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

Kovalenko, S.M.; Konovalova, I.S.; Merzlikin, S.I.; Chuev, V.P.; Kravchenko, D.V.

doi:10.1107/S2056989020010439

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 76| Part 9| September 2020| Pages 1407-1411

https://doi.org/10.1107/S2056989020010439

Open

access

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

Sergiy M. Kovalenko,^a Irina S. Konovalova,^b ^* Sergiy I. Merzlikin,^c Vladimir P. Chuev ^d,^e and Dmitry V. Kravchenko ^f

^aV.N. Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv, 61077, Ukraine, ^bState Scientific Institution Institute for Single Crystals of the National Academy of Sciences of Ukraine, 61001, Kharkov, Ukraine, ^cNational University of Pharmacy, 53 Pushkinska St., Kharkiv, 61002, Ukraine, ^dFederal State Autonomous Educational Institution of Higher Education Belgorod State University, 85, Pobedy St., Belgorod, 308015, Russian Federation, ^eExperimental Plant for Dental Materials Vladmiva, 81d, Michurin St., Belgorod, 308015, Russian Federation, and ^fChemical Diversity Research Institute, 2A Rabochaya St., Khimki, Moscow Region, 141400, Russian Federation
^*Correspondence e-mail: ikonovalova0210@gmail.com

Edited by G. Diaz de Delgado, Universidad de Los Andes, Venezuela (Received 15 May 2020; accepted 28 July 2020; online 4 August 2020)

The chiral title compound, C₁₆H₂₀N₂O₂, 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 P2₁ space group. The five-membered ring adopts a twisted conformation with the methyl-substituted C atoms displaced by −0.273 (5) and 0.407 (5) Å from the mean plane through the other three atoms. In the crystal, molecules are linked by O—H⋯N 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.

Keywords: crystal structure; Hirshfeld surface; 1H-benzo[d]imidazol-2-yl-1,2,2-trimethylcyclopentane-carboxylic acid; active pharmaceutical ingredient; anti-diabetic agents; type 2 diabetes.

CCDC reference: 2019647

1. 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., 2002 , 2019 ; Kovalenko et al., 1998 ).

Our research on the molecular design, construction and synthesis of new benzimidazole derivatives of 1,2,2,3-tetramethylcyclopentane-1-carboxylic acid has shown that (1R,3S)-3-(1H-benzo[d]imidazol-2-yl)-1,2,2-trimethylcyclopentane-1-carboxylic acid, 4, exhibits pronounced antidiabetic activity and, in particular, antihyperglycemic effect, which reduces insulin resistance and restores the physiological function of pancreatic β-cells (Jain et al., 2009 ; Chuev et al., 2017 ).

Racemic and enantiomeric crystals are known to possess different activities, which is very important in the pharmaceutical industry. We have found that the disadvantage of the (±) and (-) forms of compound 4 described in the patent of Merzlikin et al. (2009 ) is their poor bioavailability as compared to the (+) form. To obtain (1R,3S)-3-(1H-benzo[d] imidazol-2-yl)-1,2,2-trimethylcyclopentane-1-carboxylic acid 4, the enantiomerically pure (1R,3S)-camphoric acid 1 was used.

In the first stage, (1R,5S)-1,8,8-trimethyl-3-oxabicyclo[3.2.1]octane-2,4-dione [D-(+)-camphoric anhydride] 2 was obtained by refluxing a mixture of (1R,3S)-camphoric acid and acetic anhydride for 2 h (Dong et al., 2016 ) (Fig. 1).

Figure 1
Synthesis of (1R,5S)-1,8,8-trimethyl-3-oxabicyclo[3.2.1]octane-2,4-dione, 2.

In the second stage, the synthesis of (1R,3S)-3-(1H-benzo[d]imidazol-2-yl)-1,2,2- trimethylcyclopentane-1-carboxylic acid 4 was carried out according to Fig. 2 via cyclocondensation of D-(+)-camphoric anhydride 2 with o-phenylenediamine 3 in a mixture of toluene and DMF (383 K) by refluxing for several hours (Fig. 2).

