Study of lactol activation by trifluoroacetic anhydride via in situ Fourier transform infrared spectroscopy

In the activation of lactol by trifluoroacetic anhydride (TFAA), an accurate charge of TFAA is critical because of the potential formation of a lactol dimer impurity caused by a TFAA undercharge, or the extra consumption of reagents by excess TFAA in the subsequent reaction step. Monitoring the charge by chromatographic methods is difficult since TFAA is reactive and activated lactol is unstable during off-line sample preparation and subsequent analysis. By using in situ Fourier transform infrared (FTIR) spectroscopy, we overcame the difficulties in analyzing TFAA and the activated lactol with chromatographic methods. The FTIR method was based on real-time monitoring of TFAA at 1875 cm(-1) and activated lactol at 1679 cm(-1) during the activation reaction. A detection limit of less than 2% equivalent (or 5 mg/ml) for TFAA was achieved and was within the process specification. Thus, the reaction end-point can be determined based on the amount of TFAA in the reaction mixture. The formation of the lactol dimer impurity, based on the results of HPLC analysis, is temperature dependent. Significant amounts of lactol dimers were formed at high temperature, while little dimer was produced when the reactions were carried out under low temperature. In addition, two operation routes, i.e. adding lactol to TFAA or feeding TFAA to lactol, generated comparable but low levels of dimer impurities as long as the addition rate of the second reactant was controlled to maintain the reaction temperature below 0degreesC. In situ FTIR has made it possible to control the activation of lactol by TFAA promptly and effectively. (C) 2003 Elsevier B.V. All rights reserved.