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Method for preparing exenatide and product thereof

A technology for exenatide and products, applied in the field of exenatide synthesis by fragment method, which can solve the problems of low product content, high purification cost, and low efficiency of synthesizing long peptides

Active Publication Date: 2017-05-10
SHAANXI HUIKANG BIO TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem solved by the present invention is to provide a method for synthesizing exenatide in stages with high synthesis efficiency, low purification cost, easy workflow, and easy scale, which overcomes the long-term synthesis of exenatide by the traditional classic solid-phase peptide synthesis method. The shortcomings of low peptide efficiency, low product content, and high purification cost also overcome the shortcomings of complicated process and high purification cost when the solid phase and liquid phase are mixed and used

Method used

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  • Method for preparing exenatide and product thereof

Examples

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preparation example Construction

[0087] The present invention provides a kind of preparation method of exenatide, described method passes Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro -Ser-CONH 2 and the fully protected fragments of the following three fragments were prepared: Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-COOH, Thr-Ser-Asp-Leu-Ser-Lys-Gln-COOH, His-Gly-Glu-Gly-Thr-Phe-COOH. This is the result of the inventor analyzing the sequence and combining the properties of each amino acid, taking into account the cost of synthesis, choosing between various factors and experimenting, and splitting the positions of 39 amino acids into the above-mentioned Four fragments. The above selection is the result of the inventor's creative work, which effectively reduces the cost;

[0088] Wherein the fully protected fragments are respectively Fmoc-Phe-Ile-Glu(Otbu)-Trp-Leu-Lys(Boc)-Asn(Trt)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly -Ala-Pro-Pro-Pro-Ser(tBu)-Rink AmideMBHA Resin, Fmoc-Met-Glu(Otbu)-Glu(Otbu)-Gl...

Embodiment 1

[0130] 1. Synthesis of Fmoc-Phe-Ile-Glu(Otbu)-Trp-Leu-Lys(Boc)-Asn(Trt)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro- Pro-Pro-Ser(tBu)-Rink Amide MBHA Resin

[0131] (1) Synthesis of Fmoc-Ser(tBu)-MBHA Resin

[0132] Add 50g of Fmoc-Rink Amide MBHA Resin into the reactor, add 500mL N,N-dimethylformamide to soak the resin for 30 minutes to fully swell the resin, remove N,N-dimethylformamide by suction filtration, and pour into the reactor Add 500mL piperidine and N,N-dimethylformamide with a volume ratio of 1:4 mixture, react for 5 minutes, remove the mixture by suction filtration, then add 500mL piperidine and N,N-dimethylformamide The mixed solution with a volume ratio of 1:4 was reacted for 20 minutes, suction filtered, and the resin was washed twice with isopropanol and three times with N,N-dimethylformamide, 500 mL each time, to complete the Fmoc-Rink Amide MBHA Resin de-Fmoc- twice, add 500mL N,N-dimethylformamide, 13.04g Fmoc-Ser(tBu)-OH, 4.59g 1-hydroxybenzotriazole, 12....

Embodiment 2

[0158] 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( tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Asn(Trt)-OH, Fmoc-Lys(Boc)-OH, The molar ratio of Fmoc-Leu-OH, Fmoc-Trp-OH, Fmoc-Glu(Otbu)-OH, Fmoc-Ile-OH, Fmoc-Phe-OH to Fmoc-Rink Amide MBHA Resin is 3:1, Fmoc- Moles of Rink Amide MBHA Resin and 1-hydroxybenzotriazole, benzotriazole-N,N,N′,N′-tetramethylurea tetrafluoroboric acid, N,N′-diisopropylethylamine Ratio is 1:3:3:3, other steps of this step are identical with embodiment 1.

[0159] In step 2 of this example, Fmoc-Arg(pbf)-OH, Fmoc-Val-OH, Fmoc-Ala-OH, Fmoc-Glu(Otbu)-OH, Fmoc-Glu(Otbu)-OH, Fmoc-Glu The molar ratio of (Otbu)-OH, Fmoc-Met-OH and 2-chlororitylchloride resin is 3:1, 2-chlororitylchloride resin and 1-hydroxybenzotriazole, benzotriazole-N,N,N' , The molar ratio of N′-tetramethylurea tetrafluoroboric acid to N,N′-diisopropylethylamine is 1:3:3:3, and ...

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Abstract

The invention discloses a method for preparing exenatide. The exenatide is prepared from a full protection fragment of Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-CONH2 and full protection fragments of following three fragments of Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-COOH, Thr-Ser-Asp-Leu-Ser-Lys-Gln-COOH and His-Gly-Glu-Gly-Thr-Phe-COOH. By means of the method, the problems that existing solid-phase-synthesis exenatide is difficult to purify and large-scale production is difficult are solved, the synthesis efficiency is improved, impurity accumulation is reduced, and the purifying difficulty is lowered.

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-Ala-Val-Arg-Leu-Phe-Ile-Glu- Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-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 efficiency ...

Claims

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Application Information

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IPC IPC(8): C07K14/575C07K1/06C07K1/04C07K1/20
CPCC07K14/57563Y02P20/55
Inventor 王慧王惠嘉郭添张忠旗李乾高长波苏晨灿韩广王万科赵金礼杨小琳
Owner SHAANXI HUIKANG BIO TECH CO LTD
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