A kind of preparation method of icatibant acetate

A technology of icatibant acetate and amino acid, which is applied to the preparation method of peptide, chemical instrument and method, production of bulk chemicals, etc., can solve the problems of cumbersome process and low purity, and achieves simple preparation process, reduced aggregation, and reduced Effects of Deletion and Insertion Peptide Impurities

Active Publication Date: 2022-04-29
台州吉诺生物科技有限公司
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  • 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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  • A kind of preparation method of icatibant acetate
  • A kind of preparation method of icatibant acetate
  • A kind of preparation method of icatibant acetate

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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, which belongs to the technical field of medicine synthesis. The preparation method comprises: using a solid-phase synthesis method, sequentially connecting amino acids and dipeptide fragments with protective groups at the N-terminal and side chains to a resin solid-phase carrier according to the sequence of icatibant acetate main chain peptides, to obtain resin peptides , in which the guanidine group of arginine is protected by nitro group, and the N-terminal of glycine is connected with 2,4-dimethoxybenzyl group; the resin peptide is cleaved by a cleavage reagent, the cleaved peptide chain is separated, and the nitration is catalyzed by palladium carbon base to obtain the crude product of icatibant, which was purified to obtain icatibant acetate. The present invention uses a nitro protecting group to protect the arginine residue, which greatly reduces the synthesis cost; during the synthesis process, dipeptide fragments and skeletons are used to modify the peptide at the corresponding amino acid position, reducing the impurities of missing peptides and inserted peptides, and the preparation process is simple. , stable and commercially viable.

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 Patents(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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