Incompatibilities between N-bromosuccinimide (NBS) and solvents were examined by measuring the heat of reaction by an advanced reactive system screening tool (ARSST) and a reaction calorimeter (RC1e). The ARSST experiments showed that amides, THF, and toluene solutions require consideration of incompatibilities with NBS. Isothermal analyses by RC1e revealed accurate heats of incompatibilities and the autocatalytic behaviors of the incompatibilities. Experiments in the presence of a radical initiator or inhibitor demonstrated that the incompatibility is caused by the radical mechanism and the incompatibility is increased by the presence of radical initiators. Further experiments made clear that DBDMH, an alternative brominating reagent, showed behavior similar to that of NBS.
The thermal stability of sodium borohydride (NaBH 4 ) in dimethylacetamide (DMA) was examined by comparison with NaBH 4 in dimethylformamide (DMF), which is known to cause a violent runaway reaction. DMA is more thermally stable than DMF as a solvent for NaBH 4 based on consideration of the decomposition onset temperature and sensitivity to impurities.
We describe the development of a one-pot preparation process of (E)-3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)benzoic acid (3), which is a key carboxylic acid intermediate of lusutrombopag. This one-pot reaction process is composed of lithiation of 3,5-dichlorobenzoic acid with lithium diisopropylamide (LDA), formylation using N-formylmorpholine, followed by olefination employing the Horner−Wadsworth−Emmons reaction with triethyl 2-phosphonopropionate. This method enabled kilogram-scale manufacturing of carboxylic acid 3, a key intermediate of lusutrombopag with high purity, together with a reduced number of steps, improvement of yield, and avoidance of a cumbersome procedure for isolation of the intermediate.
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