Process
Safety Evaluation and Scale-up of a Lactam
Reduction with NaBH<sub>4</sub> and TFA
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Abstract
The
development of a practical and scalable method for the synthesis
of morpholine derivative <b>2</b> via reduction of lactam <b>1</b> using NaBH<sub>4</sub> and trifluoroacetic acid (TFA) is
described. Through the mechanistic studies using <sup>11</sup>B NMR
spectroscopy, we observed that active species were generated during
TFA addition, which avoids the deactivation of the active species
involved in the reduction process. Process safety assessments were
performed on the basis of the reaction mechanism using reaction calorimetry
and gas evolution analyses. Furthermore, safety equipment was prepared
to prevent the leakage of diborane gas during the reaction, and the
process was successfully scaled up to the pilot plant at a 35 kg scale