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Solid-phase synthesis method for preparing exenatide

A technology for exenatide and solid-phase synthesis, which is applied in the preparation methods of peptides, chemical instruments and methods, peptides, etc., can solve the problems of complex synthesis steps, difficult separation in the later stage, and difficult coupling, etc., and achieves reduction of residual peptides. The formation of impurities, the elimination of β-sheet secondary space structure, and the effect of improving yield

Inactive Publication Date: 2017-02-22
滨海吉尔多肽有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The object of the present invention is to provide a high yield, low cost, mild reaction conditions, less environmental pollution, and a solid-phase synthesis method for exenatide that is conducive to the realization of industrialization, and mainly solves the complex synthesis steps in the prior art. Technical problems such as difficult coupling and later separation

Method used

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  • Solid-phase synthesis method for preparing exenatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] (1) Preparation of Fmoc-Rink Amide AM PEGMatrix resin

[0063] Weigh 25 grams of AM PEGMatrix resin (0.8mmol / g, 20mmol), soak it with 500ml DCM for 30 minutes, make the resin fully swell, drain, add Fmoc-Rink Amide linker (MW:539.58, 40mmol) 21.6g, DIEA (MW : 129.24, 80mmol) 13.5ml, TBTU (MW: 321.1, 40mmol) 12.8g, HOBT (MW: 135.1, 40mmol) 5.4g, DMF / NMP 500ml with a volume ratio of 1:1, reacted for 4 hours, drained, and used DMF Wash 3 times, drain, then add 500ml of acetic anhydride:pyridine:DMF mixed solution with a volume ratio of 2:2:1, react for 1 hour, drain, wash 6 times with DMF, and drain to obtain Fmoc-RinkAmide AM PEGMatrix resin.

[0064] (2) Preparation of His(trt)-Gly-Glu(otbu)-{Gly-Thr(psi(me,me)pro)}-Phe-Thr(tbu)-Ser(tbu)-Asp(otbu)-{Leu -Ser(psi(me,me)pro)}-Lys(boc)-Gln(trt)-Met-Glu(otbu)-Glu(otbu)-Glu(otbu)-Ala-Val-Arg(pbf)-Leu -Phe-Ile-Glu(otbu)-Trp(boc)-Leu-Lys(boc)-Asn(trt)-Gly-Gly-Pro-{Ser(tbu)-Ser(psi(me,me)pro)} -Gly-Ala-Pro-Pro-Pro-Pro-Ser(tbu...

Embodiment 2

[0107] Step (1) AM PEGMatrix resin reacted with Fmoc-Rink Amide linker and DIEA for 8 hours, then added acetic anhydride: pyridine: DMF mixed solution to react for 0.5 hours, and the degree of substitution of PEGMatrix resin was 1.0mmol / g; step (2) Fmoc -Rink Amide AM PEGMatrix resin, add deprotection reagent, react for 45 minutes; add Fmoc-Ser(tbu)-OH, NMM, reaction time is 0.5 hour; step (3) Add in the peptide chain resin with fully protected side chain Peptide cutting reagent, react for 2.5 hours. All the other are with embodiment 1.

Embodiment 3

[0109] Step (1) AM PEGMatrix resin reacted with Fmoc-Rink Amide linker and TBTU for 2 hours, then added acetic anhydride:pyridine:DMF mixed solution for 2 hours, the degree of substitution of PEGMatrix resin was 0.5mmol / g; step (2) Fmoc -Rink Amide AM PEGMatrix resin, add deprotection reagent, react for 60 minutes; add Fmoc-Ser(tbu)-OH, NMM, reaction time is 2 hours; step (3) add in the peptide chain resin with fully protected side chain Peptide cutting reagent, react for 3 hours. All the other are with embodiment 1.

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Abstract

The invention discloses a method for preparing exenatide, aiming at mainly solving the technical problems in the prior art that synthesis steps are complicated, the coupling difficulty is great, post-period separation is difficult, and the like. According to the technical scheme, the method comprises the following steps: 1) mixing Fmoc-Rink Amide Linder and PEG (Polyethylene Glycol) Matrix resin, and reacting to obtain Fmoc-Rink Amide PEG Matrix resin; 2) gradually coupling amino acids with protective groups and proline pseudodipeptide segments by adopting a Fmoc solid-phase synthesis method, so as to obtain side-chain full-protection polypeptide resin; and 3) cutting the side-chain full-protection polypeptide resin, cracking polypeptides from the resin, removing side-chain protection groups so as to obtain an exenatide crude product, and carrying out high performance liquid chromatography separation and purification and freeze-drying on the crude peptide to obtain the exenatide. The process method for preparing the exenatide, provided by the invention, has the characteristics of simplicity and convenience for operation, high crude peptide purity and high comprehensive yield.

Description

technical field [0001] The invention relates to the field of solid-phase synthesis of polypeptides, in particular to a method for solid-phase synthesis of exenatide. Background technique [0002] Exenatide, a polypeptide containing 39 amino acids isolated from the saliva of Gilka monster, Heloderma Horridum, has 48% structure with human glucagon It has 53% homology with human GLP-1 (glucagon-like peptide-1). [0003] Studies have shown that, as an analog of GLP-1, Exendin-4 can interact with GLP-1 receptors, stimulate the regeneration of pancreatic β cells, promote insulin secretion, inhibit the release of glucagon, slow down the rate of gastric emptying, and inhibit food intake. Its insulin secretion-stimulating effect is carried out according to the blood sugar level, so it can reduce the incidence of hypoglycemia, and the type II diabetic patients who are insensitive to other insulin secretory agents still have the hypoglycemic effect, and GLP-1 can also alleviate the t...

Claims

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Application Information

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IPC IPC(8): C07K14/575C07K1/08C07K1/06C07K1/04
CPCY02P20/55C07K14/57563
Inventor 竺剑峰徐红岩
Owner 滨海吉尔多肽有限公司
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