Synthesis and crystal structure of topiramate azidosulfate at 90 K and 298 K

The synthesis, crystal structure, absolute configuration, spectroscopic and spectrometric details of topiramate azidosulfate, a precursor to the anti-convulsant drug topiramate, are presented.


Chemical context
Topiramate, sold under the brand name Topamax (amongst others), is a carbonic anhydrase inhibitor, used alone or with other medications, to treat epilepsy and to prevent migraines (Maryanoff et al., 1987;1998;Maryanoff, 2009). It is also prescribed for the treatment of bipolar disorder, post-traumatic stress disorder, mood instability disorder, binge-eating disorders, bulimia nervosa and obesity (Silberstein et al., 2005). The vibrational and thermal properties of topiramate were investigated by Sena et al. (2008). Topiramate azidosulfate (a topiramate intermediate) is useful as a reference impurity standard. In view of the importance of topiramate and its derivatives, this paper reports the synthesis, crystal structure, and some spectroscopic data for topiramate azidosulfate, C 12 H 19 N 3 O 8 S, at low and room temperature (90 K and 298 K).

Structural commentary
The molecule of I (see scheme and Fig. 1) has a central core consisting of three fused rings: a pyran ring (labelled A in the scheme) with two fused dioxolane rings (labelled B and C).
The points of fusion, atoms C1, C2, C3, C4 ( Fig. 1), are contiguous chiral centres, the absolute configurations of which were confirmed unambiguously from the anomalous scattering by the sulfur to be 1S, 2S, 3R, 4R (see Flack, 1983;Hooft et al., 2008;Parsons et al., 2013). All three rings are non-planar, as indicated by their r.m.s. deviations from planarity (pyran A: 0.2597 Å ; dioxolanes B, C: 0.1375, 0.1583 Å respectively) and by their Cremer-Pople (1975) ring-puckering parameters ( Table 1). The distal carbon atoms of the dioxolane rings (i.e., C6 and C9) each bear two methyl groups. The azidosulfonate group attaches to atom C1 via a methylene linker, with the position of the azide relative to the fused-ring system determined by torsions about four bonds (C1-C12, C12-O6, O6-S1, S1-N1), as summarized in Table 2. The structure was refined against both low-temperature (90 K) and room-temperature (298 K) data in order to analyse the behaviour of methyl atom C7 (see Section 3: Supramolecular features). As there are no substantive differences, unless stated otherwise, numerical quantities quoted in the discussion pertain to the low-temperature structure.

Supramolecular features
There are no strong intermolecular interactions in crystals of I.
The 'HTAB' instruction in SHELXL flags four 'potential hydrogen bonds' (Table 3), but two of these have very small C-HÁ Á ÁO angles, such that the associated interaction energy would be negligible (Wood et al., 2009). The remaining two involve contacts between the methyl group at C7 with O1 i and O5 i of an adjacent molecule [symmetry code: (i) x À 1, y, z], the latter being the stronger of the two. During structure analysis, the question arose of whether these contacts would be structurally significant, owing to the possibility of rapid methyl-group rotation at room temperature (Riddell & Rogerson, 1996;1997). To answer this, the structure was also refined using room-temperature data. At low temperature (90 K) and room temperature (298 K), difference electron density for the three C7 methyl hydrogen atoms is very well resolved (Fig. 2), implying the absence of any disorder, rotational or static. Analysis of the Hirshfeld surface (Spackman & Jayatilaka, 2009) mapped over d norm for I using Crystal-Explorer (Spackman et al., 2021) reveals only two (equivalent) prominent red spots, corresponding to the C7-H7AÁ Á ÁO5 i interactions, in which the methyl group at C7 juts into a Cremer-Pople ring-puckering parameters were calculated using PLATON (Spek, 2020). For six-membered rings, the angles for ideal 'boat', 'twist-boat', and 'screw-boat' configurations are = 90 (boat, twist-boat) and = 112.5 (screw-boat). The ' values, are quantified as either (60k) (boat) or (60k + 30) (twist-boat, screw-boat), with the one having k closest to an integer giving the conformation (Boeyens, 1978). Thus, pyran ring A in I is between 'twist-boat' and 'screw boat', though marginally closer to the former. For five-membered rings, ' quantified as either (36k) ('envelope') or (36k + 18) ('halfchair') with k closest to an integer (Cremer & Pople, 1975), assigns dioxolane B as an 'envelope' configuration and dioxolane C as between 'envelope' and 'half-chair' conformations, though somewhat closer to the latter. Table 2 Selected torsion angles ( ) for I at 90 K.

