Liquid phase synthesizing method for bivalirudin

Abstract

The invention provides a liquid phase synthesis method for bivalirudin. Firstly, three all-protected fragments, namely 6 peptide with an all-protected N-terminal, 6 peptide with an all-protected middle segment and 8 peptide with an all-protected C-terminal are gradually synthesized, then all-protected bivalirudin is obtained by orderly condensing the three fragments, finally all protective genes are removed to obtain a crude product of the bivalirudin, and then a pure product of the bivalirudin is obtained through high-efficiency liquid chromatography purification. The method does not need a resin, excessive protected amino acid and a condensing agent, is easy to realize mass production, and has relatively lower production cost.

Description

technical field [0001] The invention relates to a 20-peptide, in particular to the synthesis of bivalirudin, especially the liquid-phase synthesis method of bivalirudin, which belongs to the technical field of polypeptide synthesis. Background technique [0002] Bivalirudin (bivalirudin) is one of the direct thrombin inhibitors approved by the U.S. Food and Drug Administration (FDA) in December 2000 (trade name Angiomax, produced by Medicines Pharmaceutical Company), which is derived from hirudin derivatives and is a A synthetic polypeptide containing 20 amino acids is a direct, specific and reversible inhibitor of thrombin. Its relative molecular mass is 2180, and its amino acid sequence is: D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Ash-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tvr -Leu. [0003] The D-Phe-Pro-Arg-Pro region at the amino terminal of bivalirudin is the site that interacts with the active site of thrombin, which can be specific to the catalytic site and substrate recogni...

AI Technical Summary

Problems solved by technology

[0007] The solid-phase synthesis method of bivalirudin reported in the above literature requires the use of expensive special resins and a large excess of special protected amino acids and condensation reagents, which is difficult to achieve large-scale synthesis and high production costs

Some processes require the use of highly toxic hydrogen fluoride, special reaction equipment is required, and it is difficult to achieve large-scale production

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