Development of a Pilot-Plant-Scale Synthesis of an Alkylated Dihydrobenzothiadiazole S,S-Dioxide: Incorporation of a Late-Stage Mitsunobu Reaction

The process used to prepare a functionalized dihydrobenzothiadiazole S,S-dioxide on a pilot plant scale is described. Key changes to the original synthesis included: modifying S_NAr reaction conditions between a substituted aniline and 2-fluoronitrobenzene from n-BuLi/−78 °C to KOtAm/0 to 15 °C; replacement of a NaIO₄−RuCl₃ oxidizing system with bleach under phase transfer conditions; and a late-stage Mitsunobu reaction. The Mitsunobu reaction was used to prepare the penultimate intermediate and the process was telescoped forward through an N-Boc deprotection step that generated the active pharmaceutical ingredient. The product was efficiently extracted into the aqueous phase under acidic conditions so that the Mitsunobu byproducts could be washed away from the product with toluene. Although Mitsunobu reactions appear to be rarely used on scale, our results indicate that extraction of the API into an aqueous layer is an efficient way to separate the API from triphenylphosphineoxide and hydrazinedicarboxylate byproducts.