Preparation method of eptifibatide

一种爱啡肽、爱啡肽精肽的技术，应用在多肽制备领域

Active Publication Date: 2013-11-27
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there has been no research report on the control method of the dimer impurity of eptifibatide during the concentration process, and the cause of the dimer impurity and how to control the generation of the dimer impurity have always been a difficult problem in the field of peptide preparation

Method used

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  • Preparation method of eptifibatide
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  • Preparation method of eptifibatide

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preparation example Construction

[0029] The invention discloses a method for preparing eptifacin, and those skilled in the art can learn from the content of this article and appropriately improve the process parameters to realize it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and the relevant personnel can obviously make changes or appropriate changes and combinations to the method and application described herein without departing from the content, spirit and scope of the present invention to realize and Apply the technology of the present invention.

[0030] The present invention provides a kind of preparation method of eptifibatide, comprising the following steps:

[0031] Step A: obtaining eptifatid fine peptide solution;

[0032] Step B: Take the ep...

Embodiment 1

[0042] The preparation of embodiment 1 eptifatid fine peptide solution

[0043] Add 100.0 g of Sieber resin (with a substitution degree of 0.6 mmol / g) into the solid-phase reaction column, and swell the resin with DMF for 30 minutes. After the swelling is complete, use 20% DBLK to remove Fmoc protection (10min+20min), and then wash with DMF six times.

[0044] Add Fmoc-Cys(Acm)-OH49.74g, HBTU38.52g, HOBt16.2g and DIPEA41.8mL into the above-mentioned solid-phase reaction column, and react for two hours to obtain Fmoc-Cys(Acm)-Sieber resin.

[0045] According to the method of coupling Fmoc-Cys(Acm)-OH mentioned above, Fmoc-Pro-OH, Fmoc-Trp-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Gly-OH, Fmoc-Homoarg(pbf)-OH and Acm-Mpr-OH were used for coupling. After the coupling was completed, the resin was washed three times with DMF, three times with DCM, shrunk three times with methanol, and weighed after vacuum drying to obtain 172.1 g linear side chain full-protected epthiptide r...

Embodiment 2

[0071] The preparation of embodiment 2 aptiferin

[0072] Take 5L of the eptifibatide fine peptide solution prepared in Example 1 and carry out rotary steaming. The temperature of the rotary steaming is 30°C. During the rotary steaming process, record the volume of the spin-out solution, and stop the rotary steaming when it reaches 3.2L. It takes 1.8 h, obtaining the concentrated solution of eptifatid peptide;

[0073] The purity, concentration and volume of the above-mentioned eptifibatide fine peptide concentrate were measured. After determination, the purity was 99.28% (of which the dimer impurity was 0.01%), the concentration was 15.3mg / mL, and the total volume was 1.8L. The HPLC spectrum is shown in figure 1 .

[0074] The above-mentioned concentrated solution of eptifatid peptide is still transparent at the end of the rotary evaporation, and no obvious precipitation occurs. 29.5 g of eptifibatide was obtained by freeze-drying the above-mentioned concentrated solution o...

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Abstract

The invention relates to the field of preparation of polypeptides and particularly relates to a preparation method of eptifibatide. The preparation method comprises the following steps of: preparing a fine peptide solution of the eptifibatide; and performing rotary evaporation on the fine peptide solution of the eptifibatide to get a fine peptide concentrated solution of the eptifibatide, and freeze-drying to obtain eptifibatide, wherein the concentration of the fine peptide concentrated solution of the eptifibatide is 15-30mg / mL; and the temperature of rotary evaporation is 25 DEG C-35 DEG C. The preparation method of the fine peptide solution of the eptifibatide comprises the following steps of: coupling Cys with resin to get Cys-resin; and gradually coupling the Cys-resin with Pro, Trp, Asp, Gly, Har and Mpr to get a peptide with the sequence as shown in SEQ (sequence) ID (identity) NO: 1, and further performing oxidation, cracking, purification and salt transfer to get the fine peptide solution of the eptifibatide. By adopting the preparation method provided by the invention, the production of dimer impurities in the eptifibatide can be greatly reduced, and organic residues of acetonitrile and the like can be in line with the related standard in Chinese Pharmacopoeia.

Description

technical field [0001] The invention relates to the field of polypeptide preparation, in particular to a method for preparing eptifibatide. Background technique [0002] Thrombotic disease is a common cardiovascular and cerebrovascular disease. It is a variety of diseases caused by the stenosis and occlusion of the blood vessel cavity caused by thrombus, which causes ischemia and infarction of major organs and causes dysfunction. It often manifests as myocardial infarction, ischemia, etc. cerebral infarction and venous thromboembolism. It can affect various organs and systems of the whole body, and its morbidity, disability and mortality are all high. Every year, about 3‰ of people suffer from different forms of thrombotic disease, which seriously threatens human health. According to statistics, more than 3 million people die from cardiovascular and cerebrovascular diseases in my country every year, and 75% of the surviving patients are disabled, and more than 40% of them ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04C07K1/02
CPCC07K7/06
Inventor 康旭刘建马亚平袁建成
Owner HYBIO PHARMA
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