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Preparation method of Liraglutide

A technology of linacglutide and linacglutide, which is applied in the field of peptide drug preparation, can solve the problem of low product purity, reduce the difficulty of purification, increase product yield, and improve the effect of crude product purity

Pending Publication Date: 2020-02-07
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The invention provides a new high-efficiency preparation method, adopts Fmoc-Gly resin as the starting resin, uses special protected amino acids, and solves the problem of low product purity in the large-scale preparation method

Method used

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  • Preparation method of Liraglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Synthesis of Linaglutide Resin

[0037] Linarutide peptide resin is:

[0038] Boc-His(Trt)-Ala-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Val-Ser(tBu)-Ser(tBu)- Tyr(tBu)-Leu-Glu(OtBu)-Gly-Gln(Trt)-Ala-Ala-Lys(N α -Pal-γGlu(α-OtBu))-Glu(OtBu)-Phe-Ile-Ala-Trp(Boc)-Leu-Val-Arg(Pbf)-Gly-Arg(Pbf)-Gly-resin

[0039]Using Fmoc-Gly-resin as the starting resin, de-Fmoc protection and coupling reactions were performed, followed by coupling with the protected amino acids shown in Table 2 to prepare linacglutide resin. The protected amino acids or fragments corresponding to the protected amino acids used in this example are as follows:

[0040] Table 2

[0041] The peptide sequence n= Protected Amino Acids 2 Fmoc-Arg(Pbf) 3 Fmoc-Gly-OH 4 Fmoc-Arg(Pbf) 5 Fmoc-Val 6 Fmoc-Leu 7 Fmoc-Trp(Boc) 8 Fmoc-Ala 9 Fmoc-Ile 10 Fmoc-Phe 11 Fmoc-Glu(OtBu) 12 Fmoc-Lys(N α -Pal-γGlu(α-OtBu))

...

Embodiment 2

[0048] Example 2 Preparation of Crude Linaglutide

[0049] Take the linaglutide resin prepared in Example 1, add a lysis reagent with a volume ratio of TFA:water:EDT=95:5:5 (lysis reagent 10mL / g resin), stir evenly, and stir at room temperature for 3 hours, The reaction mixture was filtered with a sand core funnel, the filtrate was collected, the resin was washed 3 times with a small amount of TFA, the combined filtrates were concentrated under reduced pressure, anhydrous ether was added to precipitate, and anhydrous ether was used to wash the precipitate 3 times, and the off-white powder was obtained by draining. It is the crude product of linacglutide, and the purity of the crude product is 70.5%.

Embodiment 3

[0050] Example 3 Purification of Crude Linaglutide

[0051] Take the crude linacglutide obtained in Example 2, add water and stir, adjust the pH to 8.5 with ammonia water until completely dissolved, filter the solution with a 0.45 μm mixed microporous membrane, and purify it for later use;

[0052] High-performance liquid chromatography was used for purification, and the chromatographic filler for purification was 10 μm reversed-phase C18. Two mobile phase systems were used for purification alternately. The first mobile phase system was 0.1% TFA / water solution-0.1% TFA / acetonitrile solution, and the second mobile phase system was 0.1% TFA / water solution-0.1% TFA / acetonitrile solution. The two mobile phase systems are 50mmol ammonium acetate / water solution-acetonitrile. The flow rate of the 77mm*250mm chromatographic column is 90mL / min, the gradient system is used for elution, and the sample is injected and purified in a circular manner. The crude product solution is loaded on ...

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Abstract

The invention provides a preparation method of Liraglutide. In the method, a special protected amino acid fragment, namely Boc-His (Boc)-Ala-Glu (OtBu)-Gly-OH and Fmoc-Lys (N alpha-Pal-gamma Glu (alpha-OtBu)-OH, is adopted, so that the problem of low product purity in a large-scale preparation method is solved.

Description

technical field [0001] The invention belongs to the technical field of preparation methods of polypeptide drugs, and in particular relates to a preparation method of linglutide. Background technique [0002] Linaglutide is a GLP-1 analog with 97% sequence homology to human GLP-1, which can bind and activate GLP-1 receptors. The GLP-1 receptor is the target of natural GLP-1, an endogenous incretin hormone that promotes glucose-dependent insulin secretion from pancreatic β-cells. Different from Daran GLP-1, the pharmacokinetics and pharmacodynamics characteristics of linacglutide in humans are suitable for a once-a-day dosing regimen. After subcutaneous injection, the mechanism of prolonged action time includes: self-association to slow absorption; binding to albumin; dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase (NEP). Higher enzyme stability resulting in longer plasma half-life. [0003] Linaglutide has the following structure: [0004] His-Ala-Glu-Gly-Thr-P...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/04C07K1/06C07K1/16
CPCC07K14/605Y02P20/55
Inventor 曾德志董华建文永均
Owner CHENGDU SHENGNUO BIOPHARM
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