4-(3-Methyl­anilino)-N-[N-(1-methyl­ethyl)carbamo­yl]pyridinium-3-sulfon­amidate (torasemide) methanol 0.25-solvate 0.25-hydrate

Gianluca Bartolucci; Bruno Bruni; Silvia A Coran; Massimo Di Vaira

doi:10.1107/S160053680901160X

. 2009 Apr 8;65(Pt 5):o970–o971. doi: 10.1107/S160053680901160X

4-(3-Methylanilino)-N-[N-(1-methylethyl)carbamoyl]pyridinium-3-sulfonamidate (torasemide) methanol 0.25-solvate 0.25-hydrate

Gianluca Bartolucci ^a, Bruno Bruni ^a, Silvia A Coran ^a, Massimo Di Vaira ^b,^*

PMCID: PMC2977669 PMID: 21584012

Abstract

The title compound, C₁₆H₂₀N₄O₃S·0.25CH₄O·0.25H₂O, is a hydrate/methanol solvate of torasemide, a diuretic drug used in the treatment of hypertension. The asymmetric unit contains two torasemide molecules and half-occupied methanol and water molecules. It is isomorphous with the previously reported nonsolvated T–II form of torasemide. The water molecules contribute to the stability of the structure by participating in an extensive system of O—H⋯O hydrogen bonds; N—H⋯N and N—H⋯O hydrogen bonds are also present. Both asymmetric molecules of torasemide form inversion dimers in the crystal.

Related literature

For background on the medicinal properties and polymorphism of torasemide, see: Uchida et al. (1991 ▶); Broekhuysen et al. (1986 ▶); Ghys et al. (1985 ▶); Ishido & Senzaki (2008 ▶); Cosin & Diez (2002 ▶); Murray et al. (2001 ▶); Dupont et al. (1978 ▶); Danilovski et al. (2001 ▶).

Experimental

Crystal data

C₁₆H₂₀N₄O₃S·0.25CH₄O·0.25H₂O
M _r = 360.94
Monoclinic,
a = 16.8477 (2) Å
b = 11.5951 (1) Å
c = 20.3256 (2) Å
β = 108.646 (1)°
V = 3762.21 (7) Å³
Z = 8
Cu Kα radiation
μ = 1.74 mm⁻¹
T = 200 K
0.45 × 0.38 × 0.12 mm

Data collection

Oxford Diffraction Xcalibur PX Ultra CCD diffractometer
Absorption correction: multi-scan (ABSPACK; Oxford Diffraction, 2006 ▶) T _min = 0.502, T _max = 1.000 (expected range = 0.407–0.811)
50677 measured reflections
7402 independent reflections
6976 reflections with I > 2σ(I)
R _int = 0.031

Refinement

R[F ² > 2σ(F ²)] = 0.052
wR(F ²) = 0.156
S = 1.04
7402 reflections
496 parameters
6 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.95 e Å⁻³
Δρ_min = −0.57 e Å⁻³

Data collection: CrysAlisPro CCD (Oxford Diffraction, 2006 ▶); cell refinement: CrysAlisPro CCD; data reduction: CrysAlisPro RED (Oxford Diffraction, 2006 ▶); program(s) used to solve structure: SIR97 (Altomare et al., 1999 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 (Farrugia, 1997 ▶) and PLATON (Spek, 2009 ▶); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008 ▶), WinGX (Farrugia, 1999 ▶) and PARST (Nardelli, 1995 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S160053680901160X/hb2934sup1.cif

e-65-0o970-sup1.cif^{(31.4KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S160053680901160X/hb2934Isup2.hkl

