Scale-up of sevoflurane synthesis: selection of chemical route and influence of reagent characteristics

The general anaesthetic sevoflurane was prepared from chlorosevo ether using two fluorinating agents, potassium fluoride dihydrate in the presence of a phase transfer catalyst and potassium fluoride in the presence of a complexing solvent. A pure sevoflurane product could not be recovered via conventional distillation from the crude reaction mass obtained using the dehydrate (at 72% purity), due to the existence of a maximum boiling azeotrope at 368 K. The efficacy of the potassium fluoride reagent allowed for a more complete reaction and bypassing of the azeotrope. Scale-up tests showed that the quality of the potassium fluoride directly affects the selectivity and yield of sevoflurane. The salt undergoes morphological changes upon exposure to moisture that results in significantly lower yield of the target compound even after reprocessing and drying, from 73% to 28% respectively.