Synthesis, Characterization, and Crystal Chemistry of Tasimelteon, a Melatonin Agonist, in Its Anhydrous and Hemihydrate Forms

Two crystalline forms of tasimelteon, a drug approved by the U.S. Food and Drug Administration for the treatment of non-24-h sleep-wake disorder, have been studied by single crystal and powder diffraction analyses, thermogravimetric analysis, differential scanning calorimetry, spectroscopic, and optical methods. The synthetic method forming tasimelteon is described in detail, with its full analytical, spectroscopic, and enantiopurity characterization. Solid tasimelteon hemihydrate, C15H19NO2·0.5H2O, is tetragonal with a = b = 7.3573(2) Å, c = 52.062(2) Å, V = 2818.1(2) Å3; Z = 8. Its crystal structure has been solved and refined in the P43212 space group, showing the occurrence of polymeric (H-bonded) slabs, thanks to the presence of water molecule (OW) tetrahedrally linked to 4 distinct tasimelteon molecules in a N2(OW)O2 fashion. The anhydrous form of tasimelteon, C15H19NO2, crystallizes in the monoclinic P21 space group, with a = 11.130(4), b = 4.907(2), c = 12.230(6) Å, β = 91.03(3)°, V = 667.8(5) Å3; Z = 2. Thanks to the availability of good-quality specimens, the structure of the latter phase was solved by conventional single-crystal diffraction analysis, showing short intermolecular C=O…H-N interactions between (translationally related) tasimelteon molecules, forming, in the crystal, well-defined chains running along the b axis. The morphology of the 2 crystal forms has been analyzed by the means of optical microscopy and particle size distribution analysis. Worthy of note, the newly determined crystal structures enable the successful usage of full-pattern matching X-ray-based quantitative analyses of batches of industrial interest, in search for contamination or phase stability issues.