organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890

Pimobendan B from powder diffraction data

aUniversity of Latvia, Department of Chemistry, Kr. Valdemara Street 48, Riga, LV-1013, Latvia, and bLatvian Institute of Organic Synthesis, Aizkraukles Street 21, Riga, LV-1006, Latvia
*Correspondence e-mail: alvis.zvirgzdins@lais.lv

(Received 15 September 2013; accepted 15 October 2013; online 19 October 2013)

The title mol­ecule, C19H18N4O2 {systematic name: (RS)-6-[2-(4-meth­oxy­phen­yl)-1H-benzimidazol-5-yl]-5-methyl-4,5-di­hydro­pyridazin-3(2H)-one}, adopts an extended conformation. The dihedral angles between the central benzimidazole ring sytem and the pendant meth­oxy­phenyl and pyridazinone residues are 1.41 (18) and 9.7 (3)°, respectively. In the crystal, N—H⋯N hydrogen bonds link the imadazole groups into [001] chains, and pairs of N—H⋯O hydrogen bonds link the pyridazinone groups into dimers. Together, these generate a two-dimensional supra­molecular structure parallel to (010). The layers are linked by C—H⋯π inter­actions.

Related literature

For general information about pimobendan, see: Gordon et al. (2006[Gordon, S. G., Miller, M. V. & Saunders, A. B. (2006). J. Am. Anim. Hosp. Assoc. 42, 90-93.]). For related crystalline forms, see: Boeren et al. (2011[Boeren, M. M. M., Paridaans, R. J., Petkune, S., Lusis, V. & Muceniece, Dz. (2011). US Patent No. 20,110,152,283 A1 20110623.]). Semi-empirical calculations were carried out with HYPERCHEM Professional (Hypercube, 2010[Hypercube (2010). HYPERCHEM Professional. Hypercube, Inc., Gainesville, Florida, USA.]). Refinement of lattice parameters and peak profile determination were performed by Le Bail profile fitting (Le Bail et al., 1988[Le Bail, A., Duroy, H. & Fourquet, J. L. (1988). Mater. Res. Bull. 23, 447-452.])

[Scheme 1]

Experimental

Crystal data
  • C19H18N4O2

  • Mr = 334.37

  • Monoclinic, P 21 /c

  • a = 18.891 (5) Å

  • b = 9.9619 (5) Å

  • c = 9.5029 (8) Å

  • β = 90.799 (13)°

  • V = 1788.2 (5) Å3

  • Z = 4

  • Cu Kα radiation

  • λ = 1.54184 Å

  • μ = 0.68 mm−1

  • T = 293 K

  • cylinder, 16 × 0.5 mm

Data collection
  • Bruker D8 diffractometer

  • Specimen mounting: capillary

  • Data collection mode: transmission

  • Scan method: step

  • 2θmin = 3.5°, 2θmax = 70.00°, 2θstep = 0.01°

Refinement
  • Rp = 0.019

  • Rwp = 0.026

  • Rexp = 0.020

  • RBragg = 0.015

  • χ2 = 1.690

  • 6651 data points

  • 134 parameters

  • 56 restraints

  • H-atom parameters not refined

Table 1
Hydrogen-bond geometry (Å, °)

Cg1 is the centroid of the C12/C20/C15/C24/C22/C21 ring.

D—H⋯A D—H H⋯A DA D—H⋯A
N3—H42⋯O9i 0.97 1.85 2.817 (3) 174
N11—H43⋯N1ii 0.95 2.27 3.2039 (19) 168
C18—H26⋯Cg1iii 0.97 2.43 3.369 (2) 161
Symmetry codes: (i) -x+1, -y+1, -z; (ii) [x, -y+{\script{3\over 2}}, z+{\script{1\over 2}}]; (iii) [-x, y-{\script{1\over 2}}, -z-{\script{1\over 2}}].

