Keeping Count Sometimes Isn’t So Easy

“How many steps are there in a synthetic route?” is one of the foundational questions for any chemist, but as with many apparently simple questions, the answer isn’t always that simple. In many cases chemists are incentivized to give an artificially low step count because it makes their new route look better and therefore more likely to get kudos from their peers and/or get published. By contrast I have certainly felt the need to stress to management (especially non-chemists) just how many steps were needed to deliver that difficult scale-up campaign to a tight timeline. A recent commentary by Prof Jeffrey Johnson (Nature Synthesis 2023, 2, p 6-8) brings some proposals and a discussion to answer two fundamental questions:

  1. What constitutes a chemical step?
  2. Where does step count fit in as a metric for the quality of a synthesis?

This commentary gives some useful case studies before recommending four criteria for defining a step:

  1. Telescoped reactions which occur in one pot and with no change in solvent should be counted as one step
  2. A solvent switch, involving either partial or complete evaporation and the introduction of a new solvent, marks the end of a step
  3. A filtration of any sort marks the end of a step
  4. Work up, isolation and/or, if necessary, purification marks the end of a step

For an academic or medicinal chemistry setting these rules make sense to me, and I think they could be a valuable contribution if they lead to consistent practices for reporting step count. However, I think the modifier “after a synthetic transformation” should be added to Criteria 2-4 to address some edge cases that are sometimes encountered in process chemistry:

  • Often at the start of the final synthesis step a polish filtration will be performed on a solution of the active ingredient (or its immediate precursors) to ensure any residual insoluble solids are removed prior to the final isolation
  • Azeotropic drying is often the most effective way to remove water in the plant before highly sensitive reactions. Ideally this is performed using the reaction process solvent, but not always thereby requiring another solvent to be added

It is especially good to see the benefit of telescoped reactions being acknowledged in this step counting methodology. This will hopefully inspire a wider range of chemists to think about adopting this technique that is often at the core of process chemistry route development since it almost always improves the process mass efficiency and shortens the cycle time compared to two separate reactions.

The main complication that I have encountered with telescoping and step count is when the step number becomes the step name. It’s very likely that at some point we’ve referred to a sequence as something like “the Step 9 coupling is followed by the Step 10 deprotection” but once these are telescoped and combined into a single step this can lead to confusion if one is not careful. Often teams will refer to the “Step 11 HPLC method” or such like, but what happens when Steps 9 and 10 are now a single step? Is Step 11 now Step 10? Even more confusing is if a new route is developed that intersects the existing route late in the sequence. Do you still refer to a step as “Step N” if now there are three fewer steps beforehand? The takeaway is that although it is often simplest to refer to a step by its number in a sequence this practice can lead to a confusion and so should be avoided. In my experience the clearest descriptor is the name (or most commonly in the pharmaceutical industry the unique the company code number) of the targeted product.

Separate purification operations are a gray area not addressed by these proposals. Nothing is mentioned in the commentary, but I doubt the intent of Prof. Johnson is that for small-scale work that recrystallizations should be counted as a separate step, although my reading of his proposals is that they would be counted as such. Hopefully the “after a synthetic transformation” modifier would help clarify that these should not be counted for small-scale work.

For larger scale process chemistry work whether a crystallization is a separate step would be very difficult to define. In recent years I came to view and explicitly name the (re)crystallization of the active ingredient as a separate step simply because it always required a larger cross-functional team of process chemists, chemical engineers, solid form experts and analysts than most (if not all) of the other steps. Often this was the ‘step’ that was the most technically demanding of the whole sequence given the tight specifications on many factors, frequently including purity, polymorphic form and crystal size distribution. However, most intermediate crystallizations have less stringent target limits and so are often more of the final operation in the reaction sequence of a step rather than an independent step in itself.

Given all these complications my recent practice has become to refer to a large-scale synthesis sequence in terms of “step count” but as three separate descriptors: “synthetic transformations”, “isolated intermediates” and “isolation/purification procedures”. This at least seemed to help simplify the discussions among the chemists, chemical engineers and analysts!

Prof Johnson’s commentary ends with a discussion on the value of reporting step count and he mentions how one really should take a more holistic approach to evaluating synthetic work, including:

  • Material and operating costs
  • Conversion cost factors, such as process-mass intensity and E-factor
  • Material efficiency reported by a radial pentagon
  • Pot economy
  • Step count versus molecular complexity

Many of these criteria are core components of the foundational Chemical Development course and other courses taught by Scientific Update, so it is good to see these being presented to a wider audience in this commentary.

One area that the commentary does not address in detail is what material is sufficiently simple and commercially available on an appropriate scale to start counting from? That’s even more difficult to define and that highlights the additional complexity encountered by process chemists, especially when trying to communicate to a wide audience how “good” or “bad” the existing synthesis route is with a simple numerical metric that everyone can agree upon! I’ll leave that topic for another blog in the future when a good example appears in the literature.