Wednesday, October 23, 2013

Process Wednesday: coupons aren't just for clipping

Credit: Hong et al., Org. Process. Res. Dev.
In the midst of a recent OPRD ASAP [1], an interesting reminder of one of the little tools of process chemistry, the "corrosion coupon." A little explanation: It's a bad idea to do chemistry in a reactor that also destroys the surface of the reactor, be it glass or metal. A "coupon" is a piece of the same material that your reactor is constructed of; you weigh the coupon beforehand, do your chemistry with the coupon submerged in the solution and then weigh the coupon afterward. If the coupon loses mass, you have a material compatibility problem.

This group from Roche Palo Alto, in the midst of a synthesis of an isoquinolinone, used them to test their chemistry:
On a 20-g scale, the aminolysis reaction was conducted at 130 °C in a stirred Hastelloy C autoclave using 4−5 equiv of dimethylamine. At pressures ranging from 120 to 160 psig, the reaction was complete within 16 h. However, the fact that 1 equiv of fluoride will be released during the aminolysis could lead to etching of the glass-lined autoclave under the rather vigorous conditions employed. The etching test with glass coupons confirmed this possibility as the glass surfaces of the samples were seriously degraded. This observation of significant glass erosion prompted an investigation of alternate means to effect this transformation that would be more compatible with existing equipment...
...Another approach to render the aminolysis of 3 (CJ's note: the starting material) compatible
with the glass-lined autoclave would be to scavenge the fluoride ions generated from the reaction mixture as they form. To this end, several experiments incorporating TMSOEt as a component of the reaction mixture were performed in Parr Hastelloy pressure vessels containing samples of the DeDietrich glass liner. On a 10−50-g scale, addition of 1.5−3.0 equiv of the silane to the standard aminolysis mixture had no adverse effect on the course of the substitution reaction other than a modest reduction in apparent reaction rate. However, the glass liner samples were recovered essentially intact, even upon prolonged heating at 145 °C. Complete conversion of 3 was observed within 24−36 h.
The use of TMSOEt to absorb the released fluoride ion is a good idea -- I'll have to remember it. Also, it's obvious that you'd have glass coupons (as opposed to the 316 stainless or Hastelloy ones that I've seen/heard of), but I hadn't heard of them until now. (How do you not break the glass coupons? Do they just rest on the bottom of the reactor?)

1. Hong, J.-B.; Davidson, J.P.; Jin, Q.; Lee, G.R.; Matchett, M.; O’Brien, E.; Welch, M.; Bingenheimer, B.; Sarma, K. "Development of a Scalable Synthesis of a Bruton’s Tyrosine Kinase Inhibitor via C–N and C–C Bond Couplings as an End Game Strategy." Org. Process Res. Dev., ASAP. DOI: 10.1021/op4001077


  1. That I didn't make a Ron White joke somewhere in here is a sign of my maturity.

  2. Ca(OH)2 slurry would probably work equally well as F(-) scavenger but it would require filtration at the end. Another very fluorophilic metal is Al(III) - to a point that PhCF3 is incompatible with AlCl3

  3. The glass coupons I've seen look like glass beads. They look like if you took a marble, rolled it into a cylinder, and then punched a hole through the long ways to make a bead. In this way, you can suspend them above the stirring of a reaction. Alternatively, if you're using overhead stirring they should be heavy enough to not be suspended.

  4. I have to wonder if any such scavenging technique would be truly scalable beyond low kg levels as one goes to much larger vessels when mass transport issues have higher importance. I recall stories from the 80s when quinilones antibiotics were a hot area of I think was Abbott basically ruining a few large scale reactors (and possibly contaminating products) when they attempted to go to multikilo commercial batches with a F scavenger process that had worked successfully in pilot plant.

    Besides the beads I have seen "rods on a hook" of SS and glass that can be hung into reaction solution from above (cotton thread?) but away from impeller. Reminded me of fishing wh3en they were pulled out of the reactors