Eprosartan mesylate, an angiotensin II receptor antagonist

The title compound, eprosartan mesylate {systematic name: 2-butyl-1-(4-carboxybenzyl)-5-[(E)-2-carboxy-3-(thiophen-2-yl)prop-1-enyl]-1H-imidazol-3-ium methanesulfonate}, C23H25N2O4S+·CH3O3S−, one of the angiotensin II-receptor antagonists, is effective in regulating hypertension, induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, renal failure and glaucoma. In the eprosartan residue, which appears in this crystal in the cationic imidazolium form, the benzene ring plane is almost orthogonal to that of the imidazole ring, making a dihedral angle of 87.89 (2)°. The thiophene ring forms dihedral angles of 66.54 (2) and 67.12 (2)° with the benzene and imidazole rings, respectively. The imidazolium NH group and the H atom of the aromatic carboxyl group participate in hydrogen bonds with the the O atoms of the anion, thus forming centrosymmetric aggregates made up of two cations and two anions each. The second carboxyl group further links the above-mentioned aggregates through a conventional centrosymmetric hydrogen-bonding motif into infinite chains along [011].


Comment
Angiotensin-II-receptor antagonists are safe and effective agents for the treatment of hypertension and heart failure, either alone, or in conjunction with hydrochlorothiazide, a thiazide diuretic (Hillaert et al., 2003;Punzi & Punzi, 2005). The title compound, eprosartan mesylate, is one of the highly selective, orally active, non-peptide angiotensin-II-receptor antagonists, which has low likelihood for undesirable drug interactions. It is reported that eprosartan mesylate may be potentially attractive in the treatment of elderly patients who are often on multiple drug regimens (Punzi et al.,2004).
The crystal structure of eprosartan in the form of monohydrate of neutral molecule has been recently published (Wu et al., 2009). Although the title compound was known already for more than a decade (Sheng et al.,1999), its crystal structure has not yet been reported and represents the subject of the present paper.
The asymmetric unit, comprising eprosartan cation and mesylate anion, is shown in Fig.1. Geometric parameters of the cation are comparable to that of the neutral eprosartan (Wu et al., 2009). Phenyl ring plane is almost orthogonal to imidazole plane, corresponding dihedral angle being equal to 87.89 (2)°. Thiophene plane forms dihedral angles of 66.54 (2)° and 67.12 (2)°, with phenyl and imidazole planes, respectively. Conformation of the molecule in the structure of eprosartan hydrate (Wu et al., 2009) shows substantial differences; in particular the dihedral angle between thiophene and imidazole planes in hydrate structure is much smaller [24.78 (2)°].
The imidazolium NH-group and carboxyl H atom bound to O3 participate in H-bonds with the the oxygen atoms of the anion thus forming centrosymmetric aggregates made up of two cations and two anions each (Fig.2). The second carboxyl H atom (bound to O1) is involved in centrosymmetric H-bonding motive, typical for carboxyl structures; in this way the above mentioned aggregates get linked into infinite chains stretching along the [011] direction.

Experimental
Methyl-4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl) methyl] benzoate (10 g), was added to a mixture of 135 ml of n-heptane and 15 ml of dichloromethane at room temperature. The reaction mixture was maintained in Dean Stark apparatus at 343-353 K for the duration of 15-30 min. Then piperidinium acetate catalyst (2.8 g of piperidine and 5.55 g of acetic acid) dissolved in the mixture of 8.5 ml n-heptane and 1.5 ml dichloromethane was added to the reaction mixture followed by addition of 2-thiophene-2-yl-methylmalonic acid monoethyl ester (17.3 g). Reaction temperature was maintained at 343-353 K for 20 h. After reaction completion, cooling to room temperature, ethanol and de-ionized water were added, and pH was adjusted to 1 using 1M HCl. The layers were separated, and the aqueous layer was washed with n-heptane. Then pH of the aqueous layer was adjusted to 6 with 1M NaOH and the solution was extracted with toluene. Combined organic layers were concentrated under vacuum, the residue was dissolved in 130 ml of ethanol, and solution of NaOH (13.5 g of NaOH in 65 ml of water) was added and stirred for 1-2 h. Thereafter, pH of the reaction mixture was adjusted to 4.5-5 with 1M HCl. The precipitated solid was filtered, washed with water and dried under vacuum to yield 11 g of eprosartan (Bandi et al., 2010). 10 g of eprosartan was dissolved in 150 ml of isopropyl alcohol at room temperature. 6.8 g of methane sulfonic acid was added supplementary materials sup-2 to the clear solution which was then stirred for about 2 h. The solid was filtered, washed with isopropyl alcohol and dried to yield 10 g of eprosartan mesylate, which was recrystallized from ethanol solution, giving colorless crystals of the title compound suitable for X-ray diffraction.

Refinement
The difference density map indicated the presence of a possible H atom at the N2 atom, thus confirming proton transfer from mesylate to imidazole. Subsequently, this H atom was placed in calculated position with N-H 0.88 Å and refined as riding with U iso (H) = 1.2U eq (N). All other H atoms were placed in calculated positions as well with O-H 0.84 Å, and C-H bonds of 0.99 Å for methylene, 0.98 Å for methyl, and 0.95Å for aromatic H atoms; all H-atoms were included in the refinement in riding model approximation, with U iso (H) = 1.2U eq of the carrying atom (1.5 U eq in case of OH and methyl groups). Temperature factors of the O4 and C23 atoms were restrained to represent isotropic behavior [ISOR 0.003 according to SHELXL97 (Sheldrick, 2008)]. The highest peak in the residual difference map [1.35 e Å -3 ] is at a distance of 0.97 Å from the O4 atom.   supplementary materials sup-9