Getting a fluorine fix

Researchers have developed a new way to add a fluorine group to compounds using a palladium catalyst, which they say will enable them to create and test new drugs more quickly

CAMBRIDGE, Mass.—Researchers have developed a new way to add a fluorine group to compounds using a palladium catalyst, which they say will enable them to create and test new drugs more quickly.    

Massachusetts Institute of Technology (MIT) Chemistry Professor Stephen Buchwald, who led the research team, tells ddn that the focus of the group's research is "to develop useful methods for the installation of trifluoromethyl groups into pharmaceutically interesting compounds."

Some drugs are more effective if they can last inside the body for a longer period of time. In an effort to keep these drugs from being broken down too quickly, pharmaceutical manufacturers often attach a fluorine-containing structure called a trifluoromethyl group. The current process requires harsh reaction conditions or only work in a small number of cases, limiting their usefulness for synthesizing new drug candidates for testing.

The new synthesis developed by MIT chemists, reported in the June 25 issue of Science, could have an immediate impact. Buchwald explains that the introduction of fluorine atoms into a pharmaceutical compound can have pronounced effects. They can modulate the uptake of the drug and stabilize it against metabolism by the human body, keeping it in a person's system longer and making it more effective. But achieving the synthesis has been a long-standing challenge for chemists.

"Some people said it couldn't be done, so that's a good reason to try," says Buchwald, the Camille Dreyfus Professor of Chemistry at MIT.

Buchwald also points out that an advantage of a new way to attach a trifluoromethyl group to certain compounds is that "it can take place under relatively mild reaction conditions and can be used on many compounds."

The research team includes Eun Jin Cho, a postdoctoral associate in Buchwald's lab and the lead author of the paper. Other authors are graduate student Todd Senecal, postdoctoral associates Tom Kinzel and Yong Zhang, and former postdoctoral associate Donald Watson, now an assistant professor of chemistry at the University of Delaware.

The trifluoromethyl group (abbreviated CF3) is a component of several commonly used drugs, including the antidepressant Prozac, arthritis medication Celebrex and diabetes-related drug Januvia.

When foreign compounds such as drugs enter the body, they get sent to the liver, where they are broken down and shipped on to the kidneys for excretion. However, CF3 groups are hard for the body to break down because they contain three fluorine atoms.

"Fluorine is not really a component of things we eat, so the body does not know what to do with it," says Kinzel.

CF3 groups are also a common component of agricultural chemicals, such as pesticides. To add a CF3 group to organic (carbon-containing) molecules, chemists often use hydrogen fluoride under conditions that might produce undesired reactions among the many structural components found in complex molecules like pharmaceuticals or agrochemicals

According to Buchwald, with the new reaction, the CF3 group can be added at a much later stage of the overall drug synthesis. The reaction can also be used with a broad range of starting materials, giving drug developers much more flexibility in designing new compounds.

"Trifluoromethyl groups can block metabolic degradation of a drug substance," he says. "By being able to install these groups at a late stage and in a general manner,
compounds needed for testing  can be more readily accessed."

Chemists have been trying to find a widely applicable catalytic method to attach CF3 to aryl compounds (compounds containing one or more six-carbon rings) for a couple of decades.

"Some have achieved different parts of the reaction, but none successfully put all the pieces together to arrive at a method that is applicable for a wide range of different aryl compounds," Buchwald points out. "The major challenge has been finding a suitable catalyst (a molecule that speeds up a reaction) to transfer the CF3 entity from another source to the carbon ring."

CF3- (which is a trifluoromethyl negative ion) tends to be unstable when detached from other molecules, so the catalyst must act quickly to transfer the CF3 group before it decomposes.

Watson points out that about 25 percent of pharmaceuticals contain fluorine, but it's difficult to incorporate the element into drug molecules. Numerous researchers have been working to develop general methods to introduce fluorine atoms into organic molecules under mild reaction conditions.

Buchwald's team chose to use a catalyst built from palladium, a silvery-white metal commonly used in catalytic converters. The MIT team is not the first to try palladium catalysis for this reaction, but the key to their success was the use of a ligand (a molecule that binds to the metal to stabilize it and hasten the reaction) called BrettPhos, which they had previously developed for other purposes.

Coming up with a useful reaction required much testing of different combinations of palladium, ligand, CF3 source, temperature and other factors.

During the reaction, a CF3 group is transferred from a silicon carrier to the palladium, displacing a chlorine atom. Subsequently, the aryl-CF3 unit is released and the catalytic cycle begins anew. The researchers tried the synthesis with a variety of aryl compounds and achieved yields ranging from 70 percent to 94 percent of the trifluoromethylated products.

The team's new synthesis should have an immediate impact, says David MacMillan, a Princeton University chemistry professor who was not involved in the research.

"Overnight, people are going to start using this chemistry," MacMillan says in a statement. "Every single person in the pharmaceutical industry who makes molecules that incorporate fluorine to test as drugs has needed this reaction for a very long time."

While Buchwald is sure that the method as it stands will be useful for drug discovery, he admits that in its current state, the process is still too expensive for manufacturing molecules on a large scale. "We want people to be able to use the chemistry," he adds, "so we're working on understanding the mechanism better and tweaking it to make it more practical."

For drug discovery, however, it may lower overall costs because it streamlines the entire synthesis process.

"Ultimately, although this is just our first success—of hopefully many—in this regard," Buchwald says, "we hope to continue our work to develop additional processes which manifest greater scope and efficiency."

All of the reaction components are commercially available, so pharmaceutical and other companies will immediately be able to use this method and, as Buchwald points out, success will be measured "through the application of this methods by other chemists to solve their problems."



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