Date
2020-12-30
Publication Date
2025-03-21
Estimated Expiration
2040-12-30

AI Technical Summary

Technical Problem

In the existing synthesis methods of somaglutide, the solid phase step coupling method has problems such as serious resin shrinkage, many peptides are missing, and difficulty in purification. Moreover, the condensation method of the full protection peptide fragments has poor solubility due to the full protection of the polypeptide fragments, making it difficult to efficiently purify.

Method used

A somaglutide synthesis method is adopted, and the peptide fragments are synthesized and ligated by natural chemical ligation/desulfurization method of peptide fragments I and III or peptide fragments II and IV are used to utilize the glutamine backbone Allyl protection and side chain ligation resin to achieve the synthesis and ligation of peptide fragments, and finally purified by liquid chromatography.

Benefits of technology

The total yield of somaglutide is improved, the purification difficulty is reduced, and the generation of impurities is reduced. The method has high ligation efficiency and mild reaction conditions, and avoids amino acid epimerization.

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Abstract

The present invention discloses a method for synthesizing semaglutide, comprising the following steps: synthesis of peptide fragment I: synthesis of peptide fragment III: Cys 18 ‑Gly 31 ; Synthesis of Intermediate I: His 1 ‑Gln 17 ‑Cys 18 ‑Gly 31 ; Synthesis of crude semaglutide peptide; or Synthesis of peptide fragment II: #imgabs1# Synthesis of peptide fragment IV: Cys 19 ‑Gly 31 ; Synthesis of Intermediate II: His 1 ‑Ala 18 ‑Cys 19 ‑Gly 31 ; Synthesis of crude semaglutide peptide. The present invention can purify two fragment peptides synthesized in solid phase, thereby greatly reducing the impurities generated by racemization, oxidation and hydrolysis of the final semaglutide product. At the same time, since the two fragments can be synthesized at the same time, the synthesis efficiency is improved. The crude semaglutide peptide is prepared by a one-step liquid phase reaction of two fragment peptides in liquid phase. In the final liquid chromatography purification step, the impurities are not defective peptides lacking one or several amino acids, but uncondensed partial fragments, which will not cause difficulties in purification. In addition, the uncondensed partial peptide fragments can also be recycled and reused, saving costs.
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