Crystal structure of ebastinium 3,5-dinitrobenzoate

Abstract

Ebastine, 4-(benzhydryloxy)-1-[4-(4-tert-butylphenyl)-4-oxobutyl]piperidine, reacts with 3,5-dinitrobenzoic acid in methanol solution to give the title 1:1 salt, ebastinium 3,5-dinitrobenzoate, C 32 H 40 NO 2 + ÁC 7 H 3 N 2 O 6 À . In the cation, the disubstituted aryl ring exhibits orientational disorder over two sets of atomic sites having occupancies 0.706 (4) and 0.294 (6), with a dihedral angle of 41.2 (5) between the two orientations: the bulky Ph 2 CH-O-substituent occupies an axial site on the piperidine ring. The two ions in the selected asymmetric unit are linked by a nearly linear N-HÁ Á ÁO hydrogen bond and this, in combination with two C-HÁ Á ÁO hydrogen bonds, links the ions into complex sheets. Chemical contextEbastine, or 4-(benzhydryloxy)-1-[4-(4-tert-butylphenyl)-4-oxobutyl]piperidine, is a non-sedating second generation H 1 receptor antagonist, which is effective in the treatment of both allergic rhinitis, whether seasonal or perennial, and chronic idiopathic urticaria (Wiseman & Faulds, 1996;Van Cauwenberge et al., 2004). The structure of ebastine has been the subject of two recent reports (Cheng et al., 2005: Sharma et al., 2015. Herein, we report the molecular and supramolecular structure of the 1:1 salt ebastinium 3,5-dinitrobenzoate (I), formed in the reaction between ebastine and 3,5-dinitrobenzoic acid. Structural commentaryThe title compound (I), consists of an N-protonated ebastinium cation and a 3,5-dinitrobenzoate anion (Fig. 1), which ISSN 2056-9890 are linked within the selected asymmetric unit a by a fairly short and nearly linear N-HÁ Á ÁO hydrogen bond (Fig. 1, Table 1). The disubstituted aryl ring in the cation is disordered over two sets of atomic sites having occupancies 0.706 (4) for the major ring orientation, labelled C161-C166, and 0.294 (4) for the minor orientation, labeled C171-C176: the dihedral angle between these two ring planes is 41.2 (5) (Fig. 1). The piperidine ring adopts an almost perfect chair conformation, with a ring-puckering angle, calculated for the atom sequence (N1,C2,C3,C4,C5,C6) of = 0.0 (3), identical within experimental uncertainty to the idealized value for a perfect chair form of = 0.0 (Boeyens, 1978). However, although the non-H substituent at atom N1 in the ring occupies an equatorial site, as expected, the bulky Ph 2 CHO substituent at atom C4 unexpectedly occupies an axial site. This observation is the more surprising since in ebastine itself, both non-H substituents on the piperidine ring occupy equatorial sites (Cheng et al., 2005: Sharma et al., 2015. The 3,5-dinitrobenzoate anion in compound (I) is nearly planar: the dihedral angles between the aryl ring and the substituents at atoms C21, C23 and C25 are 1.4 (2), 4.2 (2) and 10.7 (2) , respectively: only the O atoms of the 5-nitro group are significantly displaced from the mean plane of the anion as a whole, 0.219 (2) Å for atom O25 and 0.187 (2) Å for atom O26: the r.m.s. deviation from the mean plane for the entire anion is only 0.082 Å . Supramolecular featuresIn addition to the ...

Synthesis and crystal structure of ebastinium hydrogen fumarate

“…1), which in turn forms a strong N-HÁ Á ÁO hydrogen bond to the carboxylate O4 atom of the hydrogen fumarate anion [N1Á Á ÁO4 = 2.697 (11) A ˚, Table 1]. The piperidinium ring of the cation is in the expected chair conformation, with the 4-tbutylphenyl-4-oxobutyl substituent equatorial at N1 and the diphenylmethoxy substituent axial at C4, similar to the salt described by Shaibah et al (2017), who also noted that this axial substitution is in contrast to the equatorial placement in free-base ebastine (Cheng et al, 2005;Sharma et al, 2015). The phenyl-4-oxobutyl fragment is largely planar (r.m.s.…”

“…Formulations of ebastine and its salts with various counter-anions have been the subject of numerous patents (see, for example, Bobee et al, 1995;Roma-Millan et al, 2011;Bilgic, 2013). In spite of this, only the crystal structures of the neutral free-base molecule (Cheng et al, 2005;Sharma et al, 2015) and the salt ebastinium 3,5-dinitrobenzoate (Shaibah et al, 2017) have been reported to date. By contrast, fumarates (di-anion fumarate and mono-anion hydrogen fumarate) are common counter-anions in compounds of pharmacological importance; examples include opipramolium fumarate (Siddegowda et al, 2011), cinnarizinium fumarate (Kavitha et al, 2013) (technically, both hydrogen fumarates), and the recently reported structure of bis(4-acetoxy-N,N-dimethyltryptammonium)fumarate, a new crystalline form of psilacetin (Chadeayne et al, 2019).…”

“…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).…”

“…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.…”

“…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.…”