Telescoping reactions reduces emissions
One of the primary tools available to the process development chemist to simplify a reaction sequence is to run multiple steps without isolating and purifying the intermediates. This is commonly referred to as “telescoping” reactions. The reasons for telescoping are many; limiting contact with a potentially hazardous compound, reducing cycle times, and reducing pollution and emissions among others. Some concerns are finding the correct solvent to allow the reactions to proceed as well as ensuring no reduction in quality occurs (no new impurities or elevated levels of known impurities). There can be cases where a new impurity is generated but others are eliminated and the new impurity is easily removed.
The Eli Lilly process group recently published an example os using telescoping to reduce toxic and odorous emissions. The first two steps involve formation of a sulfur ylide and the formation of a cyclopropane ring. Initially the steps were in two different solvents (acetone and MeCN). The major concern here is the use and emission of Me2S.
After screening several solvents it was found that both reactions would take place in MeCN and that DBU was the best base of those studied. I do have some concerns about how this was carried out, but that’s a story for another post. They determined the solvent first, then the base, and finally the addition times. This ignores the possibility of interactions between base, solvent and additions times. I better way is to use a designed experiment to determine the correct combination. It could be that one of the other bases with another solvent might give a better result.
Using MeCN as solvent and DBU as the base with quick addition of both DBU and the cyclopentenone gave good results (58% yield).
Process Development of (1S,2S,5R,6S)-Spiro[bicyclo[3.1.0]hexane-2′,5′-dioxo-2,4′-imidazolidine]-6-carboxylic Acid, (R)–Methylbenzenemethanamine Salt (LSN344309) Org. Process Res. Dev. 2006, 10, 28–32
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