Method for synthesizing leconotide

A technology of leconotide and crude peptide, which is applied in the field of drug synthesis, can solve the problems of increasing removal reaction process steps, increasing production costs, and inconvenient production processes, so as to reduce synthesis costs, shorten time, and avoid heavy metal residues Effect

Inactive Publication Date: 2015-02-11
HYBIO PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the cyclization reaction system is simple, only 1 to 10% DMSO or 0.2% H 2 o 2 To speed up the reaction, and the reaction time is longer, usually 48 hours
In addition, this method needs to use Acm-protected Cys, which is more expensive than Trt-protected, and special removal reagents such as AgOTf, Hg(OAc) are needed in the removal process 2 , Tl(Tfa) 3 etc., which not only increased the process steps of removal reaction, but also brought about the problem of sewage treatment, increased production cost, and brought inconvenience to the production process.

Method used

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  • Method for synthesizing leconotide
  • Method for synthesizing leconotide
  • Method for synthesizing leconotide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: the preparation of Fmoc-Cys(Trt)-Rink Amide Resin resin

[0038] Weigh 224g of dry Rink Amide Resin resin (the degree of substitution is 0.6mmol / g) and add it to the solid-phase reaction column. First, wash the resin twice with DMF, and swell the resin with 2 to 3 times the volume of the resin bed layer with DCM for 1 hour, and then use 20 % volume of hexahydropyridine / DMF to remove Fmoc twice, react for 5 minutes and 7 minutes respectively, wash with DMF 6 times, and wait for feeding.

[0039]Under the condition of cooling in an ice bath, dissolve 78.7g (135mmol) Fmoc-Cys(Trt)-OH, 18.3g HOAt, and 51.1g HATU in a mixed solvent of DMF and DCM. After the amino acid is dissolved, continue to keep the ice bath , slowly add TMP35.4mL, activate for 5min. Then the activated Fmoc-Cys(Trt)-OH was added to the reaction column and reacted for 2 hours. After the reaction, the resin was washed 4 times with DMF, and then the blocking solution composed of 108mL pyridine...

Embodiment 2

[0040] Embodiment 2: the preparation of Fmoc-Cys(Trt)-Rink Amide MBHA Resin resin

[0041] Weigh 243g of dry Rink Amide-MBHA Resin resin (the degree of substitution is 0.5mmol / g) and add it to the solid-phase reaction column. First, wash the resin twice with DMF, and swell the resin with 2 to 3 times the volume of the resin bed layer with DCM for 1 hour, and then Use 20% volume of hexahydropyridine / DMF to remove Fmoc twice, react for 5 minutes and 7 minutes respectively, wash with DMF 6 times, and wait for feeding.

[0042] Under the condition of cooling in an ice bath, dissolve 64.1g (110mmol) Fmoc-Cys(Trt)-OH, 16.6g HOAt, and 46.2g HATU in a mixed solvent of DMF and DCM. After the amino acid is dissolved, continue to keep the ice bath , slowly add TMP29.0mL, activate for 5min. Then the activated Fmoc-Cys(Trt)-OH was added to the reaction column and reacted for 2 hours. After the reaction, the resin was washed 4 times with DMF, and then the blocking solution composed of 97mL...

Embodiment 3

[0043] Embodiment 3: the preparation of Fmoc-Cys(Trt)-Rink Amide AM Resin resin

[0044] Weigh 215g of dry Rink Amide-AM Resin resin (the degree of substitution is 0.5mmol / g) and add it to the solid-phase reaction column. First, wash the resin twice with DMF, and swell the resin with 2 to 3 times the volume of the resin bed layer with DCM for 1 hour, and then Use 20% volume of hexahydropyridine / DMF to remove Fmoc twice, react for 5 minutes and 7 minutes respectively, wash with DMF 6 times, and wait for feeding.

[0045] Under the condition of cooling in an ice bath, dissolve 50.4g (86mmol) Fmoc-Cys(Trt)-OH, 11.7g HOAt, and 32.7g HATU in a mixed solvent of DMF and DCM. After the amino acid is dissolved, continue to keep the ice bath , slowly add TMP22.7mL, activate for 5min. Then the activated Fmoc-Cys(Trt)-OH was added to the reaction column and reacted for 2 hours. After the reaction, the resin was washed 4 times with DMF, and then 69mL of pyridine, 168ml of acetic anhydride...

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PUM

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Abstract

The invention belongs to the technical field of medicine synthesis and discloses a method for synthesizing leconotide. The method comprises the following steps: firstly, carrying out a solid phase coupling method to obtain a linear coarse peptide; and carrying out one-step oxidization according to a liquid phase synthesis method to generate three pairs of disulfide bonds, thus obtaining leconotide. According to the method, Trt is taken as a side chain protective group of Cys; the purity of the linear coarse peptide is improved under the action of a corresponding coupling agent so that the linear coarse peptide is directly used in the next oxidization step without being purified; in addition, by virtue of optimizing a buffering system, an oxidizing agent and pH value in a cyclization reaction, the time of cyclization reaction is effectively shortened and the reaction efficiency is improved.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing Leconotide. Background technique [0002] Leconotide, the English name is Leconotide, its molecular structure is shown in the following formula: [0003] [0004] Leconotide, a type of omega-conotoxin, is a new non-opioid analgesic that selectively blocks N-type calcium channels. Compared with Ziconotide (Ziconotide), it has fewer side effects and can be injected intravenously, so it has better application prospects. Its amino acid sequence is as follows: [0005] [0006] Studies have shown that over the years, many drugs for the treatment of chronic pain have undergone preclinical research, but only a few drugs are currently available for clinical treatment of chronic pain. At present, people have paid great attention to the use of omega-conotoxins (eonotoxins) to control human pain. Among them, GVIA and MVIIA are potent and selective b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/435C07K1/20C07K1/06C07K1/04
CPCY02P20/55C07K14/43504
Inventor 陈新亮宓鹏程马亚平袁建成
Owner HYBIO PHARMA
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