Reducing nitro groups to amines is a well-known and frequently applied method, which is useful in the synthesis of various classes of compounds of interest in the pharmaceutical and fragrances industries, as well as fine chemicals in general.

A new, patented metal-free invention made by professor Maurizio Benaglia at the University of Milan relates to a completely new production pathway based on the use of trichlorosilane (a very cost-efficient reducing agent that is widely used in the semiconductor industry) and an organic base. Berlin-based startup DexLeChem has taken over its commercialization. This case serves as a good example of a successful translation of scientific findings into the industry — beyond national borders.

Complex Routes

There is a trend in the production of fine chemicals and active pharmaceutical ingredients (APIs) toward the synthesis of increasingly complex molecule structures that consist of multiple functional groups. A reliable methodology to insert amino groups without harming the remaining molecule structure is of great industrial importance, although technically challenging.

All roads lead to Rome, but which road is the best? When it comes to nitro reductions, state-of-the-art processes involve the hydrogenation of nitro groups with heterogeneous noble metal catalysts such as palladium or platinum on charcoal. As often as not, problems tend to arise during these processes, especially when it comes to complex drugs. Other functional groups of the API can be attacked and alter the needed molecule structure in an undesirable way; metal residues from the catalysts in the product also can cause problems and hinder the drug approval process.

Furthermore, every organic chemist has probably experienced the problem that compounds lose halogen groups when exposed to hydrogen during a nitro reduction step, resulting in a drop in selectivity and increasing the manufacturing costs significantly.

Chemical reduction methods, on the other hand, have the large drawback that an environmentally safe waste disposal creates prohibitive costs for industrial applications.

Until now, no solution to most of these problems has been commercially available. In a bilateral approach, involving the University of Milan (UNIMI) and the Berlin-based startup DexLeChem, this shortcoming has been solved.

Academia And Industry Converge

The partnership started at the beginning of 2013, when Benaglia from UNIMI made an important discovery. As a well-known expert in the field of organocatalysis, he had already worked extensively with trichlorosilane to reduce imines, improving the performances of these transformations considerably. Through his research, he then found that trichlorosilane itself could also perform nitro reductions. This revelation was unprecedented by even the foremost experts in his field. It was previously well-known that in the case of the presence of a nitro group in an imine, trichlorosilane reduces only the C=N bond and not the nitro group. However, Benaglia changed the reaction protocol so that he was able to forge a new path in nitro reductions via trichlorosilane.

This new methodology enables a completely new pathway that possesses certain advantages against the former state-of-the-art technologies:

• It does not attack other parts of the compounds (which is described as a high chemoselectivity).
• The work-up is very easy, and enables an environmentally safe waste disposal as the totally nontoxic waste can be discharged into aqueous wastewater.
• There are no risks of product contamination by metals.
• Restrictive patents can be bypassed because of the increasing range of alternative synthesis routes.
• No high-pressure equipment is needed.
• The chirality of drugs, which is of high importance for the pharmacological effect in the human body, is not affected as the new pathway respects the stereochemical integrity of the stereogenic elements of the molecule.

Benaglia recognized the high market potential of his invention immediately and filed an international patent application under the Patent Cooperation Treaty (PCT). He also quickly found his first customer, the Italian pharmaceutical company Zambon and its chemical business, Zambon Chemicals (abbreviated ZaCh System), with which he already had a close relationship.

When Benaglia approached ZaCh, the company was in the middle of a process development for a second-generation synthesis route of Aliskiren. ZaCh directly bought a license to his patent: “The possibility to perform a nitro reduction in the last stage of the production with 100% selectivity and 99% yield solved all of our problems at once: This new method secured us the whole freedom-to-operate of the process and the great performance secured our profitability,” said Dr. Massimo Verzini, head of process development.

But after this early success, something happened that happens quite frequently with scientific innovations: the commercialization stopped. Benaglia simply did not have the time to go to fairs or cold call other companies. The end of the PCT application drew closer.

At a scientific symposium in December 2014, Benaglia met Sonja Jost, founder and CEO of Berlin-based chemistry startup DexLeChem. From her own experience, she knew that most scientific findings just do not reach the industry. This was the starting point for DexLeChem.

So Jost asked Benaglia whether he had identified any maturing markets for his scientific findings. Despite his high scientific reputation, no one had ever asked him this question. The nitro reduction method came to his mind, and Jost immediately recognized its potential. A lot of DexLeChem’s customers had had problems with nitro reductions. DexLeChem then spent the next January analyzing competitive pathways for nitro reductions.

The company also assigned external specialists to further evaluate Benaglia’s discovery. His very mild reaction conditions and the high performance indicators of his process (which were and remain unbeatable for many applications) convinced DexLeChem’s team as well as the external specialists. DexLeChem was then able to start the negotiation process about the patent application with UNIMI in February — only one month before the application would have expired. The contract of sale was signed just in time to start with the nationalization.

“Some of our main advantages are the flexibility and short decision-making process that we offer as a startup company,” Jost said of the quick closure.

Today, DexLeChem provides the development of the new nitro reduction method as a service to the chemical and pharmaceutical industries. Manufacturers who have internal development departments can also just acquire a license. In addition, ZaCh offers to directly produce compounds in-house with this new method.

“I am very happy that my scientific findings are now much more applied in industry, and I think that startups in general can help to close the gap between academia and the industry, which is still there,” Benaglia said.