Low-Temperature\nContinuous Mechanochemical Synthesis\nof Hydantoin-Based Active Pharmaceutical Ingredients by Spiral Gas–Solid\nTwo-Phase Flow

Although the mechanochemical synthesis\nof many active\npharmaceutical\ningredients (APIs) has been demonstrated, a technology that enables\nthe large-scale continuous synthesis of thermosensitive APIs is lacking.\nIn this work, we investigated the low-temperature continuous mechanochemical\nsynthesis of a series of hydantoin-based derivatives, including the\nAPIs nitrofurantoin and dantrolene, by using the previously proposed\nspiral gas–solid two-phase flow (S-GSF) technique. The structures\nof the prepared products were determined by using Fourier transform\ninfrared spectroscopy, nuclear magnetic resonance, and powder X-ray\ndiffractometry. Results showed that not a drop of organic solvent\nwas used for the entire process, and high yields (not less than 94%)\nof <i>E-</i>isomer pure compounds were obtained without\na complex purification step. Even with the low melting point of the\nraw material 5-nitrofurfural, nitrofurantoin could be synthesized\ncontinuously without remarkable amorphization. This situation distinguishes\nS-GSF from the existing mechanochemical methods. In addition, by improving\nsystem reactivity through cocrystallization and the highly efficient\nS-GSF technology, a continuous mechanochemical complete conversion\nof dantrolene was achieved for the first time, with a corresponding\nspace-time yield up to 7.5 × 10<sup>4</sup> kg m<sup>–3</sup> day<sup>–1</sup>. In particular, the crystalline form of\ndantrolene prepared in this way is a substable form dantr-V.