Two weeks ; one tonne
“ Our story is of one week in the lab to one week in production to make one tonne of product ,” says Dr Dirk Hütten , senior director of business development at small molecule CDMO Raybow Pharmaceutical , which has used Corning ’ s AFR equipment to make a methylated pyrazole derivative . The chemistry begins with a halogen-lithium exchange , in which butyl lithium reacts with an organic bromide to form a corresponding organolithium derivative . Next is a simple methylating reaction with iodomethane to form the desired product , using THF as the solvent . This reaction , Hütten says , is significantly limited by the presence of other reaction products , such as a bromide that can be involved in a side reaction with the pyrazole lithium intermediate or BuLi . This and the nature of the reactants themselves were among the reasons for looking at flow . BuLi can react violently with water , oxygen and THF . Dry solvents and dry equipment , excluding oxygen from the atmosphere and very low temperatures are all used to avoid this . Iodomethane is highly carcinogenic and requires very good containment . Other physical parameters , like the
Hütten - Key advantage of flow is efficiency density and melting or boiling points of the reactants , can further limit the reaction window . Raybow carried out a lab evaluation in a Corning G1 . It also did some orthogonal Design of Experiments to set reaction parameters , like heating or cooling , mixing and residence time , and also to look at every possible safety issue before scaling up . The process itself was determined in a 24-hour process intensification run in an in-house made pipeline reactor to simulate the Corning G4 . The pump system was an initial concern but was not ultimately an issue because the flow rate turned out not to be the limiting factor . The high density of iodomethane was another potential problem for a pump running 24 / 7 for up to two weeks . Raybow engineered its way around this by using gravity to get the pump to do the work . To address the potential for clogging , the company installed automated emergency shutdowns in both the G1 and the G4 . If necessary , these stopped feeding and slowly added solvent into the system to flush the reaction . Another tank was added to collect the waste . In the end , scale-up proved both straightforward and seamless .
The key to the flow chemistry was controlling the temperature at or below -30 º C . This prevents lithium salts from precipitating and blocking the pump – every start-up and shutdown phase means the loss of 20 kg of product – and keeps the selectivity of the reaction high . The three key criteria for Raybow , Hütten concludes , were safety , efficiency and time . The company wanted to control how it carried out the reaction to ensure safety , both by controlling the parameters and by containment , automated shutdowns and other means . “ Efficiency is the key advantage of running the reaction in continuous flow . Setting the right parameters , dosing , temperature controls and flow rate all allows us to prevent the build-up of side products and impurities , and gives a steady quality , which is very important for us .” Looking at time , Raybow did the chemistry development in the lab in one week and scaled directly up to the G4 in another . The output is 10 kg / hour , or 1 tonne / week , which would not have been possible in batch because of all the safety precautions involved . •
22 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981