Crystal structure of azilsartan methyl ester ethyl acetate hemisolvate

Zhengyi Li; Rong Liu; Meilan Zhu; Liang Chen; Xiaoqiang Sun

doi:10.1107/S2056989014028023

. 2015 Jan 3;71(Pt 2):o84–o85. doi: 10.1107/S2056989014028023

Crystal structure of azilsartan methyl ester ethyl acetate hemisolvate

Zhengyi Li ^a, Rong Liu ^a, Meilan Zhu ^b, Liang Chen ^a, Xiaoqiang Sun ^a,^*

PMCID: PMC4384622 PMID: 25878884

Abstract

The title compound, C₂₆H₂₂N₄O₅ (systematic name: methyl 2-ethoxy-1-{4-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]benzyl}-1H-1,3-benzodiazole-7-carboxylate ethyl acetate hemisolvate), was obtained via cyclization of methyl (Z)-2-ethoxy-1-{(2′-(N′-hydroxycarbamimidoyl)-[1,1′-biphenyl]-4-yl)methyl}-1H-benzo[d]imidazole-7-carboxylate with diphenyl carbonate. There are two independent molecules (A and B) with different conformations and an ethyl acetate solvent molecule in the asymmetric unit. In molecule A, the dihedral angle between the benzene ring and its attached oxadiazole ring is 59.36 (17); the dihedral angle between the benzene rings is 43.89 (15) and that between the benzene ring and its attached imidazole ring system is 80.06 (11)°. The corresponding dihedral angles in molecule B are 58.45 (18), 50.73 (16) and 85.37 (10)°, respectively. The C—O—C—C_m (m = methyl) torsion angles for the ethoxy side chains attached to the imidazole rings in molecules A and B are 93.9 (3) and −174.6 (3)°, respectively. In the crystal, the components are linked by N—H⋯N and C—H⋯O hydrogen bonds, generating a three-dimensional network. Aromatic π–π stacking interactions [shortest centroid–centroid separation = 3.536 (3)Å] are also observed.

Keywords: crystal structure, azilsartan, azilsartan methyl ester, antihypertension

Related literature

For general background to azilsartan, an angiotensin II type 1 (AT1) receptor blocker (ARB) having a perfect antihypertensive effect, see: Michel et al. (2013 ▸); Weltman et al. (2012 ▸); Ojima et al. (2011 ▸). For the synthesis of azilsartan methyl ester, the key synthetic intermediate of azilsartan, see: Kohara et al. (1996 ▸); Rádl et al. (2013 ▸). graphic file with name e-71-00o84-scheme1.jpg

Experimental

Crystal data

2C₂₆H₂₂N₄O₅·C₄H₈O₂
M _r = 1029.06
Triclinic,
a = 13.662 (5) Å
b = 14.928 (6) Å
c = 15.356 (10) Å
α = 95.459 (11)°
β = 106.226 (11)°
γ = 116.524 (8)°
V = 2601 (2) Å³
Z = 2
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 293 K
0.25 × 0.20 × 0.18 mm

Data collection

Bruker APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2009 ▸) T _min = 0.977, T _max = 0.983
14182 measured reflections
9024 independent reflections
6365 reflections with I > 2σ(I)
R _int = 0.030

Refinement

R[F ² > 2σ(F ²)] = 0.064
wR(F ²) = 0.221
S = 1.01
9024 reflections
699 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.55 e Å⁻³
Δρ_min = −0.28 e Å⁻³

Data collection: APEX2 (Bruker, 2009 ▸); cell refinement: SAINT (Bruker, 2009 ▸); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▸); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S2056989014028023/hb7346sup1.cif

e-71-00o84-sup1.cif^{(39.7KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989014028023/hb7346Isup2.hkl

e-71-00o84-Isup2.hkl^{(441.4KB, hkl)}

Click here for additional data file.^{(10.9KB, cml)}

Supporting information file. DOI: 10.1107/S2056989014028023/hb7346Isup3.cml

Click here for additional data file.^{(1.4MB, tif)}

. DOI: 10.1107/S2056989014028023/hb7346fig1.tif

The molecular structure of the title compound. Displacement ellipsoids are drawn at the 30% probability level. All H atoms have been omitted for clarity.

