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Preparation method of synthesizing bivalirudin from solid phase polypeptide

A technology for solid-phase peptide synthesis and bivalirudin, which is applied in the field of solid-phase peptide synthesis for bivalirudin preparation, and can solve the problems of strong stimulation, limitation of large-scale production and use of bivaporidine, and the like.

Active Publication Date: 2007-09-12
SHANGHAI SOHO YIMING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] U.S. Patent 5196404 has reported the method for preparing this product, is to adopt the Boc route, every step removes Boc and all needs to use trifluoroacetic acid, cuts peptide and adopts strong stimulation, highly toxic anhydrous hydrogen fluoride; mass production and use

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] In the embodiment:

[0112] The peptide reagent is: NMM:DMF=1:10, volume ratio;

[0113] The decapping reagent is: PIP:DMF=1:3.5, volume ratio;

[0114] (1) Preparation of Fmoc-Leu-resin:

[0115] Weigh 50 grams of 2-chlorotrityl chloromethyl resin (100-400 mesh, 1.0mmol / g), soak in 500ml DMF for 30 minutes, add 44ml DIPEA, Fmoc-Leu-OH (FW: 353.4) 17.7g, 25℃ React for 1 hour. Add 20 ml of methanol, react for 1 hour at 25°C, drain the resin, wash the resin six times with DMF, and drain it.

[0116] (2) Preparation of Fmoc-Tyr(tBu)-Leu-resin:

[0117] In the Fmoc-Leu-resin of step (1), add 500ml of decapping reagent, react for 30 minutes at 25°C, drain, wash with DMF, drain, and add Fmoc-Tyr(tBu)-OH dissolved with 400ml peptide reagent (459.6) 68.9g, a mixture of TBTU (FW: 321.1) 48.1g and HOBt (FW: 135.1) 20.2g, reacted at 25°C for 2 hours, drained, washed with DMF and ethanol, and drained to obtain Fmoc-Tyr( tBu)-Leu-resin;

[0118] (3) Preparation of Fmoc-Glu(OtBu)-T...

Embodiment 2

[0162] The same method and process conditions as in Example 1 are adopted, wherein:

[0163] Using Wang resin as starting material, DMF swelling, adding Fmoc-Leu-OH, TBTU, HOBt, NMM and DMF, reacting at 25°C for 2 hours, washing with DMF and absolute ethanol three times respectively.

[0164] Add decap reagent and react for 0.5 hour at 25°C. After washing thoroughly, add the mixture of Fmoc-amino acid, TBTU / HOBt or HBTU / HOBt or BOP / HOBt dissolved with peptide reagent and react at 25°C for 2 hours. Same operation as in Example 1. , Until the eicosopeptide is received. After the peptide cleavage and other reactions, 14.6 g of white loose lumpy product was obtained.

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PUM

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Abstract

This invention discloses a preparation method of solid-phase peptide synthesizing bivalirudin. It includes the following steps: taking any one of triphenyl methyl chloride resin, 4-methyl-triphenyl methyl chloride resin, 4-methoxy-triphenyl methyl chloride resin, 2-chlorine-triphenyl methyl chloride resin, or Wang resin as the starting raw materials, connecting amino acids in turn according to the method of solid-phase synthesis, to get a protective 28-peptide resin, removing Fmoc-protective group in turn, side-chain protecting group and cutting the peptide to get a crude, then purifying the crude through C18 (or C8) high-pressure column to get bivalirudin exquisite article. In this invention, the peptide yield of every step is more than 99%, and the total yield is 14%.

Description

Technical field [0001] The present invention relates to a preparation method of bivanodine (including acetate, trifluoroacetate and free peptide), in particular to a preparation method of solid-phase peptide synthesis bivanodine. Background technique [0002] Bivanodine, Chinese name: Bifaluding, Bivanodine, Bivaludin, [0003] Trade name: Angiomax_. English name: Bivalirudin. [0004] Structural formula: [0005] D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH [0006] Molecular formula and molecular weight: C 98 H 138 N 24 O 33 , 2178.99. [0007] On November 10, 2004, Medicines announced the first commercial sale of the thrombin-specific inhibitor "Bivanodine" or "Bivalirudin" (Bivalirudin) in Europe, under the trade name Angiomax_ in the United States. It has been approved by Europe and the United States, as well as other regions, such as Canada, Israel, New Zealand, and Argentina to allow its listing. Angiomax is a direct thrombin inhibit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/04C07K1/14C07K7/08C07K14/81
CPCC07K14/001Y02P20/55
Inventor 周逸明
Owner SHANGHAI SOHO YIMING PHARMA
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