kilomentor | 01 February, 2011 09:19
The Kilomentor approach to process development is geared towards the simple, rugged and dependable process step and avoids the technically demanding step, which uses sophisticated and expensive equipment. This keeps with the tenor of the times wherein so much process work is being moved to the developing economies where at least for now labour is plentiful, so long as the work process is rugged.
The Kilomentor approach to every process step is to divide it into the reaction phase, the success of which is measured by:
(i) the assay yield (the quantity of desired product in the reaction mixture as a percentage of theory)
(ii) the isolation yield which assesses the success of the effort to separate a product of practical purity out of the reaction soup (again expressed as % of the theoretical possible
The standard overall yield That is all that is normally reported is the product of these (as fractions) expressed as a percentage.
Because of our historic addiction to the assessment of synthetic elegance by counting reaction steps-with the fewer the better, there has been a bias against isolating intermediates as functional group derivatives and then decomposing them back to the original product intermediate. Because we so often only looked at the overall yield, we could not specifically see that we were leaving good product behind just because we were using less effective isolation means in order to minimize the reaction steps.
At the same time, we often convinced ourselves that even this advantage forming a functional group derivative to improve the isolated yield, would be given back in the step of decomposing the derivative to recover the original functionality. For example, the isolation of a pure ketone intermediate might be done by a painstaking vacuum fractional distillation without adding any additional reaction steps to the’ academic’ step count. The same ketone might readily and quantitatively form a solid oxime or hydrazone. Yet we would make arguments to ourselves that the backwards hydrolysis of clean oxime to ketone could be difficult and inefficient and messy when really actual hydrolysis technology made the cleavage trivial and efficient.
Another bad reason that we prefer challenging physical separations (fractional distillation or chromatography) to chemical derivatization is that the reagents for chemical derivatization would add to the chemical cost, while the challenging separation uses labour, time, and equipment which are not considered in the early, small-scale, chemicals-only costing.