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Preparation method and product of exenatide

A technology for exenatide and products, applied in the field of exenatide synthesis by fragment method, which can solve the problems of high cost, high price and high price

Active Publication Date: 2017-05-31
SHAANXI HUIKANG BIO TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Zhang Teng published the synthesis of exenatide in "Fine Chemical Industry" in October 2014. The synthesis method divides exenatide into six fragments for solid-phase synthesis. In this method, the traditional peptide synthesis carbon-terminal amide is used. The amino acids used are fully protected amino acids, which are more expensive, and expensive amino resins such as Rink Amide-AM Resin or Rink Amide-MBHA Resin are used in the fragment synthesis, and the cost is relatively high

Method used

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  • Preparation method and product of exenatide
  • Preparation method and product of exenatide

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Experimental program
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Effect test

preparation example Construction

[0106] A preparation method of exenatide, the method is synthesized through the protection fragments of the following 13 fragments: His-Gly-COOH, Glu-Gly-Thr-COOH, Phe-Thr-Ser-COOH, Asp-Leu -Ser-COOH, Lys-Gln-COOH, Met-Glu-Glu-COOH, Glu-Ala-Val-COOH, Arg-Leu-Phe-Ile-COOH, Glu-Trp-Leu-COOH, Lys-Asn-Gly -COOH, Gly-Pro-Ser-COOH, Ser-Gly-Ala-COOH and Pro-Pro-Pro-Ser-Rink AmideMBHA Resin.

[0107] In a specific embodiment, the method is synthesized through the following 13 fragments: Fragment 1: Fmoc-His(Trt)-Gly-COOH, Fragment 2: Fmoc-Glu(otBu)-Gly-Thr-COOH, Fragment 3: Fmoc-Phe-Thr-Ser-COOH, Fragment 4: Fmoc-Asp(otBu)-Leu-Ser-COOH, Fragment 5: Fmoc-Lys(Boc)-Gln-COOH, Fragment 6: Fmoc-Met- Glu-Glu-COOH, Fragment 7: Fmoc-Glu(otBu)-Ala-Val-COOH, Fragment 8: Fmoc-Arg(pbf)-Leu-Phe-Ile-COOH, Fragment 9: Fmoc-Glu(otBu)- Trp-Leu-COOH, Fragment 10: Fmoc-Lys(Boc)-Asn-Gly-COOH, Fragment 11: Fmoc-Gly-Pro-Ser-COOH, Fragment 12: Fmoc-Ser(tBu)-Gly-Ala-COOH . Fragment 13: Pro-Pro-Pro-Ser(tBu)...

Embodiment approach

[0110] In a specific embodiment, the method includes the steps of:

[0111] (1) fragments 1-12 were synthesized by liquid phase, and fragment 13 was synthesized by solid phase; and

[0112] (2) Assembling and connecting to obtain the product.

[0113] Wherein, the liquid-phase synthesis method of the fragments 1-12 is to activate the carboxyl terminal of the fragments by N-hydroxysuccinimide and link them with amino acids to extend the amino acid chain.

[0114] The synthesis method of the fragment 1: Fmoc-His(Trt)-Gly-COOH comprises the following steps:

[0115] (1) Synthesis of Fmoc-His(Trt)-COOSu

[0116] Mix Fmoc-His(Trt)-OH, organic solvent and N-hydroxysuccinimide until dissolved, then add dicyclohexylcarbodiimide dissolved in organic solvent for reaction, and obtain Fmoc-His by solid-liquid separation An organic solution of (Trt)-COOSu;

[0117] (2) Synthesis of Fmoc-His(Trt)-Gly-COOH

[0118] Add the mixed aqueous solution of glycine and sodium bicarbonate to the ...

Embodiment 1

[0152] 1. Synthesis of Fmoc-His(Trt)-Gly-COOH

[0153] (1) Synthesis of Fmoc-His(Trt)-COOSu

[0154] Mix 30.99g of Fmoc-His(Trt)-OH with 300ml of 1,4-dioxane, stir at room temperature, add 6.33g of N-hydroxysuccinimide, stir until dissolved, slowly add dicyclohexylcarbodiimide dropwise Mixed solution with 1,4-dioxane at a mass-volume ratio of 11.35g:23mL, reacted at room temperature for 3 hours, filtered under reduced pressure to remove solid insolubles, and obtained 1,4 of Fmoc-His(Trt)-COOSu - dioxane solution.

[0155] (2) Synthesis of Fmoc-His(Trt)-Gly-COOH

[0156] 4.13g of glycine and 4.62g of sodium bicarbonate were dissolved in distilled water, and the resulting solution was added dropwise to the 1,4-dioxane solution of Fmoc-His(Trt)-COOSu obtained in step (1), and stirred at room temperature for 20 hours, concentrated under reduced pressure, adjusted the pH value to 2-3 with a 10% aqueous solution of citric acid, extracted with ethyl acetate, washed the organic pha...

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Abstract

The invention discloses a preparation method of exenatide. The exenatide is prepared from protection fragments of 13 fragments in a synthesis mode: His-Gly-COOH, Glu-Gly-Thr-COOH, Phe-Thr-Ser-COOH, Asp-Leu-Ser-COOH, Lys-Gln-COOH, Met-Glu-Glu-COOH, Glu-Ala-Val-COOH, Arg-Leu-Phe-Ile-COOH, Glu-Trp-Leu-COOH, Lys-Asn-Gly-COOH, Gly-Pro-Ser-COOH, Ser-Gly-Ala-COOH and Pro-Pro-Pro-Ser-Rink Amide MBHA Resin. By adopting the preparation method, the synthesis efficiency is improved, impurity accumulation is reduced, and the purification difficulties can be alleviated.

Description

technical field [0001] The invention belongs to the technical field of polypeptide synthesis, and in particular relates to a method for synthesizing exenatide through a fragment method. 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-Al a-Val-Arg-Leu-Phe-Ile-Glu -Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Pro-Ser-CONH 2 , is an analogue of GLP-1, which can stimulate the regeneration of pancreatic β cells, promote insulin secretion, inhibit the release of glucagon, and have the effect of controlling blood sugar. Exenatide injection can reduce fasting and postprandial blood sugar in patients with type 2 diabetes concentrations to improve blood sugar control. [0003] The preparation method of exenatide mainly adopts the traditional classic solid-phase peptide synthesis method at present, which has low synthesis effici...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/575C07K1/08C07K1/06C07K1/04C07K1/20
CPCC07K14/57563Y02P20/55
Inventor 王慧苏晨灿张忠旗王惠嘉李乾王万科高长波郭添韩广赵金礼杨小琳
Owner SHAANXI HUIKANG BIO TECH CO LTD
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