Development of a Pilot-Plant-Scale Synthesis of an Alkylated Dihydrobenzothiadiazole <i>S</i>,<i>S</i>-Dioxide: Incorporation of a Late-Stage Mitsunobu Reaction
Bibliographic record
Abstract
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 N Ar reaction conditions between a substituted aniline and 2-fluoronitrobenzene from n -BuLi/−78 °C to KO t Am/0 to 15 °C; replacement of a NaIO 4 −RuCl 3 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".