Choose Moderate Reduce Pressure for Distillation At-Scale

The KiloMentor Blog has highlighted methods for isolation and purification from transformations at scale. One might think that a good place to look for examples of such procedures would be the famous series, Organic Syntheses. This doesn’t turn out to be the case. Organic Syntheses procedures may be good for making multigram samples of intermediate molecular weight intermediates but the techniques used very frequently have no kilo scale equivalent. The most common isolation/purification method used is simple or fractional distillation usually under some vacuum. From my limited experience, it is used in more than 50% of the procedures.  Increasingly in the more recent submissions, some chromatography is used and this is even more unacceptable for large scale work.

Moreover, the distillations are most often performed at diminished pressures that are not readily accessible using standard process equipment. It is a rule of thumb for the plant to not count on getting reduced pressure below 50 mm of mercury. In a sample of 63 procedures I examined at random, only 10 distillations were done at or above this pressure. Nine were performed between 20-49 mm; 22 from 5.0-19 mm; 11 from 1.0-4.9 mm; six from 0.2-0.95 mm; and 5 less than 0.19 mm.