Preparation method of ester peptide

A technique for lipopeptides and crude peptides, applied in the field of chemical synthesis of peptides, can solve the problems of difficult control of fermentation process, increased difficulty of purification, and unfavorable industrial production.

Inactive Publication Date: 2013-05-01
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The starting material WS9326A used in this method must be obtained through fermentation and multi-step purification. Since the fermentation process is carried out in organisms, it is very difficult to identify the structure of impurities contained in the product, and the removal of impurities can only be done in the purification stage. , thus increasing the difficulty of purification
And because fermentation process is difficult to control, therefore, is unfavorable for industrialized production

Method used

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  • Preparation method of ester peptide
  • Preparation method of ester peptide
  • Preparation method of ester peptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] The connection of embodiment 1Fmoc-Asp-OAll and Rink amide resin

[0111] Put 100g of Rink amide resin (10mmol, substitution degree 0.1mmol / g) into the solid-phase reaction column, wash it twice with DMF, add 1L DMF to swell for 30min. Add 1L of 20% DBLK for deprotection for 10 minutes, add 1L of 20% DBLK for deprotection for 15 minutes, and wash with DMF for 6 times. Dissolve 11.86g of Fmoc-Asp-OAll and 4.26g of HOBt in 100ml of DMF, ice-bath for 10 minutes, add 4.9ml of DIC, pre-activate for 2-5min, add the activated solution to the solid-phase reaction column, stir for 2h, the ninhydrin detection shows feminine. Dried, washed 3 times with DMF, deprotected DBLK twice (5+5min), washed 6 times with DMF, and obtained The resin is ready for use.

Embodiment 2

[0112] The connection of embodiment 2Fmoc-Asp-OAll and Rink amide resin

[0113] Put 10 g (10 mmol, substitution degree 1.0 mmol / g) of Rink amide resin into the solid phase reaction column, wash it twice with DMF, add 100 ml DMF to swell for 30 min. Add 100ml 20% DBLK for deprotection for 10 minutes, add 100ml 20% DBLK for deprotection for 15 minutes, and wash with DMF for 6 times. Dissolve 11.86g of Fmoc-Asp-OAll and 4.26g of HOBt in 60ml of DMF, ice bath for 10 minutes, add 4.9ml of DIC, pre-activate for 2~5min, put the activated solution into the solid-phase reaction column, stir for 2h, the ninhydrin detection shows feminine. Dried, washed 3 times with DMF, deprotected DBLK twice (5+5min), washed 6 times with DMF, and obtained The resin is ready for use.

Embodiment 3

[0114] The connection of embodiment 3Fmoc-Asp-OAll and Rink amide resin

[0115] Put 20g of Rink amide resin (10mmol, substitution degree 0.5mmol / g) into the solid-phase reaction column, wash it twice with DMF, add 200ml DMF to swell for 30min. Add 200ml 20% DBLK for deprotection for 10 minutes, add 200ml 20% DBLK for deprotection for 15 minutes, and wash with DMF for 6 times. Dissolve 11.86g of Fmoc-Asp-OAll and 4.26g of HOBt in 60ml of DMF, ice bath for 10 minutes, add 4.9ml of DIC, pre-activate for 2~5min, put the activated solution into the solid-phase reaction column, stir for 2h, the ninhydrin detection shows feminine. Dried, washed 3 times with DMF, deprotected DBLK twice (5+5min), washed 6 times with DMF, and obtained The resin is ready for use.

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Abstract

The invention relates to the field of chemically synthesized peptides, and particularly relates to a preparation method of an ester peptide. The method employs step-by-step coupling; a carboxyl group of Asp and an amino group of Ser are subjected to a dehydration condensation reaction through a coupling agent to connect into a ring; after removal of a protective group of Thr, 3-(2-amyl)-phenylpropionic acid and an amino terminal of Thr are subjected to a dehydration condensation reaction; and the reaction product is subjected to cracking, precipitation and purification to obtain the ester peptide with a structure shown as a formula I. The method has characteristics of oriented synthesis, better traceability and controllability of analysis on related impurities compared with a fermentation method, and can reduce related impurities to a certain extent in the synthesis phase, so as to reduce the difficulty in purification and improve product yield on the premise of increasing product purity. The method only requires a simple Kaiser detection to monitor the process, and the detection is simple for operation, and has low requirement on equipment.

Description

technical field [0001] The invention relates to the field of chemically synthesized peptides, in particular to a method for preparing an ester peptide. Background technique [0002] FK224 is a cyclic peptide substance developed by Fujisawa (Originator). Animal experiments have shown that it has strong NK-1 and NK-2 receptor antagonistic effects, and the strength of the two receptors is similar. However, in experiments with isolated smooth muscle, it has a lower affinity for NK-2 receptors than for NK-1 receptors. Clinical trials have shown that: FK224 can inhibit asthmatic bronchoconstriction induced by inhalation of bradykinin, but has no effect on NKA-induced bronchoconstriction. [0003] FK224 is a heptapeptide compound whose structure is shown in Formula I: [0004] [0005] Formula I. [0006] In Chinese patent CN89102100, WS9326A is first obtained by fermentation, and then FK224 is obtained by reduction. The starting material WS9326A used in this method must be ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/06C07K1/04
CPCY02P20/55
Inventor 陈友金刘建马亚平袁建成
Owner HYBIO PHARMA
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