Figure 2
Synthesis of (1R,3S)-3-(1H-benzo[d]imidazol-2-yl)-1,2,2- trimethylcyclopentane-1-carboxylic acid, 4.

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.

2. Structural commentary

The asymmetric unit contains one molecule of the title compound 4 (Fig. 3). The bicyclic fragment is planar with a maximum deviation of 0.016 (6) Å (for atom C16). The saturated five-membered ring adopts a twisted conformation in which the deviations of atoms C11 and C12 from the mean-square plane through the remaining ring atoms are −0.273 (5) and 0.407 (5) Å, respectively. The cyclopentane ring is turned in relation to the N1—C1 endocyclic bond, the N1—C1—C8—C9 torsion angle being −30.0 (7)°. It can be assumed that the weak intramolecular C9—H9B⋯N1 (H⋯N = 2.53 Å, C—H⋯N = 108°) hydrogen bond additionally stabilizes such a location of the saturated ring. The methyl group on the C11 atom is located in the axial position [C9—C10—C11—C15 = 87.5 (6)°]. The carboxyl group has an equatorial orientation and is almost coplanar to the endocyclic C10–C11 bond [the C9—C10—C11—C16 and C10—C11—C16—O1 torsion angles are −150.8 (5) and 13.9 (8)°, respectively]. This position is stabilized by the formation of weak intramolecular C10—H10A⋯O1 and C15—H15B⋯O2 hydrogen bonds between the vicinal and geminal substituents (H⋯O = 2.43 and 2.42 Å, C—H⋯O = 103 and 100°, respectively). The presence of geminal substituents on neighboring atoms of the pentane ring leads to significant steric repulsion (the shortened intramolecular contacts are given in Table 1), which causes elongation of the C8—C12 bond to 1.571 (7) Å, compared with its mean value of 1.556 Å (Burgi et al., 1994 ).

Table 1
Intramolecular short contacts (Å) in compound 4 together with the sums of the respective van der Waals radii

The van der Waals radii sum values (Zefirov et al., 1997 ) are given in parentheses.

H8⋯H15A	2.26 (2.34)	H15B⋯H14C	2.32 (2.34)
H13C⋯C1	2.57 (2.87)	H13B⋯C16	2.54 (2.87)

Figure 3
The molecular structure of the title compound 4 with the atom labeling. Displacement ellipsoids are drawn at the 50% probability level.

3. Supramolecular features

In the crystal, molecules of 4 form layers parallel to the (100) plane as a result of the strong N2—H⋯O1 and O2—H⋯N1 and weak C14—H14C⋯C2(π) 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—H⋯N 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 of π– π interactions, C—H⋯π interactions are formed (Table 2, Fig. 4b).

Table 2
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O2—H2⋯N1ⁱ	0.82	1.82	2.631 (6)	170
N2—H2A⋯O1ⁱⁱ	0.86	2.16	2.871 (6)	140
C14—H14C⋯C2ⁱⁱⁱ	0.96	2.81	3.439 (8)	124
Symmetry codes: (i) $[-x+1, y+{\script{1\over 2}}, -z+1]$ ; (ii) x, y, z-1; (iii) $[-x+1, y+{\script{1\over 2}}, -z]$ .

Figure 4
(a) View of the structure of compound 4 down the b axis and (b) hydrogen bonds within a layer in the crystal of 4.

4. 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 −0.716 (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.

Figure 5
Two orientations of the Hirshfeld surface for the title compound mapped over d_norm.

Figure 6
(a) The two-dimensional fingerprint plot for compound 4, and those delineated into (b) H⋯H (61.7%), (c) C⋯H/H⋯C (18.1%), (d) O⋯H/H⋯O (13.5%) and (e) N⋯H/H⋯N (6.6%) contacts.

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 H⋯H (61.7%; Fig. 6b), C⋯H/H⋯C (18.1%; Fig. 6c), O⋯H/H⋯O (13.5%; Fig. 6d) and N⋯H/H⋯N (6.6%; Fig. 6e) contacts. The H⋯H interactions appear in the middle of the plot scattered over a large area, while the C⋯H/H⋯C contacts are represented by the `wings' of the plot. O⋯H/H⋯O interactions appear as inner spikes and the N⋯H/H⋯N contacts, corresponding to the O—H⋯N interaction, are represented by a pair of sharp outer spikes, which indicate they are the strongest interactions in the crystal of 4.

