‘A one-step, one-flask process’

Scientists stumble upon revolutionary process in drug design and synthesis

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HOUSTON—Researchers at Rice University, the University of Texas Southwestern Medical Center (UTSWMC) and Brigham Young University inadvertently discovered a one-step process to make nitrogen-laden molecular precursors for the development and preparation of drugs, agrochemicals and other bioactive natural products.
The breakthrough will simplify the process and cut the costs of creating key nitrogen-containing functional groups for pharmaceuticals, according to László Kürti, a synthetic chemist at Rice who developed the technique with his colleague at UTSWMC, John Falck.
“The methodology is operationally simple, scalable and fast at or below ambient temperature, furnishing arylamines in moderate-to-good yields and with good regioselectivity,” says Kürti. “Anybody who is interested in streamlining the synthesis of complex compounds that contain nitrogen now has a one-step, one-flask process. Agrochemical companies, drug-discovery companies and anybody who makes fine chemicals will find this a very interesting tool.”
The technique involves making free amines, compounds with one or more nitrogen atoms that are essential to metabolic processes. Aromatic amines, which incorporate stable molecular fragments called aromatic rings, are substructures in more than a third of drug candidates, Kürti said.
“Nitrogen atoms give polarity to the molecules,” he explained. “They also help bind to molecules like proteins and enzymes. That’s why you see an abundance of nitrogen atoms in biologically active compounds, especially in active pharmaceutical ingredients that are used in medicines; they need to interact with biological systems.”
The technique in question was discovered by accident. The labs were experimenting with reactions within the synthesis of heterocycles, and noticed anomalous results in one of the reactions. Careful analysis of the reactions led Kürti to the conclusion that a different reaction was happening in the presence of aromatics, leading to a control experiment testing the hypothesis.
“It was one-and-a-half years of hard teamwork,” says Kürti. “We ran hundreds of experiments and carefully evaluated the reaction mixtures in each case in order to establish the scope and limitations of this method.”
The new discovery is a breakthrough long sought by chemists, pharmaceutical companies and other scientists.
“There is huge demand for making these aromatic amines quickly and efficiently, and for decades now, people have been trying to make them with catalysts that contain transition metals (often used to speed up chemical reactions),” he said. “But the free aromatic amine products readily bind to these metal catalysts and can essentially poison the process.”
The new process still makes use of a transition metal catalyst, a dirhodium complex, that effectively catalyzes the direct introduction of unprotected alkylamino groups into aromatic rings, thus significantly simplifying the procedure. Scientists have been able to generate such aromatic amines, but only via a complicated and multistage process.
“When you do things in multiple steps, you lose material with each step,” noted Kürti. “With our process, you gain not only speed but also efficiency and high material throughput, because you’re going to have the desired compound in just one step.”
“Anything you can do that expedites the introduction of nitrogen in these molecules and reduces the cost of production is going to be beneficial for drug development and for reducing the cost of drugs,” said Falck, who is the Robert A. Welch Distinguished Chair in Chemistry at UTSWMC. “Up to now, chemists have had to rely on circuitous routes to be able to introduce these nitrogens. And we’ve achieved access directly in a much more efficient process than the alternatives.”
Additional authors of the paper include Mahesh Paudyal, a postdoctoral researcher, and Adeniyi Adebesin, a graduate student, at UTSWMC; Scott Burt, an associate teaching professor, and Daniel Ess, an associate professor of chemistry and biochemistry at Brigham Young; and Zhiwei Ma, a postdoctoral researcher at Rice.
Supporting the research were the National Institutes of Health, the Robert A. Welch Foundation, Rice University, the National Science Foundation, the American Chemical Society Petroleum Research Fund, Amgen and Biotage.

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