Wednesday, November 26, 2014

Process Wednesday: (not so?) stinky burn at 200 gallon scale

Graphic adapted from Pesti and Anzalone [1]
I happened upon a copy of "Asymmetric Catalysis on Industrial Scale" and rather enjoyed this passage
in a chapter by Pesti and Anzalone [1]:
Our first pilot plant run was designed to prepare 45 kg of thioester. As safety was particularly important with the use of mercaptans, our two reaction vessels (200- and 300-gallon glass-lined reactors) would be vented through a scrubber containing bleach and sodium hydroxide solution to control emissions. Another unexpected consideration was the late-stage replacement of n-butyllithium for n-hexyllithium. n-Hexyllithium is preferred since the conjugate acid, hexane, is safer to handle as compared with the volatile butane, but this had become necessary due to a shortage of hexyllithium. At this scale, we could not vent outside the quantity of butane we would form from the use of n-butyllithium, but instead it was directed to our thermal oxidizer to be burned. The rate of natural gas uptake to the burners would also provide a handy means of measuring the butane produced and in turn the endpoint of the reaction.  
The preparation of the silylated mercaptan went smoothly; 24.5 kg of 1-propanethiol was reacted with 2.5M n-butyllithium followed by chlorotrimethylsilane in THF/heptane as in our established procedure. As we had calculated, a 6 hour sparge of nitrogen through this 30°C solution eliminated all the butane. This solution was transferred via a cartridge filter to the larger vessel that already contained 50.0 kg of [isobutyl ester] in THF.  
Addition of the aluminum chloride at this point required careful planning. It is a reactive solid and we wanted to minimize operator exposure. Our engineering designed a solids-charging adapter for safe delivery in portions without exposing the reaction or the operators. 
I thought the idea of using the thermal oxidizer burn rate as a measurement of the reaction progress was pretty interesting. I've never had experience with a thermal oxidizer unit before (I presume that one of those comes with boatloads of paperwork.) Also, the shift to nBuLi because of a shortage of hexyllithium is a fun, real part of the story -- logistics issues always pop up and it's neat to see that they were able to adapt.

Sure wish there was an explanation of how they adapted to the challenge of adding a reactive, hygroscopic solid to a reactor. I know that there are "glovebox" mountings to add reactive solids to reactors, but I'd be curious to know what is done at larger scale...

1. Pesti, J.A.; Anzalone, L. "Multi-Kilo Resolution of XU305, a Key Intermediate to the Platelet Glycoprotein IIb/IIIa Receptor Antagonist Roxifiban via Kinetic and Dynamic Enzymatic Resolution." Asymmetric Catalysis on Industrial Scale: Challenges, Approaches and Solutions. 2004, Copyright © 2004 Wiley-VCH Verlag GmbH & Co. KGaA


  1. I really have no experience with industrial scale chemistry. However, it seems overkill to generate the thiolate with an alkyllithium. pKa of 1-propanethiol is more or less 10, which is on par with phenol. AlCl3 is not very fun to handle. I wonder if they could get away with using ionic liquid HNEt3, AlCl3, which is easier to handle.