Advanced Intermediate Flow Studies: Nevirapine

After looking through a number of flow articles that describe and illustrate processes toward the production of drug final products and advanced intermediates, I thought an article from Florida State — Tyler McQuade (open source Beilstein JOC 2013) was informative and storytelling. He was able to show some of the challenges that go into designing a flow methodology around process that have already been worked out in batch mode, and had been looked at in a number of labs already.

Before talking about the chemistry, Professor McQuade talks about a number of concerns in transferring technology from batch to flow: DOE, solvent exchange (precipitation and moving from one reaction to another), Cost of Goods Analysis – reaction concentrations, solvent costs, process time, by-product formation and purification. There certainly is a lot that goes into the strategy. To give you the framework: this group was looking to make a continuous process for an advanced intermediate left-hand piece from the regulated materials in the production of nevirapine. His group uses Vapourtec R Series flow reactor for completion of the studies.

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In thinking of the forward process — formation of a pyridone through the condensation of isopropylidenemalononitrile is a well known process, but there are a number of challenges with the route — chlorination for the next step, by-products of the Knoevenagel condensation and so on…..and how to change these to a flow process. An illustration of the thinking is shown:

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Attack 1 – enamine 5 formation: Armed with some of the issues the group performed a number a modified DOE from prior experience: in order to move the reaction from batch to flow, they needed a solvent that would handle all reactants and enamine, and they had to choose a solvent that could handle the temperature and pressure generated. In the end they were able to move from toluene to DCM and study the solvent concentrations for yield and shortened processing times.

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Attack 2: Condensation of acetone and malononitrile turned out to be rather challenging — finding the right drying bedding column to prevent water build-up during the reaction time provided Al2O3 provided the adduct 4 which was processed through a sieve column for the next step in enamine formation and prevent water and by-product formation.

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Without stealing McQuade’s thunder, there are a number of anecdotal discussions that make this an excellent paper to have in your collection. Happy Reading!

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