There is only one way to find out if a reaction developed at a small scale really works and that is repeating the reaction on a big scale. Not milligrams, not grams but KILOGRAMS. Wenjie Li et al. of Boehringer Ingelheim Pharmaceuticals report on the pilot plant synthesis of cyclopropyl-aminopyridine-(L)-alanine dipeptide in a recent edtion of Org. Process Res. Dev. (DOI). The key reaction is a Kulinkovich-Szymoniak cyclopropanation with starting materials titanium isopropoxide (unlikely C2 delivery agent), ethylmagnesium bromide pacified with ligand bis-2-(N,N-dimethylaminoethyl)-ether and 2-cyanopyridine in 2-methylfuran. So what does that feel like?, filling a 400 L reactor with 175 kilograms of an Grignard reagent?
This reaction was quenched with lots of acetic acid and water to produce the free amine. In the meanwhile in reactor number two the BOC derivative of alanine was itself derivatized with carbonyldiimidazole and the entire reactor content was then added to reactor number 1 forming the dipeptide. Big advantage of this procedure according to the researchers: only the derivatised amine can be separated from all the titanium and magnesium salts.