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A novel reduction-oxidation system for preparing eptifibatide

A technology for eptifibatide and crude peptide is applied in the field of a novel reduction-oxidation system for preparing eptifibatide, which can solve the problems of high purification difficulty and low yield of crude peptide, and achieve easy large-scale production and reduce production costs. , the effect of reducing the difficulty of purification

Inactive Publication Date: 2019-02-05
JINAN KANGHE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The present invention aims at the easy production of various impurities during the synthesis process of eptifibatide, especially the difficult purification of crude peptides due to the generation of dimer impurities (two linear peptides connected by disulfide bonds) and the low yield. , providing a technical solution for the preparation of eptifibatide by a novel reduction-oxidation system

Method used

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  • A novel reduction-oxidation system for preparing eptifibatide

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Embodiment 1: the preparation of Fmoc-Cys(Trt)-Rink Amide AM resin

[0036] Accurately weigh 600 g of Rink Amide AM resin (initial substitution degree 0.97 mmol / g) and place it in a peptide resin synthesis reactor, add 6LDCM to swell for 2 h. After the swelling is completed, wash with DMF three times, 5 L each time, and then add 5 L of 20% piperidine / DMF solution for deprotection twice, for 10 min and 10 min respectively. After the deprotection was completed, the resin was washed 6 times with DMF, 5 L each time. Weigh 852g of Fmoc-Cys(Trt)-OH and 196g of HOBt and dissolve it in 4LDMF, add 250mL of DIC to activate, add the solution into the reactor, react for 2h, and monitor the reaction progress by Kaiser test. After the reaction was completed, the resin was washed with DMF for 3 times, and then the pre-prepared capping reagent (1 L of acetic anhydride, 850 mL of pyridine, 3 L of DMF) was added, and the capping reaction was carried out for 40 minutes. After the cappin...

Embodiment 2

[0037] Example 2: Preparation of linear eptifibatide resin with fully protected side chains

[0038]Weigh 429g (300mmol) of the Fmoc-Cys(Trt)-Rink Amide AM resin with a substitution degree of 0.7mmol / g in Example 1 and place it in a peptide resin synthesis reactor, add 4LDCM to swell for 2h. After swelling, wash 3 times with DMF, 4L each time, and then add 4L of 20% piperidine / DMF solution to deprotect twice, for 5min and 5min respectively.

[0039] The abbreviations used in the specification and claims have the following meanings:

[0040] Fmoc 9-fluorenylmethoxycarbonyl

[0041] OtBu tert-butoxy

[0042] Boc tert-butoxycarbonyl

[0043] Pbf 2,2,4,6,7-pentamethylbenzofuran-5-sulfonyl

[0044] Trt Trityl

[0045] DIC N,N-Diisopropylcarbodiimide

[0046] HOBt 1-Hydroxybenzotriazole

[0047] DTT dithiothreitol

[0048] DMSO dimethyl sulfoxide

[0049] Embodiment 1: the preparation of Fmoc-Cys(Trt)-Rink Amide AM resin

[0050] Accurately weigh 600 g of Rink Amide AM res...

Embodiment 5

[0053] Embodiment 5: the preparation of eptifibatide fine peptide

[0054] After the oxidation reaction solution in Example 4 was filtered with a 0.45 μm microporous membrane, a C18 preparation column with an internal diameter of 100 mm was selected, purified, salted, and freeze-dried to obtain 18.5 g of eptifibatide fine peptide, with a purity greater than 99.8%. Yield 71.7%.

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Abstract

The invention relates to the field of polypeptide synthesis and particularly relates to a novel reduction-oxidation system for preparing Eptifibatide. According to the technical scheme of the invention, the novel reduction-oxidation system for preparing Eptifibatid is provided to solve the problems of high crude peptide purification difficulty and low product yield due to dimer impurities that easily occur during the cracking process of Eptifibatide. According to the technical scheme of the invention, the linear peptides of Eptifibatid are synthesized based on the Fmoc solid-phase synthesis method. Firstly, the reduction reaction of intermolecular disulfide bonds of dimer impurities in the linear peptide solution is realized by DTT, and then the pH value of the solution is regulated. An oxidizing agent is added and subjected to oxidization reaction so as to form intermolecular disulfide bonds, so that a crude peptide product of Eptifibatid is obtained. Finally, the crude peptide product is subjected to chromatography purification, salt transferring and freeze-drying to obtain the pure peptide product of Eptifibatid. The preparation method is simple to operate and the obtained pure peptide product is high in both purity and yield. Therefore, the method is suitable for scale-up production.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a novel reduction-oxidation system for preparing eptifibatide. Background technique [0002] Eptifibatide was jointly developed by American COR Therapeutics (COR Therapeutics) Company and American Schering-Plough (Schering-Plough) Company. On May 18, 1998, the US FDA approved Schering's production and marketing. In 1999 in the European Union, in 2001, Argentina, Hong Kong, Thailand launched one after another. On October 30, 2012, the State Food and Drug Administration approved Jiangsu Hansoh Medicine Co., Ltd. to produce eptifibatide API (National Drug Approval H20120092) and Eptifibatide Injection (National Approval H20120093) for acute coronary Treatment of patients with arterial syndromes (unstable angina / non-ST-segment elevation myocardial infarction), including patients who are about to receive medical therapy and patients undergoing percutaneous coronary intervention (...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K1/04
Inventor 张颖王德龙王仁友李同金石鑫磊
Owner JINAN KANGHE MEDICAL TECH
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