Liquid phase synthesizing method for bivalirudin

A bivalirudin, liquid-phase synthesis technology, which is applied to the preparation methods of peptides, chemical instruments and methods, blood diseases, etc., can solve the problems of high production cost, difficulty in large-scale production, and difficulty in realizing large-scale synthesis, etc. To achieve the effect of simple equipment, easy and safe production, and safe production

Active Publication Date: 2009-07-08
苏州天马医药集团天吉生物制药有限公司
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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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  • Liquid phase synthesizing method for bivalirudin
  • Liquid phase synthesizing method for bivalirudin
  • Liquid phase synthesizing method for bivalirudin

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Embodiment Construction

[0018] The present invention aims at synthesizing bivalirudin in liquid phase, and integrates the advanced method and technology of polypeptide synthesis by solid phase method and liquid phase method, through the orthogonal protection strategy of amino acids contained in bivalirudin, the selection of The optimization of reaction conditions, the purification of crude products and other factors were comprehensively analyzed, and a novel liquid-phase synthesis route of bivalirudin was designed, which can minimize the production of bivalirudin while ensuring product quality. synthetic cost.

[0019] Main technical route of the present invention is——

[0020] First synthesize three larger fully protected fragments: "Fragment A" N-terminal fully protected hexapeptide, R 1 -D-Phe-Pro-Arg(R 2 )-Pro-Gly-Gly-OR 3 ; The fully protected 6-peptide in the middle of "fragment B", R 1 -Gly-Gly-Asn-Gly-Asp(R 4 )-Phe-OR 3 ; "Fragment C" C-terminal fully protected 8-peptide, R 1 -Glu(R 4...

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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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/08A61P7/02C07K1/02C07K1/06
CPCY02P20/55
Inventor 王良友黄仰青
Owner 苏州天马医药集团天吉生物制药有限公司
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