Synthesis and crystal structure of ebastinium hydrogen fumarate

Crystals of the title salt are twinned by pseudo-merohedry and the structure shows extensive disorder. A strong N—H⋯O hydrogen bond links the cation and the anion and the anions are linked into [010] chains by O—H⋯O hydrogen bonds.


Structural commentary
All examined samples of I were twinned by pseudo-merohedry, as is common for monoclinic crystals with close to 90 (see, for example, Parkin, 2021). Further details on how this was handled are given in section 6 (Crystal handling, data collection and structure refinement). The asymmetric unit of I ( Fig. 1) consists of a single ebastinium cation-hydrogen fumarate anion pair. The cation is extensively disordered, with over half (20 out of 35) its non-H atoms modelled as occupying two sets of sites, with refined occupancy factors of 0.729 (4) and 0.271 (4), as shown in Fig. 2. Unless stated otherwise, the numerical details in the following description apply to the major conformation.
The hydrogen fumarate anion deviates substantially from planarity, as indicated by the dihedral angle between its carboxylate and carboxylic acid groups of 23.51 (14) . As expected, the C-O bond lengths in the deprotonated carboxylate group [1.2638 (18) Table 1 Hydrogen-bond geometry (Å , ).

Figure 1
An ellipsoid plot (50% probability) of I. The N-HÁ Á ÁO hydrogen bond is shown as a dashed line. The minor component of disorder is omitted to enhance clarity.

Figure 2
A ball-and-stick plot showing the superposition of major (solid bonds) and minor (open bonds) in ebastinium hydrogen fumarate, I. Hydrogen atoms (except for piperidinium NH) are omitted to enhance clarity.
limitations of the spherical-atom scattering-factor approximation (see, for example, Dawson, 1964) . Much weaker C-HÁ Á ÁO hydrogen bonds connect the ebastinium cations along the b-axis direction (C7-H7AÁ Á ÁO2 i ), ebastinium and hydrogen fumarate ions via the c-glide (C8-H8BÁ Á ÁO6 ii ) and hydrogen fumarate anions into chains parallel to the b-axis direction (C34-H34Á Á ÁO5 i and C35-H35Á Á ÁO3 iii ). The symmetry operations are those defined in the footnote to Table 1. Since these weaker interactions do not involve disordered atoms, the above description applies equally well to both major and minor components. There are no aromaticstacking interactions, but there are C-HÁ Á Á close contacts between the phenyl rings of the disordered diphenylmethoxy group, which are also summarized in Table 1.
The main structural motif in the extended structure of I is the cation-anion pair (Fig. 1). In the crystal, chemically distinct groups are segregated such that the 4-t-butylphenyl groups interdigitate with c-glide-related copies of themselves ( Fig. 3) and the diphenylmethoxy groups interact via the aforementioned C-HÁ Á Á contacts (Fig. 4), forming layers that extend parallel to the bc plane and stack along the a-axis direction. The hydrogen fumarate anions form chains that propagate along the b-axis direction by virtue of the O5-H5OÁ Á ÁO3 iii , C34-H34Á Á ÁO5 i and C35-H35Á Á ÁO3 iii  A packing plot of I viewed down the b-axis direction showing how the 4-tbutyl phenyl groups interdigitate with c-glide related copies of themselves, leading to layers that extend parallel to the bc-plane centered on a = 0 (and 1), and stack along the a-axis direction. The strong hydrogen bonds between cation and anion (i.e., N1-H1NÁ Á ÁO4) are shown as thick dashed lines.

Figure 4
A partial packing plot of I viewed down the b-axis direction showing C-HÁ Á Á contacts (thin dashed lines) between the diphenylmethoxy groups, thereby forming the interface, centered on a = 1/2, between layers parallel to the bc plane. In the interests of clarity, the minor component of disorder is suppressed. hydrogen bonds (Fig. 5), which form pairs of R 2 2 (6) ring motifs (Etter et al., 1990).

