A kind of preparation method of eptifibatide

Abstract

The invention relates to the field of preparation of polypeptide medicines, in particular to a preparation method of eptifibatide. The method includes: synthesizing Fmoc-Cys(x)-Rink amide Resin; according to the peptide sequence of eptifatid, sequentially coupling-Pro,-Trp,-Asp, ‑Gly, ‑Har, and ‑Mpr are used to obtain the linear eptifibatide resin, which is cracked to obtain the linear eptifibatide; the linear eptifattin is obtained, and the crude product of the eptifacin is obtained through oxidation, which is obtained after purification. The simple impurity content is lower than 0.15% by low temperature reaction. Through liquid-phase oxidation, the pH value is adjusted to 7.2-7.5, which can not only ensure the oxidation rate but also reduce the solubility of the eptifibatide product in the oxidation solution, and avoid the problem of difficult recovery caused by a large amount of dissolution. The purity of the eptifibatide prepared by this method is more than 99%, and the single impurity content is less 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...

AI Technical Summary

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 product impurities; Gly is also prone to double Gly impurities during the coupling process

Therefore, the current eptifibatide products often contain a large amount of impurities, which seriously affects the safety of medication.

Studies have shown that although the yield of eptifibin can reach more than 50% by using the existing method, the simple impurity content in the product is often as high as about 0.5%.

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