Just about all chemical syntheses add a tremendous amount of time and waste that isn't necessary, especially for long multistep reactions. Eliminating the song and dance of purifying the product, isolating it, and transferring it to another reaction vessel for a subsequent reaction would brighten the day of many synthetic chemists.
This isn't just about making chemists happy. Less time and waste will reduce the cost of drug discovery, and will help lead the way towards a more sustainable future.
Tyler McQuade (Florida State University, Tallahassee) and coworkers have made an important contribution towards this goal. They have rapidly synthesized a widely-used anti-inflammatory drug, with no intermediate purification or isolation procedures.
Synthesizing ibuprofen.
The scientists' main challenge was to design a synthesis of ibuprofen such that any side products or unused chemicals from one step of the synthesis do not interfere with subsequent chemical reactions. This was not an easy task.
Their first synthetic step, a Friedel-Crafts acylation, is generally done with an aluminum chloride catalyst. However, aluminum chloride reacts in subsequent steps of the synthesis.
They found that a triflic acid catalyst can also work, while actually enhancing the second step of the synthetic procedure. They mixed isobutylbenzene, propionic acid, and the catalyst in a microreactor at 150°C for 5 minutes.
Subsequently, this solution was mixed with phenyliodine diacetate and trimethyl orthoformate in an adjoining microreactor, and heated to 50°C for 2 minutes. Heating the products of this reaction to 65°C for 3 minutes in a third adjoining microreactor containing potassium hydroxide gave the final product, ibuprofen, in greater than 50% yield after purification.
Further development.
A limitation of this research is that these scientists' specific synthetic protocol cannot be safely scaled up from their demonstrated milligram scale (less than 5 milligrams of pure ibuprofen per minute) to something much larger. This is because it would require a lot of energy to hold a different constant temperature in each adjoining microreactor.
However, if another synthetic procedure can be developed that utilizes a similar temperature at each step of the synthesis, the reactions could easily be scaled up. This is much easier said than done (now one must hunt for a compatible three-step protocol that's done at only one temperature), but it's not infeasible.
It does seem that this approach to chemical synthesis would be much more difficult to apply to molecules that require many steps to prepare. Such cases probably still require solid-phase synthesis, a complimentary synthetic approach that enables the product to be quickly washed of impurities before subsequent steps are performed.
for more information:
Bogdan AR, Poe SL, Kubis DC, Broadwater SJ, & McQuade DT (2009). The continuous-flow synthesis of Ibuprofen. Angewandte Chemie (International ed. in English), 48 (45), 8547-50 PMID: 19810066