Wednesday, July 10, 2013

Process Wednesday: when "old school" meant a bunker

How do you know when things might be a little dicey? When your operators have to get into a bunker to produce your desired intermediates.

From the compiled reviews [1] in the book Organometallics in Process Chemistry (emphasis mine), a look at the production of ethyl diazoacetate for the synthesis of the mixture of insecticidal compounds known as allethrins in the 1950s:
As mentioned previously, the generation and handling of ethyl diazoacetate on large scale is not a trivial operation. To mitigate the risk to human operators, early manufacturers were reported to conduct the cyclopropanation reaction by remote control from behind concrete barriers. 
Another creative processing approach to minimize the handling of and exposure to ethyl diazoacetate is embodied in a patent from ICI. They used a large excess of [the above diene] as the organic solvent to extract the EDA as it was generated. After removing the aqueous phase, copper was added as a catalyst and the mixture was heated to effect cyclopropanation. The excess diene was recycled into the process during the distillative isolation of the product. 
I think it is instructive to me how one of the ways to both maximize throughput and minimize operations is to run the reaction basically neat; that the cyclopropanation wouldn't run without copper present is probably an important aspect of the reaction as well.

Perhaps it is not a surprise that the review notes next that in 1975, another company patented a continuous process to generate the desired intermediate above. Good on them -- no one wants to run reactions from a bunker, I'll bet.

1. DelMonte, A.J.; Dowdy, E.D.; Watson, D.J. "Development of Transition Metal-Mediated Cyclopropanation Reactions." Topics Organomet. Chem. 2004, 6, 97-122. 

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