Mechanochemistry could provide a safer and greener route to anticancer drugs

The IMPACTIVE team has looked into the manufacturing of imatinib: an anticancer drug on the Essential Medicines’ list of the Worlds’ Health Organisation. Thanks to mechanochemistry, we discovered a synthetic route to do it in a way that is safer, greener and more efficient than the commercial method used nowadays.

Tags: Green chemistry, Mechanochemistry, Synthesis

Not all cancer treatments aim at curing the disease. Some of them focus on controlling and preventing it from progressing – an equally valuable and important endeavour. This is the case of imatinib: an anticancer drug available since 2001, which is used to keep different cancers at bay, including certain types of leukemia and gastrointestinal tumours and serves as a successful treatment for chronic patients. Imatinib is currently sold by Novartis, an associated partner of the IMPACTIVE project, under the commercial names Gleevec and Glivec and features on the World Health Organization’s List of Essential Medicines. Now, our team has published an article that explains how to make the most of mechanochemistry and manufacture this drug in a safer, greener and more efficient way. As Tatsiana Nikonovich and Dzmitry Kananovich, from TalTech explain: “Previously, we developed new mechanochemical approaches for amide coupling and the synthesis of amines from alcohols in our lab. Our objective was to demonstrate the practical application of these methods in pharmaceutical synthesis. Most excitingly, we found that imatinib, a well-known anticancer drug, can be manufactured, starting from inexpensive 4-(hydroxymethyl)benzoic acid, assembling two carbon-nitrogen bonds consecutively.” For more details about this new process and the green metrics associated with it, keep reading below.

Current commercial method vs. mechanochemical method

The key, once again, is mechanochemistry. IMPACTIVE researchers in Novartis, Switzerland, and Taltech, Estonia, have designed a two-step synthesis method that uses ball-mills. It’s one step shorter than the most common commercial route, which requires three steps of solution-based chemistry. Additionally, the newly-develop method also exhibits enhanced safety and sustainability profiles.

A diagram comparing two methods to produce imatinib: the mechanochemical one and the previously know route. The previously known route has three steps, the three produce solvents and the component generated by the second step is a genotoxic one. The mechanochemical method has two steps, done by ball milling, and doesn't generate genotoxic compounds.
The mechanochemical alternative is one step shorter and avoids generating genotoxic compounds.

When compared to other methods available in the literature, the new mechanochemical route offers a series of key advantages. In this case, IMPACTIVE researchers used two different methods as a benchmark: a large-scale procedure described by Liu et al. and an example of large-scale preparation patented by Natco Pharma Ltd. Some of the key results include:

  • Room temperature: while both Liu and Natco methods require mid to high temperatures (140 °C and 60 °C respectively), the mechanochemical method is performed at room temperature. When scaled up, this is intimately tied with a reduced energy consumption.
  • Better overall yield: the mechanochemical method showcases a similar or, in some cases, superior yield to both benchmarks.
  • Less excess, less waste: when accounting atom-economy, and how efficient the use of reactants is, the mechanochemical method comes on top, meaning that the older methods produce a greater excess of chemicals.
  • By-passing a genotoxic intermediate: the common commercial routes involve a chlorinated intermediate with genotoxic properties. The mechanochemical route is designed to avoid it.

“The proposed method demonstrates that we can develop safer and more sustainable alternatives to existing solution-based approaches, by incorporating mechanochemical methods into production chains.”, remarks Tatsiana Nikonovich, “Significantly, our synthetic route is one step shorter and eliminates a genotoxic intermediate. Moreover, beyond practical aspects, we had to re-examine several known mechanochemical amide coupling protocols to identify the one with the best tolerance towards free hydroxyl groups, which can also react under amide coupling conditions. This issue had not been systematically investigated before, laying a foundation for the development of more efficient syntheses for a wide range of other drugs in the future.” Overall, the results are promising: a shorter synthetic path with better sustainability and safety profile and efficient reactions that works at room temperature.

Greener metrics

At IMPACTIVE, our key focus is designing greener processes to produce APIs. Therefore, we take a close look at Green Chemistry metrics. After all, mechanochemistry wouldn’t be useful if the new methodologies had a higher impact than the current chemical methods.

A diagram comparing the green metrics associated to two methods to manufacture imatinib. The mechanochemical method has a 70% Relative Process Greenness and produces 2.22 times less waste. The traditional chemistry method has a 30% Relative Process Greenness and produces 1.16 mor waste.
When compared to other methods, the mechanochemical synthesis has better green metrics and produces less waste.

To measure this, our researchers used the “innovation Green Aspiration Level” (iGAL) methodology, that illustrates the impact of innovation on waste reduction during drug development and manufacturing. When compared to the benchmarks, the mechanochemical methodology offers a better result across the board. In particular, the mechanochemical approach exhibits a waste output 2.22 times lower, when compared with an average early stage development drug synthesis.

In particular, the protocol in the paper “relies on the use of green and sustainable solvents for work-up (water) and as liquid-assisted grinding additives (ethyl acetate, dimethyl isosorbide)”, as Dzimitry Kananovich explains. “Conversely, the solution-based methods require a larger range of solvents, including toxic ones (dimethyl formamide, dichloromethane, chloroform). On the other hand, there are still aspects to consider for further improvement of our approach, as it involves the use of stoichiometric coupling reagents to facilitate the reactions.” So, as always, there’s room for improvement and we can expect future advancements from the team!

Safer manufacturing

In drug manufacturing, health and safety issues play a key role when designing synthetic methods. Current regulation ensures that the best practices are in place, to protect not only the health and safety of the employees, but also the public’s and the environment.

In particular, the new mechanochemical route to produce imatinib is re-designed to avoid an unwanted intermediate that is genotoxic—meaning that they have the capacity to damage the genetic information within a cell, causing mutations, which may lead to cancer. This, together with eliminating the use of toxic solvents—like dichloromethane, chloroform or toluene—in the manufacturing process, provides a safety improvement for the new synthesis route.

Altogether, this article is an additional proof of the potential that mechanochemistry has to provide us with a safer, greener and more efficient route to anticancer drugs. You can read the paper in full here, and do not hesitate to get in touch if you want to know more!