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Method for preparing Eptifibatide with solid phase method

A technology of solid-phase method and solid-phase reaction, which is applied to peptide preparation methods, chemical instruments and methods, blood diseases, etc., can solve the problems of complex operation production cycle and low application value, and achieve considerable economic and practical value and low cost. Low, high yield effect

Inactive Publication Date: 2012-09-05
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
  • Method for preparing Eptifibatide with solid phase method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Preparation of Epifibatide Peptide Resin with Fully Protected Linear Side Chains

[0037]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 for 10min+20min, and then wash with DMF six times. Add 49.74g of Fmoc-Cys(Acm)-OH, 38.52g of HBTU, 16.2g of HOBt and 41.8ml of DIPEA into the reaction column, and the reaction is completed in two hours. Repeat the previous operation to couple Fmoc-Pro-OH, Fmoc-Trp-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Gly-OH, Fmoc-Homoarg(pbf)-OH and Acm-Mpr-OH respectively couplet. 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 fully protected Epifibatide peptide resin. Another preferred solution of this embodiment is: add ...

Embodiment 2

[0038] Example 2 Preparation of Epifibatide Peptide Resin with Fully Protected Oxidized Side Chains

[0039] 172.1 g of linear side chain fully protected Epifibatide peptide resin was swelled with DMF for 30 minutes. After the swelling is complete, 304.8g of iodine dissolved with an appropriate amount of DMF is added to the reaction column equipped with the 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, and shrunk three times with methanol. After vacuum drying, it was weighed to obtain 164.1 g of oxidized side chain fully protected Epifibatide peptide resin.

Embodiment 3

[0040] Example 3 Preparation of Epifibatide Peptide Resin with Fully Protected Oxidized Side Chains

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

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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 invention belongs to the technical field of pharmacy, and in particular relates to a new method for synthesizing Eptifibatide by a solid-phase method. Background technique [0002] Eptifibatide, also known as Eptifibatide, Eptifibatide, English name: Eptifibatide, molecular formula: C 35 h 49 N 11 o 9 S 2 , CAS accession number 148031-34-9, whose structure is [0003] [0004] Epifibatide is an anti-platelet aggregation agent jointly developed by American COR Therapeutics Company and American Schering-Plough Company. In July 1998, it was first listed in the United States under the trade name Intrifiban by Schering-Plough Company, and in 1999 it was launched in Europe under the trade name Intrifiban. Synonyms IntrifibanTM, Sch-60936, C68-22, SB-1. [0005] Eptifibatide, a cyclic peptide, is a platelet glycoprotein GP IIb / IIIa receptor antagonist, which can block the platelet aggregation reaction caused by various activators. It is the stro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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