CHAPTER 19: Large-scale Automated Synthesis of Therapeutic Oligonucleotides: A Status Update

An increasing number of therapeutic oligonucleotides are entering human clinical trials, leading to multiple marketed drugs. Thus, large-scale automated synthesis of these products has become a high priority for process chemists. This chapter summarizes the advances in the large-scale solid-support synthesis of oligonucleotides using conventional phosphoramidite chemistry. An overview of the most prevalent modifications currently utilized for the assembly of modified oligonucleotides along with a four-step automated process is presented. A brief description of the post-synthesis processes is also included with protocols for characterization of drug substance. A glimpse of possible future technologies that may tackle the economic and ecological challenges of the 21st century when oligonucleotides will be required in metric-tonne quantity is also discussed.