I visited Alphora Research about 10 days ago. Alphora is a company that specializes in organic synthesis and leverages their tremendous process research expertise in projects that involve production of pharmaceuticals (under GMP standards). I think this is a great place to practice one’s synthetic skills because pretty much everything that is remotely interesting in the pharmaceutical process research is nowadays outsourced from places such as Pfizer (who are busy doing acquisitions) to smaller companies such as Alphora. As a result, students who are trained in synthesis may get jobs in such smaller companies and practice what they are passionate about – making molecules. I was really impressed with the kinds of projects Alphora scientists get to work on. They really solve important problems. For a representative recent example I direct you to a paper they put out earlier this year in Tetrahedron Letters (see the link below). The target of synthesis here is Eisai’s Eribulin molecule, which is a truncated version of the natural product Halichondrin B. I am amazed that molecules of this complexity (there are 15 chiral centers here!) have reached the market. The innovation in Alphora’s approach was to introduce nitrogen early in synthesis, which is something you typically want to avoid as the risks outweigh the benefits: according to conventional wisdom, one is better off introducing nitrogen atoms towards the end of synthesis. But, under the leadership of Dr. Boris Gorin, Alphora scientists took the risk of the “early nitrogen game plan” and, as a result, reaped the benefits of dealing with crystalline intermediates along the way.
There was something else during this trip that attracted my attention. It was one of those Chemtrix instruments that perform flow synthesis. I have seen a ton of flow synthesis machines in recent times at various venues, but Chemtrix really caught my eye. My beef with flow synthesis has always been about what happens next. It is ok to make a few mg’s really well. Or a gram. But what if you need to make 100 kg’s or 100 tons? Apparently, this Chemtrix instrument is a result of a ton of work on behalf of a very dedicated team of engineering geeks who promise linearity in scale-up. In other words, they have figured out an appropriate scaling algorithm that enables one to take the results of flow synthesis on a very small scale and have close to a guarantee that it will produce the same yield on a multi-kg or a multi-ton scale. All you need are fancier pumps and larger surface area in your tubes and reactors (which they produce and supply). None of this is random, but is calculated with utmost precision taking into account flow dynamics, mixing times, turbulence, etc. I need to buy one of these instruments one day.