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A kind of solid-liquid phase combination prepares the method for cinapultide

A technology of cinaputide and solid-liquid phase, which is applied in the field of solid-liquid phase preparation of cinaputide, which can solve the problems of long production cycle, low purity of crude product and high production cost

Inactive Publication Date: 2019-03-05
JINAN KANGHE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method still needs to undergo multi-step peptide grafting reactions, the purity of the crude product is low, the yield is between 52.3% and 57.1%, the production cycle is long, and the production cost is high
[0010] In summary, in the currently reported synthetic methods of cinapultide, there are problems of long production cycle, high production cost, unfavorable scale-up production, and low yield.

Method used

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  • A kind of solid-liquid phase combination prepares the method for cinapultide
  • A kind of solid-liquid phase combination prepares the method for cinapultide
  • A kind of solid-liquid phase combination prepares the method for cinapultide

Examples

Experimental program
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Effect test

Embodiment 1

[0059] Embodiment 1: Preparation of Boc-Leu-OSu

[0060] Accurately weigh 1156g (5.0mol) of Boc-Leu-OH and 633g (5.5mol) of HOSu, dissolve them in 12L of tetrahydrofuran, and stir in an ice-water bath. Accurately weigh 1238g (6.0mol) of DCC, dissolve it in 7L tetrahydrofuran, slowly add it dropwise to the above solution, stir the reaction, and monitor the end point of the reaction by TLC. After the reaction was completed, filter with suction, concentrate the reaction solution to 6-7L, add 35L of petroleum ether to the concentrated solution, a large amount of white solid precipitated out, and the solution stood at -20°C for 1 hour. After standing still, filter with suction, dissolve the filter cake with 6L of ethyl acetate, add 35L of petroleum ether, crystallize, filter with suction, and dry the filter cake in vacuum to obtain 1538g of Boc-Leu-OSu with a purity greater than 99% and a yield of 93.7%.

Embodiment 2

[0061] Embodiment 2: Preparation of H-Leu-Leu-OH

[0062] Accurately weigh 511g (3.9mol) of H-Leu-OH and 615g (5.8mol) of sodium carbonate and dissolve them in 7L of water, and slowly add 8L of tetrahydrofuran solution of 1538g (4.7mol) of Boc-Leu-OSu obtained in Example 1 under an ice-water bath , the reaction was stirred, and the end point of the reaction was monitored by TLC. After the reaction is complete, filter, add 10% citric acid aqueous solution to the filtrate under an ice-water bath, adjust the pH value of the solution to 2-3, extract with 10L ethyl acetate, combine the organic phases, concentrate to 5-6L by rotary evaporation, and add to the concentrated solution Add 30L of petroleum ether, place it at -20°C to crystallize to obtain Boc-Leu-Leu-OH, filter it and suck it dry, dissolve it with 60% TFA / water solution, stir and react for 2 hours, wash it with cold ether, and dry it in vacuo to obtain H-Leu-Leu-OH 883g, purity greater than 99%, yield 92.7%.

Embodiment 3

[0063] Embodiment 3: Preparation of Fmoc-Leu-OSu

[0064]Accurately weigh 1767g (5.0mol) of Fmoc-Leu-OH and 633g (5.5mol) of HOSu, dissolve them in 14L of tetrahydrofuran, and stir in an ice-water bath. Accurately weigh 1238g (6.0mol) of DCC, dissolve it in 7L tetrahydrofuran, slowly add it dropwise to the above solution, stir the reaction, and monitor the end point of the reaction by TLC. After the reaction was completed, filter with suction, concentrate the reaction solution to 6-7L, add 35L of petroleum ether to the concentrated solution, a large amount of white solid precipitated out, and the solution stood at -20°C for 1 hour. After standing still, filter with suction, dissolve the filter cake with 6L of ethyl acetate, add 35L of petroleum ether, crystallize, filter with suction, and dry the filter cake in vacuum to obtain 2020g of Fmoc-Leu-OSu with a purity greater than 99% and a yield of 89.7%.

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Abstract

The invention relates to the field of polypeptide synthesis, and in particular relates to a method for preparing sinapultide by combining a solid phase and a liquid phase. The method provided by the invention comprises the following steps of firstly, preparing polypeptide fragments I: Fmoc-Leu-Leu-Leu-Leu-Lys(Boc)-OH, then adopting an Fmoc solid-phase synthesis method to sequentially couple four polypeptide fragments I onto carrier resin, and finally, coupling protected amino acid Lys to prepare the sinapultide through a cleavage reaction. By adopting the method to prepare the sinapultide, only five steps of transpeptidase reactions are needed, the production cycle is short, the crude peptide purity is high, the cost is low, the operation is simple and the method is applicable to industrial production.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a method for preparing cinaputide through solid-liquid phase combination. Background technique [0002] Neonatal respiratory distress syndrome (RDS) refers to the symptoms of progressive dyspnea and respiratory failure in newborns shortly after birth, mainly due to the lack of alveolar surfactant, which leads to progressive alveolar collapse. Progressive dyspnea, moaning, cyanosis, and inspiratory depressions appeared within 4-12 hours afterward, and respiratory failure occurred in severe cases. The incidence rate is related to gestational age, the smaller the gestational age, the higher the incidence rate, the lighter the body weight, and the higher the mortality rate. [0003] On March 6, 2012, Discovery Laboratories' intratracheal suspension Surfaxin (Lucinactant, Lucinactant) was approved by the US Food and Drug Administration (FDA) for the treatment of respiratory distr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/00C07K1/06C07K1/04
CPCC07K14/00
Inventor 张颖王德龙王仁友李同金石鑫磊
Owner JINAN KANGHE MEDICAL TECH
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