Combined in Situ Monitoring Method for Analysis and Optimization of the Lithiation-Fluoroacetylation of N-(4-Chlorophenyl)-Pivalamide

Lithiation-fluoroacetylation of N-(4-chlorophenyl)-pivalamide (NCP) is a key step in the synthesis of a potent inhibitor of the HIV type 1 reverse transcriptase. The reaction comprises a heterogeneous lithiation step catalyzed by the solvent, fluoroacetylation with ethyl-trifluoroacetate (TFAEt), and hydrolysis. We investigate the reaction in our in-house developed small-scale low-temperature reaction calorimeter (CRC.v6 LT) employing in situ monitoring methods, such as reaction calorimetry, in situ spectroscopy (ATR FT-IR and UV/vis), and endoscopy, complemented by off-line GC/FID and GC/MS. The dynamic behavior of the reaction steps including end point prediction/detection is discussed, giving insights into a possible reaction mechanism and optimized reaction conditions.