e-65-0o970-Isup2.hkl^{(354.9KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1N⋯N3	0.83 (3)	2.37 (3)	2.986 (2)	131 (2)
N1—H1N⋯N3ⁱ	0.83 (3)	2.38 (3)	3.060 (2)	139 (2)
N2—H2N⋯O5ⁱⁱ	0.84 (3)	2.14 (3)	2.847 (2)	142 (3)
N2—H2N⋯O6ⁱⁱ	0.84 (3)	2.21 (3)	2.822 (2)	130 (2)
N4—H4N⋯O1ⁱ	0.90 (3)	2.02 (3)	2.919 (2)	174 (3)
N5—H5N⋯N7	0.86 (3)	2.21 (3)	2.910 (2)	138 (2)
N5—H5N⋯N7ⁱⁱⁱ	0.86 (3)	2.47 (3)	3.098 (2)	130 (2)
N6—H6N⋯O2^iv	0.92 (3)	2.53 (3)	3.036 (2)	115 (2)
N6—H6N⋯O3^iv	0.92 (3)	1.79 (3)	2.667 (2)	158 (2)
N8—H8N⋯O4ⁱⁱⁱ	0.85 (3)	2.21 (3)	3.034 (3)	164 (3)
O7—H7O⋯O8	0.923 (8)	1.70 (5)	2.480 (8)	140 (7)
O7—H7O⋯O8^v	0.923 (8)	2.50 (10)	2.995 (9)	114 (8)
O8—H82O⋯O6	0.75 (5)	2.00 (6)	2.735 (5)	166 (11)
O8—H81O⋯O6^v	0.75 (5)	2.02 (6)	2.721 (5)	158 (12)

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

Acknowledgments

The authors acknowledge financial support from the Italian Ministero dell’Istruzione, dell’Universitá e della Ricerca.

supplementary crystallographic information

Comment

Torasemide has been developed as a longlasting loop diuretic that combines the effects of both furosemide and spironolactone (Uchida et al., 1991; Broekhuysen et al., 1986; Ghys et al., 1985). It is used in the treatment of hypertension and of edema associated with congestive heart failure (Ishido & Senzaki, 2008). Torasemide has been reported to be more effective than furosemide in chronic heart failure, with a lower mortality (Cosin & Diez, 2002; Murray et al., 2001).

Three polymorphic forms have been reported up to now for torasemide, denoted T–I, T–II (Dupont et al., 1978) and T–N (Danilovski et al., 2001). We have obtained crystals of a solvate (I) which, besides being isomorphous with form T–II (with the a and c unit cell axes interchanged), contains water and methanol molecules interspersed in the lattice. The solvate molecules are disorderly arranged in proximity of a twofold rotation axis and one molecule of each type resides, with 0.50 occupancy, in the asymmetric unit of the monoclinic unit cell which comprises, in addition, two independent torasemide molecules (Fig. 1), as found for form T–II. Although data collection for I was carried out at a temperature of 200 K, only a 0.8% decrease in the cell volume was found with respect to the room–temperature value of T–II; this might be ascribed in part to the presence of the additional solvate molecules in the lattice of I. The 200 K data collection temperature represented a compromise between conditions of high thermal motion at room temperature, particularly affecting the terminal methyl groups of the chain, and crystal deterioration at lower temperatures. The conformations of the two independent molecules in the structure of I (respectively formed by carbon atoms C1 to C16 and C17 to C32, hereafter referred to as molecules A and B, in the above order, for consistency with previous notation) are similar to those of the A and B molecules of the T–II form, with an 8.4° largest difference in the value of the C22—N8—C23—C24 torsion angle (this corresponds to the C6—N4—C7—C9 chain of molecule B of the T–II form, according to Dupont's notation for the non–solvated form). The present values of the dihedral angles between the best planes through the phenyl and pyridyl rings in the two molecules, of 61.18 (7)° (A) and 78.71 (7)° (B), match those reported (61.2° and 79.1°) for the corresponding molecules of form T—II.

It should be noted that the present set of data, contrary to the older one for T–II, has allowed to assign unambiguously and refine the positions of all hydrogen atoms attached to the N atoms in the two molecules. In particular, the N—H amine bond formed by N1 in molecule A and by N5 in B, is almost parallel, in each case, to the plane of the pyridyl ring, yielding a substantially planar immediate environment of the nitrogen atom, whereas such bond is considerably displaced from the plane of the phenyl ring. This may rationalize the large difference, ca 0.09 Å, between the lengths of the two N—C bonds formed by N1 and, respectively, N5 in the two molecules. Indeed, as a consequence of the above N—H bond orientations, the nitrogen lone pair may favourably interact with antibonding orbitals of the pyridyl ring, but not with those of the phenyl ring, yielding shorter N1—C1 and N5—C17 bonds compared to the N1—C10 and N5—C26 ones (with the additional consequence that the two contiguous C—C bonds in each pyridyl ring are the longest of all bonds in the present rings).

