Iclaprim mesylate displaying a hydrogen-bonded molecular tape

Iclaprim and mesylate molecules are linked into a hydrogen-bonded molecular tape, the central section of which is composed of fused rings.

The title compound, 2,6-diamino-5-[(2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl)methyl]pyrimidin-1-ium methanesulfonate, C 19 H 23 N 4 O 3 + ÁCH 3 O 3 S À , is a salt made up from a protonated iclaprim molecule and a mesylate anion. The pyrimidine and chromene units of the iclaprim molecule form an orthogonal arrangement [interplanar angle of 89.67 (6) ], and the 3-nitrogen position of the pyrimidine ring is protonated. Four distinct N-HÁ Á ÁO interactions and an additional N-HÁ Á ÁN hydrogen bond connect iclaprim and mesylate molecules to one another, resulting in an infinite hydrogen-bonded molecular tape structure. The central section of the tape is formed by a sequence of fused hydrogen-bonded rings involving four distinct ring types.

Chemical context
Iclaprim is a dihydrofolate reductase (DHFR) inhibiting antibiotic containing a 2H-chromene structure that targets Gram-positive bacteria (Masciadri, 1997). The current study is part of an investigation aimed at improving the synthetic route to iclaprim and accessing its salts (Nerdinger et al., 2020).
Iclaprim was synthesized according to the original route described by Jaeger et al. (2005), using 3-hydroxy-4,5-dimethoxybenzaldehyde (Cervi et al., 2013), which was further purified by recrystallization from ethanol/n-hexane. We achieved a much better purity by trituration in hot ethanol and subsequent recrystallization from boiling acetonitrile. The title compound, (I), is the corresponding mesylate salt, and it was produced in a subsequent step.

Supramolecular features
The iclaprim molecule displays two NH 2 groups attached to the pyrimidine ring (N3, N4) and the protonated N1 atom of the pyrimidine ring as potential hydrogen-bond donor groups.
These hydrogen-bond donor functions are engaged in five distinct intermolecular N-HÁ Á ÁA interactions (Table 1). N1 and N3 are linked to two O sites, each belonging to the same mesylate anion, i.e. N1-H1NÁ Á ÁO4 i and N3-H3AÁ Á ÁO5 i . In Fig. 2, the resulting ring motif is denoted as a, and it has the graph-set symbol R 2 2 (8) (Etter et al., 1990;Bernstein et al., 1995). N3 is additionally linked, via an N3-H3BÁ Á ÁO5 ii interaction, to a second mesylate unit. The resulting centrosymmetric ring b (Fig. 2) comprises two iclaprim and two mesylate units (with O5 accepting two hydrogen bonds) and is described by the symbol R 2 4 (8). The second NH 2 group forms an N4-H4BÁ Á ÁO6 interaction with a mesylate anion, and it is also hydrogen-bonded to the unprotonated pyrimidine N atom of a second iclaprim molecule via N4-H4AÁ Á ÁN2 ii . The latter two interactions generate two additional ring motifs, namely the R 3 3 (10) ring c linking two pyrimidine molecules with one anion and the centrosymmetric R 2 2 (8) ring d. The diagram in Fig. 2 illustrates that certain hydrogen-bonded rings are fused together because of shared N-HÁ Á ÁA interactions, i.e. a + b, b + c and c + d. Altogether, the five distinct interactions listed in Table 1 Table 1 Hydrogen-bond geometry (Å , ). (3) 163 (2) Symmetry codes: (i) x À 1; y þ 1; z; (ii) Àx; Ày þ 1; Àz.

Figure 1
The structures of the molecular entities with displacement ellipsoids drawn at the 50% probability level and hydrogen atoms drawn as spheres of arbitrary size.
iclaprim molecule is bonded to two different mesylate anions, one is a two-point and the other a one-point connection. It is also two-point connected to a neighbouring iclaprim molecule. In turn, the mesylate anion accepts four hydrogen-bonds from three iclaprim molecules, and all of its O atoms participate in hydrogen bonding.

Database survey
The

Synthesis and crystallization
Iclaprim mesylate was prepared according to a modified procedure based on the original synthesis by Jaeger et al. (2005) shown in Fig. 3. The iclaprim free base (500 mg, 1.41 mmol) was suspended in 75 ml of acetonitrile and heated to reflux. The resulting clear solution was slowly cooled to room temperature overnight and then kept at 253 K to complete the crystallization process. The resulting white solid was isolated by filtration and dried under high vacuum at room temperature. The obtained iclaprim free base (1.00 g, 2.82 mmol) was recrystallized in acetonitrile and was suspended in 35 ml of ethanol and heated to reflux. Heating was interrupted and a solution of 183 ml methylsulfonic acid (2.82 mmol) in 5 ml of ethanol was added in a dropwise manner. Refluxing was resumed and a further 10 ml of ethanol were added to obtain a clear solution. The solution was concentrated and allowed to cool slowly to room temperature, at which point aggregates of colourless columnar crystals started to form. The crystals were isolated via filtration and dried under high vacuum overnight; yield: 900 mg (71%).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The structure was refined as a twocomponent twin with the components being related by a 179.9 rotation about the a axis. The refined value of the minor twin component fraction was 0.260 (1). All H atoms were identified in difference-Fourier maps and those of NH and NH 2 groups were refined with a restrained N-H distance of 0.88 (2) Å and their U iso parameters refined freely. The H atoms at the cyclopropyl ring (C15, C16, C17) were refined with a restrained C-H distance of 0.96 (2) Å and with U iso (H) = 1.2U eq (C). Other H atoms bonded to secondary CH 2 (C-H = 0.98 Å ) or aromatic CH (C-H = 0.94 Å ) carbon atoms were positioned geometrically. Their U iso parameters were set to 1.2U eq (C). Methyl H atoms were idealized and included as rigid groups allowed to rotate but not tip (C-H = 0.97 Å ) and their U iso parameters were set to 1.5 U eq (C) of the parent carbon atom.

Special details
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.