Bosentan monohydrate

Manpreet Kaur; Jerry P Jasinski; Amanda C Keeley; H S Yathirajan; Richard Betz; Thomas Gerber; Ray J Butcher

doi:10.1107/S1600536812048969

. 2012 Dec 5;69(Pt 1):o12–o13. doi: 10.1107/S1600536812048969

Bosentan monohydrate

Manpreet Kaur ^a, Jerry P Jasinski ^b,^*, Amanda C Keeley ^b, H S Yathirajan ^a, Richard Betz ^c, Thomas Gerber ^c, Ray J Butcher ^d

PMCID: PMC3588285 PMID: 23476382

Abstract

In the title compound, C₂₇H₂₉N₅O₆S·H₂O {systematic name: 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide monohydrate], the dihedral angle between the mean planes of the pyrimidine rings is 27.0 (1)°. The dihedral angle between the mean planes of the benzene rings is 47.7 (8)°, forming a U-shaped channel around the chain of twisted pyrimidine rings. The crystal packing is stabilized by O—H⋯O, O—H⋯N and N—H⋯O hydrogen bonds with a single water molecule, and weak O—H⋯N intermolecular interactions between the hydroxy group and one of the pyrimidine rings producing an two-dimensional supramolecular array in the bc plane. The title compound studied was a merohedral twin with the major component being approximately 57%.

Related literature

For reviews of bosentan in the management of pulmonary arterial hypertension and systemic sclerosis, see: Gabbay et al. (2007 ▶); Kumar et al. (2011 ▶); Oldfield & Lyseng-Williamson (2006 ▶). For related structures, see: Singh et al. (1985 ▶); El-Ghamry et al. (2008 ▶); Kant et al. (2012 ▶).

Experimental

Crystal data

C₂₇H₂₉N₅O₆S·H₂O
M _r = 569.63
Monoclinic,
a = 12.3393 (4) Å
b = 15.1238 (6) Å
c = 14.6988 (4) Å
β = 95.037 (3)°
V = 2732.46 (16) Å³
Z = 4
Cu Kα radiation
μ = 1.52 mm⁻¹
T = 123 K
0.79 × 0.43 × 0.22 mm

Data collection

Agilent Xcalibur (Ruby, Gemini) diffractometer
Absorption correction: analytical (CrysAlis RED; Agilent, 2012 ▶) T _min = 0.535, T _max = 0.766
9563 measured reflections
9563 independent reflections
7477 reflections with I > 2σ(I)

Refinement

R[F ² > 2σ(F ²)] = 0.055
wR(F ²) = 0.163
S = 1.03
9563 reflections
373 parameters
3 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.44 e Å⁻³
Δρ_min = −0.77 e Å⁻³

Data collection: CrysAlis PRO (Agilent, 2012 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis RED (Agilent, 2012 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Click here for additional data file.^{(35.7KB, cif)}

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812048969/tk5176sup1.cif

e-69-00o12-sup1.cif^{(35.7KB, cif)}

Click here for additional data file.^{(467.7KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812048969/tk5176Isup2.hkl

e-69-00o12-Isup2.hkl^{(467.7KB, hkl)}

Click here for additional data file.^{(10.3KB, cml)}

Supplementary material file. DOI: 10.1107/S1600536812048969/tk5176Isup3.cml

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
O6—H6⋯N3ⁱ	0.84	2.51	3.317 (2)	162
O6—H6⋯N4ⁱ	0.84	2.60	3.141 (2)	124
O1W—H1W⋯O4	0.80 (2)	2.30 (2)	3.013 (2)	150 (3)
O1W—H2W⋯N4ⁱⁱ	0.81 (2)	2.07 (2)	2.873 (2)	174 (3)
N1—H1A⋯O1W	0.88	1.87	2.721 (2)	163

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

Acknowledgments

MK thanks the UOM for research facilities. RJB acknowledges the NSF–MRI program (grant No. CHE-0619278) for funds to purchase the X-ray diffractometer.

supplementary crystallographic information

Comment

Bosentan (chemically, 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy) -2-(pyrimidin-2-yl)pyrimidin-4-yl]benzene-1-sulfonamide) is a dual endothelin receptor antagonist used in the treatment of pulmonary artery hypertension (PAH). Bosentan is used to treat pulmonary hypertension by blocking the action of endothelin molecules that would otherwise promote narrowing of the blood vessels and lead to high blood pressure. A review of bosentan in the management of pulmonary arterial hypertension is published (Gabbay et al., 2007). Another review on the use of bosentan in pulmonary arterial hypertension and systemic sclerosis is also published (Oldfield & Lyseng-Williamson, 2006). A spectrophotometric method for the determination of bosentan monohydrate in bulk and pharmaceutical dosage forms is reported (Kumar et al., 2011). The crystal structures of some related compounds, viz., N1-(2,6-dimethyl-4-pyrimidinyl)sulphanilamide (Singh et al., 1985), 4-[(3-formyl-4-hydroxyphenyl)diazenyl]-N-(pyrimidin-2-yl)benzenesulfonamide (El-Ghamry et al., 2008) and N-(2-{[5-bromo-2-(morpholin-4-yl)pyrimidin-4-yl]sulfanyl}-4-methoxyphenyl)- 4-methyl benzenesulfonamide (Kant et al., 2012), have been reported. In view of the importance of the title compound, (I), the paper reports its crystal structure.

In (I), the dihedral angle between the mean planes of the two pyrimidine rings is 27.0 (1)° (Fig. 1). The dihedral angle between the mean planes of the two benzene rings is 47.7 (8)° forming a U-shaped channel around the chain of twisted pyrimidine rings. Crystal packing is stabilized by O—H···O, O—H···N and N—H···O hydrogen bonds with a single water molecule and weak O—H···N intermolecular interactions between the hydroxy group and one of the nearby pyrimidine rings (Fig. 2).

Experimental

The title compound was obtained as a gift sample from R. L. Fine Chem, Bengaluru, India. X-ray quality crystals were obtained by slow evaporation of ethanol solution (m.p.: 383–385 K).