Oxyma-Mediated Acylation of Cyclic Peptides
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Solution Overview
Problem
Existing methods for acylating cyclic peptides bearing an amino group, such as those used in the production of anidulafungin and micafungin, rely on hazardous chemicals like carbodiimides and benzotriazole derivatives, which are allergenic and explosive, respectively, posing safety concerns and necessitating the development of safer alternatives.
Innovation Solution
A method involving the reaction of an acid with a compound of general formula (1) to form an intermediate oxyma-ester, which is then used to acylate a cyclic peptide, avoiding the use of hazardous chemicals by employing a one-pot procedure and using a base like diisopropylamine, allowing for selective acylation at a single amino group without protecting other functionalities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If carbodiimides are used for acylation of cyclic peptides, then acylation efficiency is improved, but safety deteriorates due to allergenic properties
Solution Approach 1:
The patent uses oxyma (1-hydroxy-5-nitro-1H-tetrazole) as an intermediary coupling agent to activate carboxylic acids for acylation of cyclic peptides. This intermediary approach replaces the harmful carbodiimide coupling agents while maintaining efficient amide bond formation. The oxyma ester intermediate enables high-yield acylation without the allergenic side effects of carbodiimides.
2Productivity
If benzotriazole derivatives are used for acylation, then acylation efficiency is improved, but safety deteriorates due to explosive properties
Solution Approach 1:
The patent employs oxyma (1-hydroxy-5-nitro-1H-tetrazole) as a safe intermediary coupling agent that activates carboxylic acids for acylation reactions. This intermediary replaces the explosive benzotriazole derivatives while maintaining effective amide bond formation. The oxyma ester intermediate provides a non-explosive pathway for high-yield acylation of cyclic peptides.
3Adaptability or versatility
If multiple amino groups are present in cyclic peptides, then functional versatility is improved, but manufacturing complexity deteriorates due to need for protecting groups
Solution Approach 1:
The patent employs oxyma-activated esters that exhibit high selectivity for acylation at specific amino groups. This local quality approach allows selective acylation at a single amino group even when multiple amino groups are present in the cyclic peptide, without requiring protecting groups on other amino groups. The reaction conditions and oxyma activation enable site-specific acylation that simplifies the manufacturing process.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach enables the high-yield acylation of complex cyclic peptides like anidulafungin and micafungin without the need for allergenic carbodiimides or explosive benzotriazole derivatives, ensuring safety and efficiency in the production process while maintaining high purity and low residual chemical traces in the final products.
Implementation Method 1
Reacting an acid R1CO2H with a compound of general formula (1) to give a compound of general formula (2)... Mixing said compound of general formula (2) with said cyclic peptide bearing an amino group to form a cyclic lipopeptide
Data Source
AI summary
The present invention relates to a process for acylating cyclic peptides bearing an amino group and to the application of said process in the preparation of anidulafungin and micafungin.