Synthesis and Crystal Structure of Anhydrous Analog of 1,25-Dihydroxyvitamin D3

As predicted by single crystal X-ray crystallography, and contrary to the reported suggestions, the anhydrous form of calcipotriol, a therapeutically important vitamin D analog, was found stable enough to be used as an active pharmaceutical ingredient. The crystal and molecular structure of calcipotriol anhydrate was solved and refined using single crystal X-ray diffraction. The analog was obtained by a novel convergent synthesis from the vitamin D C-22 sulfone, as an advanced intermediate and a side-chain fragment. The homo-chiral side-chain aldehyde was obtained from cyclopropanecarboxyaldehyde by the chromatographic separation of the intermediate diastereomeric salts with (S)-naproxen. Calcipotriol anhydrate showed a single peak in differential scanning calorimetry and the absence of a peak from a water molecule, typical for the monohydrate. Calcipotriol anhydrate, as the only 1,25-dihydroxylated analog of vitamin D3, exists as a mixture of both α- and β-forms of the A-ring, present in the asymmetric part of the unit cell of the crystal lattice. The intermolecular hydrogen bonding between both conformers in the crystal lattice indicated that the stability of calcipotriol anhydrate might be at least the same as for the known monohydrate. The usefulness of calcipotriol anhydrate as an active pharmaceutical ingredient was confirmed by the stability study in the standard conditions used for the storage of vitamin D analogs.