Pimobendan B from powder diffraction data

Zvirgzdins, A.; Delina, M.; Mishnev, A.; Actins, A.

doi:10.1107/S1600536813028353

organic compounds

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doi:10.1107/S1600536813028353

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Pimobendan B from powder diffraction data

Alvis Zvirgzdins,^a ^* Mara Delina,^a Anatoly Mishnev ^b and Andris Actins ^a

^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.

CCDC reference: 966608

Related literature

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 )

Experimental

Crystal data

C₁₉H₁₈N₄O₂
M_r = 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
2θ_min = 3.5°, 2θ_max = 70.00°, 2θ_step = 0.01°

Refinement

R_p = 0.019
R_wp = 0.026
R_exp = 0.020
R_Bragg = 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	D⋯A	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 ); cell refinement: FOX (Favre-Nicolin & Černý, 2002 ); data reduction: FOX; program(s) used to solve structure: FOX; 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 ).

Supporting information

CCDC reference: 966608

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536813028353/hb7139sup1.cif

Rietveld powder data: contains datablock I. DOI: 10.1107/S1600536813028353/hb7139Isup2.rtv

Supporting information file. DOI: 10.1107/S1600536813028353/hb7139Isup3.cdx

Supporting information file. DOI: 10.1107/S1600536813028353/hb7139Isup4.cml

checkCIF report

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

	Fig. 1. The molecular structure of the title compound showing 50% probability ellipsoids and hydrogen atoms are shown as small spheres of arbitrary radii.
	Fig. 2. Packing diagram of the title compound viewed along the b axis. Blue lines indicate hydrogen bonds.
	Fig. 3. Stacking interactions in the crystal structure of title compound
	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

C₁₉H₁₈N₄O₂	V = 1788.2 (5) Å³
M_r = 334.37	Z = 4
Monoclinic, P2₁/c	D_x = 1.24 Mg m⁻³
Hall symbol: -P 2ybc	Cu Kα radiation, λ = 1.54184 Å
a = 18.891 (5) Å	µ = 0.68 mm⁻¹
b = 9.9619 (5) Å	T = 293 K
c = 9.5029 (8) Å	white
β = 90.799 (13)°	cylinder, 16 × 0.5 mm

Data collection top

Bruker D8 diffractometer	Data collection mode: transmission
Radiation source: sealed X-ray tube	Scan method: step
None monochromator	2θ_min = 3.5°, 2θ_max = 70.00°, 2θ_step = 0.01°
Specimen mounting: capillary

Refinement top

Refinement on I_net	134 parameters
Least-squares matrix: full	56 restraints
R_p = 0.019	75 constraints
R_wp = 0.026	Hydrogen site location: inferred from neighbouring sites
R_exp = 0.020	H-atom parameters not refined
R_Bragg = 0.015
χ² = 1.690	(Δ/σ)_max = 0.01
6651 data points	Background function: linear extrapolation
Profile function: Pseudo Voigt

Crystal data top

C₁₉H₁₈N₄O₂	V = 1788.2 (5) Å³
M_r = 334.37	Z = 4
Monoclinic, P2₁/c	Cu Kα radiation, λ = 1.54184 Å
a = 18.891 (5) Å	µ = 0.68 mm⁻¹
b = 9.9619 (5) Å	T = 293 K
c = 9.5029 (8) Å	cylinder, 16 × 0.5 mm
β = 90.799 (13)°

Data collection top

Bruker D8 diffractometer	Scan method: step
Specimen mounting: capillary	2θ_min = 3.5°, 2θ_max = 70.00°, 2θ_step = 0.01°
Data collection mode: transmission

Refinement top

R_p = 0.019	6651 data points
R_wp = 0.026	134 parameters
R_exp = 0.020	56 restraints
R_Bragg = 0.015	H-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

	x	y	z	U_iso*/U_eq
N1	0.01915 (12)	0.62643 (12)	−0.14418 (12)	0.01267*
C2	0.17167 (12)	0.65440 (12)	0.07706 (12)	0.01267*
N3	0.41366 (13)	0.52345 (13)	0.03230 (13)	0.01267*
N4	0.34263 (13)	0.53781 (13)	−0.01834 (13)	0.01267*
C5	0.43319 (13)	0.53662 (13)	0.17085 (13)	0.01267*
C6	0.22286 (12)	0.58183 (12)	0.01645 (12)	0.01267*
O7	−0.27870 (17)	0.93069 (17)	0.00050 (17)	0.01267*
C8	−0.00564 (12)	0.70860 (12)	−0.04114 (12)	0.01267*
O9	0.49920 (13)	0.54750 (13)	0.19404 (13)	0.01267*
C10	0.10535 (12)	0.66256 (12)	0.01531 (12)	0.01267*
N11	0.04376 (12)	0.73283 (12)	0.05732 (12)	0.01267*
C12	−0.13383 (17)	0.70975 (17)	−0.11682 (17)	0.01267*
C13	0.20788 (12)	0.51835 (12)	−0.11605 (12)	0.01267*
C14	0.29607 (13)	0.58849 (13)	0.06534 (13)	0.01267*
C15	−0.09123 (17)	0.88148 (17)	0.04048 (17)	0.01267*
C16	0.31636 (13)	0.63793 (13)	0.21183 (13)	0.01267*
C17	0.37363 (13)	0.54600 (13)	0.27154 (13)	0.01267*
C18	0.14285 (12)	0.52292 (12)	−0.18095 (12)	0.01267*
C19	0.09089 (12)	0.59914 (12)	−0.11154 (12)	0.01267*
C20	−0.07552 (17)	0.77153 (17)	−0.04901 (17)	0.01267*
C21	−0.20225 (17)	0.76004 (17)	−0.10811 (17)	0.01267*
C22	−0.21504 (17)	0.87352 (17)	−0.02608 (17)	0.01267*
C23	0.34340 (13)	0.78483 (13)	0.19844 (13)	0.01267*
C24	−0.15891 (17)	0.93136 (17)	0.05152 (17)	0.01267*
C25	−0.33907 (17)	0.86902 (17)	−0.06608 (17)	0.01267*
H26	0.13416	0.47697	−0.26987	0.0152*
H27	0.24355	0.46651	−0.16258	0.0152*
H28	0.18217	0.69913	0.16336	0.0152*
H29	−0.05380	0.92376	0.09189	0.0152*
H30	−0.16806	1.00299	0.11652	0.0152*
H31	−0.24066	0.72624	−0.16210	0.0152*
H32	−0.12618	0.63253	−0.17586	0.0152*
H33	−0.38045	0.92304	−0.04037	0.0152*
H34	−0.34437	0.78145	−0.02928	0.0152*
H35	−0.33452	0.86891	−0.16468	0.0152*
H36	0.27557	0.63704	0.27202	0.0152*
H37	0.35319	0.45789	0.28346	0.0152*
H38	0.39052	0.57826	0.36071	0.0152*
H39	0.35524	0.82003	0.29000	0.0152*
H40	0.30710	0.84168	0.15603	0.0152*
H41	0.38474	0.78628	0.14061	0.0152*
H42	0.44322	0.50470	−0.04847	0.0152*
H43	0.03860	0.78640	0.13920	0.0152*