Database survey
A search of the Cambridge Structure Database (version 5.43 with updates as of June 2022; Groom et al., 2016) for the keywords 'ebastine' or 'ebastinium' revealed only two hits, CSD refcode QATJIF (Cheng et al., 2005) and the duplicate QATJIF01 (Sharma et al., 2015); both are structures of the free base, ebastine. An ebastinium salt with 3,5-dinitrobenzoate was not returned in this search, but is present as entry HECMIO (Shaibah et al., 2017). A search using the molecular fragment that extends from the ether oxygen atom through to and including the benzene ring (atoms O1/O2/N1/C2-C16 in this report) but including no other atoms, gave 38 unique structures (46 hits, eight of which were duplicates). Many of these were originally published in the pharmaceutical chemistry literature, highlighting the medicinal importance of the central core of the ebastine molecule. In contrast, a search for the keyword 'fumarate' gave 434 hits, covering a wide variety of structures with both the mono-anion and di-anion.
A detailed comparison of the ebastine structure (coordinates taken from QATJIF01) with the 3,5-dinitrobenzoate salt (HECMIO) was made by Shaibah et al. (2017). The free base (i.e., QATJIF and QATJIF01) is not disordered, but HECMIO has a relatively simple two-component disorder of the benzene ring of its 4-t-butylphenyl substituent. Of particular note (Shaibah et al., 2017) was the placement of the (C 6 H 5 ) 2 CHO group relative to the piperidine/piperidinium ring, which is equatorial in ebastine, but axial in the ebastinium salt. The (C 6 H 5 ) 2 CHO substituent in both disorder components of the hydrogen fumarate salt presented here is axial, as in HECMIO. The conformation of the C 4 H 6 O-4-tbutylphenyl fragment in I, however, is more similar to that in the neutral molecule (QATJIF and QATJIF01). An overlay of the major and minor disorder components of I with QATJIF01 and HECMIO highlights these conformational differences (Fig. 7).    and fumaric acid (25 mg, 0.21 mmol) were dissolved in hot ethyl acetate and DMF and stirred over a heating magnetic stirrer for 30 minutes at 333 K. The resulting solution was allowed to cool slowly to room temperature with slow evaporation. Crystallization was carried out using several solvents (ethyl acetate/DMF, acetone, acetonitrile, and methylethyl ketone) via slow evaporation to give plate-shaped crystals in about a week (m.p. 468-470 K). All crystals observed were twinned by pseudo-merohedry, but those grown from acetonitrile were the largest and gave the best diffraction patterns [see section 6 (Crystal handling, data collection and structure refinement) for further details].
In addition to the twinning, the structure is extensively disordered. This disorder consists of a rotation of the (C 6 H 5 ) 2 CHO group of the cation followed by a relaxation into the available space, which in turn places the whole of the (C 6 H 5 ) 2 CHO group in two distinct orientations [see section 2 (Structural commentary)]. This of necessity must also cause minor site splitting of the piperidinium ring, albeit not discernible in electron-density maps calculated to 0.77 Å 920 An overlay of the major and minor conformations of the ebastinium cation in I (this work) with ebastine (CSD: QATJIF01) and ebastinium cation from the 3,5-dinitrobenzoate salt (CSD: HECMIO, major conformation only), from a least-squares fit of non-H atoms in the piperidine/piperidinium rings. The axial placement of the diphenylmethoxy group (at left) in the salts is clearly different from the equatorial placement of the free base (blue). For the sake of clarity, only the major disorder component of HECMIO is shown. Diagram generated using Mercury (Macrae et al., 2020). resolution. The two largest difference map peaks are only about 0.5 and 0.4 electrons, but are in positions that suggest a third, much smaller, disorder component. Such an additional disorder component, however, was not modelled due to its necessarily minuscule occupancy fraction. To ensure satisfactory refinement for disordered atom sequences in the structure, a combination of restraints were employed. The SHELXL commands SAME and SADI were used to maintain the chemical integrity and similarity of the disordered groups, while RIGU and SIMU were used to ensure physically reasonable displacement parameters for closely proximate disordered atom pairs. Crystal data, data collection and structure refinement details are summarized in Table 2. All non-disordered and major-component H atoms were found in difference-Fourier maps. Carbon-bound hydrogen atoms were subsequently included in the refinement using riding models, with constrained distances set to 0.95 Å (R 2 Csp 2 H), 0.98 Å (RCH 3 ), 0.99 Å (R 2 CH 2 ) and 1.00 Å (R 3 CH). The N-H hydrogen atom was included using a riding model that allowed the N-H distance to refine, while that of the minor component was constrained. The O-H hydrogen atom coordinates of the hydrogen fumarate anion were refined freely. U iso (H) parameters were set to values of either 1.2U eq (R 2 C ar H, R 2 CH 2 , R 3 CH, NH) or 1.5U eq (RCH 3 , OH) of the attached atom. The final structure was checked using validation tools in PLATON (Spek, 2020) and checkCIF.

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. Refined as a 2-component twin.