Speciality Chemicals Magazine JUL / AUG 2025 | Page 25

HIGH POTENCY APIS

Figure 4- Synthetic route to topotecan using cascade radical reaction

Case study 2

Topotecan is a synthetic, watersoluble analogue of the natural chemical compound camptothecin. Its hydrochloride salt is used to treat ovarian, lung and other cancers. After GlaxoSmithKline received final FDA approval in 2007, it became the first topoisomerase I inhibitor for oral use.

A convergent second-generation synthesis was reported using a radical cascade reaction with an isonitrile derivative( Figure 4). 5 N-Propargylation of lactone( 7) under optimised conditions with propargyl bromide provided the intermediate( 8) in 88 % yield.

In the key radical cascade, a solution of 8, p-hydroxyphenylisonitrile, and hexamethyldistannane( 1.5 eq.) in benzene was warmed to 70 ° C and irradiated with a sun lamp, providing 9 in 51 % yield, and subsequent demethylation with HBr provided 10-hydroxycamptothecin( 10). This highly active natural product is the precursor of topotecan( 11).

The key intermediate 5 can be combined in as few as two steps with two variable modules, propargyl bromide and aryl isonitrile derivative, to prepare a range of known and new camptothecin analogues. This strategy was adapted because the radical reaction tolerates various functional groups. It shows the power of cascade radical reactions and, with its short, modular‘ mix-and-match’ strategy, may be useful for preparing larger quantities of these compounds.

Conclusion & perspectives

Scaling up HPAPI production presents significant challenges that require expertise across various fields. Success depends on the processes and mindset used to manage these challenges.

Rational risk-based approaches provide an integrated platform for synthesis and drug product manufacturing at the critical interface from the pre-clinical through to the clinical stage. The approach follows a long-term perspective by accruing product and process knowledge and controls based on QbD principles to ensure scalability and transferability, as well as manufacturing optimisation and simplification, as more safety data become available.

While some pharmaceutical companies have in-house capabilities, the development of HPAPIs, especially cytotoxics, is often outsourced to CMOs and CDMOs. Flexibility in manufacturing techniques, equipment, and containment options can enhance safety, reduce costs, and increase capacity for HPAPIs.

The demand for better treatments for cancer and other diseases is driving the growth of ultra-high potency APIs. These include ADC toxins and certain psychedelics, which require stringent containment and security measures due to their high potency.

Containment levels for these can be as low as single-digit nanograms or picograms, and they are often cytotoxic or genotoxic, necessitating strict exposure guidelines. Manufacturing these APIs is challenging due to the small dosages needed, typically ranging from 1 to 200 grams. Process development must be done at the milligram scale.

For CDMOs, the ability to handle HPAPIs has almost become a standard, as an increasing number of molecules in development are classified as such. Proper risk assessment is paramount for companies working in this space. Process chemistry-based expertise can shape the solutions and strategies required for manufacturing these compounds safely and routinely, alongside regulatory compliance and specialised assets. ●

Juliette Martin

SCIENTIFIC COMMUNICATION MANAGER

JUL / AUG 2025 SPECCHEMONLINE. COM

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