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Method for synthesizing icatibant

A peptide resin and coupling technology, which is applied in the field of synthesizing icatibant, can solve the problems of peptide chain shedding, high impurity content, and low application value, so as to improve the yield, optimize the synthesis process, and improve the overall effect

Inactive Publication Date: 2014-10-01
CHENGDU SHENGNUO BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Yet the preparation method of existing icatibant still mainly continues to use about 1990, by the solid-phase synthesis method invented by Herchester AG of Germany, the icatibant product purity that this method makes is low, impurity content is high, Low yield, not suitable for industrial production, low application value
[0007] The application number is 201210028377.9, which reports the method of direct solid-phase synthesis of icatibant, using 2-chlorotriphenyl chloride resin as the initial carrier, but because the resin is prone to peptide chain shedding in the process of grafting peptides, it directly affects the synthesis of icatibant. Total Yield of Substitute

Method used

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  • Method for synthesizing icatibant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Synthesis of Peptide Resin 1

[0042] 100 g of Wang resin with a substitution degree of 0.80 mmol / g was added to a solid-phase reaction column, and DMF was added to swell the resin for 30 minutes and then drained. Take 155.6g Fmoc-Arg(Pbf)-OH and 32.5g HOBt, dissolve them in DMF, add them to the above resin, stir well, then add 33mL DIC and 3.0g DMAP, stir and react at room temperature for 6 hours, remove the reaction liquid, wash with DMF After 3 times, DCM was washed 3 times, methanol was washed 3 times, each washing time was 3min, and Fmoc-Arg(Pbf)-Wang resin was obtained, and the detection substitution degree was 0.51mmol / g.

Embodiment 2

[0043] Example 2: Synthesis of Peptide Resin 1

[0044] Add 100 g of HMP resin with a substitution degree of 0.75 mmol / g into the solid-phase reaction column, add DMF to swell the resin for 30 minutes, and drain it. Take 145.8g Fmoc-Arg(Pbf)-OH and 30.4g HOBt, dissolve them in DMF, add them to the above resin, stir well, then add 30.5mL DIC and 2.8g DMAP, stir at room temperature for 6 hours, remove the reaction solution, DMF After washing 3 times, DCM washed 3 times, methanol washed 3 times, each washing time was 3min, and Fmoc-Arg(Pbf)-Wang resin was obtained, and the detection substitution degree was 0.49mmol / g.

Embodiment 3

[0045] Example 3: Synthesis of Peptide Resin 2 (Coupling of Fmoc-Oic-OH)

[0046] Take 0.1mol Fmoc-Oic-OH and 0.1mol HOBt, and dissolve them with an appropriate amount of DMF; take another 0.1mol DIC, slowly add it under stirring, stir and react at room temperature for 30 minutes, and obtain the activated amino acid solution for later use;

[0047] Take 0.05mol of the Fmoc-Arg(pbf)-Wang resin of Example 1 (i.e. peptide resin 1, the substitution value is about 0.51mmol / g peptide resin 1), deprotect it with 1000mL 20% PIP / DMF solution for 25 minutes, wash and filter to obtain De-Fmoc Peptide Resin 1;

[0048] The activated amino acid solution is added to the peptide resin 1 without Fmoc, the coupling reaction is 60-300 minutes, the reaction end point is determined by the ninhydrin method, and the peptide resin 2 is obtained by filtering and washing, Fmoc-Oic-Arg (pbf )-Wang Resin.

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Abstract

The invention relates to the field of medicine synthesis and discloses a method for synthesizing icatibant. The method comprises the following steps: protection arginine of a protecting group is coupled on the N end and the side chain of arginine; the protection arginine and a resin carrier are subjected to esterification reaction under the action of a coupling reagent and a reactivate reagent to obtain peptide resin 1; the resin carrier is Wang resin or HMP; according to amino acid sequence from C end to N end of icatibant and starting from the peptide resin 1, at presence of a condensation reagent and the reactivate reagent, the protection amino-acid are coupled in sequence in an extending manner to obtain icatibant resin eventually; then the icatibant resin is subjected to acid decomposition to obtain the crude icatibant; the crude icatibant is purified to obtain the pure icatibant. According to the invention, as proper Wang resin or HMP is selected, the whole synthesis process is optimized and the total yield of the icatibant is improved significantly; compared with the prior art, the total yield is increased over 20 %.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a method for synthesizing icatibant. Background technique [0002] Icatibant, known as Icatibant in English, is a selective competitive antagonist for slow B2 receptors developed by Jerini Company of Germany (Shire plc Company in the United States). In August 2011, icatibant was approved by the U.S. FDA for marketing, and the trade name is Firazyr. The drug is an injection and is used for the treatment of acute attacks of hereditary angioedema (HAE) in people over 18 years old. [0003] HAE, also known as C1 Inhibitor Deficiency, is a rare autosomal dominant genetic disorder caused by a genetic defect. It is caused by low levels or dysfunction of a protein called C1 Inhibitor, with an incidence of 1 in 10,000- 1 / 50000. HAE is characterized by unpredictable episodic edema and swelling of the hands, feet, face, larynx, and abdomen, resulting in disfigurement, disability, o...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/08C07K1/06C07K1/04
CPCY02P20/55
Inventor 李向群郭德文董华建曾德志文永均
Owner CHENGDU SHENGNUO BIOPHARM
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