5. Database survey

A search of the Cambridge Structural Database (CSD, Version 5.41, November 2019; Groom et al., 2016 ) for the 1,2,2-trimethylcyclopentane-1-carboxylic acid skeleton yielded 27 hits. Only one structure involves a benzothiazol-2′-yl ring in position 3, viz. (1R,3S)-(+)-cis-1,3-bis(benzothiazol-2′-yl)-1,2,2-trimethylcyclopentane (CSD refcode XUMXIM; Gilbert et al., 2002 ). The cyclopentane ring has the twist conformation with the atoms C1 and C4 displaced by 0.48 (1) and −0.26 (2) Å from the mean plane through the other three atoms [cf. 0.407 (5) Å and −0.273 (5) Å in the title compound].

6. Synthesis and crystallization

(1R,3S)-3-(1H-Benzo[d]imidazol-2-yl)-1,2,2-trimethylcyclopentane-1-carboxylic acid, 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 348±5 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) λmax (∊): 204 nm (48960), 245 nm (6800), 275 nm (9160), 281 nm (9320); IR (KBr): ν (cm⁻¹) 3450 (O—H), 3286 (N—H), 2970, 2935, 2887 (C—H), 1673 (C=O), 1529, 1456, 1436, 1373, 1279, 1358, 1167, 1124, 1057, 740; ¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s.br, 1H, OH), 12.10 (s.br, 1H, NH), 7.52 (s.br, 1H, H-4, H-7), 7.44 (s.br, 1H, H-4, H-7), 7.10 (t, J = 4.5 Hz, 2H, H-5, H-6), 3.41–3.31 (m, 1H, CH), 2.64–2.54 (m, 1H,CH), 2.43–2.33 (m, 1H, CH), 2.05–1.95 (m, 1H, CH), 1.55–1.45 (m, 1H, CH), 1.25 (s, 3H, CH3), 1.14 (s, 3H, CH₃), 0.61 (s, 3H, CH₃); LC/MS m/z (%): 273.2 [MH]+ (100); found, %: C 70.88; H 7.83; N 10.55. C₁₆H₂₀N₂O₂. Calculated, %: C 70.56; H 7.40; N 10.29.

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.

Figure 7
Crystals of the title compound 4.

7. 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 O-hydroxyl) 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.

Table 3
Experimental details

Crystal data
Chemical formula	C₁₆H₂₀N₂O₂
M_r	272.34
Crystal system, space group	Monoclinic, P2₁
Temperature (K)	293
a, b, c (Å)	7.9805 (7), 10.8671 (8), 8.4912 (7)
β (°)	94.056 (7)
V (Å³)	734.55 (10)
Z	2
Radiation type	Mo Kα
μ (mm⁻¹)	0.08
Crystal size (mm)	0.3 × 0.2 × 0.1

Data collection
Diffractometer	Rigaku Oxford Diffraction Xcalibur, Sapphire3
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku OD, 2018 $[Rigaku OD (2018). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ )
T_min, T_max	0.182, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	4859, 2455, 1731
R_int	0.058
(sin θ/λ)_max (Å⁻¹)	0.594

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.065, 0.180, 1.04
No. of reflections	2455
No. of parameters	185
No. of restraints	1
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.15, −0.19
Absolute structure	Flack x determined using 459 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	−1.8 (10)
Computer programs: CrysAlis PRO (Rigaku OD, 2018 $[Rigaku OD (2018). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]$ ), SHELXT (Sheldrick, 2015a ), SHELXL (Sheldrick, 2015b ), OLEX2 (Dolomanov et al., 2009 ).

Supporting information

CCDC reference: 2019647

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989020010439/dj2007sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989020010439/dj2007Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989020010439/dj2007Isup3.cml

checkCIF report

Computing details top

Data collection: CrysAlis PRO (Rigaku OD, 2018); cell refinement: CrysAlis PRO (Rigaku OD, 2018); data reduction: 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).

