|Wow. (Credit: C&EN)|
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."Someday, an awesome set of Organic Process Research and Development papers is going to come out about this molecule. It will be great to hear the story of figuring out how to put this beast together. Until then, we'll just have to live on internet rumors and bang our heads on the wall that Eisai has only decided to publish in Japanese journals about the development of the process.