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Method for solid-phase synthesis of semaglutide

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

Active Publication Date: 2021-09-28
台州吉诺生物科技有限公司
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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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  • Method for solid-phase synthesis of semaglutide
  • Method for solid-phase synthesis of semaglutide
  • Method for solid-phase synthesis of semaglutide

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Embodiment 1

[0059] Such as Figure 1-3 as shown,

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

[0061] Weigh 50.0 g of Wang resin with a substitution degree of 1.1 mmol / g, and add it to a solid-phase peptide synthesizer. Subsequently, the resin was washed twice with DMF and swelled 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 then loaded into the above synthesizer loaded with resin. After 5 minutes, 0.1 g of DMAP was added and stirred for 2 hours. Subsequently, the resin was washed 3 times with DMF and DCM respectively, blocked with a mixed solution of acetic anhydride / pyridine / DMF with a volume ratio of (15mL:15mL:500mL) for 30 minutes, and then sucked dry. After shrinking the resin with methanol, the methanol was drained to obtain 70 g of Fmoc-Arg(Pbf)-Gly-King resin with a substitution degree of 0...

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Abstract

The invention discloses a method for solid-phase synthesis of semaglutide. The method comprises the following steps of 1, preparing polypeptide resin by a solid-phase synthesis method, firstly coupling a dipeptide fragment Fmoc-Arg (Pbf)-Gly-OH protected by N-terminal Fmoc to a resin solid-phase carrier to obtain Fmoc-Arg (Pbf)-Gly-resin, then coupling amino acid protected by N-terminal Fmoc and side chain and the dipeptide fragment sequentially according to a peptide chain sequence of semaglutide; 2, cracking the polypeptide resin to obtain a polypeptide skeleton; and 3, connecting the side chain to epsilon-NH2 of 20-site lysine, removing a protecting group, and purifying a semaglutide crude product. In the synthesis process, by using a proper dipeptide fragment, the aggregation of the polypeptide is inhibited, the deletion, insertion and racemization of impurities are avoided, and the method 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 Novo Nordisk, Denmark, is a glucagon-like peptide-1 (GLP-1) receptor agonist for the treatment of type 2 diabetes. [0003] In the prior art, a patent application such as Chinese Patent Publication No. CN108059666B describes the synthesis of semaglutide by using Alloc-Lys(Fmoc)-OH at the lysine position. Another example is Chinese Patent Publication Nos. CN106928343, CN109456402A and patent application No. WO2018032843A1 describing 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, the catalysts are sensitive to ...

Claims

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Application Information

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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
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