Click here for additional data file.^{(2.3MB, tif)}

. DOI: 10.1107/S2056989014028023/hb7346fig2.tif

Crystal packing of (I). Hydrogen bonds are shown as dashed lines.

CCDC reference: 934880

Additional supporting information: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (, ).

DHA	DH	HA	D A	DHA
N5H5AN4ⁱ	1.01	1.85	2.862(3)	176
N7H7N2ⁱ	0.90	2.01	2.905(3)	173
C12H12AO5ⁱⁱ	0.97	2.58	3.421(4)	145
C30H30O9ⁱⁱⁱ	0.93	2.58	3.484(3)	163

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Acknowledgments

We gratefully acknowledge financial support from the NSFC (No. 21002009), the Scientific and Technological Project of Jiangsu Province (BY2014037–01), the Major Program for Natural Science Research of Jiangsu Colleges and Universities (12 K J A150002, 14 K J A150002) and the Qing Lan Project of Jiangsu Province.

supplementary crystallographic information

S1. Comment

Azilsartan (TAK-536) as an angiotensin II type 1 (AT1) receptor blocker (ARB) has perfect antihypertensive effect (Ojima et al., 2011; Michel et al., 2013; Weltman et al., 2012). Azilsartan methyl ester, as the key synthetic intermediate of azilsartan has being paid widely attention. Although the synthesis of azilsartan methyl ester has been descripted in many literatures (Kohara et al., 1996; Rádl et al., 2013), there was no particular work on the structural characterization involving crystal structure. We herein present the crystal structure of methyl 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) -[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7- carboxylate (I).

In the molecular structure (Fig. 1), there are two independent title molecules with different conformations and an ethyl acetate solvent molecule to form the minimum repeat unit of the crystal. The dihedral angles between the two phenyl rings (C38–C43 with C44–C49; C13–C18 with C19–C24) of phenylbenzenes are 50.7 (2)° and 43.9 (1)°, respectively. The new constructed 5-oxo-1,2,4-oxadiazole heterocycle (N5–C26–O4–N6–C25 or N7–C51–O10–N8–C50) adopts a planer structure. In the packing structure (Fig. 2), the two different title compound molecules formed a dimer through two intermolecular N–H···N hydrogen bond (N5–H5A···N4 and N7–H7···N2) between the imidazole rings and 5-oxo-1,2,4-oxadiazole rings. Then intermolecular π–π stacking (Cg1···Cg2ⁱ, 3.62 (2) Å, symmetry codes: (i), -x, 1 - y, 1 - z. Cg1 and Cg2 are the centroids of the N3–C33–C32–N4–C34 and C28–C33 rings, respectively) between the two benzo[d]imidazole rings and C–H···O weak interactions (C12–H12A···O5 and C30–H30···O9) link the adjacent dimers.

S2. Experimental

A mixture of methyl (Z)-2-ethoxy-1-((2'-(N'-hydroxycarbamimidoyl) -[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (6 g, 13.5 mmol), diphenyl carbonate (4.34 g, 20.25 mmol) and K₂CO₃ (2.8 g, 20.25 mmol) in DMSO (150 ml) was stirred at room temperature for 5 h. After the reaction, the mixture was poured into water (400 ml) and the insoluble portion was filtered off. The aqueous solution was acidified with 1 N HCl to PH = 3–4, and the formed precipitate was filtered off, washed with sodium carbonate solution, and dried in vacuo to afford a white solid (5.28 g, 83% yield, m.p. 468–470 K). Colourless blocks were obtained by slow evaporation of an ethyl acetate solution at room temperature.