New chemical reactions create a faster and easier way to produce tertiary amines for pharmaceuticals.

Researchers at the University of Illinois at Urbana-Champaign have discovered a way to generate a special class of molecules that can open the door to new drugs for the treatment of currently incurable diseases.

If you open the household medicine rack, you may find an organic derivative of ammonia called an amine. They are one of the most common structures found in today’s medicines. Since more than 40% of drugs and drug candidates contain amines, and 60% of those amines are tertiary, they are named after the three carbons bound to nitrogen.

Tertiary amines are included in some of the most influential human medicines, including antibiotics, breast cancer and leukemia medicines, opioid analgesics, antihistamines, blood diluents, HIV treatments, and anti-mitiginal pain medicines. I am. They increase the solubility of the drug and can cause its important biological function.

Despite the widespread use of this special class of molecules in today’s pharmaceuticals, much of the functional potential of tertiary amines may remain undeveloped.

This is because the traditional process of making them requires specific controlled conditions that essentially limit the discovery of new tertiary amines and may treat a variety of diseases that are currently incurable.

Currently, a new chemical reaction, the carbon-hydrogen amine cross-coupling reaction, has been discovered by a research team in Illinois, led by Professor M. Christina White of Lycan Chemistry and graduate students Syradiali, Brennab Daitis and Devon Fontaine. A simpler method for producing tertiary amines without the limitations inherent in conventional methods. Researchers believe that this can also be used to discover new reactions with nitrogen.

This new reaction in the chemist’s toolbox is a conventional tertiary amine construction process that requires highly specialized conditions specific to each molecule, under general conditions exposed to air and moisture. Convert to a procedure that can be performed. Possibility of automation.

As explained in a recently published paper by researchers Chemistry (DOI: 10.1126 / science.abn8382), this new procedure uses a metal catalyst and two building blocks discovered by their group (Ma-WhiteSOX / palladium)-; abundant hydrocarbons (adjacent C). -; Olefin containing H-bonds) and secondary amines-; Produces a variety of tertiary amines.

According to White, this has the potential for chemists to take many different secondary amines and bind them to many different olefins. Both can be purchased or easily made.

And these are stable starting materials. You can put them in individual containers, mix them, and use our catalysts to make many different combinations of tertiary amines. The flexibility of this reaction facilitates the process of discovering tertiary amine drugs. “

M. Christina White, Professor of Lycan Chemistry

The difference between the classic reaction and this new reaction for making tertiary amines is like the difference between choosing a special sandwich from the menu and making your own sandwich from a different set of ingredients. .. It’s much more flexible in terms of choice.

This highly flexible system for producing tertiary amines is also very practical.

“In principle, you can run it on the stove,” White explains. “You don’t have to handle it with a lot of care. You can expose it to the air and you don’t have to eliminate the water. All you need is a starting material, a palladium / SOX catalyst, and a small amount of heat. It should work the same as. “

White explained that pharmaceutical companies often need to use special procedures if they want to produce tertiary amines, but this reaction produces two simple, often commercially available starting materials. You can take and combine them using the same procedure.

“The conditions are so simple that they work with so many different amines and olefins that there is great potential for adopting this reaction for automation,” White said.

The main challenge the team overcame with this discovery was to solve long-standing problems in C-; H functional chemistry. It replaces the hydrogen atom on the carbon skeleton of the molecule with a basic secondary amine to create a direct tertiary amine.

Metal catalysts prefer to interact with basic amines over the C-; H bonds of olefins. The team hypothesized that an amine salt (an easy-to-use and easy-to-store amine-BF3 salt) could prevent interaction with this catalyst.

Like a dam that regulates water flow, the team’s palladium / SOX catalysts not only regulate the sustained release of amines from salts, but also mediate the coupling of secondary amines to hydrocarbons to produce tertiary amines. Form things.

Demonstrating the power of this new chemical reaction, researchers have created 81 tertiary amines in their studies, a wide range of complex and medically relevant secondary amines to many complex olefins containing reactive functional groups. Was combined. This includes the ability to react with secondary amines in traditional tertiary amine manufacturing processes.

The research team further demonstrated the potential to discover new drugs, and this new reaction is the efficiency of 12 existing drug compounds, including the antipsychotic drug Abilify, the antifungal drug Naftin, and 11 complex drug derivatives. It was also applied to various compositing. Includes the antidepressants Paxil and Prozac, and the blood-thinning Plavix.

In addition to this reaction, which is used as a platform to accelerate the discovery of new tertiary amine drugs in the pharmaceutical industry, researchers have used a catalytically controlled sustained-release strategy with nitrogen.