Crystal structure of 4-benzylcarbamoyl-1-methylpyridin-1-ium iodide: an efficient multimodal antiviral drug

Polymorph screening of the title compound, an efficient multimodal antiviral drug, revealed only a single polymorph, for which the crystal structure is determined in this work.


Chemical context
4-Benzylcarbamoyl-1-methylpyridin-1-ium iodide, [MeC 5 H 4 NCONHCH 2 C 6 H 5 ]I, is a multimodal antiviral drug (Buhtiarova et al., 2003;Frolov et al., 2004). For pharmaceutical applications, it is of utmost importance to identify possible polymorphs (Bernstein, 2002;Brittain, 1999;Hilfiker, 2006), see also https://www.fda.gov/downloads/Drugs/ Guidances/UCM072866.pdf; https://newdrugapprovals.org/ 2014/02/12/fda-guidance-on-polymorphic-compounds-ingeneric-drugs/. Polymorphism screening varying crystallization solvents (water, acetone 90%-water, ethanol 90%water, isopropanol 90%-water, DMF, DMSO, MeOH, CH 3 CN) and conditions (solution temperature, heating and cooling protocols) did not reveal any other polymorphs than the one reported in this work as has been confirmed by DSC (METTLER TOLEDO DSC 822e, 5 min À1 in N 2 , samples ISSN 2056-9890 Figure 1 IR spectra of the title compound. 1/6-3/5 mg), IR spectroscopy (IR-FT spectrometer FT-801, spectroscopic resolution 0.5 cm À1 and systematic error AE0,05 cm À1 ; samples studied in KBr discs, 1.0 mg of substance in 200 mg of KBr; 4000-600 cm À1 , and FTIR ATR spectrometer DigiLab Excalibur 3100, Varian spectrometer equipped with a MIRacle ATR accessory in the range 4000-600 cm À1 with resolution of 2 cm À1 without addition of KBr) and X-ray powder diffraction (STOE STADI MP diffractometer, CuK 1 radiation, curved Ge monochromator, transmission mode). The same thermal effect at the DSC curves related to sample melting at 464 K has been observed for all the samples. The position and relative intensities of the bands in the IR spectra were also the same (see section 5, Fig. 1). There were no differences between the IR spectra recorded with and without addition of KBr. The X-ray diffraction patterns were also the same for all the samples (Fig. 2) and matched the pattern calculated for the structural model based on single-crystal diffraction data (see next sections). WinXPOW (Stoe & Cie, 2011) was used to analyze the diffraction patterns.

Structural commentary
The asymmetric unit of the title compound contains a [MeC 5 H 4 NCONHCH 2 C 6 H 5 ] + cation and an I À anion (Fig. 3). All the bond lengths and angles are within normal ranges. A cation and an anion form an ionic pair linked by a strong N2-H2Á Á ÁI1 hydrogen bond (Table 1). The central part of the molecule (N2/C8/O1) and the pyridyl ring are located practically in the same plane [the average deviation of the atoms from the N1/N2/O1/C8-C13 plane is 0.015 (3) Å and the maximum deviation is 0.025 (3) Å ]. The I À anion is also close to this plane [at a distance of 0.504 (3) Å ]. The dihedral angle between the pyridyl and benzene rings is 62.8 (1) .

Supramolecular features
In addition to the strong NHÁ Á ÁI hydrogen bond, two weak C-HÁ Á ÁI hydrogen bonds are present in the crystal structure (Table 1, Fig. 4). Ionic pairs linked by these hydrogen bonds form infinite ribbons along the crystallographic a axis (Fig. 4). No hydrogen bonds link the ribbons with each other.

Database survey
No crystal structures containing the [MeC 5 H 4 NCONH-CH 2 C 6 H 5 ] + cation could be found in the Cambridge Structural Database (CSD, Version 5.38, update November 2016;Groom et al., 2016). A crystal structure of 4-benzoylamino-1-methylpyridinium iodide (CSD refcode ESESUS; Navarro et al., 2016) is also formed by ionic pairs linked by a strong N-HÁ Á ÁI hydrogen bond [the donor-acceptor distance is 3.675 (1) Å ]. Similarly to the compound studied in this work, the organic cation of ESESUS also contains a benzene and an Nmethylpyridine ring, with the N atom forming an N-HÁ Á ÁI hydrogen bond in the centre of the cation ( The molecular structure of the title compound, showing the atomlabelling scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are shown as spheres of arbitrary radius. The dotted line indicates the N-HÁ Á ÁI À hydrogen bond. Table 1 Hydrogen-bond geometry (Å , ). Symmetry codes: (i) x þ 1 2 ; Ày þ 1 2 ; Àz þ 1; (ii) x þ 1; y; z.

Figure 2
Powder diffraction patterns of the samples recrystallized from different solvents (an overlay) (a) and the diffraction pattern calculated for the structural model obtained based on single-crystal X-ray diffraction data in this work (b).
central part of the cation in the case of ESESUS is shorter than that of the title compound, the molecular conformation is very different, as is the molecular packing (Fig. 5).

Synthesis and crystallization
The title compound can be synthesized from N-benzylamide 4-pyridinecarboxylic acid C 5 H 4 NCONHCH 2 C 6 H 5 and methyl iodide MeI in a 1:2 (Trinus et al., 1994) or 1:1.2 (Buhtiarova et al., 1997) molar ratio. N-Benzylamide 4-pyridinecarboxylic acid, in turn, was synthesized by the condensation of isonicotinic acid C 5 H 4 NCOOH with benzylamine C 6 H 5 CH 2 NH 2 taken in a 1:2 molar ratio (Trinus et al., 1994). 12.31 g (0.1 mol) of isonicotinic acid were added with constant stirring over a period of one hour to 12.86 g (0.12 mol) of benzylamine heated to 413 K. After all of the isonicotinic acid had been added, the mixture was heated steadily to 493-503 K. After water and the excess of benzamine had been distilled, the residue was cooled to 373-383 K and added on stirring to 100 ml of toluene. The hot solution was filtered and cooled to 288 K. After cooling, the precipitate was filtered, washed on the filter with 20 ml of toluene and dried in the air at ambient temperature. The yield was 18.57 g (0.0875 mol; 87.5%) (Sysoljatin et al., 2011). 18.57 g (0.0875 mol) of N-benzylamide 4-pyridinecarboxylic acid were added to 110 ml of acetone with stirring. After the dissolution was complete, 14.9 g (0.105 mol) of methyl iodide MeI were added and the reaction mixture kept at 323 K for five h after which it was cooled to 283-288 K and filtered. The precipitate was washed on the filter with 50 ml of acetone and dried in the air. The yield was 24.65 g (0.0696 mol; 79.5%) (Sysoljatin et al., 2011). Crystal packing of the title compound, viewed (a) along the b axis and (b) along the a axis. The dotted lines indicate the hydrogen bonds, N-HÁ Á ÁI (blue) and C-HÁ Á ÁI (olive).