4.6 Article

A Study on Synthesis and Upscaling of 2′-O-AECM-5-methyl Pyrimidine Phosphoramidites for Oligonucleotide Synthesis

Journal

MOLECULES
Volume 26, Issue 22, Pages -

Publisher

MDPI
DOI: 10.3390/molecules26226927

Keywords

2 '-O-(N-(aminoethyl)carbamoyl)methyl modification; phase transfer catalysis (PTC); 5-methyluridine; 5-methylcytidine; oligonucleotides; alkylation; monoacetylation

Funding

  1. European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant [721613]

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This study reported for the first time the synthesis of 2'-O-(N-(aminoethyl)carbamoyl)methyl-modified 5-methyluridine (AECM-MeU) and 5-methylcytidine (AECM-MeC) phosphoramidites in multigram quantities. By optimizing synthesis steps and work-up strategies, large-scale production was achieved with significantly reduced chromatographic purification steps.
2'-O-(N-(Aminoethyl)carbamoyl)methyl-modified 5-methyluridine (AECM-MeU) and 5-methylcytidine (AECM-MeC) phosphoramidites are reported for the first time and prepared in multigram quantities. The syntheses of AECM-MeU and AECM-MeC nucleosides are designed for larger scales (approx. 20 g up until phosphoramidite preparation steps) using low-cost reagents and minimizing chromatographic purifications. Several steps were screened for best conditions, focusing on the most crucial steps such as N-3 and/or 2'-OH alkylations, which were improved for larger scale synthesis using phase transfer catalysis (PTC). Moreover, the need of chromatographic purifications was substantially reduced by employing one-pot synthesis and improved work-up strategies.

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