The crystal structure is stabilized by an extensive system of hydrogen bonds (Table 1), several of these in bifurcated mode. There are centrosymmetric dimers of molecule A, internally connnected by the N1···N3 (N1···N3 = 2.986 (2) Å, N1—H1N···N3 = 131 (2)°), N1···N3ⁱ (N1···N3ⁱ = 3.060 (2) Å, N1—H1N···N3ⁱ = 139 (2)°; symmetry code (i): - x, 1 - y, - z) and N4···O1ⁱ (N4···O1ⁱ = 2.919 (2) Å, N4—H4N···O1ⁱ = 174 (3)°) hydrogen bonds and centrosymmetric dimers of molecule B, linked by the N5···N7 (N5···N7 = 2.910 (2) Å, N5—H5N···N7 = 138 (2)°), N5···N7ⁱⁱⁱ (N5···N7ⁱⁱⁱ = 3.098 (2) Å, N5—H5N···N7ⁱⁱⁱ = 130 (2)°; symmetry code (iii): 1 - x, - y, - z) and N8···O4ⁱⁱⁱ (N8···O4ⁱⁱⁱ = 3.034 (3) Å, N8—H8N···O4ⁱⁱⁱ = 164 (3)° hydrogen bonds. Dimers of the above two types, connected through the N2···O5ⁱⁱ (N2···O5ⁱⁱ = 2.847 (2) Å, N2—H2N···O5ⁱⁱ = 142 (3)°; symmetry code (ii): 1 - x, 1 - y, - z) and N2···O6ⁱⁱ (N2···O6ⁱⁱ = 2.822 (2) Å, N2—H2N···O6ⁱⁱ = 130 (2)°) hydrogen bonds, form chains in an AABBAA fashion, which are stacked, with no intervening hydrogen bonds among them, on planes parallel to the ab cell face (Fig. 2). On contiguous planes of this set, spaced by c/2 intervals, the chains are alternatively parallel to the [110] and [1–10] directions. Furthermore, a three–dimensional network arises since dimeric groups from the above adjacent planes are connected through the N6···O2^iv (N6···O2^iv = 3.036 (2) Å, N6—H6N···O2^iv = 115 (2)°; symmetry code (iv): 1/2 + x, 1 - y, 1/2 + z) and N6···O3^iv (N6···O3^iv = 2.667 (2) Å, N6—H6N···O3^iv = 158 (2)°) linkages. Also the latter system of connections gives rise to planar arrays of AABBAA chains, these being parallel to the bc cell face (Fig. 3). Also in this case, there are alternative [01–1] and [011] chain orientations on adjacent planes, at a/2 intervals. It is remarkable that a similar arrangement (with one exception, see the accompanying paper) is found for the structure of the T–N polymorph, in spite of quite different cell settings. The (disordered) water molecule bridges between the chains (Fig. 4), through the O8···O6 (O8···O6 = 2.735 (5) Å, O8—H82O···O6 = 166 (11)°) and O8···O6^v (O8···O6^v = 2.721 (5) Å, O8—H81O···O6^v = 158 (12)°; symmetry code (v): 3/2 - x, y, 1/2 - z) hydrogen bonds and each water fraction accepts one such bond, O7···O8 (O7···O8 = 2.480 (8) Å, O7—H7O···O8 = 140 (7)°), from the closest fraction of the methanol molecule.

Experimental

Samples of torasemide were kindly provided by SIMS (SIMS srl, Reggello Firenze, Italy). Crystals of (I), in the form of colourless prisms suitable for X-ray diffraction analysis, were obtained by slow evaporation from 2:1 methanol:butanol solutions. The presence of a small amount of water molecules in the structure may be rationalized considering that the operations were not performed in completely anhydrous conditions.