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A method for solid-phase synthesis of semaglutide

A technology of solid-phase synthesis and solid-phase carrier, which is applied to the preparation method of peptides, chemical instruments and methods, peptides, etc., and can solve problems such as insufficient synthesis methods

Active Publication Date: 2022-07-19
台州吉诺生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] In summary, there are deficiencies in the synthetic method of semaglutide in the prior art

Method used

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  • A method for solid-phase synthesis of semaglutide
  • A method for solid-phase synthesis of semaglutide
  • A method for solid-phase synthesis of semaglutide

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Embodiment 1

[0059] like Figure 1-3 shown,

[0060] Synthesis of Fmoc-Arg(Pbf)-Gly-king Resin with a Degree of Substitution of 0.9 mmol / g (Peptide Resin Prepared by Fractional Solid Phase Synthesis)

[0061] Weigh 50.0 g of Wang resin with a degree of substitution of 1.1 mmol / g and add it to the solid-phase peptide synthesizer. Subsequently, the resin was washed twice with DMF and swollen in DMF for 30 minutes. Then 77.64 g of Fmoc-Arg(Pbf)-Gly-OH and 13.9 g of DIC were dissolved in DMF under an ice-water bath and loaded into the resin loaded synthesizer described above. After 5 minutes, 0.1 g of DMAP was added and stirred for 2 hours. Subsequently, the resin was washed three times with DMF and DCM, respectively, blocked with a mixed solution of acetic anhydride / pyridine / DMF in a volume ratio of (15mL:15mL:500mL) for 30 minutes, and then drained. After shrinking the resin with methanol, the methanol was drained to obtain 70 g of Fmoc-Arg(Pbf)-Gly-king resin with a degree of substituti...

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Abstract

The invention discloses a method for solid-phase synthesis of semaglutide, comprising the following steps. In step 1, a solid-phase synthesis method is used to prepare a polypeptide resin, and the N-terminal Fmoc-protected dipeptide fragment Fmoc-Arg(Pbf)-Gly- OH is coupled to the resin solid phase carrier to obtain Fmoc-Arg(Pbf)-Gly-resin, and then the N-terminal Fmoc-protected and side-chain-protected amino acids and dipeptide fragments are sequentially coupled according to the peptide chain sequence of semaglutide. Step 2, the above-mentioned polypeptide resin is cleaved to obtain a polypeptide backbone; Step 3, the side chain is connected to the ε-NH of the 20-position lysine 2 , the protecting groups were removed and the crude semaglutide was purified. In the synthesis process of the present invention, by using suitable dipeptide fragments, the aggregation of the polypeptide is suppressed, deletion, insertion and racemization impurities are avoided, and it is suitable for commercialization.

Description

Technical field: [0001] The invention relates to the field of solid-phase synthesis of polypeptide drugs, in particular to a method for solid-phase synthesis of semaglutide. Background technique: [0002] Semaglutide, developed by the Danish company Novo Nordisk, is a glucagon-like peptide-1 (GLP-1) receptor agonist for the treatment of type 2 diabetes. [0003] In the prior art, for example, Chinese Patent Publication No. CN108059666B describes the synthesis of semaglutide by using Alloc-Lys(Fmoc)-OH at the lysine position. For another example, Chinese Patent Publication Nos. CN106928343, CN109456402A and Patent Application No. WO2018032843A1 describe the synthesis of semaglutide by using Fmoc-Lys(Alloc)-OH at the lysine position. These methods are complicated in process and high in cost, and are not suitable for large-scale production. The deprotection of Alloc requires expensive metal catalysts such as Pd(PPh 3 ) 4 . In addition, catalysts are sensitive to moisture, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/605C07K1/04C07K1/06C07K1/10C07K1/20
CPCC07K14/605Y02P20/55
Inventor 王丰健拉及库马尔塔尔拉维塞米拉
Owner 台州吉诺生物科技有限公司