Data collection: Dicvol (Boultif & Louër, 2004[Boultif, A. & Louër, D. (2004). J. Appl. Cryst. 37, 724-731.]); cell refinement: FOX (Favre-Nicolin & Černý, 2002[Favre-Nicolin, V. & Černý, R. (2002). J. Appl. Cryst. 35, 734-743.]); data reduction: FOX; program(s) used to solve structure: FOX; program(s) used to refine structure: FULLPROF (Rodriguez-Carvajal, 1993[Rodriguez-Carvajal, J. (1993). Physica B, 192, 55-69.]), CRYSTALS (Betteridge et al., 2003[Betteridge, P. W., Carruthers, J. R., Cooper, R. I., Prout, K. & Watkin, D. J. (2003). J. Appl. Cryst. 36, 1487.]) and PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]); molecular graphics: Mercury (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]); software used to prepare material for publication: WinPlotr (Roisnel & Rodriguez-Carvajal, 2000[Roisnel, T. & Rodriguez-Carvajal, J. (2000). EPDIC, 7, 118-123.]) and publCIF (Westrip, 2010[Westrip, S. P. (2010). J. Appl. Cryst. 43, 920-925.]).

Supporting information


Experimental top

Indexing of patterns was performed with WinPlotr (Roisnel & Rodriguez-Carvajal, 2000) and Dicvol (Boultif & Louër, 2004) using reflections in the 2θ range of 3.00 – 30.00°. Space groups for all polymorphs were determined using FOX 1.9.7.0 (Favre-Nicolin & Černý, 2002). The correct space group was selected based on possible systematic extinctions. The compositions of unit cell and the values of Z were determined in all cases from the unit cell volume.

Refinement of lattice parameters and peak profile determination were performed by Le Bail profile fitting (Le Bail et al., 1988) using FOX. Structures were determined with FOX by parallel tempering algorithm. The best cost function values were reached by using automatic temperature schedule and Cauchy-type displacement amplitude schedule.

The input model of pimobendan molecule was obtained from semiempirical calculations by HYPERCHEM Professional (Hypercube, 2010) for both - R and S enentiomer. The molecules were described in terms of Fenske-Hall Z-matrix format ans structure solutions The dihedral angles C21—C22—O7—C25; N11—C8—C20—C15 and C2—C6—C14—N4 were defined as intra­molecular degrees of freedom and were varied during the structure determinations.

Synthesis and crystallization top

Pimobendan form B was prepared in three steps. At the first step, its dioxane solvate was held in a thermostat at 100°C for one day. At the second step obtained powder were suspended in methanol and suspension were hold in a dry box while all methanol evaporates. At the end obtained methanol solvate were desolvatated at 100°C.

Refinement top

Rietveld refinement for the final structure was performed by Fullprof. Hydrogen atoms were added with Crystals according to the molecular geometry and their positions were not refined. Since the bond lengths and angles departed to unacceptable values, atomic parameters for (N3, N4, C5, O9, C14, C16, C17,C23), (N1, N11, C2, C6, C8, C10, C13, C18, C19) and (O7, C12, C15, C20, C21, C22, C24, C25) were refined as rigid bodies.

Results and discussion top

Several crysltalline forms of pimobendan and its preparation are patented (Boeren et al., 2011) but there are no crystal data for these polymorphs or pseudopolymorhs. This article is focused on the structure determination from powder data and description of the pimobendan B form.

Lowest value of cost function were obtained by using molecular model of R enanti­omer in structure determination process. The final structure of pimobendane B form shows that pimobendane molecule is almost linear because the dihedral angle value of N11—C8—C20—C15 = 9.7 (3)° and C13—C6—C14—N4 = 1.41 (18)°. The crystal structure of title compound consist of molecules that are conected via hydrogen bonds that are formed between two imidazole groups (N11—H43···N1ii) and two di­hydro­pyradazinone groups (N3—H42···O9i and N3i—H42···O9). There are T-shaped C—H···π stacking inter­actions between benzol in meth­oxy­phenyl and benzimidazol groups.

Modeling with PLATON (Spek, 2009) showed that the crystal structure contain voids ( 69Å3) accessible to solvent molecules. Since pimobendan B form are obtained from its methanol solvate by desolvation at 100°C, these voids may be result of desolvation at temperature that is almost twice as large as boiling point this solvent. Pimobendan B form at ambient conditions tends to form monohydrate. Unstabilty of pimobendane B form at ambient conditions may be explained by penetration of water molecules into voids of crystal structure.

