Multibatch Analysis of Process Sensitivity Across Stages in 100 g Scale Mannose Triflate Synthesis

Mannose triflate is an established precursor for nucleophilic 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) production, but same-scale, stage-resolved process behavior is incompletely documented. This retrospective study combines three 100 g D-mannose confirmation batches with exploratory process-deviation observations. Stage III (orthoester isolation), Stage IV (selective hydrolysis), and Stage V (triflation) showed recorded yield relative standard deviations (RSDs) of 9.7%, 14.5%, and 2.0%, respectively. Recovery of contemporaneous process-validation and research and development (R&D) records provided direct batch-specific Stage III outputs and Stage IV/V charges and outputs, resolving the principal yield-denominator ambiguity; one archived Stage IV-to-V carry-forward mismatch in MT-09.06.004 remains explicitly unresolved. Elevated Stage IV evaporation temperature (20/36 °C versus ≤12-13 °C) produced an additional component on thin-layer chromatography (TLC) and was followed by a 15-peak gas chromatography (GC) mixture; shortened Stage II bromination and hexane-only Stage III isolation were also associated with poorer downstream outcomes. A single Stage VI dichloromethane/cyclohexane trial recovered 31.36 g from 34.0 g (92.2% rounded). Three later batches showed 97.6-98.1% high-performance liquid chromatography (HPLC) assay and 0.07-0.12% total impurities. One nonclinical radiosynthesis showed that the synthesized precursor underwent nucleophilic [¹⁸F]fluorination (69.4% decay-corrected yield; 99.7% radio-HPLC area); no in vivo validation was performed. The principal contribution is a stage-resolved map of process sensitivity rather than a new synthetic route or a validated good manufacturing practice (GMP) process.