Geometric parameters (Å, º) top

O7—C22	1.358 (4)	C16—C23	1.556 (2)
O7—C25	1.435 (4)	C16—C17	1.521 (3)
O9—C5	1.268 (3)	C18—C19	1.412 (3)
N1—C8	1.3642 (19)	C21—C22	1.396 (2)
N1—C19	1.413 (3)	C22—C24	1.407 (4)
N3—N4	1.426 (3)	C2—H28	0.95
N3—C5	1.3687 (19)	N3—H42	0.97
N4—C14	1.296 (3)	N11—H43	0.95
N11—C8	1.334 (3)	C12—H32	0.96
N11—C10	1.420 (3)	C13—H27	0.96
C2—C6	1.344 (3)	C15—H29	0.95
C2—C10	1.378 (3)	C16—H36	0.97
C5—C17	1.490 (3)	C17—H37	0.97
C6—C14	1.454 (3)	C17—H38	0.96
C6—C13	1.4337 (17)	C18—H26	0.97
C8—C20	1.462 (4)	C21—H31	0.94
C10—C19	1.3848 (17)	C23—H39	0.96
C12—C20	1.410 (4)	C23—H40	0.97
C12—C21	1.390 (4)	C23—H41	0.96
C13—C18	1.368 (3)	C24—H30	0.96
C14—C16	1.5207 (19)	C25—H33	0.98
C15—C24	1.377 (4)	C25—H34	0.95
C15—C20	1.421 (3)	C25—H35	0.94

C22—O7—C25	116.05 (17)	C14—C16—C17	108.38 (13)
C8—N1—C19	107.21 (14)	C14—C16—C23	107.98 (10)
N4—N3—C5	123.69 (18)	C17—C16—C23	111.36 (18)
N3—N4—C14	118.38 (14)	C5—C17—C16	109.74 (12)
C8—N11—C10	106.35 (12)	C13—C18—C19	115.67 (12)
N4—N3—H42	107.00	N1—C19—C18	132.23 (13)
C5—N3—H42	129.00	C10—C19—C18	121.47 (19)
C10—N11—H43	127.00	N1—C19—C10	106.28 (15)
C8—N11—H43	127.00	C8—C20—C12	122.36 (16)
C6—C2—C10	120.30 (13)	C8—C20—C15	119.7 (2)
O9—C5—C17	129.25 (14)	O7—C22—C21	127.2 (3)
N3—C5—C17	115.3 (2)	C10—C2—H28	121.00
O9—C5—N3	115.26 (18)	C6—C13—H27	121.00
C13—C6—C14	118.42 (17)	C15—C24—C22	120.41 (18)
C2—C6—C13	118.65 (19)	C12—C21—C22	119.6 (2)
C2—C6—C14	121.70 (13)	C21—C22—C24	119.3 (3)
N11—C8—C20	125.48 (14)	C6—C2—H28	119.00
N1—C8—C20	122.63 (16)	C20—C12—H32	119.00
N1—C8—N11	111.60 (19)	C20—C15—H29	119.00
N11—C10—C19	108.49 (17)	C24—C15—H29	119.00
C2—C10—C19	120.71 (17)	C21—C12—H32	118.00
N11—C10—C2	130.76 (12)	C12—C20—C15	116.2 (3)
C20—C12—C21	122.47 (18)	C18—C13—H27	116.00
C6—C13—C18	123.12 (17)	O7—C22—C24	113.20 (18)
N4—C14—C6	115.89 (14)	C14—C16—H36	110.00
C6—C14—C16	122.25 (17)	C17—C16—H36	110.00
N4—C14—C16	121.6 (2)	C23—C16—H36	109.00
C20—C15—C24	121.7 (2)	C5—C17—H37	109.00

Hydrogen-bond geometry (Å, º) top

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

D—H···A	D—H	H···A	D···A	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+3/2, z+1/2; (iii) −x, y−1/2, −z−1/2.

Hydrogen-bond geometry (Å, º) top

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

D—H···A	D—H	H···A	D···A	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+3/2, z+1/2; (iii) −x, y−1/2, −z−1/2.

Acknowledgements

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

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