Related literature top

For general information about pimobendan, see: Gordon et al. (2006). For related crystalline forms, see: Boeren et al. (2011). Semi-empirical calculations were carried out with HYPERCHEM Professional (Hypercube, 2010). Refinement of lattice parameters and peak profile determination were performed by Le Bail profile fitting (Le Bail et al., 1988)

Computing details top

Data collection: WinPlotr (Roisnel & Rodriguez-Carvajal, 2000) and Dicvol (Boultif & Louër, 2004); cell refinement: FOX (Favre-Nicolin & Černý, 2002); data reduction: FOX (Favre-Nicolin & Černý, 2002); program(s) used to solve structure: FOX (Favre-Nicolin & Černý, 2002); program(s) used to refine structure: FULLPROF (Rodriguez-Carvajal, 1993), CRYSTALS (Betteridge et al., 2003) and PLATON (Spek, 2009); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: WinPlotr (Roisnel & Rodriguez-Carvajal, 2000) and publCIF (Westrip, 2010).

Figures top
[Figure 1] Fig. 1. The molecular structure of the title compound showing 50% probability ellipsoids and hydrogen atoms are shown as small spheres of arbitrary radii.
[Figure 2] Fig. 2. Packing diagram of the title compound viewed along the b axis. Blue lines indicate hydrogen bonds.
[Figure 3] Fig. 3. Stacking interactions in the crystal structure of title compound
[Figure 4] Fig. 4. Scattered X-ray intensities of title compound at ambient conditions as a function of diffraction angle 2θ. The observed pattern (red dots), the best Rietveld fit profiles (line) and the difference curve between the observed and calculated profiles (below) are shown.
(RS)-6-[2-(4-Methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2H)-one top
Crystal data top
C19H18N4O2V = 1788.2 (5) Å3
Mr = 334.37Z = 4
Monoclinic, P21/cDx = 1.24 Mg m3
Hall symbol: -P 2ybcCu Kα radiation, λ = 1.54184 Å
a = 18.891 (5) ŵ = 0.68 mm1
b = 9.9619 (5) ÅT = 293 K
c = 9.5029 (8) Åwhite
β = 90.799 (13)°cylinder, 16 × 0.5 mm
Data collection top
Bruker D8
diffractometer
Data collection mode: transmission
Radiation source: sealed X-ray tubeScan method: step
None monochromator2θmin = 3.5°, 2θmax = 70.00°, 2θstep = 0.01°
Specimen mounting: capillary
Refinement top
Refinement on Inet134 parameters
Least-squares matrix: full56 restraints
Rp = 0.01975 constraints
Rwp = 0.026Hydrogen site location: inferred from neighbouring sites
Rexp = 0.020H-atom parameters not refined
RBragg = 0.015
χ2 = 1.690(Δ/σ)max = 0.01
6651 data pointsBackground function: linear extrapolation
Profile function: Pseudo Voigt
Crystal data top
C19H18N4O2V = 1788.2 (5) Å3
Mr = 334.37Z = 4
Monoclinic, P21/cCu Kα radiation, λ = 1.54184 Å
a = 18.891 (5) ŵ = 0.68 mm1
b = 9.9619 (5) ÅT = 293 K
c = 9.5029 (8) Åcylinder, 16 × 0.5 mm
β = 90.799 (13)°
Data collection top
Bruker D8
diffractometer
Scan method: step
Specimen mounting: capillary2θmin = 3.5°, 2θmax = 70.00°, 2θstep = 0.01°
Data collection mode: transmission
Refinement top
Rp = 0.0196651 data points
Rwp = 0.026134 parameters
Rexp = 0.02056 restraints
RBragg = 0.015H-atom parameters not refined
χ2 = 1.690
Special details top

