Diazomethane and flow chemistry: filling a gap in pharma R&D
A scale-up of hazardous reactions in batch requires extensive safety investigations which can cause massive delays for the scale-up process of pharmaceutical intermediates and active molecules. Continuous flow chemistry as an enabling technology nowadays can help to reduce the safety hazards thus bringing back neglected chemistries into synthesis laboratories where in the past the application of those reactions often was avoided. One of those hazardous but very useful reagents is diazomethane which is a valuable C1-building block for organic synthesis. A safe handling of diazomethane on larger scale in a batch reactor is almost impossible whereas the hazards of preparing and reacting diazomethane can be minimized significantly under continuous flow conditions. In the past, various groups developed flow procedures for an on demand preparation of diazomethane however most of them suffered from low productivity. In this article, the various existing methods are discussed, including the one, we recently developed to fill this gap.
The development of new active molecules and bringing them to the market as fast as possible is a highly competitive area. In pharmaceutical industry, the pressure on medicinal chemists to synthesize new active compounds and on process chemists to develop a scalable and safe synthesis process nowadays is immense. In this context, the ability to generate and handle hazardous reagents not only on a very small scale in research but also on hundred gram scale in process development today is an essential advantage. The tool which allows chemists to cover this gap at present is continuous flow chemistry, which matured in the past and which has become an established technology in pharma R&D. As a consequence, almost all big pharma companies today are using flow reactors across all phases (1-3). The advantages of continuous flow chemistry and its potential to facilitate the drug discovery and development process have been discussed and highlighted in several reviews (4-8). Nevertheless those benefits are depending on the scale of the desired reaction and may vary significantly when a synthesis on milligram scale in research is compared with a synthesis on ...