Insights from Approved Drugs in 2021: Chemists’ Training for Innovation

Here is a review of 50 approved drugs in the US.1) In 2021, 29 small-molecule drugs appeared in the fields of oncologic, CNS, anti-infective etc.. This review is significantly stimulating for chemistry folks because the synthetic routes of small-molecule drugs are summarized in a simple fashion. Scientists would enjoy the art of synthetic schemes, which are finalized for practical production.

In order to realize commercial production, the whole scheme as well as each reaction and reagent meet the demand of robustness and safety. A reaction and a reagent with a long history are generally utilized because of the trustworthiness. Amide formation with a condensation reagent (HATU, EDCI, etc.) is a typical example of reliable reactions with a variety of reagent choices. Knowledge on condensation reaction through experiments are indispensable for setting the best conditions. Hence, accumulation of reaction knowledge is undoubtedly a huge value.

However, classical chemistry is not always the very best. An innovative approach changes the game on facing a predicament. You would understand the meaning by looking at the case of a cardiovascular drug vericiguat, the first-in-class sGC (soluble guanylate cyclase) stimulator. At the beginning, no one would start a synthesis of tetracyclic aromatic compound from a linear alcohol, but vericiguat was synthesized from 2,2,3,3-tetrafluoropropanol. There should have been a problem to solve and they came up with a drastic idea to use this material.
Taking another example, a CNS drug samidorphan, a μ-opioid receptor antagonist, was synthesized by a beautiful, rhodium-catalyzed aza-Diels-Alder-like cyclization/phenolic cyclization sequence. This is an elegant combination of classical and novel approaches with the complete control of the requisite stereochemistry. A cycloaddition reaction is effective in synthesis, as you know, because it allows a simultaneous formation of two bonds. Cycloaddition reactions are applied smartly in some drugs as well.

Working with the schemes in this review definitely provides us invaluable insights and ideas, which expand the imagination and potential of synthetic strategies and approaches. It also provides us an opportunity of brainstorming through presuming the possible troubles and issues on the realization of practical synthesis.

From the synthetic route in this review, we reacknowledged that a fusion of classical and novel technologies is a straightforward way for a breakthrough. It is absolutely sure that a deep discussion together would expand creativity and imagination. Let’s meet and discuss your and our technologies to seek an excellent and promising way to produce an innovative technology and application.


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