(1R,3S)-3-(1H-Benzo[d]imidazol-2-yl)-1,2,2-trimethylcyclopentane-1-carboxylic acid top

Crystal data top

C₁₆H₂₀N₂O₂	F(000) = 292
M_r = 272.34	D_x = 1.231 Mg m⁻³
Monoclinic, P2₁	Mo Kα radiation, λ = 0.71073 Å
a = 7.9805 (7) Å	Cell parameters from 748 reflections
b = 10.8671 (8) Å	θ = 3.6–20.3°
c = 8.4912 (7) Å	µ = 0.08 mm⁻¹
β = 94.056 (7)°	T = 293 K
V = 734.55 (10) Å³	Plate, colourless
Z = 2	0.3 × 0.2 × 0.1 mm

Data collection top

Rigaku Oxford Diffraction Xcalibur, Sapphire3 diffractometer	2455 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source	1731 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.058
Detector resolution: 16.1827 pixels mm^-1	θ_max = 25.0°, θ_min = 3.1°
ω scans	h = −9→8
Absorption correction: multi-scan (CrysAlisPro; Rigaku OD, 2018)	k = −12→11
T_min = 0.182, T_max = 1.000	l = −9→10
4859 measured reflections

Refinement top

Refinement on F²	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F² > 2σ(F²)] = 0.065	w = 1/[σ²(F_o²) + (0.0794P)²] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.180	(Δ/σ)_max < 0.001
S = 1.04	Δρ_max = 0.15 e Å⁻³
2455 reflections	Δρ_min = −0.19 e Å⁻³
185 parameters	Absolute structure: Flack x determined using 459 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
1 restraint	Absolute structure parameter: −1.8 (10)
Primary atom site location: dual

Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.3639 (6)	0.5406 (4)	0.7106 (5)	0.0801 (12)
O2	0.2632 (6)	0.7051 (3)	0.5806 (5)	0.0755 (12)
H2	0.289977	0.738749	0.665107	0.113*
N1	0.6692 (5)	0.3376 (4)	0.1635 (5)	0.0593 (11)
N2	0.5767 (6)	0.4717 (4)	−0.0168 (5)	0.0673 (13)
H2A	0.510294	0.522765	−0.067258	0.081*
C1	0.5454 (7)	0.4112 (5)	0.1190 (6)	0.0584 (13)
C2	0.7894 (7)	0.3527 (5)	0.0550 (7)	0.0604 (14)
C3	0.7336 (8)	0.4365 (5)	−0.0588 (7)	0.0654 (14)
C4	0.8269 (10)	0.4678 (6)	−0.1848 (8)	0.0831 (19)
H4	0.786965	0.523797	−0.261269	0.100*
C5	0.9807 (11)	0.4124 (8)	−0.1914 (9)	0.096 (2)
H5	1.047951	0.432369	−0.272757	0.115*
C6	1.0379 (9)	0.3261 (7)	−0.0773 (9)	0.090 (2)
H6	1.142413	0.289532	−0.084821	0.108*
C7	0.9429 (8)	0.2942 (7)	0.0460 (8)	0.0759 (17)
H7	0.980342	0.235604	0.120267	0.091*
C8	0.3928 (7)	0.4359 (5)	0.2036 (6)	0.0580 (13)
H8	0.300846	0.455808	0.125078	0.070*
C9	0.3372 (7)	0.3271 (5)	0.3025 (7)	0.0679 (15)
H9A	0.245558	0.283181	0.246369	0.082*
H9B	0.429868	0.270412	0.324145	0.082*
C10	0.2806 (9)	0.3803 (5)	0.4556 (8)	0.0716 (16)
H10A	0.360495	0.359711	0.543071	0.086*
H10B	0.171604	0.347548	0.477382	0.086*
C11	0.2707 (6)	0.5205 (5)	0.4334 (7)	0.0597 (14)
C12	0.4144 (6)	0.5465 (5)	0.3225 (6)	0.0575 (12)
C13	0.5865 (7)	0.5408 (6)	0.4150 (7)	0.0707 (15)
H13A	0.597970	0.463626	0.469595	0.106*
H13B	0.595652	0.606974	0.490044	0.106*
H13C	0.673547	0.548409	0.343119	0.106*
C14	0.3983 (9)	0.6692 (5)	0.2366 (8)	0.0764 (17)
H14A	0.491174	0.679383	0.171902	0.115*
H14B	0.398423	0.734744	0.312382	0.115*
H14C	0.295039	0.670837	0.171336	0.115*
C15	0.0964 (7)	0.5560 (7)	0.3588 (8)	0.0811 (18)
H15A	0.079109	0.518462	0.256632	0.122*
H15B	0.089416	0.643848	0.348102	0.122*
H15C	0.011624	0.527941	0.425166	0.122*
C16	0.3042 (6)	0.5877 (5)	0.5895 (7)	0.0612 (15)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.100 (3)	0.086 (3)	0.053 (2)	0.005 (2)	−0.011 (2)	0.006 (2)
O2	0.103 (3)	0.063 (2)	0.058 (3)	0.012 (2)	−0.014 (2)	−0.0111 (18)
N1	0.067 (3)	0.060 (3)	0.051 (3)	0.004 (2)	0.001 (2)	0.001 (2)
N2	0.083 (3)	0.067 (3)	0.050 (3)	0.003 (2)	−0.004 (2)	0.006 (2)
C1	0.070 (3)	0.060 (3)	0.043 (3)	−0.001 (3)	−0.006 (2)	−0.001 (2)
C2	0.063 (3)	0.066 (3)	0.051 (3)	−0.002 (3)	0.000 (2)	−0.006 (3)
C3	0.078 (4)	0.063 (3)	0.055 (3)	−0.010 (3)	0.004 (3)	−0.005 (3)
C4	0.104 (5)	0.088 (4)	0.059 (4)	−0.026 (4)	0.016 (3)	−0.001 (3)
C5	0.098 (5)	0.119 (6)	0.073 (5)	−0.039 (5)	0.027 (4)	−0.019 (4)
C6	0.075 (4)	0.113 (6)	0.083 (5)	−0.011 (4)	0.012 (4)	−0.026 (5)
C7	0.071 (4)	0.090 (4)	0.066 (4)	0.000 (3)	0.001 (3)	−0.011 (3)
C8	0.068 (3)	0.056 (3)	0.049 (3)	0.002 (2)	−0.007 (2)	−0.002 (2)
C9	0.074 (4)	0.055 (3)	0.074 (4)	−0.001 (3)	0.003 (3)	−0.001 (3)
C10	0.088 (4)	0.061 (3)	0.066 (4)	−0.005 (3)	0.008 (3)	0.005 (3)
C11	0.056 (3)	0.055 (3)	0.067 (4)	0.003 (2)	−0.004 (2)	0.000 (3)
C12	0.061 (3)	0.052 (3)	0.058 (3)	0.001 (2)	−0.002 (2)	0.003 (2)
C13	0.064 (3)	0.071 (3)	0.075 (4)	0.000 (3)	−0.005 (3)	−0.010 (3)
C14	0.102 (5)	0.058 (3)	0.069 (4)	0.007 (3)	0.003 (3)	0.007 (3)
C15	0.063 (3)	0.097 (4)	0.081 (4)	0.005 (4)	−0.012 (3)	−0.019 (4)
C16	0.057 (3)	0.068 (4)	0.058 (4)	0.001 (3)	0.001 (3)	−0.005 (3)

Geometric parameters (Å, º) top

O1—C16	1.216 (6)	C5—C6	1.401 (11)
O2—C16	1.319 (6)	C6—C7	1.380 (9)
N1—C1	1.307 (7)	C8—C9	1.533 (8)
N1—C2	1.386 (7)	C8—C12	1.571 (7)
N2—C1	1.366 (7)	C9—C10	1.520 (9)
N2—C3	1.381 (8)	C10—C11	1.536 (8)
C1—C8	1.481 (8)	C11—C12	1.560 (8)
C2—C3	1.378 (8)	C11—C15	1.537 (7)
C2—C7	1.387 (8)	C11—C16	1.520 (8)
C3—C4	1.388 (8)	C12—C13	1.534 (7)
C4—C5	1.372 (10)	C12—C14	1.521 (8)

