Chemists find easier method for drug synthesis
pharmafile | June 29, 2010 | News story | Manufacturing and Production |Â Â manufacturingÂ
Researchers in the US have developed a new synthetic pathway that could make the development of new pharmaceuticals quicker, cleaner and greener.
While the process is currently too expensive to be used at the commercial scale, the scientists believe it could reduce the cost of synthesising compounds for drug discovery and – in time – could be modified for use in larger-scale syntheses.
The team from Massachusetts Institute of Technology have devised a simpler method of fluorinating organic molecules, a process which is used by medicinal chemists in the synthesis of many pharmaceutical compounds because it can increase their bioavailability and longevity in the body.
Currently the process of coupling trifluoromethyl (CF3) groups to compounds requires the use of harsh reaction conditions – often including the use of hydrogen fluoride as a reagent – with a tendency to react with other elements in a molecule. The approach has also been limited by a meagre selection of compound types that have been amenable to fluorination.
Now, the MIT team, led by Stephen Buchwald and Eun Jin Cho, have developed a synthesis using a palladium-based catalyst and a ligand molecule called BrettPhos, which can achieve fluorination by swapping an aryl chloride group on a 6-carbon ring molecule for a CF3 group, even under mild reaction conditions.
“Some people said it couldn’t be done, so that’s a good reason to try,” said Buchwald, who notes that chemists have been trying to find a way to carry out this type of reactions for nearly two decades.
Using the MIT approach 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.
CF3 groups have been used to improve the properties of a number of widely-used medicines, including the antidepressant fluoxetine, Pfizer’s Celebrex (celecoxib) for arthritis and Merck & Co’s Januvia (sitagliptin) for diabetes. They also feature prominently among agrochemicals.
The new synthesis, reported in the June 25 edition of the journal Science, will have an immediate impact, according to David MacMillan, a chemistry professor at Princeton University.
“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,” said MacMillan.
Phil Taylor
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