Solid-Phase Peptide Condensation with Carbodiimide Additives

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Solution Overview

Problem

Existing peptide synthesis methods, particularly those using a membrane as a stationary phase, face challenges with low reaction conversion rates and crystal precipitation during amidation reactions, especially when synthesizing drug-like peptides containing N-alkylamino acids, leading to inefficient and impure peptide production.

Innovation Solution

A method involving the use of specific carbodiimide-based condensing agents and additives in the presence of a carbodiimide-based condensing agent represented by formula (A) to enhance the condensation reaction, allowing for high-purity peptide production by avoiding crystal precipitation and improving reaction conversion rates.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If existing amidation conditions are used for synthesizing drug-like peptides with N-alkylamino acids, then the synthesis can be performed, but the reaction conversion rate is low (3-64%)

Engineering Contradiction:

Improvereaction conversion rateVSAvoidsynthesis reliability

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent changes the chemical parameters of the amidation reaction by introducing a specific condensing agent system (formula A) with optimized molecular structure and stoichiometric ratios, transforming the reaction from low conversion (3-64%) to high conversion (>90%), thereby resolving the contradiction between productivity and reliability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs a specific condensing agent (formula A) as an intermediary substance that facilitates the amidation reaction between carboxylic acid and amino acid, acting as a mediator to achieve high conversion rates without direct harmful interactions, thus improving both productivity and reliability

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If reagent concentration is doubled to improve reaction conversion rate, then conversion rate increases, but crystal precipitation occurs causing clogging and impurities

Engineering Contradiction:

Improvereaction conversion rateVSAvoidcrystal precipitation

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent optimizes the concentration parameters of reagents by establishing a specific ratio relationship between condensing agent and amino acid (1:1 to 1:2), achieving high conversion rates without crystal precipitation, thus resolving the contradiction between productivity and harmful factors

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent converts the potential harmful effect of high reagent concentration (which causes crystal precipitation) into a beneficial high conversion rate by precisely controlling the concentration ratio, transforming what would be a harmful condition into an optimized reaction parameter

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Productivity

If automated liquid delivery is employed to speed up synthesis, then efficiency improves, but crystal precipitation causes clogging

Engineering Contradiction:

Improvesynthesis efficiencyVSAvoidautomation feasibility

Core Design Contradiction:

ProductivityVSEase of operation

Solution Approach 1:

The patent adjusts the concentration and ratio parameters of reagents to be compatible with automated liquid delivery systems, enabling high-efficiency automated synthesis without crystal precipitation-induced clogging, thus resolving the contradiction between productivity and ease of operation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent replaces manual operation considerations with optimized chemical parameters that are inherently compatible with automated systems, allowing mechanical/automated liquid delivery without the crystal precipitation problem that would otherwise limit automation feasibility

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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

The method achieves higher reaction conversion rates and prevents crystal precipitation, enabling efficient and automated synthesis of high-purity peptides using both membrane and polymer resin as stationary phases.

Implementation Method 1

a condensation step of condensing the first amino acid or first peptide, and a second amino acid having a protected amino group and/or protected hydroxy group and a carboxy group, or a second peptide having a protected amino group and/or protected hydroxy group and a carboxy group in the presence of at least one carbodiimide-based condensing agent

Methodology Applied

Scientific EffectCondensation reaction:

Data Source

PatentUS20250276995A1Production method for peptide compound

Publication Date: 2025.09.04 CHUGAI PHARMA CO LTD

AI summary

A method for producing a peptide compound by a solid phase method, the method comprising:a preparation step of preparing a first amino acid having an amino group or a first peptide having an amino group supported on a solid phase; anda condensation step of condensing the first amino acid or first peptide, and a second amino acid having a protected amino group and/or protected hydroxy group and a carboxy group, or a second peptide having a protected amino group and/orprotected hydroxy group and a carboxy group in the presence of a predetermined carbodiimide-based condensing agent and an additive.