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A solid-phase synthesis method, the technology of liraglutide, which is applied in the preparation methods of peptides, peptides, specific peptides, etc., can solve the problems of complex synthesis steps and difficult purification.
Inactive Publication Date: 2017-08-08
GL BIOCHEM SHANGHAI
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[0005] The purpose of the present invention is to provide a solid-phase synthesis method of liraglutide with high yield, low cost, mild reaction conditions, little environmental pollution, and beneficial to realize industrialization, which mainly solves the existing problems of using heavy metal catalysts and Technical defects such as complicated synthesis steps and difficult purification
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Embodiment 1
[0069] (1) Preparation of Polypeptide Resin I
[0070] Weigh 57.1 grams of Fmoc-Gly-King resin (0.35mmol / g, 20mmol), soak in 500ml DMF for 30 minutes, drain, add 500ml decapping reagent, react for 30 minutes, drain, wash 5 times with DMF, add Fmoc- Arg(Pbf)-OH (MW: 648.8, 40mmol) 26.0g, HBTU (MW: 379.2, 40mmol) 15.2g, HOBT (MW: 135.1, 40mmol) 5.4g, NMM (MW: 102.1, 80mmol) 9.0ml, DMF500ml , reacted for 0.5-2 hours, ninhydrin detection resin was colorless and transparent, drained, washed 3 times with DMF, drained to obtain Fmoc-Arg(Pbf)-Gly-King resin, and then added deprotection reagent, deprotection Reaction, then add the amino acid with Fmoc protection group, and so on, until the 12th lysine is connected, DMF washes 3 times to obtain the polypeptide resin I: Dde-Lys(mmt)-Glu(Otbu)-Phe- Ile-Ala-Trp(Boc)-Leu-Val-Arg(Pbf)-Gly-Arg(Pbf)-Gly-Wang resin.
[0071] The amount of amino acid added in each step of condensation reaction is respectively:
[0072] Fmoc-Gly-OH (MW: 297.3,...
Embodiment 2
[0115] The degree of substitution of the selected Fmoc-Gly-King resin was 0.3mmol / g; the rest was the same as in Example 1, and finally 37g of Liraglutide fine product was obtained, with a total yield of 50%.
Embodiment 3
[0117] The degree of substitution of the selected Fmoc-Gly-King resin was 0.5mmol / g; the rest was the same as in Example 1, and finally 35g of liraglutide was obtained, with a total yield of 46%.
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Abstract
The invention discloses a method for preparing liraglutide. The technical defects that heavy metal catalysts are used, synthetic steps are complicated, purification is difficult and the like in the prior art are overcome. The technical scheme of the invention comprises the following steps: 1) with Fmoc-Gly-Wang resin as a carrier, coupling 2nd to 12th amino acids one by one by adopting an Fmoc solid phase synthetic method to obtain polypeptide resin I; 2) removing an mmt protecting group of the 11th Lys side chain through acidolysis, modifying Pal-gamma-Glu on the resin, and removing a Dde protecting group through hydrazinolysis to obtain polypeptide resin II; 3) continuously coupling 13th to 31st amino acids to obtain polypeptide resin III; 4) cutting the polypeptide resin III, splitting polypeptide from the resin and simultaneously removing the protecting group of the side chain to obtain a liraglutide crude product; carrying out high-efficient liquid chromatography separation and purification on the liraglutide crude product, and then lyophilizing the liraglutide curde product to obtain liraglutide. The process method for preparing liraglutide adopted by the invention has the characteristics of simple operation, high purity of crude peptide and high comprehensive yield.
Description
technical field [0001] The invention relates to the field of solid-phase synthesis of polypeptides, in particular to a solid-phase synthesis method of liraglutide. Background technique [0002] Liraglutide, the English name is liraglutide, molecular formula: C 172 h 265 N 43 o 51 , molecular weight: 3751.20, CAS number: 204656-20-2. Its peptide sequence is: NH 2 -His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(γ-Glu-Pal)-Glu- Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-COOH. [0003] Liraglutide, developed by Novo Nordisk, Denmark, is a glucagon-like peptide-1 (GLP-1) receptor agonist. As a subcutaneous injection preparation, it can play a good role in lowering blood sugar. Compared with the natural GLP-1 molecular structure, liraglutide has an amino acid difference and adds a 16-carbon palmitoyl fatty acid side chain, which is 95% homologous to natural human GLP-1. And due to the presence of fatty acid side chains, its molecules are not e...
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