Crystal structure of an antidiabetic agent, (+/-)-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazollidine, troglitazone dihydrate.

ramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazollidine, troglitazone, is a mixture of two racemic diasteromers, the (±)(2R*,5S*) and (±)-(2R*,5R*) diastereomers. The molecular and crystal structures of both diastereomers have been reported.1,2 Slow crystallization of troglitazone with an aqueous acetone solution gave dihydrated single crystals that were different from the reported diastereomer crystals. These dihydrated crystals contained both diastereomers, (±)-(2R*,5S*) and (±)-(2R*,5R*) isomers, in a ratio of 66:34, measured by HPLC. An aqueous acetone solution of the mixture with both diastereomers was slowly evaporated to form colorless crystalline prisms. Intensity data were measured with the ω–2θ scan mode on a diffractometer using graphite-monochromated Cu-Kα radiation. The size of the crystal was 0.50 × 0.30 × 0.20 mm, and an absorption correction was made on the basis of a psi-scan. The crystal and experimental data are given in Table 1. The dihydrate form had the same space group and similar unit-cell dimensions as the crystal of the (±)-(2R*,5S*) isomer.1 The structure was determined by the direct method using the program SIR92. Asymmetric carbon atom in thiazoridine ring is disordered and has the two peaks of C(5a) and C(5b) in a DFourier synthesis; occupancies were estimated at 0.67 and 0.33, respectively. The molecular structure is shown in Fig. 2, together with an atomic numbering scheme. The bond distances and selected angles are summarized in Table 3. The dihydrate crystal consisted of the (±)-(2R*,5S*) and (±)(2R*,5R*) isomers in a ratio of about 2:1, which is in agreement with measurements obtained by HPLC. Both diastereomer molecules were disordered at the asymmetric C(5) atom in the crystal packing. The conformation of the (±)-(2R*,5S*) isomer in the dihydrate was similar to that of the pure (±)-(2R*,5S*) isomer crystal,1 but the (±)-(2R*,5R*) isomer had a different 467 ANALYTICAL SCIENCES MARCH 2001, VOL. 17 2001 © The Japan Society for Analytical Chemistry