Crystal structure of memantine–carboxyborane

The crystal structure of a modified anti-Alzheimer’s drug features O—H⋯O and N—H⋯O hydrogen bonds.


Chemical context
Memantine is a drug used for the treatment of mild and moderate-to-severe Alzheimer's disease as an inhibitor for N-methyl-d-aspartate (NMDA) receptors. As a result of its property as a low-affinity, open-channel blocker, memantine does not substantially interfere with normal synaptic activity, thereby reducing side effects. This has led to clinical trials for other neurological disorders (Bullock, 2006;Lipton, 2005;Olivares et al., 2012;Parsons et al., 2007). While memantine in its hydrochloride form is useful in various treatment methods, some modifications were done on this drug to optimize the desired concentration in the system. As a means to preventing drug degradation, memantine has been further processed in a mixture with other compounds (McInnes et al., 2010;Plosker, 2015). The one-week extended release formula by Lyndra Therapeutics is currently under clinical trial phase I (clinicaltrials.gov, NCT03711825). Though efforts to maintain the long-term stability of memantine are underway, chemical modification of the memantine structure itself is rarely reported. Our attempt was to mask the compound with an additional moiety that can be removed under certain conditions, therefore releasing the drug. With this goal, memantinecarboxyborane was synthesized since the carboxyborate group is known to decompose into carbon monoxide and boric acid, leaving the drug molecule itself (Ayudhya et al., 2017(Ayudhya et al., , 2018. The single crystal structure of the said compound, (I), was solved and its features are described in this report.
Assessment of available crystal structures deposited with the Cambridge Structural Database (Version 5.39; Groom et al., 2016) indicates that not all amine-carboxyboranes form dimers during crystallization. While some amine-carboxyboranes described above are dimers, others such as piperidine-carboxyborane and hexamethylenetetraminecarboxyborane do not form dimers, suggesting that the aminegroup interaction may influence the overall packing Ayudhya et al., 2017). The extended structure of (I) is shown in projection down the b-and c-axis directions in Fig. 3a and 3b, respectively. No other contacts beyond the hydrogen bonds already mentioned are observed in this packing. Although the dimers appear to be parallel in Fig. 3a, the twisted planes of hydrogen bonds are better represented in Fig. 3b.

Database survey
The memantine structure in its free (unprotonated) base form is not found in the literature, although the hydrochloride salt with water molecules of crystallization has been solved (Lou et al., 2009) Detail of the hydrogen bonds in (I) showing the carboxylic acid inversion dimers and N-HÁ Á ÁO links between dimers. Table 1 Hydrogen-bond geometry (Å , ).

Figure 1
The molecular structure of (I) with displacement ellipsoids drawn at the 50% probability level.

Synthesis and crystallization
Memantine, a derivative of adamantine, was first synthesized by Eli Lilly and Company. In an attempt to modify memantine into memantine-carboxyborane, a reaction scheme as shown in Fig. 4 was carried out. Addition of the carboxyborane moiety to memantine was done in a one-step reaction using an amine-exchange process as previously described (Spielvogel et al., 1980). Trimethylamine carboxyborane (117 mg, 1.0 mmol) and memantine (780 mg, 4.4 mmol) were dissolved in tetrahydrofuran (8.0 ml), and maintained at 328 K for 24 h under a nitrogen atmosphere. The solution was concentrated by vacuum distillation and the resulting solid was dissolved in dichloromethane. The product was precipitated from the solvent by using 15 ml of hexane and the white solid crude product (208 mg) was filtered. This residue was purified by multiple recrystallization in dichloromethane/hexane to yield a white solid (15 mg, 6.3%). Crystals suitable for X-ray analysis were prepared by dissolving in toluene and slow cooling of the solution.

Refinement
Crystal data collection and structure refinement details are summarized in Table 2 Reaction scheme for the synthesis of (I) through an amine-exchange process.  Data collection: APEX3 (Bruker, 2017); cell refinement: SAINT (Bruker, 2017); data reduction: SAINT (Bruker, 2017); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009). 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. Refinement. Refined as a two-component twin.