Eptifibatide preparation method

A technology of eptifibatide and fmoc-cys, which is applied in the field of polypeptide drug preparation, can solve the problems of affecting drug safety, many synthesis steps, complicated processes, etc., and achieves the effects of avoiding difficulty in recovery, ensuring oxidation rate, and reducing solubility

Active Publication Date: 2015-06-17
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] At present, there are many synthesis methods of eptifibatide, some adopt liquid-phase synthesis method, some adopt solid-phase synthesis method; some adopt the method of fragment synthesis, and some adopt the method of one-by-one coupling; The disadvantages of many steps, complicated process, and difficulty in industrialization
And in solid phase synthesis, Cys is very easy to produce racemic prod

Method used

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  • Eptifibatide preparation method

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preparation example Construction

[0031] The present invention provides a method for preparing eptifibatide, which can be achieved by those skilled in the art by referring to the content of this article and appropriately improving the process parameters. 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.

[0032] The reagents used in the present invention are all commercially available and can be purchased in the market.

[0033] Wherein, the Chinese and English names of reagents used in ...

Embodiment 1～3

[0038] Example 1-3 Synthesis of Fmoc-Cys(Trt)-Rink amide Resin

[0039]Take 5kg of Rink amide Resin resin (sub=0.5mmol / g, synthesis scale: 2.5mol), add it to the reaction column, wash it twice with 15L DMF, swell with 15L DMF for more than 30 minutes, and use 15L 20% piperidine / DMF solution (DBLK) Remove Fmoc twice, 10 minutes each time, wash six times with 15LDMF after removing Fmoc protection. Weigh Fmoc-Cys (Trt)-OH (4.4Kg, 7.5mol) and HOBt (1.2kg, 9mol) and dissolve it with 6.5L of DCM and DMF mixed solution (V / V=1:1), and cool the mixed solution to Add the activator DIC (1.5L, 9.75mol) after 0°C, activate for 5 minutes and then add to the reaction, react at 0±10°C for 2 hours. The reaction was terminated after the ninhydrin test was negative. Washed 6 times with 15L DMF to obtain Fmoc-Cys(Trt)-Rink amide Resin.

Embodiment 1～4

[0041]

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Abstract

The invention relates to the field of polypeptide medicine preparation, and especially relates to an eptifibatide preparation method. The method comprises the following steps: synthesizing Fmoc-Cys(x)-Rink amide Resin; sequentially coupling -Pro, -Trp, -Asp, -Gly, -Har and -Mpr to the Fmoc-Cys(x)-Rink amide Resin through adopting a solid phase synthesis technology according to the peptide sequence of eptifibatide to prepare eptifibatide linear resin, and cracking to prepare linear eptifibatide; and taking the linear eptifibatide, oxidizing to prepare crude eptifibatide, and purifying to obtain eptifibatide. A low temperature reaction makes the single impurity content below 0.15%. Liquid phase oxidation is carried out to adjust the pH value to 7.2-7.5, so the oxidation rate is guaranteed, and the solubility of the eptifibatide product in an oxidation liquid is reduced, thereby a problem of difficult recovery due to massive dissolution is avoided. The purity of eptifibatide prepared through the method is greater than 99%, and the single impurity content is smaller than 0.15%.

Description

technical field [0001] The invention relates to the technical field of preparation of polypeptide drugs, in particular to a preparation method of eptifibatide. Background technique [0002] Eptifibatide, also known as Eptifibatide, Eptifibatide, English name: Eptifibatide, molecular formula: C 35 h 49 N ll o 9 S 2 , the CAS accession number is 148031-34-9, its amino acid sequence is shown in SEQ ID NO: 1, and its structure is: [0003] [0004] Aptifertin is an anti-platelet aggregation agent jointly developed by COR Therapeuties and Schering-Plough of the United States. 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] Aptifertin is a cyclic peptide and is an antagonist of platelet glycoprotein GPIIb / IIIa receptors, which can block the platelet aggregation reaction caused by...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/06C07K1/04C07K1/02
CPCY02P20/55
Inventor 肖庆刘建马亚平袁建成
Owner HYBIO PHARMA
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