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Solid-phase fragment synthetic method of exenatide

A technology of exenatide and a synthesis method, which is applied in the field of solid-phase peptide synthesis, can solve the problems of low product content, high purification cost, low efficiency of synthesizing long peptides, etc.

Active Publication Date: 2014-03-05
SHAANXI HUIKANG BIO TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is to overcome the disadvantages of low efficiency, low product content, and high purification cost of the traditional classic solid-phase peptide synthesis method for synthesizing long peptides, as well as the disadvantages of complicated process and high purification cost when solid-phase and liquid-phase are mixed and used , to provide a method for synthesizing exenatide with high synthesis efficiency, low purification cost, easy process flow, and easy scale-up.

Method used

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Examples

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Embodiment 1

[0043] 1. Synthesis of Fmoc-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-MBHA Resin

[0044] (1) Synthesis of Fmoc-Ser(tBu)-MBHA Resin

[0045] Add 1.0g Fmoc-Rink Amide MBHA Resin into the reactor, add 10mL N,N-dimethylformamide to soak the resin for 30 minutes to fully swell the resin, remove N,N-dimethylformamide by suction filtration, and add to the reaction Add 10mL of piperidine and N,N-dimethylformamide with a volume ratio of 1:4 to the container, react for 5 minutes, remove the mixture by suction filtration, then add 10mL of piperidine and N,N-dimethylformamide The volume ratio of formamide is a mixture of 1:4, react for 20 minutes, filter with suction, wash the resin twice with isopropanol, and wash the resin three times with N,N-dimethylformamide, 10 mL each time, to complete the Fmoc- Rink Amide MBHA Resin de-Fmoc- twice, add 10mL N,N-dimethylformamide, 0.53g Fmoc-Ser(tBu)-OH, 0.19g 1-hydroxybenzotriazole, 0.44g benzene Ditriazole-N,N,N',N'-tetramethyluro...

Embodiment 2

[0073] In step 1 of this implementation, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser( The molar ratio of tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH and Fmoc-Rink Amide MBHA Resin is 2:1, Fmoc-Rink Amide MBHA Resin and 1- The molar ratio of hydroxybenzotriazole, benzotriazole-N,N,N′,N′-tetramethylurea tetrafluoroboric acid, N,N′-diisopropylethylamine is 1:2:2 : 2, other steps of this step are identical with embodiment 1. In step 2 of this example, the molar ratios of Fmoc-Asn(Trt)-OH, Fmoc-Lys(Boc)-OH and 2-chlorotrityl chloride resin are all 2:1, 2-chlorotrityl chloride resin and 1-hydroxybenzene The molar ratio of propanetriazole, benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid, N,N'-diisopropylethylamine is 1:2:2:2, Other steps of this step are the same as in Example 1. In steps 3 to 6 of this example, 2-chlororityl chloride resin and Fmoc-amino acid, 1-hydroxybenzotriazole, benzotriazole-N,N,N',N'-tet...

Embodiment 3

[0075] In step 1 of this implementation, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Gly-OH, Fmoc-Ser( The molar ratio of tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH and Fmoc-Rink Amide MBHA Resin is 3:1, Fmoc-Rink Amide MBHA Resin and 1- The molar ratio of hydroxybenzotriazole, benzotriazole-N,N,N′,N′-tetramethylurea tetrafluoroboric acid, N,N′-diisopropylethylamine is 1:3:3 : 3, other steps of this step are identical with embodiment 1. In step 2 of this example, the molar ratios of Fmoc-Asn(Trt)-OH, Fmoc-Lys(Boc)-OH and 2-chlorotrityl chloride resin are all 3:1, 2-chlorotrityl chloride resin and 1-hydroxybenzene The molar ratio of propanetriazole, benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid, N,N'-diisopropylethylamine is 1:3:3:3, Other steps of this step are the same as in Example 1. In steps 3 to 6 of this example, 2-chlororityl chloride resin and Fmoc-amino acid, 1-hydroxybenzotriazole, benzotriazole-N,N,N',N'-...

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Abstract

The invention discloses a solid-phase fragment synthetic method of exenatide. The solid-phase fragment synthetic method comprises the following steps: dividing 39 amino acids of the exenatide into 6 sections of full-protection fragments; firstly respectively synthesizing the 6 sections of the full-protection fragments; sequentially carrying out solid-phase fragment assembling and connection on the 6 sections of the full-protection fragments to obtain exenatide resin; then cutting to obtain an exenatide crude product; and purifying the crude product to obtain an exenatide product. According to the solid-phase fragment synthetic method of the exenatide, the problems that the existing solid-phase exenatide synthesizing process is complicated, is low in efficiency and difficult to purify and scale are solved; the synthesizing efficiency is improved and connection steps are simplified greatly; the accumulation of impurities is reduced; the invention provides a novel method for realizing the large-scale synthesis of the exenatide, improving the product purity and reducing the purification difficulty.

Description

technical field [0001] The invention belongs to the technical field of solid-phase polypeptide synthesis, and in particular relates to the synthesis of exenatide by assembling all solid-phase fragments. Background technique [0002] Exenatide is an active polypeptide containing 39 amino acids, the amino acid sequence is: H 2 N-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu- Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-COOH, which is an analog of GLP-1, can stimulate the regeneration of pancreatic beta cells and promote insulin secretion , Inhibit the release of glucagon, and have the effect of controlling blood sugar. Exenatide injection can improve blood sugar control by reducing fasting and postprandial blood sugar concentrations in patients with type 2 diabetes. [0003] The preparation method of exenatide mainly adopts the traditional classic solid-phase peptide synthesis method, that is, the 39 protected ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/575C07K1/06C07K1/04
CPCC07K14/575
Inventor 张忠旗王慧张腾景山岗韩彬杨晓琳
Owner SHAANXI HUIKANG BIO TECH CO LTD
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