C1—N1—C2	106.3 (5)	C10—C9—C8	106.8 (5)
C1—N2—C3	107.9 (5)	C9—C10—C11	106.7 (5)
N1—C1—N2	111.0 (5)	C10—C11—C12	102.7 (4)
N1—C1—C8	127.0 (5)	C10—C11—C15	109.7 (5)
N2—C1—C8	121.9 (5)	C15—C11—C12	112.9 (5)
N1—C2—C7	129.6 (6)	C16—C11—C10	111.4 (5)
C3—C2—N1	109.9 (5)	C16—C11—C12	110.4 (4)
C3—C2—C7	120.5 (6)	C16—C11—C15	109.7 (4)
N2—C3—C4	132.6 (6)	C11—C12—C8	101.4 (4)
C2—C3—N2	104.9 (5)	C13—C12—C8	110.6 (4)
C2—C3—C4	122.5 (6)	C13—C12—C11	110.7 (4)
C5—C4—C3	117.0 (7)	C14—C12—C8	111.1 (4)
C4—C5—C6	120.9 (6)	C14—C12—C11	114.0 (5)
C7—C6—C5	121.6 (7)	C14—C12—C13	108.8 (5)
C6—C7—C2	117.5 (7)	O1—C16—O2	122.4 (5)
C1—C8—C9	113.9 (5)	O1—C16—C11	124.8 (5)
C1—C8—C12	113.2 (4)	O2—C16—C11	112.8 (5)
C9—C8—C12	105.1 (4)

N1—C1—C8—C9	−30.0 (7)	C7—C2—C3—N2	177.5 (5)
N1—C1—C8—C12	90.0 (6)	C7—C2—C3—C4	−1.0 (8)
N1—C2—C3—N2	−0.1 (6)	C8—C9—C10—C11	10.7 (7)
N1—C2—C3—C4	−178.6 (5)	C9—C8—C12—C11	−35.1 (5)
N1—C2—C7—C6	179.1 (5)	C9—C8—C12—C13	82.4 (6)
N2—C1—C8—C9	153.8 (5)	C9—C8—C12—C14	−156.6 (5)
N2—C1—C8—C12	−86.2 (6)	C9—C10—C11—C12	−32.7 (6)
N2—C3—C4—C5	−178.8 (6)	C9—C10—C11—C15	87.5 (6)
C1—N1—C2—C3	−1.0 (6)	C9—C10—C11—C16	−150.8 (5)
C1—N1—C2—C7	−178.3 (6)	C10—C11—C12—C8	41.1 (5)
C1—N2—C3—C2	1.1 (6)	C10—C11—C12—C13	−76.3 (5)
C1—N2—C3—C4	179.4 (6)	C10—C11—C12—C14	160.6 (5)
C1—C8—C9—C10	140.0 (5)	C10—C11—C16—O1	13.9 (8)
C1—C8—C12—C11	−160.0 (4)	C10—C11—C16—O2	−166.9 (5)
C1—C8—C12—C13	−42.5 (6)	C12—C8—C9—C10	15.6 (6)
C1—C8—C12—C14	78.5 (6)	C12—C11—C16—O1	−99.5 (6)
C2—N1—C1—N2	1.7 (6)	C12—C11—C16—O2	79.7 (5)
C2—N1—C1—C8	−174.8 (5)	C15—C11—C12—C8	−76.9 (5)
C2—C3—C4—C5	−0.8 (9)	C15—C11—C12—C13	165.7 (5)
C3—N2—C1—N1	−1.8 (6)	C15—C11—C12—C14	42.6 (6)
C3—N2—C1—C8	174.9 (5)	C15—C11—C16—O1	135.5 (6)
C3—C2—C7—C6	2.0 (8)	C15—C11—C16—O2	−45.3 (7)
C3—C4—C5—C6	1.4 (10)	C16—C11—C12—C8	160.0 (4)
C4—C5—C6—C7	−0.4 (10)	C16—C11—C12—C13	42.6 (6)
C5—C6—C7—C2	−1.3 (9)	C16—C11—C12—C14	−80.5 (5)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···N1ⁱ	0.82	1.82	2.631 (6)	170
N2—H2A···O1ⁱⁱ	0.86	2.16	2.871 (6)	140
C14—H14C···C2ⁱⁱⁱ	0.96	2.81	3.439 (8)	124

