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Method for preparing Eptifibatide with solid phase method

A technology of solid-phase method and solid-phase oxidation, which is applied in the preparation method of peptides, chemical instruments and methods, blood diseases, etc., can solve the problems of low application value, complicated operation and production cycle, and achieve low cost and considerable economy Practical value, less environmental pollution

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

AI Technical Summary

Problems solved by technology

The preparation process of Epifibatide that has been announced so far has certain defects, and cannot achieve a good combination in terms of operational complexity, risk, production cycle, total product yield, product cost and environmental pollution; the application value is not high

Method used

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  • Method for preparing Eptifibatide with solid phase method
  • Method for preparing Eptifibatide with solid phase method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Preparation of Eptifibatide peptide resin with full protection of linear side chains

[0037]Add 100.0 g of Sieber resin with a degree of substitution of 0.6 mmol / g to 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 for 10min+20min, and then wash with DMF six times. Fmoc-Cys(Acm)-OH 49.74g, HBTU 38.52g, HOBt16.2g and DIPEA 41.8ml were added to the reaction column, and the reaction was completed in two hours. Repeat the previous operation to perform the evening of Fmoc-Pro-OH, Fmoc-Trp-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Gly-OH, Fmoc-Homoarg(pbf)-OH and Acm-Mpr-OH respectively. United. After the coupling was completed, the resin was washed three times with DMF, three times with DCM, three times with methanol, and dried in vacuum and weighed to obtain 172.1 g of a fully protected Eptifibatide peptide resin with linear side chains. Another preferred solution of this embodiment is: addin...

Embodiment 2

[0038] Example 2 Preparation of Eptifibatide peptide resin with full protection of oxidized side chain

[0039] 172.1 g of a fully protected Eptifibatide peptide resin with linear side chains was swollen with DMF for 30 minutes. After the swelling is complete, 304.8 g of iodine dissolved in an appropriate amount of DMF is added to the reaction column filled with resin, and the oxidation reaction is carried out for 2 hours. After the reaction was completed, it was washed ten times with DMF, three times with DCM, three times with methanol, and dried in vacuum and weighed to obtain 164.1 g of oxidized side chain fully protected Eptifibatide peptide resin.

Embodiment 3

[0040] Example 3 Preparation of Eptifibatide peptide resin with full protection of oxidized side chain

[0041] 1893 g of Eptifibatide peptide resin with fully protected linear side chains was swollen with DMF for 30 minutes. After the swelling is complete, 3350 g of iodine dissolved in an appropriate amount of DMF is added to the reaction column filled with resin, and the oxidation reaction is carried out for 3 hours. At the end of the reaction, it was washed ten times with DMF, three times with DCM, and three times with methanol. After drying in vacuum, it was weighed to obtain 1740 g of oxidized side chain fully protected Eptifibatide peptide resin.

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PUM

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Abstract

The invention discloses a method for preparing Eptifibatide with a solid phase method, which comprises the following steps of: 1) selecting Sieber resin to remove Fmoc, and obtaining H2N-Sieber resin; 2) adopting Fmoc / tBu solid phase method to couple and synthesize linear peptide Eptifibatide-Sieber resin with full protective lateral chains in sequence; 3) conducting solid phase oxidation to the resin, and obtaining oxidant peptide Eptifibatide-Sieber resin with full protective lateral chains; 4) cutting the resin and removing the lateral chain protection, and obtaining crude product of Eptifibatide; and 5) conducting separation and purification, and breeze drying by a freeze dryer, and obtaining refined Eptifibatide peptide. The technology is characterized by simple operation, easy post treatment, less investment of raw material, low cost, high yield and the like, and has considerable economical and practical value and wide application prospect in the field of polypeptide drug design and synthesis simultaneously.

Description

Technical field [0001] The present invention belongs to the field of pharmaceutical technology, and in particular relates to a new method for synthesizing Eptifibatide by solid-phase method. Background technique [0002] Eptifibatide, also known as Efibatide, Eptifibatide, English name: Eptifibatide, Molecular formula: C 35 H 49 N 11 O 9 S 2 , CAS registration number 148031-34-9, its structure is [0003] [0004] Eptifibatide is an anti-platelet aggregation agent, jointly developed by COR Therapeutics and Schering-Plough. In July 1998, Schering-Plough was listed for the first time in the United States under the trade name Intrifiban, and in 1999 in Europe under the trade name Intrifiban. Synonyms IntrifibanTM, Sch-60936, C68-22, SB-1. [0005] Eptifibatide is a cyclic peptide. It is a platelet glycoprotein GP IIb / IIIa receptor antagonist. It can block the platelet aggregation reaction caused by various activators. It is the strongest known specific platelet aggregation inhibit...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/04A61P7/02A61P9/10
Inventor 覃亮政李红玲马亚平袁建成
Owner HYBIO PHARMA
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