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

A team at the University of Illinois has found a way to make a special class of molecule that could be used to treat diseases that are currently untreatable.

If you open the medicine cabinet, you will likely find organic ammonia derivatives. They are one of the most common structures in medicines. More than 40 percent of drugs and drug candidates contain amines, and 60 percent of those amines are tertiary.

Antibiotics, breast cancer and leukemia drugs, opioid pain medications, antihistamines, blood thinners, HIV treatments, antimigraine medications and more are some of the most impactful human medicines. They increase a drug's ability to work.

The functional potential of tertiary amines is likely to remain undiscovered despite the prevalence of this special class of molecule in medicines today.

The traditional process of making them requires specific, controlled conditions that limit the discovery of new tertiary amines, which could potentially treat a wide range of currently untreatable diseases.

A research team led by M. Christina White and graduate students Siraj Ali, Brenna Budaitis, and Devon Fontaine discovered a new chemical reaction that creates a faster, simpler way of making things. This could be used to discover new reactions with nitrogen.

This new reaction transforms the traditional tertiary amine building process with its classic chemical reactions that require highly-specialized conditions specific to each molecule, into a procedure that can be carried out in general conditions.

The new procedure uses a metal catalyst and two building blocks that were discovered by the researchers.

White said that this could be used to take a lot of different secondary amines and couple them to a lot of different olefins.

These are stable starting materials. You could mix and match them and use our catalyst to make many different combinations of tertiary amine.

The difference between classical reactions and this new reaction for making tertiary amines is like the difference between choosing a specialty sandwich from a menu or making your own sandwich from a diverse set of ingredients.

The system for making tertiary amines is very flexible.

White says that you could run it on your stove top and not have to worry about water. You don't need much more than the materials, catalyst and heat. It should work the way we are doing it in the lab.

When a pharmaceutical company wants to make tertiary amines, they often have to use specialized procedures, but this reaction allows you to take two simple, often commercial, starting materials and put them together using the same procedure.

The conditions are so simple and work for so many different amine and olefins that there is great potential to adopt this reaction for automation, according to White.

The biggest challenge the team overcame was replacing a hydrogen atom on a molecule with a basic, secondary amine to make tertiary amine.

Metal catalysts prefer interacting with basic amines. Amine salts, which are easy to use and store, can prevent this interaction with the catalyst.

Like a dam, the team's catalyst regulates the slow release of amine from the salts as well as the secondary amine and hydrocarbon to form the tertiary amine product.

The researchers made 81 tertiary amine in their study, which was shown to have a wide range of useful secondary amines. The traditional tertiary amine manufacturing processes use secondary amines.

The research team applied this new reaction to the efficient synthesis of 12 existing drug compounds, including Abilify, an anti-psychotic medication, Naftin, an anti-fungal, as well as 11 complex drug derivatives.

The researchers believe that their slow-release strategy could be used by other researchers to discover many more new reactions with nitrogen, as well as being used in the pharmaceutical industry as a platform to expedite the discovery of new tertiary amine drugs.

More information: Siraj Z. Ali et al, Allylic C–H amination cross-coupling furnishes tertiary amines by electrophilic metal catalysis, Science (2022). DOI: 10.1126/science.abn8382 Journal information: Science Citation: Research could enable assembly line synthesis of prevalent amine-containing drugs (2022, April 15) retrieved 15 April 2022 from https://phys.org/news/2022-04-enable-line-synthesis-prevalent-amine-containing.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.