(1R,3S)-3-(1H-Benzo[d]imidazol-2-yl)-1,2,2-trimethylcyclopentane-1-carboxylic acid as a new anti-diabetic active pharmaceutical ingredient

The chiral title compound, which can be used for producing active pharmaceutical ingredients for treatment of type 2 pancreatic diabetes and other pathologies dependent on insulin resistance, was prepared from (1R,3S)-camphoric acid and o-phenylenediamine.

The chiral title compound, C 16 H 20 N 2 O 2 , which can be used for producing active pharmaceutical ingredients for treatment of type 2 pancreatic diabetes and other pathologies dependent on insulin resistance, was prepared from (1R,3S)camphoric acid and o-phenylenediamine. It crystallized from an ethanol solution in the chiral monoclinic P2 1 space group. The five-membered ring adopts a twisted conformation with the methyl-substituted C atoms displaced by À0.273 (5) and 0.407 (5) Å from the mean plane through the other three atoms. In the crystal, molecules are linked by O-HÁ Á ÁN hydrogen bonds, forming chains along the a-axis direction. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to analyze the intermolecular contacts present in the crystal.

Chemical context
The incidence of diabetes has taken on the character of an epidemic in the world. According to the forecasts of the World Health Organization, the number of patients with diabetes will double and reach 300 million people by 2025(Zimmet et al., 2001. In this regard, developing and introducing new antidiabetic drugs is of great importance. A great number of camphoric acid as well as benzimidazole derivatives exhibit different types of biological activities (Merzlikin et al., 2008;Ivachtchenko et al., 2002Ivachtchenko et al., , 2019Kovalenko et al., 1998).
It should be noted that during the synthesis, the configuration of the chiral centers did not change and the structure of the title molecule was unambiguously confirmed by X-ray analysis.

Supramolecular features
In the crystal, molecules of 4 form layers parallel to the (100) plane as a result of the strong N2-HÁ Á ÁO1 and O2-HÁ Á ÁN1 and weak C14-H14CÁ Á ÁC2() intermolecular hydrogen bonds ( Table 2, Fig. 4a,b). The neighboring layers are not bound any specific interactions (Fig. 4a). It is interesting to note that the molecules are linked by hydrogen bonds that use the O-HÁ Á ÁN heterosynthon instead of the carboxylic acid dimer homosynthon. Despite the presence of an aromatic ring in the molecule, no stacking interactions are observed in the crystal of 4. Instead ofinteractions, C-HÁ Á Á interactions are formed (

Figure 3
The molecular structure of the title compound 4 with the atom labeling. Displacement ellipsoids are drawn at the 50% probability level.  Table 2 Hydrogen-bond geometry (Å , ).

Hirshfeld surface analysis
Crystal Explorer 17.5 (Turner et al., 2017) was used to analyze the interactions in the crystal and fingerprint plots mapped over d norm (Figs. 5 and 6) were generated. The molecular Hirshfeld surfaces were obtained using a standard (high) surface resolution with the three-dimensional d norm surfaces mapped over a fixed color scale of À0.716 (red) to 1.406 (blue) a.u. The red spots indicate regions of donor-acceptor interactions or short contacts. There are three red spots in the d norm surface for 4 (Fig. 5), which correspond to the interactions listed in Table 2.
All of the intermolecular interactions of the title compound are shown in the two-dimensional fingerprint plot presented in Fig. 6a. The fingerprint plots indicate that the principal contributions are from HÁ Á ÁH (61.7%; Fig. 6b), CÁ Á ÁH/HÁ Á ÁC (18.1%; Fig. 6c), OÁ Á ÁH/HÁ Á ÁO (13.5%; Fig. 6d) and NÁ Á ÁH/ HÁ Á ÁN (6.6%; Fig. 6e) contacts. The HÁ Á ÁH interactions appear in the middle of the plot scattered over a large area, while the CÁ Á ÁH/HÁ Á ÁC contacts are represented by the 'wings' of the plot. OÁ Á ÁH/HÁ Á ÁO interactions appear as inner spikes and the NÁ Á ÁH/HÁ Á ÁN contacts, corresponding to the O-HÁ Á ÁN interaction, are represented by a pair of sharp outer spikes, which indicate they are the strongest interactions in the crystal of 4. In a glass reactor equipped with a Dean-Stark receiver, d-(+)-camphoric anhydride 2 (2.20 kg, 12.1 mol), o-phenylenediamine 3 (1.31 kg, 12.1 mol), toluene (11.46 L) and dimethylformamide (0.91 L) were charged. Under stirring, the reaction mixture was heated to boiling (383 K). The mixture was refluxed and the released water was collected in the Dean-Stark receiver. When the removal of water had finished, the reaction mixture was cooled to room temperature. The     precipitate that formed was filtered in vacuo using a Nutsche filter. The precipitate was thoroughly squeezed, washed twice with toluene (1.4 L) and re-squeezed. Then the precipitate was washed on the filter with 70% water-ethanol (3.7 L), heated to a temperature of 348AE5 K. Finally, the precipitate of the product 4 was thoroughly squeezed and dried at 343 K for 4 h, yielding 2.41 kg (73.2%) of a white crystal-like powder that is practically insoluble in water, soluble in 96% alcohol, m.p. 527-528 K. UV (ethanol) max ("): 204 nm (48960) Further crystallization by slow evaporation of an ethanol solution was carried out to provide single block-like colorless crystals (Fig. 7) suitable for X-ray diffraction analysis.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. H atoms were included in calculated positions and treated as riding on their parent C atom: C-H = 0.82-0.98 Å with U iso (H) = 1.5U eq (C-methyl and Ohydroxyl) and 1.2U eq (C) for other H atoms. The Flack parameter cannot be determined reliably, because there is no X-ray anomalous scattering because of the absence of heavy atoms in the molecule.
Acta Cryst. (2020). E76, 1407-1411 research communications   CrysAlis PRO (Rigaku OD, 2018); program(s) used to solve structure: ShelXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (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.