Hydrogen Fluoride Imidazole: A Simple, Efficient, Mild, and Cost-Effective Silyl-Ether Deprotection Reagent.

Despite the availability of numerous -OH silyl protection and deprotection methods, the selective cleavage of silyl ethers in highly complex molecules can still be a challenge. In this article, we present results from a full investigation of a novel, efficient, and mild desilylation protocol using HF/imidazole. Imidazole significantly enhances the desilylation reaction efficiency of HF, allowing clean and complete deprotection of TBDPS ethers in substrates containing both acid and base sensitive groups.

Simplified Oligonucleotide Phosphorus Deprotection Process with Reduced 3-(2-Cyanoethyl) Thymidine Impurities.

Oligonucleotides have emerged as valuable new therapeutics. Presently, oligonucleotide manufacturing consists in a series of stepwise additions until the full-length product is obtained. Deprotection of the phosphorus backbone before cleavage and deprotection (C&D) by ammonolysis is necessary to control the 3-(2-cyanoethyl) thymidine (CNET) impurity.

Use of ultrafiltration/diafiltration for the processing of antisense oligonucleotides.

Ultrafiltration/diafiltration (UF/DF) has been the hallmark for concentrating and buffer exchange of protein and peptide-based therapeutics for years. Here we examine the capabilities and limitations of UF/DF membranes to process oligonucleotides using antisense oligonucleotides (ASOs) as a model. Using a 3 kDa UF/DF membrane, oligonucleotides as small as 6 kDa are shown to have low sieving coefficients (<0.

Development of Kilogram-Scale Convergent Liquid-Phase Synthesis of Oligonucleotides.

Oligonucleotide drugs show promise to treat diseases afflicting millions of people. To address the need to manufacture large quantities of oligonucleotide therapeutics, the novel convergent liquid-phase synthesis has been developed for an 18-mer oligonucleotide drug candidate. Fragments containing tetra- and pentamers were synthesized and assembled into the 18-mer without column chromatography, which had a similar impurity profile to material made by standard solid-phase oligonucleotide synthesis.

Sustainability Challenges and Opportunities in Oligonucleotide Manufacturing.

With a renewed and growing interest in therapeutic oligonucleotides across the pharmaceutical industry, pressure is increasing on drug developers to take more seriously the sustainability ramifications of this modality. With 12 oligonucleotide drugs reaching the market to date and hundreds more in clinical trials and preclinical development, the current state of the art in oligonucleotide production poses a waste and cost burden to manufacturers. Legacy technologies make use of large volumes of hazardous reagents and solvents, as well as energy-intensive processes in synthesis, purification, and isolation.