Symmetry codes: (i) −x+1, y+1/2, −z+1; (ii) x, y, z−1; (iii) −x+1, y+1/2, −z.

Intramolecular short contacts (Å) in compound 4 together with the sums of the respective van der Waals radii top

The van der Waals radii sum values (Zefirov et al., 1997) are given in parentheses.

H8···H15A	2.26 (2.34)	H15B···H14C	2.32 (2.34)
H13C···C1	2.57 (2.87)	H13B···C16	2.54 (2.87)

References

Burgi, H.-B. & Dunitz, J. D. (1994). Structure correlation, Vol. 2, pp. 741-784. Weinheim: VCH. Google Scholar
Chuev, V. P., Buzov, A. A., Kovalenko, S. N., Merzlikin, S. I. & Shtrygol, S. Yu. (2017). Pharmaceutical antidiabetic composition based on (+)-cis-3-(1H-benzimidazol-2-yl)-1,2,2-trimethylcyclopentane carboxylic acid. Patent RU 2624872, C1, 07 July 2017. Google Scholar
Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339–341. Web of Science CrossRef CAS IUCr Journals Google Scholar
Dong, Y., Li, Q., Wang, J., Lu, L., Wang, Y., Bao, L., Wang, Z. & Zhang, Y. (2016). Mendeleev Commun. 26, 166–168. Web of Science CrossRef CAS Google Scholar
Gilbert, J. G., Addison, A. W., Palaniandavar, M. & Butcher, R. J. (2002). J. Heterocycl. Chem. 39, 399–404. Web of Science CSD CrossRef CAS Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
Ivachtchenko, A., Kovalenko, S., Parkhomenko, O. & Chernykh, V. (2002). Heterocycl. Commun. 8, 329–330. CAS Google Scholar
Ivachtchenko, A. V., Mitkin, O. D., Kravchenko, D. V., Kovalenko, S. M., Shishkina, S. V., Bunyatyan, N. D., Konovalova, I. S., Ivanov, V. V., Konovalova, O. D. & Langer, T. (2019). Crystals, 9, 644–660. Web of Science CSD CrossRef Google Scholar
Jain, M., Merzlikin, S. I. & Merzlikin, D. S. (2009). Benzimidazole derivatives and the use thereof, PCT Int. Appl., WO 2009/093990, 30 July 2009. Google Scholar
Kovalenko, S. N., Vasil'ev, M. V., Sorokina, I. V., Chernykh, V. P., Turov, A. V. & Rudnev, S. A. (1998). Chem. Heterocycl. Compd. 34, 1412–1415. CrossRef CAS Google Scholar
Merzlikin, S. I. & Jain, M. (2009). Method for the treatment of metabolic syndrome X, PCT Int. Appl., WO 2009005483, A1, 08 January 2009. Google Scholar
Merzlikin, S. I. & Podgayny, D. G. (2008). Zh. Org. Farmats. Khim. 6, 67–71. CAS Google Scholar
Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249–259. Web of Science CrossRef CAS IUCr Journals Google Scholar
Rigaku OD (2018). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England. Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Spackman, P. R., Jayatilaka, D. & Spackman, M. A. (2017). CrystalExplorer17. University of Western Australia. https://hirshfeldsurface.net. Google Scholar
Zefirov, Yu. V. (1997). Kristallographiya, 42, 936-958. CAS Google Scholar
Zimmet, P., Alberti, K. G. M. M. & Shaw, J. (2001). Nature, 414, 782–787. Web of Science CrossRef PubMed CAS Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.