Cerium margin silver to make drug precursor

Save your silver! It is better used for jewelry than as a catalyst for drugs.

Scientists from Rice University have developed a very simple method of making fluoroketones, precursors for the design and manufacture of drugs that usually require a silver catalyst.

Rice chemist Julian West and graduate students Yen-Chu Lu and Helen Jordan instituted a process for the rapid and scalable synthesis of fluoroketones that has so far been challenging and expensive to make.

Their open-access work covers the cover of the February 21 issue of the Royal Society of Chemistry ChemComm.

The laboratory’s new process replaces silver with cerium-based cerium ammonium nitrate (CAN) which produces functional precursors under mild conditions in about 30 minutes.

“We can do a lot of this in a bath,” West said.

Cerium has shown such potential in other labs, and the fact that it is 800 times more abundant in the earth’s crust than silver has made it very interesting for the Rice team.

“Ketones are a gateway functional group in molecules that you can use to make different things, like anti-cancer compounds,” said West, who came to Rice in 2019 with funding from the Cancer Prevention and Research Institute of Texas and as Forbes was named 30 Under 30 scientific “game changer” last year.

“They are an excellent foothold to turn into an olefin or an aromatic ring,” he said. ‘The important part of this article is that we incorporate fluorine into these fragments. Fluorine is an interesting element and is very abundant, but it is rarely used in biology.

“Fluorine has some extreme properties: it’s incredibly electronegative, so it retains its electrons,” West said. “This makes it difficult for enzymes in biological processes to handle it in pharmaceuticals such as cancer molecules.”

Hydrogen atoms in drug molecules are easy for the liver to process, but replacing them with fluorine is “like an armor at that position,” he said. “It helps to keep drugs in the body longer so you don’t have to take as much. It is desirable for chemotherapeutics.” He noted that atorvastatin (aka Lipitor), one of the most commonly prescribed drugs in the United States, contains fluoride for the same purpose.

“We want to place fluoride in specific places in the molecule where we know it will make a difference, and this ketone-functional group enables us to do that,” West said. ‘People use a silver catalyst, but the process requires a lot of silver, it takes a long time at high temperature and it has to be done under a carefully controlled nitrogen or argon atmosphere.

“Our process is cheap bucket chemistry, and we think the reaction will be done within five minutes,” he said. “But we leave it for 30, just to be safe.”

The process is very scalable. “When Yen-Chu tripled the initial recipe, he got exactly the same result,” West said. “It’s rare in these kinds of reactions.”