Refinement. Rietveld refinement for the final structure was performed by Fullprof. Hydrogen atoms were added with Crystals according to the molecular geometry and their positions were not refined, but final refinement was performed with hydrogen atoms. Since the bond lengths and angles departed to unacceptable values, atomic parameters for (N3, N4, C5, O9, C14, C16, C17,C23), (N1, N11, C2, C6, C8, C10, C13, C18, C19) and (O7, C12, C15, C20, C21, C22, C24, C25) were refined as rigid bodies.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
N10.01915 (12)0.62643 (12)0.14418 (12)0.01267*
C20.17167 (12)0.65440 (12)0.07706 (12)0.01267*
N30.41366 (13)0.52345 (13)0.03230 (13)0.01267*
N40.34263 (13)0.53781 (13)0.01834 (13)0.01267*
C50.43319 (13)0.53662 (13)0.17085 (13)0.01267*
C60.22286 (12)0.58183 (12)0.01645 (12)0.01267*
O70.27870 (17)0.93069 (17)0.00050 (17)0.01267*
C80.00564 (12)0.70860 (12)0.04114 (12)0.01267*
O90.49920 (13)0.54750 (13)0.19404 (13)0.01267*
C100.10535 (12)0.66256 (12)0.01531 (12)0.01267*
N110.04376 (12)0.73283 (12)0.05732 (12)0.01267*
C120.13383 (17)0.70975 (17)0.11682 (17)0.01267*
C130.20788 (12)0.51835 (12)0.11605 (12)0.01267*
C140.29607 (13)0.58849 (13)0.06534 (13)0.01267*
C150.09123 (17)0.88148 (17)0.04048 (17)0.01267*
C160.31636 (13)0.63793 (13)0.21183 (13)0.01267*
C170.37363 (13)0.54600 (13)0.27154 (13)0.01267*
C180.14285 (12)0.52292 (12)0.18095 (12)0.01267*
C190.09089 (12)0.59914 (12)0.11154 (12)0.01267*
C200.07552 (17)0.77153 (17)0.04901 (17)0.01267*
C210.20225 (17)0.76004 (17)0.10811 (17)0.01267*
C220.21504 (17)0.87352 (17)0.02608 (17)0.01267*
C230.34340 (13)0.78483 (13)0.19844 (13)0.01267*
C240.15891 (17)0.93136 (17)0.05152 (17)0.01267*
C250.33907 (17)0.86902 (17)0.06608 (17)0.01267*
H260.134160.476970.269870.0152*
H270.243550.466510.162580.0152*
H280.182170.699130.163360.0152*
H290.053800.923760.091890.0152*
H300.168061.002990.116520.0152*
H310.240660.726240.162100.0152*
H320.126180.632530.175860.0152*
H330.380450.923040.040370.0152*
H340.344370.781450.029280.0152*
H350.334520.868910.164680.0152*
H360.275570.637040.272020.0152*
H370.353190.457890.283460.0152*
H380.390520.578260.360710.0152*
H390.355240.820030.290000.0152*
H400.307100.841680.156030.0152*
H410.384740.786280.140610.0152*
H420.443220.504700.048470.0152*
H430.038600.786400.139200.0152*
Geometric parameters (Å, º) top
O7—C221.358 (4)C16—C231.556 (2)
O7—C251.435 (4)C16—C171.521 (3)
O9—C51.268 (3)C18—C191.412 (3)
N1—C81.3642 (19)C21—C221.396 (2)
N1—C191.413 (3)C22—C241.407 (4)
N3—N41.426 (3)C2—H280.95
N3—C51.3687 (19)N3—H420.97
N4—C141.296 (3)N11—H430.95
N11—C81.334 (3)C12—H320.96
N11—C101.420 (3)C13—H270.96
C2—C61.344 (3)C15—H290.95
C2—C101.378 (3)C16—H360.97
C5—C171.490 (3)C17—H370.97
C6—C141.454 (3)C17—H380.96
C6—C131.4337 (17)C18—H260.97
C8—C201.462 (4)C21—H310.94
C10—C191.3848 (17)C23—H390.96
C12—C201.410 (4)C23—H400.97
C12—C211.390 (4)C23—H410.96
C13—C181.368 (3)C24—H300.96
C14—C161.5207 (19)C25—H330.98
C15—C241.377 (4)C25—H340.95
C15—C201.421 (3)C25—H350.94
C22—O7—C25116.05 (17)C14—C16—C17108.38 (13)
C8—N1—C19107.21 (14)C14—C16—C23107.98 (10)
N4—N3—C5123.69 (18)C17—C16—C23111.36 (18)
N3—N4—C14118.38 (14)C5—C17—C16109.74 (12)
C8—N11—C10106.35 (12)C13—C18—C19115.67 (12)
N4—N3—H42107.00N1—C19—C18132.23 (13)
C5—N3—H42129.00C10—C19—C18121.47 (19)
C10—N11—H43127.00N1—C19—C10106.28 (15)
C8—N11—H43127.00C8—C20—C12122.36 (16)
C6—C2—C10120.30 (13)C8—C20—C15119.7 (2)
O9—C5—C17129.25 (14)O7—C22—C21127.2 (3)
N3—C5—C17115.3 (2)C10—C2—H28121.00
O9—C5—N3115.26 (18)C6—C13—H27121.00
C13—C6—C14118.42 (17)C15—C24—C22120.41 (18)
C2—C6—C13118.65 (19)C12—C21—C22119.6 (2)
C2—C6—C14121.70 (13)C21—C22—C24119.3 (3)
N11—C8—C20125.48 (14)C6—C2—H28119.00
N1—C8—C20122.63 (16)C20—C12—H32119.00
N1—C8—N11111.60 (19)C20—C15—H29119.00
N11—C10—C19108.49 (17)C24—C15—H29119.00
C2—C10—C19120.71 (17)C21—C12—H32118.00
N11—C10—C2130.76 (12)C12—C20—C15116.2 (3)
C20—C12—C21122.47 (18)C18—C13—H27116.00
C6—C13—C18123.12 (17)O7—C22—C24113.20 (18)
N4—C14—C6115.89 (14)C14—C16—H36110.00
C6—C14—C16122.25 (17)C17—C16—H36110.00
N4—C14—C16121.6 (2)C23—C16—H36109.00
C20—C15—C24121.7 (2)C5—C17—H37109.00
Hydrogen-bond geometry (Å, º) top
Cg1 is the centroid of the C12/C20/C15/C24/C22/C21 ring.
D—H···AD—HH···AD···AD—H···A
N3—H42···O9i0.971.852.817 (3)174
N11—H43···N1ii0.952.273.2039 (19)168
C18—H26···Cg1iii0.972.433.369 (2)161
Symmetry codes: (i) x+1, y+1, z; (ii) x, y+3/2, z+1/2; (iii) x, y1/2, z1/2.
Hydrogen-bond geometry (Å, º) top
Cg1 is the centroid of the C12/C20/C15/C24/C22/C21 ring.
D—H···AD—HH···AD···AD—H···A
N3—H42···O9i0.971.852.817 (3)174
N11—H43···N1ii0.952.273.2039 (19)168
C18—H26···Cg1iii0.972.433.369 (2)161
Symmetry codes: (i) x+1, y+1, z; (ii) x, y+3/2, z+1/2; (iii) x, y1/2, z1/2.
 

