The downsizing in the Pharma industry has created a huge pressure on R&D to create more with less resources. Their job is made more difficult by the fact that synthesis routes have to be more and more complex in order to generate molecules which haven’t been patented. This has led to a rise in costs coupled with a decrease year on year of New Chemical Entities (NCEs) being approved by the FDA. How can our flow reactor range help you to make novel molecules or improve synthesis routes? Here are some examples:

Hydrogenation of heterocycles to produce novel compounds

H-Cube ProIt has already been well established that the H-Cube Series make significant advances for hydrogenation in terms of safety, speed, and capabilities, but how can they generate new molecules? One method is to utilize their high pressure capability (100 bar, 1450 psi) coupled with short residence times in order to selectively reduce a heterocycle in a potential molecule in order to dramatically alter its properties, such as LogP, LogD, and pKa. The molecules would also be non-planar to give a more three-dimensional profile. A simple illustrative example is given below. Standard batch equipment do not typically have the reaction parameter capabilities or the ability to react selectively, so this is really only specific to the H-Cube.

The main advantage of this method is that you can use chemical material that is currently available to you from your stock. This means compounds could be tested quickly and cheaply.

Please also see our applications section on hydrogenation.

Generation of novel heterocycles using high temperature flash synthesis

Heterocyclic carbonyl compounds e.g. quinolones, pyridopyrimidinones, naphthyridinones are important structural motifs in various biological active compounds (e.g. norfloxacin, nalidixic acid). One of the most practical approaches for their synthesis is the thermal cyclisation of the appropriate open chain intermediates containing suitably substituted 3 carbon extension on the nitrogen. Such intermediates can be derived either from a condensation product of formaldehyde acetal and a CH-acidic methylene containing precursor (e.g. malonic ester, Meldrum’s acid), or cyano-acetic acid ester by Gould-Jacobs type of reaction. Using this method in combination with the Phoenix Flow Reactor™ at temperatures in excess of 300°C and high pressure, to utilize low boiling point solvents at these high temperatures, we were able to generate a series of bicyclic compounds.

If you utilize 5 or 6 member S, O, or N type heterocyclic anilines, then novel heterocyclic scaffolds can be made in this manner very effectively and very quickly.

Please also see our applications section on high temperature reactions.