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Method for preparing eptifibatide

A technology for the preparation of eptifibatide and solid phase, applied in the preparation method of peptides, chemical instruments and methods, peptides, etc., can solve the problems of no large-scale production, low yield of purification process, etc., and reduce exposure to alkali The probability of increasing the yield and reducing the effect of Asp allosterism

Inactive Publication Date: 2012-10-03
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In the published literature and patents, there is no large-scale production, and the yield of the purification process is relatively low

Method used

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  • Method for preparing eptifibatide
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  • Method for preparing eptifibatide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1: Preparation of Fmoc-Asp(OtBu)-CTC Resin with a degree of substitution of 0.6mmol / g

[0060] Weigh 300g of 2-CTC resin with a substitution degree of 1.0mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, take 86.31g of Fmoc-Asp(OtBu)-OH for use DMF was dissolved, activated by adding 89.38mL DIPEA in an ice-water bath, then added to the above-mentioned reaction column equipped with resin, and reacted for 2 hours at a controlled reaction temperature of -5°C. Add 260mL of anhydrous methanol to block for 30min. Wash with DMF for 3 times, DCM for 3 times, shrink and dry with methanol to obtain Fmoc-Asp(OtBu)-CTC resin, and the detected substitution degree is 0.615mmol / g.

Embodiment 2

[0061] Example 2: Preparation of Fmoc-Asp(OtBu)-CTC Resin with a degree of substitution of 1.0mmol / g

[0062] Weigh 300 g of 2-CTC resin with a substitution degree of 1.2 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, then take 147.96 g of Fmoc-Asp(OtBu)-OH for use DMF was dissolved, activated by adding 153.23mL DIPEA under an ice-water bath, then added to the above-mentioned reaction column equipped with resin, and reacted for 2 hours at a controlled reaction temperature of -5°C. Add 260mL of anhydrous methanol to block for 30min. Wash with DMF for 3 times, DCM for 3 times, shrink and dry with methanol to obtain Fmoc-Asp(OtBu)-CTC resin, the detection degree of substitution is 0.975mmol / g.

Embodiment 3

[0063] Example 3: Preparation of Fmoc-Asp(OtBu)-CTC Resin with a degree of substitution of 0.8mmol / g

[0064]Weigh 300g of 2-CTC resin with a substitution degree of 1.0mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 30 minutes, take 111.09g of Fmoc-Asp(OtBu)-OH for use DMF was dissolved, activated by adding 114.93mL DIPEA under an ice-water bath, then added to the above-mentioned reaction column equipped with resin, and reacted for 2 hours at a controlled reaction temperature of -5°C. Add 260mL of anhydrous methanol to block for 30min. Wash with DMF for 3 times, DCM for 3 times, shrink and dry with methanol to obtain Fmoc-Asp(OtBu)-CTC resin, the detection degree of substitution is 0.775mmol / g.

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Abstract

The invention relates to a method for preparing eptifibatide serving as a polypeptide medicament by combing solid and liquid phases, which belongs to the technical field of synthesis of polypeptides. According to the technical scheme of the invention, the method comprises the following steps of: (1) preparing a fragment A, i.e., 4peptide2-CTC resin by using a solid phase; (2) preparing a fragmentB, i.e., 3peptide-Sieber resin by using a solid phase; (3) cracking peptide resin; (4) preparing a fully-protected linear peptide from the fragments A and B by adopting a liquid phase fragment condensation method; (6) oxidizing with I2 in a liquid phase; (7) cracking to obtain crude eptifibatide; and (8) purifying the crude eptifibatide with a HPLC (High Performance Liquid Chromatography) method to obtain fine eptifibatide finally. According to the method, racemization products of Cys and Asp can be reduced greatly, and the yield and purity of a product are increased.

Description

technical field [0001] The invention relates to a preparation method of polypeptide medicine, in particular to a method for preparing polypeptide medicine eptifibatide through solid-liquid phase combination. 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, its structure is [0003] [0004] Epifibatide is an anti-platelet aggregation agent jointly developed by American CORTherapeuties 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. [0005] Eptifibatide is a cyclic peptide, a platelet glycoprotein GPIIb / IIIa receptor antagonist, which can block the platelet aggregation reaction caused by various activators, and is mainly used to prevent myocardi...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04C07K1/02
Inventor 王宇恩康旭马亚平袁建成
Owner HYBIO PHARMA
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