Peptide Synthesis Using BOP-OPPF6 Activation
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Solution Overview
Problem
Existing methods for producing peptides with N-alkylamino acids face challenges such as low conversion rates, residual starting materials, and the need for additional deprotection steps, which affect yield and quality.
Innovation Solution
A method involving the mixing of an N-terminal protected amino acid or peptide with a carboxylic acid activating agent and an amino acid or peptide with an N-alkyl group, using specific activating agents and silylating agents to achieve efficient peptide synthesis with an unprotected C-terminal.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional activation methods (pivaloyl chloride, isobutylchloroformate, HATU) are used to produce peptides with N-alkylamino acids, then peptide bonds can be formed, but the conversion rate is insufficient and large amounts of starting material remain
Solution Approach 1:
The patent changes the chemical parameters of the activation method by using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP-OPPF6) instead of conventional activating agents. This parameter change in the reagent structure and properties enables sufficient conversion of N-alkylamino acids to peptide bonds, resolving the incomplete reaction issue while maintaining high reaction completeness.
2Ease of manufacture
If methods with C-terminal protection are used, then peptide synthesis can proceed, but additional deprotection steps are required which reduce efficiency
Solution Approach 1:
The patent extracts and removes the C-terminal protection step from the synthesis pathway by directly producing peptides with unprotected C-terminals. The use of BOP-OPPF6 activation enables the reaction to proceed without requiring subsequent deprotection operations, thereby reducing the total number of steps while maintaining ease of manufacture through a streamlined process.
3Productivity
If HATU is used as activating agent, then peptide bonds can be formed, but the explosive triazole structure makes it unsuitable for industrial production
Solution Approach 1:
The patent replaces the hazardous HATU reagent with BOP-OPPF6, which lacks explosive properties. This substitution maintains high reaction efficiency for peptide bond formation while eliminating the safety hazard associated with the triazole structure, making the process suitable for industrial production where safety is paramount.
4Adaptability or versatility
If N-alkylamino acids are introduced using conventional methods, then peptide diversity can be achieved, but residual starting materials form peptides lacking amino acids which are difficult to remove
Solution Approach 1:
The patent changes the reaction parameters by using BOP-OPPF6 activation which achieves complete conversion of N-alkylamino acids. This parameter change eliminates residual starting materials that would otherwise contaminate the final product, thereby maintaining peptide structure variety while significantly improving product purity and reducing the difficulty of removal.
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 method allows for the production of peptides with N-alkylamino acids in higher yields and with improved quality, eliminating the need for additional deprotection steps and using industrially applicable reagents.
Implementation Method 1
the C-terminal of an N-terminal protected amino acid is activated with pivaloyl chloride
Implementation Method 2
a benzyl ester of an N-methylamino acid is reacted therewith
Implementation Method 3
silylated N-methylglycine (sarcosine) or proline
Implementation Method 4
a peptide in which the C-terminal of the product is protected... a method in which the C-terminal of an N-terminal protected amino acid is activated with pivaloyl chloride, and a benzyl ester of an N-methylamino acid is reacted therewith
Data Source
AI summary
The present invention is to provide a method for producing a peptide containing an N-alkylamino acid, which comprises the following Steps (1) to (3). Step (1): a step of mixing an N-terminal protected amino acid or an N-terminal protected peptide with a carboxylic acid halide or a halogenated alkyl formate; Step (2): a step of mixing an amino acid or a peptide in which the N-terminal and the C-terminal are not protected with a trialkylsilylating agent; and Step (3): a step of mixing the product obtained in Step (1) with the product obtained in Step (2).