Drug synthesis simplified
Revolutionary method reduces steps in producing Ritalin

By ELLEN GOLDBAUM
News Services Editor

A revolutionary method for synthesizing specialty chemicals-especially pharmaceuticals-that makes it possible to activate the normally unreactive carbon-hydrogen bonds in organic molecules has been developed by a team of UB chemists.

The new findings demonstrate an extremely robust and practical method for synthesizing new, complex chemicals from cheap bulk chemicals. The new method is significant because it generates catalytic reactions and allows for control of the resulting three-dimensional structure, features that make it extremely useful for industrial applications. It is applicable to the synthesis of a wide range of specialty chemicals.

The research was published this month in the Journal of the American Chemical Society (Vol. 122, No. 13, pp. 3063-3070) and authored by Huw M.L. Davies and Melvyn Rowen Churchill, both professors of chemistry, and Tore Hansen, a doctoral candidate in the Department of Chemistry in the College of Arts and Sciences.

The method marks a new milestone in the search for what is often called the "holy grail" of organometallic chemistry: the catalytic activation of carbon-hydrogen bonds.

In the paper, the UB scientists highlight the method's effectiveness in synthesizing two very important pharmaceuticals: Ritalin, the treatment for children with attention-deficit disorders, and sertraline, the commonly prescribed antidepressant marketed as Zoloft.

"Our method of synthesis significantly reduces the number of potential steps involved in producing pharmaceutical agents," said Davies. "For example, the traditional method for asymmetric synthesis of Ritalin takes eight to 10 steps; ours takes only three."

UB is seeking a licensing partner for this synthesis method for Ritalin, which was described in more detail in an earlier paper by Davies. A patent application on it has been filed.

According to Davies, the selective activation of carbon-hydrogen bonds by metal complexes that leads to the direct formation of carbon-carbon bonds has been sought for decades. For such reactions to be useful in industry, the amount of metal complex must be used in catalytic (i.e., minute) amounts.

Davies explained that the strategy traditionally followed by other groups involves activation of carbon-hydrogen bonds through the use of a special high-energy metal complex, but because it is very difficult to regenerate the high-energy complex, a catalytic cycle cannot be achieved.

"Our approach circumvents these problems by starting with a nice, stable rhodium complex that can catalyze the decomposition of a class of compounds known as diazo compounds. These compounds lose nitrogen and, in turn, generate a transient, high-energy complex with the catalyst," he said.

"This transient high-energy complex does the carbon-hydrogen activation, which generates the product you want, but it also regenerates the catalyst, creating a natural catalytic cycle. With all the other methods, scientists have struggled with the catalytic cycle; here it's automatic."

Because it regenerates the catalyst, the UB method requires the use of only a minute amount of catalyst; the catalytic cycle is repeated easily anywhere from 100 to 1,000 times.

It was during experiments on synthesizing potential medications for treatment of cocaine addiction that Davies and his colleagues discovered that these more stable, diazo compounds they had developed could generate a controllable, high-energy intermediate that could, in turn, cause the activation of carbon-hydrogen bonds.

"It turned out that the compounds we had created combined with our own class of chiral catalysts beautifully," said Davies.

According to Davies, the work also represents the first general asymmetric activation of carbon-hydrogen bonds. That means that due to the addition of the chiral catalyst developed by Davies, the three-dimensional structure of the resulting products can be controlled. The reaction is therefore capable of producing a single isomer of a molecule and not its mirror image, a critical advance, especially for synthesis of pharmaceutical agents.

Chiral, or "handed," molecules can exist in two different forms that are mirror images of each other, Davies explained, and drug companies prefer to develop new chiral drugs as single isomers in order to avoid possible negative interactions of the inactive mirror-image structure, as well as extremely expensive toxicity studies of such mixtures.

Ritalin, for example, is still sold as a mixture of two isomers and a big push is on to develop its pure single isomer, which could reduce the dosage required and side effects.