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Method for preparing exenatide

A technology of exenatide and preparation process, applied in the field of preparation of polypeptide drugs, can solve the problems of unsuitability for large-scale production, low yield and high cost

Active Publication Date: 2014-08-20
ADLAI NORTYE BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The invention relates to a method for preparing exenatide, which solves the problems of high cost, low yield and impurity des-Glu in the prior art. 15 ,Glu 16 - The content of exenatide is relatively large, which is not suitable for large-scale production

Method used

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  • Method for preparing exenatide

Examples

Experimental program
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Embodiment 1

[0099] Example 1: Synthesis of Fmoc-Ser(tBu)-Rink amide AM resin with a degree of substitution of 0.20 mmol / g

[0100] Weigh 5.00 g of Rink amide AM resin (1 mmol) with a substitution degree of 0.20 mmol / g, add it to the solid phase reaction column, wash with DMF once, swell the resin with DCM for 30 minutes, and use a volume ratio of 1:4 The deprotection solution composed of piperidine and DMF was reacted for 5 minutes, DMF was washed once, and the deprotection solution composed of piperidine and DMF in a volume ratio of 1:4 was used to react for 10 minutes. DMF was washed 6 times, and 1.92 g Fmoc was weighed. -Ser(tBu)-OH (5 mmol) and 0.68 g HOBt (5 mmol) were added to a 1:1 volume ratio of DCM and DMF mixed solution, 0.8 ml DIC (5 mmol) was added under ice-water bath for activation and then added to the above In the reaction column of the resin, react for 2 hours, wash 3 times with DMF, 3 times with DCM, 3 times with MeOH, 3 times with DCM, 3 times with MeOH, and dry to ob...

Embodiment 2

[0101] Example 2: Synthesis of Fmoc-Ser(tBu)-Rink amide MBHA resin with a degree of substitution of 0.20 mmol / g

[0102] Weigh 5.00 g of Rink amide MBHA resin (1 mmol) with a substitution degree of 0.20 mmol / g, add it to the solid phase reaction column, wash with DMF once, swell the resin with DCM for 30 minutes, and use a volume ratio of 1:4 The deprotection solution composed of piperidine and DMF was reacted for 5 minutes, DMF was washed once, and the deprotection solution composed of piperidine and DMF in a volume ratio of 1:4 was used to react for 10 minutes. DMF was washed 6 times, and 1.92 g Fmoc was weighed. -Ser(tBu)-OH (5 mmol) and 0.68 g HOBt (5 mmol) were added to a 1:1 volume ratio of DCM and DMF mixed solution, 0.8 ml DIC (5 mmol) was added under ice-water bath for activation and then added to the above In the reaction column of the resin, react for 2 hours, wash 3 times with DMF, 3 times with DCM, 3 times with MeOH, 3 times with DCM, 3 times with MeOH, and dry to ob...

Embodiment 3

[0103] Example 3: Synthesis of Fmoc-Ser(tBu)-Sieber resin with a degree of substitution of 0.20 mmol / g

[0104] Weigh 5.00 g of Rink amide Sieber resin (1 mmol) with a degree of substitution of 0.20 mmol / g, add to the solid phase reaction column, wash with DMF once, swell the resin with DCM for 30 minutes, and use a volume ratio of 1:4 The deprotection solution composed of piperidine and DMF was reacted for 5 minutes, DMF was washed once, and the deprotection solution composed of piperidine and DMF in a volume ratio of 1:4 was used to react for 10 minutes. DMF was washed 6 times, and 1.92 g Fmoc was weighed. -Ser(tBu)-OH (5 mmol) and 0.68 g HOBt (5 mmol) were added to a 1:1 volume ratio of DCM and DMF mixed solution, 0.8 ml DIC (5 mmol) was added under ice-water bath for activation and then added to the above In the resin reaction column, react for 2 hours, wash 3 times with DMF, 3 times with DCM, 3 times with MeOH, 3 times with DCM, 3 times with MeOH, and dry to obtain 5.15 g of...

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Abstract

The invention relates to a method for preparing exenatide, and solves the problems that cost is high, yield is low, impurity (des-Glu<15>, Glu<16>-exenatide) content is relatively large and large-scale production cannot be realized in the prior art. The concrete steps comprise: A) taking amino resin as initial resin, employing an Fmoc solid-phase synthesis method, according to the peptide sequence of the exenatide main chain to successively couple with amino acids with Fmoc protection at N terminal and with protected side chains, wherein in the amino acid coupling reactions of the peptide sequence 15-17, a solution DMF is added with 2,2,2-trifluoroethyl alcohol accounting for 20% by volume of the solution and 1.5 mol / L of urea; and B) after peptide resin is subjected to cracking, employing a reverse-phase filling material for first purification, and employing anion resin for second purification, desalinating to enable the content of impurities des-Glu<15>, Glu<16>-exenatide to be reduced to 0.1% or less, and performing freeze drying, so as to obtain exenatide. The method is a low-cost preparation technology suitable for large-scale production of exenatide with high purity, and the technology is capable of effectively controlling the content of des-Glu<15>, Glu<16>-exenatide and does not influence the yield of exenatide.

Description

technical field [0001] The present invention relates to a preparation method of polypeptide drugs, which is the preparation of exenatide, a synthetic specific drug for treating type II diabetes with glucagon-like peptide-1 (GLP-1) receptor agonist method. Background technique [0002] Exenatide, English name: Exenatide, is a straight chain 39 peptide, the structural formula is as follows: [0003] [0004] The peptide sequence is: [0005] H-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-NH 2 [0006] Exenatide is an incretin-mimetic hormone developed by Amylin Company, which is mainly used for the treatment of type II diabetes and was approved by the US FDA on April 28, 2005. Exenatide has the effect of GLP-1 receptor agonist, and is similar to GLP-1 in terms of molecular structure, biological activity, target and immunogenicity. The molecular structure of ...

Claims

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Application Information

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IPC IPC(8): C07K14/575C07K1/20C07K1/18C07K1/06C07K1/04
CPCY02P20/55C07K14/575
Inventor 路杨杨东晖陈晓航周亮
Owner ADLAI NORTYE BIOPHARMA CO LTD
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