Journal
JOURNAL OF ORGANIC CHEMISTRY
Volume 87, Issue 4, Pages 2087-2110Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.joc.1c01756
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A novel convergent liquid-phase synthesis has been developed for manufacturing large quantities of oligonucleotide therapeutics, showing promise for treating diseases affecting millions of people. The method allows for the assembly of an 18-mer drug candidate without the need for column chromatography, resulting in similar purity to standard solid-phase synthesis. The process demonstrates potential for eliminating chromatography in the purification steps, enhancing scalability and reducing environmental impact.
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. Two of the fragments have been synthesized at similar to 3 kg/batch sizes and four additional tetra- and pentamer fragments were synthesized at >300-g scale, and a 34-mer was assembled from the fragments. Critical impurities are controlled in the fragment syntheses to provide oligonucleotides of purities suitable for clinical use after applying standard full-length product purification process. Impurity control in the assembly steps demonstrated the potential to eliminate chromatography of full-length oligonucleotides, which should enhance scalability and reduce the environmental impact of the process. The convergent assembly and telescoping of reactions made the long synthesis (>60 reactions) practical by reducing production time, material loss, and chances for impurity generation.
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