A formylation-cyclization reaction in the synthesis of an Active Pharmaceutical Ingredient (API) required excess ethyl formate (EF), potassium tert-butoxide (KOtBu), and guanidine●HCl (G●HCl), when performed as a batch process.  Decreasing any one of these reagents resulted in either more impurities or lower conversion. The final process, which has been performed in flow on ca. 100 kg scale, can now be run with only 1.2 equiv. of EF (an 80% reduction in CO generated), 1.4 equiv. of KOtBu (a 38% reduction), and 3.0 equiv. of G.HCl (a 63% reduction).  This decrease in the amount of EF, KOtBu, and G●HCl used and CO generated is significant, as production of the final API is expected to be on ton scale.  And, these improvements, along with a 2x increase in concentration, have resulted in a Step PMI reduction from 29 to 6 without sacrificing reaction performance.

Formylation with ethyl formate in flow: Reduction of process mass intensity (PMI) and CO generated

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.