Researchers at the Massachusetts Institute of Technology have designed a new way to synthesize a widely used chemical structure, used to allow drugs to stay in the body longer, that could lead to faster and cheaper drug development. The work, published in the journal Science, describes a new way to attach the fluorine-containing structure trifluoromethyl group, also known as CF3, to drugs. CF3 is a component of several commonly used drugs, including the antidepressant Prozac, arthritis medication Celebrex, and the diabetes drug Januvia.

Right now, the processes used to synthesize CF3 require harsh reaction conditions or only work in a small number of cases, limiting their usefulness for synthesizing new drug candidates for testing. MIT Chemistry Professor Stephen Buchwald, who led the research team, says 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 Stephen Buchwald, an MIT professor of chemistry.

When foreign compounds such as drugs enter the body, they get sent to the liver, where they are broken down and sent to the kidneys for excretion. CF3 groups are hard for the body to break down because they contain three fluorine atoms, a substance that is not normally found in food and foreign to the body.

 

To add a CF3 group to organic molecules, chemists often use hydrogen fluoride under conditions that might produce undesired reactions that can alter the structural components of pharmaceuticals.

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.

Chemists have been trying to find a widely applicable catalytic method to attach CF3 to compounds containing one or more six-carbon rings for decades. Some have achieved different parts of the reaction, but none successfully put all the pieces together to arrive at a method applicable to a wide range of such compounds. The major challenge has been finding a suitable catalyst to transfer the CF3 from another source to the carbon ring.

CF3 tends to be unstable when detached from other molecules, so the catalyst must act quickly to transfer the CF3 group before it decomposes. The MIT team chose to use a catalyst built from palladium and the use of a ligand—a molecule that binds to the metal to stabilize it and speed the reaction.

In its current state, the researchers say the process is too expensive for manufacturing use. For drug discovery, however, it may lower overall costs because it streamlines the entire synthesis process. "For discovery chemistry, the price of the metal is much less important," says Kinzel. All of the reaction components are commercially available, so pharmaceutical and other companies will immediately be able to use this method.