Figure 2
Difference-electron density showing the presence of well-ordered hydrogen atoms at both (a) 90 K and (b) 298 K for the methyl group at C7. Ellipsoids are drawn at the 50% probability level. Diagram generated using ShelXle (Hü bschle et al., 2011).

Figure 1
An ellipsoid plot of I (50% probability) for the structure at 90 K. The structure at 298 K is essentially unchanged, other than having much larger ellipsoids.
concave recess of an adjacent molecule. These hydrogen bonds link the molecules into chains that extend along the aaxis direction (Fig. 3). There are no especially short contacts involving the azido group; N2 and N3 are 3.118 (2) and 3.166 (2) Å , respectively from a screw-related sulfonyl O7 (via 1 2 + x, 3 2 À y, 1 À z), but these are marginally greater than the sum of van der Waals radii of Bondi (1964). In spite of the lack of extensive intermolecular interactions, the overall packing exhibits segregation of like groups, leading to double layers that extend in the ab plane (Fig. 4). A summary of the various atom-atom contacts obtained using CrystalExplorer fingerprint plots is given in Fig. 5      A plot of the Hirshfeld surface calculated over d norm for I at 90 K, showing two adjacent molecules. Hydrogen bonds are drawn as green dashed lines. The red spot at the left corresponds to the C7-H7AÁ Á ÁO5 i [symmetry code: (i) x À 1, y, z] hydrogen bond ( Table 3). The symmetryequivalent red spot on the right side of the Hirshfeld surface is obscured from view. disregarding stereochemistry yielded 239 hits. A search fragment also including -CH 2 -Z (where Z is not H) attached to the equivalent of C1 in I returned 26 hits (21 excluding duplicates). A search using the keyword 'topiramate' gave only three hits, all being the structure of topiramate itself (with NH 2 in place of N 3 in I): SEQKAA (Maryanoff et al., 1998) and duplicates SEQKAA01 (Kubicki et al., 1999) and SEQKAA02 (Bolte, 2005). An amido derivative (with NHCHMePh in place of N 3 ) is present as entry ZARCEC (Xie et al., 2012). These crystal structures all have the symmetry of P2 1 2 1 2 1 , but pack differently from I. SEQKAA (and duplicates) form a tri-periodic hydrogen-bonded supramolecular assembly, while ZARCEC forms C(4) chains (notation after Etter et al., 1990).

Special details
Experimental. The crystal was mounted using polyisobutene oil on the tip of a fine glass fibre, which was fastened in a copper mounting pin with electrical solder. It was placed directly into the cold gas stream of a liquid-nitrogen based cryostat (Hope, 1994;Parkin & Hope, 1998). Diffraction data were collected with the crystal at 90K, which is standard practice in this laboratory for the majority of flash-cooled crystals. Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement progress was checked using Platon (Spek, 2020) and by an R-tensor (Parkin, 2000). The final model was further checked with the IUCr utility checkCIF.

Special details
Experimental. The crystal was mounted glued to the tip of a fine glass fibre, which was fastened in a copper mounting pin with electrical solder. Data were collected at room temperature to investigate the possibility of the methyl group at C7 undergoing rapid spinning.

sup-7
Acta Cryst. (2022). E78, 984-988 Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement progress was checked using Platon (Spek, 2020) and by an R-tensor (Parkin, 2000). The final model was further checked with the IUCr utility checkCIF.