Acknowledgements

This work was supported by the European Regional Development Fund (No. 2011/0014/2DP/2.1.1.1.0/10/APIA/ VIAA/092).

References

First citationBetteridge, P. W., Carruthers, J. R., Cooper, R. I., Prout, K. & Watkin, D. J. (2003). J. Appl. Cryst. 36, 1487.  Web of Science CrossRef IUCr Journals
First citationBoeren, M. M. M., Paridaans, R. J., Petkune, S., Lusis, V. & Muceniece, Dz. (2011). US Patent No. 20,110,152,283 A1 20110623.
First citationBoultif, A. & Louër, D. (2004). J. Appl. Cryst. 37, 724–731.  Web of Science CrossRef CAS IUCr Journals
First citationFavre-Nicolin, V. & Černý, R. (2002). J. Appl. Cryst. 35, 734–743.  Web of Science CrossRef CAS IUCr Journals
First citationGordon, S. G., Miller, M. V. & Saunders, A. B. (2006). J. Am. Anim. Hosp. Assoc. 42, 90–93.  Web of Science CrossRef PubMed
First citationHypercube (2010). HYPERCHEM Professional. Hypercube, Inc., Gainesville, Florida, USA.
First citationLe Bail, A., Duroy, H. & Fourquet, J. L. (1988). Mater. Res. Bull. 23, 447–452.  CrossRef CAS Web of Science
First citationMacrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466–470.  Web of Science CrossRef CAS IUCr Journals
First citationRodriguez-Carvajal, J. (1993). Physica B, 192, 55–69.  CrossRef CAS Web of Science
First citationRoisnel, T. & Rodriguez-Carvajal, J. (2000). EPDIC, 7, 118–123.
First citationSpek, A. L. (2009). Acta Cryst. D65, 148–155.  Web of Science CrossRef CAS IUCr Journals
First citationWestrip, S. P. (2010). J. Appl. Cryst. 43, 920–925.  Web of Science CrossRef CAS IUCr Journals

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.

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Follow Acta Cryst. E
Sign up for e-alerts
Follow Acta Cryst. on Twitter
Follow us on facebook
Sign up for RSS feeds