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Preparation method of icatibant acetate

A technology of icatibant acetate and amino acid, which is applied to the preparation methods of peptides, chemical instruments and methods, organic chemistry and other directions, can solve the problems of cumbersome process and low purity, and achieves simple preparation process, stable commercial use, and reduced synthesis cost effect

Active Publication Date: 2020-11-17
台州吉诺生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The object of the present invention is to provide a method with low cost and high benefit to synthesize icatibant acetate of low racemization, so as to overcome the problems such as complicated process and low purity in the prior art

Method used

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  • Preparation method of icatibant acetate
  • Preparation method of icatibant acetate
  • Preparation method of icatibant acetate

Examples

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Embodiment 1

[0082] 1. Fmoc-Arg (NO 2 )-Pro-OH Synthesis

[0083] a) Fmoc-Arg (NO 2 )-OSu

[0084] Weigh Fmoc-Arg (NO 2 )-OH (50.0 g, 113 mmol) and added to a three-necked flask containing 250 mL of tetrahydrofuran. The mixture was stirred at 25±2°C for 5 min. Then 15.64 g (135.9 mmol) of N-hydroxysuccinimide were added and allowed to stir for 5-10 min. In another separate round-bottomed flask, 28.04g of dicyclohexylcarbodiimide (135.9mmol) was dissolved in 250mL of tetrahydrofuran, and then slowly added dropwise to the above-mentioned Fmoc-Arg (NO 2 )-OH in THF solution, the temperature is controlled at 27±2°C, and the dropping time is 30-45 minutes. After the dropwise addition was completed, the system was warmed up to room temperature and reacted for another 3 hours. The starting material was monitored by thin layer chromatography (TLC) until the reaction was complete. The reaction solution was filtered to remove urea, and the next reaction was directly carried out without furth...

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Abstract

The invention discloses a preparation method of icatibant acetate, and belongs to the technical field of medicine synthesis. The preparation method comprises the steps that by adopting a solid-phase synthesis method, amino acid with protective groups at the N end and the side chain and dipeptide fragments are sequentially connected to a resin solid-phase carrier according to a main chain peptide sequence of the icatibant acetate so as to obtain resin peptide, wherein guanidyl of arginine is protected by nitryl, and the N end of glycine is connected with 2,4-dimethoxybenzyl; and the resin peptide is cracked by using a cracking reagent, a cracked peptide chain is separated out, the nitryl is removed by using palladium-carbon catalysis to obtain an icatibant crude product, and purification isperformed to obtain the icatibant acetate. According to the method, the nitryl protective group is used for protecting arginine residue, so that the synthesis cost is greatly reduced; in the synthesis process, the dipeptide fragments and skeleton modification peptide are utilized at corresponding amino acid positions, so that missing peptide and inserted peptide impurities are reduced; and the preparation process is simple, stable and commercially feasible.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for preparing icatibant acetate. Background technique [0002] Icitibant is a selective competitive antagonist of the bradykinin B2 receptor with an affinity similar to that of bradykinin. Bradykinin, a vasodilator, is thought to be responsible for the typical hereditary angioedema symptoms of local swelling, inflammation, and pain. Icibant inhibits the binding of bradykinin to B2 receptors, thereby treating the clinical symptoms of acute attacks of hereditary angioedema. Icitibant is a synthetic decapeptide composed of five non-protein amino acids. In 2011, icatibant, developed by Shire Orphan Therapies, received preliminary approval in the United States as a subcutaneous injection. [0003] Patent document US5648333A discloses icatibant and its preparation method. [0004] Patent document CN107417770A discloses that by using a novel coupling reagent, such as...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/36C07K1/34C07K1/20C07K1/06C07K1/04
CPCC07K7/06Y02P20/55
Inventor 王丰健拉及库马尔·塔尔拉维·塞米拉
Owner 台州吉诺生物科技有限公司
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