Research could enable assembly-line synthesis of drugs containing prevalent amines

A research team from the University of Illinois at Urbana-Champaign has discovered a way to produce a special class of molecules that could open the door to new drugs to treat currently incurable diseases.

Open the medicine cabinet and you’ll likely find organic derivatives of ammonia, called amines. They are one of the most prevalent structures in drugs today. Over 40% of drugs and drug candidates contain amines, and 60% of these amines are tertiary, so named for the three carbons bonded to a nitrogen.

Tertiary amines are found in some of the most effective human medicines, including antibiotics, breast cancer and leukemia drugs, opioid painkillers, antihistamines, blood thinners, HIV treatments, migraine medications, and more. . They increase the solubility of a drug and can trigger its main biological functions.

Despite the prevalence of this particular class of molecules in drugs today, much of the functional potential of tertiary amines likely remains untapped.

Indeed, their traditional manufacturing process requires specific and controlled conditions that inherently limit the discovery of new tertiary amines, which could potentially treat a wide range of currently incurable diseases.

Now, an Illinois research team led by Lycan Professor of Chemistry M. Christina White and graduate students Siraj Ali, Brenna Budaitis, and Devon Fontaine have discovered a new chemical reaction, a carbon-carbon amination cross-coupling reaction. hydrogen, which creates a faster reacting, easier way to make tertiary amines without the inherent limitations of conventional methods. The researchers think it could also be used to discover new reactions with nitrogen.

This new reaction in the chemist’s toolbox transforms the traditional process for manufacturing tertiary amines – with its classic chemical reactions that require very specific conditions specific to each molecule – into a process that can be carried out under general conditions open to air and to humidity with the potential for automation.

As the researchers describe in their recently published article in Sciencethis new procedure uses a metal catalyst discovered by their group (Ma-WhiteSOX/palladium) and two building blocks – abundant hydrocarbons (olefins containing an adjacent C – H bond) and secondary amines – to generate a variety of tertiary amines .

This has the potential, White explained, for chemists to take lots of different secondary amines and couple them to lots of different olefins, which you can buy or make easily.

“And these are stable feedstocks. You can have them in individual containers, mix and match them, and use our catalyst to create many different combinations of tertiary amines,” White said. “The flexibility of this reaction facilitates the process of tertiary amine drug discovery.”

The difference between classic reactions and this new reaction for making tertiary amines is like the difference between choosing a specialty sandwich from a menu and creating your own sandwich from a diverse set of ingredients – you have much more flexibility in terms of choice.

This very flexible system for manufacturing tertiary amines is also very practical.

“You could, in principle, run it on your stovetop,” says White. “You don’t need to handle it very carefully, you can run it in the open air and you don’t have to exclude water. You just need your raw materials, the palladium catalyst/ SOX and a little heat. It should work just like we do in the lab.”

White explained that when a pharmaceutical company wants to manufacture tertiary amines, they often have to use specialized procedures, but this reaction allows you to take two simple, often commercial, raw materials and put them together using the same procedure.

“Because the conditions are so simple and work for so many different amines and olefins, there is great potential to adopt this reaction for automation,” White said.

The major challenge the team overcame in this discovery was to solve a long-standing problem in the chemistry of C–H functionalization: replacing a hydrogen atom on the carbon structure of a molecule with a secondary amine base to directly manufacture tertiary amines.

Metal catalysts prefer to interact with basic amines rather than CH bonds in the olefin. The team hypothesized that amine salts (easy to use and store amine-BF3 salts) may prevent this interaction with the catalyst.

Like a dam modulating the flow of water, the team’s palladium/SOX catalyst regulates the slow release of amines from the salts and ensures the coupling of the secondary amine and the hydrocarbon to form the tertiary amine product.

Demonstrating the power of this new chemical reaction, the researchers made 81 tertiary amines in their study, coupling a wide range of complex and medically relevant secondary amines to numerous complex olefins containing reactive functionality. This includes functionality that is reactive with secondary amines in traditional tertiary amine manufacturing processes.

Further demonstrating the potential for new drug discovery, the research team also applied this novel reaction to efficient syntheses of 12 existing drug compounds, including Abilify, an antipsychotic drug, Naftin, an antifungal, as well as 11 complex drug derivatives. , including the antidepressants, Paxil and Prozac, and the blood thinner, Plavix.

In addition to this reaction being used in the pharmaceutical industry as a platform to accelerate the discovery of new tertiary amine drugs, the researchers also believe that their catalyst-controlled slow release strategy could be used by others. researchers to discover many additional new reactions with nitrogen.


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