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Method for preparing Exenatide

A technology for exenatide and crude peptide, which is applied in the field of synthesis technology for preparing exenatide, can solve problems such as the lack of specific research on the large-scale synthesis method of Exenatide, and achieve the effects of stable process, easy post-processing and less input of raw materials

Active Publication Date: 2009-09-23
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, based on these literatures, it is found that when exenatide is synthesized by solid-phase methods, peptide synthesizers are often used for direct synthesis. More literature focuses on the physiological activity of exenatide, and there is basically no specific study on the large-scale synthesis method of exenatide

Method used

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  • Method for preparing Exenatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Preparation of Fmoc-Ser(tBu)-Sieber Amide Resin

[0031] Fmoc-Ser(tBu)-Sieber Amide Resin 25g with a degree of substitution of 0.1mmol / g, the Fmoc-Ser(tBu)-Sieber Amide Resin obtained by the above operation, the detection degree of substitution is 0.021mmol / g; the degree of substitution is 0.8mmol / g Fmoc-Sieber Amide Resin 25g, Fmoc-Ser(tBu)-Sieber Amide Resin obtained according to the above operation, the detection degree of substitution is 0.529mmol / g.

[0032] The more preferred scheme of this embodiment is to add 25g of Fmoc-Sieber Amide Resin, with a degree of substitution of 0.535mmol / g, into the solid phase reactor, add DCM to swell the resin for 30 minutes, and use 20% DBLK to remove the Fmoc protection to obtain H-Sieber Amide Resin, washed 4 times with DMF and 2 times with DCM. 4.22g of Fmoc-Ser(tBu)-OH, 4.14g of HATU, 1.80g of HOAt, and 2.4ml of TMP were dissolved in DMF under ice-cooling conditions, and added to the above resin to react for 45 min...

Embodiment 2

[0033] Example 2 Scale preparation of Fmoc-Ser(tBu)-Sieber Amide Resin

[0034] Add 2500g of Fmoc-Sieber Amide Resin, with a substitution degree of 0.535mmol / g, into the solid phase reaction, add DCM to swell the resin for 30 minutes, use 20% DBLK to remove Fmoc protection, and obtain H-Sieber Amide Resin, wash with DMF 8 times , washed 4 times with DCM.

[0035]4220g of Fmoc-Ser(tBu)-OH, 4140g of HATU, 1800g of HOAt, and 2.4L of TMP were dissolved in DMF under ice-cooling conditions, and added to the above resin to react for 55 minutes. After the reaction was completed, it was alternately washed with DMF and methanol for 3 times to obtain Fmoc-Ser(tBu)-Sieber Amide Resin, and the detected substitution degree was 0.315 mmol / g.

Embodiment 3

[0036] Example 3 Preparation of Exenatide-Sieber Amide Resin with Fully Protected Side Chains

[0037] Weigh 3.2g (1mmol) Fmoc-Ser(tBu)-Sieber Amide Resin into the reactor, use 20% DBLK to remove Fmoc protection, dissolve 1.012g Fmoc-Pro-OH, 0.49g HOBt, 0.61ml DIC in DCM , added to a solid-phase reactor, and reacted at room temperature for 2 hours, and the end point of the reaction was determined to be negative in the ninhydrin test. Repeat the above steps to complete the connection of the protected amino acids from position 37 to position 1 in sequence to obtain Exenatide-Sieber Amide Resin with fully protected side chains.

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Abstract

The invention discloses a method for preparing Exenatide, which comprises the following steps of: 1) using Fmoc-Ser(tBu)-OH and Sieber Amide resin with substitutability of 0.1 mmol / g to 0.8 mmol / g as starting material, and obtaining Fmoc-Ser(tBu)-Sieber Amide resin; 2) linking amino acids with protective groups in sequence by adopting a coupling way, synthesizing and obtaining Exenatide-Sieber Amide resin with full-protective lateral chains; and 3) conducting pyrolysis to the resin to remove the protective groups, precipitating with ether and obtaining crude peptides; and conducting high pressure liquid phase purification and freeze drying to the crude peptides and obtaining the Exenatide. The technology for preparing the Exenatide is characterized by simple reaction operation, easy post treatment, high yield, low cost and the like, and has considerable economical and practical value and wide application prospect.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and in particular relates to a synthesis process for preparing exenatide. Background technique [0002] Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia caused by a variety of etiologies. Hyperglycemia is mainly caused by defects in insulin secretion or action. Diabetes can be divided into two types, insulin-dependent diabetes (type I diabetes) and non-insulin-dependent diabetes (type II diabetes), wherein type II diabetes patients account for more than 90%. According to the statistics of WHO, there are currently 130 million people with type 2 diabetes diagnosed in the world, and my country has more than 40 million people. It is the second largest country with diabetes after India. [0003] Commonly used drugs for treating type II diabetes include: biguanides, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones and insulin. However, studies have found th...

Claims

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Application Information

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IPC IPC(8): C07K14/47C07K1/04C07K1/06A61P3/10
CPCY02P20/55
Inventor 宓鹏程李红玲覃亮政马亚平袁建成
Owner HYBIO PHARMA
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