Phosphoramidite Activator Using Piperidine to Enhance BTT Solubility
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Solution Overview
Problem
Existing phosphoramidite activators, such as those containing N-alkylimidazole, improve the solubility of 5-benzylthio-1H-tetrazole (BTT) in acetonitrile but result in lower yields and purities of target products compared to using a BTT-acetonitrile solution without additives.
Innovation Solution
The addition of at least one compound selected from piperidine, pyrrolidine, N-alkylpiperidine, and N-alkylpyrrolidine to a BTT-acetonitrile solution enhances the solubility of BTT while maintaining or improving the yield and purity of the target product.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If N-alkylimidazole is added to improve the solubility of BTT in acetonitrile, then the solubility of BTT is improved, but the yield and purity of the target product are reduced
Solution Approach 1:
The patent changes the chemical parameter by substituting N-alkylimidazole with piperidine or pyrrolidine, which have different chemical properties. These alternative compounds improve BTT solubility through different mechanisms while not negatively affecting the coupling reaction, thus resolving the contradiction between solubility improvement and product purity maintenance.
2Productivity
If the concentration of BTT-acetonitrile solution is increased to activate phosphoramidite more quickly and efficiently, then the activation efficiency is improved, but BTT crystals precipitate at low temperature causing piping clogging
Solution Approach 1:
The patent introduces piperidine or pyrrolidine as an intermediary substance that mediates between BTT and acetonitrile. This intermediary compound enables higher concentrations of BTT to be dissolved in acetonitrile without precipitation, as piperidine/pyrrolidine form soluble complexes or alter the solvent properties, thus allowing both high activation efficiency and storage stability.
3Productivity
If BTT is used at high concentration in acetonitrile, then the phosphoramidite activation is more efficient, but the solution cannot be stored due to crystal precipitation
Solution Approach 1:
The patent creates a composite activator solution containing BTT, acetonitrile, and piperidine/pyrrolidine. This composite formulation allows the solution to maintain high BTT concentration for efficient activation while the piperidine/pyrrolidine component prevents crystal precipitation during storage, thus extending the storage duration without sacrificing activation efficiency.
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 allows for efficient activation of phosphoramidites, achieving high yields and purities of phosphate esters or thiophosphate esters, and provides improved storage stability of the phosphoramidite activator without precipitation of BTT crystals.
Implementation Method 1
the addition of at least one compound selected from piperidine, pyrrolidine, N-alkylpiperidine, and N-alkylpyrrolidine to a BTT-acetonitrile solution enhances the solubility of BTT
Implementation Method 2
an activator of a phosphoramidite is indispensable in a case where (B) the coupling reaction is performed
Data Source
AI summary
The present invention has an object to provide a phosphoramidite activator that improves a solubility of 5-benzylthio-1H-tetrazole in acetonitrile and does not reduce the yield and a purity of a target product.The present invention relates to a phosphoramidite activator containing (i) at least one compound that is selected from the group consisting of piperidine, pyrrolidine, N-alkylpiperidine, and N-alkylpyrrolidine, (ii) 5-benzylthio-1H-tetrazole, and (iii) acetonitrile; and a method for activating a phosphoramidite and a method for synthesizing a phosphate ester or a thiophosphate ester, both methods using the activator.