If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.



Drug Development

Taking The Long Route

by Bethany Halford
October 24, 2011 | A version of this story appeared in Volume 89, Issue 43


Drug Development

Drugmakers have been known to shy away from molecules that must be made via lengthy multistep syntheses. But taking the long route, chemically speaking, to make a medicine is not unheard of. Late last year the pharmaceutical company Eisai introduced Halaven (eribulin mesylate), a compound that requires 62 chemical transformations to make.

Halaven is used to treat patients with late-stage metastatic breast cancer. It is an analog of halichondrin B, a natural product first isolated from the sea sponge Halichondria okadai in 1986 by researchers in Japan (Pure Appl. Chem., DOI: 10.1351/pac198658050701). The molecule is a beast, with a 54-carbon backbone and 32 stereogenic centers. A team led by Harvard University’s Yoshito Kishi completed the first total synthesis of halichondrin B in 1992 (J. Am. Chem. Soc., DOI: 10.1021/ja00034a086). Kishi’s team—working with collaborators at Eisai, where Kishi was a scientific adviser—began making analogs of the compound soon after.

An intermediate in the Harvard synthesis containing only the macrolide sector was screened at Eisai and found to retain bioactivity. Eisai chemists then created a range of analogs based on the structure, settling on ­Halaven as the most promising by the late 1990s. Although simpler than its parent structure, Halaven is “a very challenging target by anybody’s assessment,” according to Frank Fang, vice president of U.S. process research and development at Eisai. The structure features a complex ring system and 19 stereocenters.

Fang says that Halaven’s potency and unique biological profile made it too ­attractive a target to pass up simply because it could be made only through a lengthy synthesis. “The perception wasn’t so much that this was an obstacle but rather it was a challenge that we knew how to deal with,” he says.

And even though it takes a total of 62 steps to make Halaven, Fang points out that the synthesis is fairly convergent; the longest linear sequence is 30 steps. “The number of steps of a ­synthesis is one feature that people tend to focus on because it’s easy to remember,” he says. “But what really is critical to the successful implementation of a process in commercial manufacturing is not so much the number of steps but the types of purifications that are employed during the processing of the material.”

Chromatography, for example, takes a lot more time and generates a lot more waste than crystallization, Fang notes. “If you can take a 60-step synthesis and get rid of most of the chromatographies and replace them with crystallizations, then it’s a much more manageable process than even a 10- or 15-step synthesis that has entirely chromatographic purifications,” he says.

Step count, Fang says, is nothing to be scared of. “Our feeling at Eisai is that natural products represent a large space of untapped potential new medicines,” he says. “We’re not deterred by a chemical obstacle. If the biological activity warrants it, we’re more than happy to go after a compound.”


This article has been sent to the following recipient:

Chemistry matters. Join us to get the news you need.