Pharmaceutical Innovation
|
THE MAGAZINE DEVOTED TO NICKEL AND ITS APPLICATIONS |
|
ARYL ETHER BASED BIARYL COUPLING. |
|
ARYL HALIDE |
|
ARYL NITRILE |
|
|
A process that uses a low-cost nickel catalyst could prove to be a key breakthrough for
developing less expensive drugs by Dean Jobb
Nickel Magazine, December 2006 -- Chemist Joe Miller was experimenting with a nickel catalyst, looking for ways to forge better molecular bonds, when one reaction produced an unexpected array of new products.
“It was by chance,” he recalls of his 1998 discovery of a new way to make carbon-to-carbon bonds. “No one had heard of this type of thing, so we did quite a few experiments to make sure it was real and that we weren’t being misled. But it’s real, and the absolute key for much of this chemistry is the nickel catalyst.”
The discovery was a breakthrough since it makes it easier and less expensive to test and produce new drugs.
Miller is now vice-president of chemistry for PharmaCore Inc., the North Carolina, U.S.A.-based R&D company that acquired and patented the new process. Patent 7,105,467, issued by the United States Patent Office in mid-September 2006, protects a process that employs a nickel catalyst – either nickel chloride, NiCl2, or nickel acetylacetonate Ni(acac)2 – to create compounds that are the building blocks of pharmaceuticals.
The invention, one of a dozen Miller has to his credit, is a major improvement over the Suzuki process, the traditional method of producing biaryls, which are used to make drugs as well as liquid crystal displays for electronic devices.
“At least five per cent of all known drugs contain the biaryl structural unit,” Miller says. “It’s the basic building block of all the sartan anti-hypertension drugs out there today. Its synthesis is very important.”
He adds that although a Suzuki reaction works fine in the lab, it is much easier to scale up the PharmaCore process to production levels and manufacture compounds by the kilogram or tonne.
Price is also a key advantage. Similar reactions can be run using palladium as a catalyst, but nickel is much less expensive. Moreover, phosphine ligands, the chemicals used to make the nickel compounds soluble and kick-start the reaction, are less costly than the corresponding chemicals needed when palladium is the catalyst.
As well, nickel is easier than palladium to remove at the end of the manufacturing process, so it’s also less expensive to purify the finished product.
Miller discovered two processes for creating carbon bonds using a nickel catalyst, with potential applications to the pharmaceutical industry. “The special reactivity of nickel has allowed us to use unconventional cross-coupling substrates,” namely aryl nitriles and aryl ethers, which likewise have a cost advantage over the commonly used aryl halides.
“We can now use different starting materials to get the same products,” Miller explains. “We can make drugs and drug candidates in a much cheaper manner, or from different starting materials, and this allows for a much more efficient synthesis than before.”
PharmaCore’s process is already being applied to the development of new drugs, though given the long testing and approval process, it will be years before medicines made using the process ultimately reach the market.
PHOTOS: Pharmacore Inc.
PharmaCore Inc. Suite 160 E-mail: info@pharmacore.com |
