2-{2-[4-(4-Fluoro­phen­yl)piperazin-1-yl]-2-oxoeth­yl}-6-(morpholin-4-yl)-4-phenyl­pyridazin-3(2H)-one

Abdullah Aydın; Murat Şüküroğlu; Mehmet Akkurt; Orhan Büyükgüngör

doi:10.1107/S1600536811005071

. 2011 Feb 19;67(Pt 3):o666–o667. doi: 10.1107/S1600536811005071

2-{2-[4-(4-Fluorophenyl)piperazin-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)-4-phenylpyridazin-3(2H)-one

Abdullah Aydın ^a,^*, Murat Şüküroğlu ^b, Mehmet Akkurt ^c, Orhan Büyükgüngör ^d

PMCID: PMC3052151 PMID: 21522416

Abstract

In the title compound, C₂₆H₂₈FN₅O₃, the morpholine ring adopts a chair conformation. The piperazine ring is puckered [Q _T = 0.5437 (15) Å, θ = 8.89 (15) and ϕ = 357.2 (11)°]. The 1,6-dihydropyridazine ring makes dihedral angles of 28.03 (7) and 77.46 (7)° with the phenyl and benzene rings, respectively. In the crystal, molecules are linked along the c axis by C—H⋯O interactions and are flattened parallel to the ac plane. C–H⋯π interactions also contribute to the stability of the structure.

Related literature

For the pharmacological effects, biological activity and synthesis of 3(2H)-pyridazinones, see: Şüküroğlu et al. 2006 ▶; Brogden 1986 ▶. For bond-length data, see: Allen et al. (1987 ▶). For ring conformational analysis, see: Cremer & Pople (1975 ▶). For the quantum mechanical CNDO/2 approximation, see: Pople & Beveridge (1970 ▶).

Experimental

Crystal data

C₂₆H₂₈FN₅O₃
M _r = 477.53
Triclinic,
a = 8.9168 (5) Å
b = 10.7106 (6) Å
c = 13.5147 (8) Å
α = 73.489 (4)°
β = 71.309 (4)°
γ = 83.486 (4)°
V = 1171.87 (12) Å³
Z = 2
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 296 K
0.60 × 0.49 × 0.20 mm

Data collection

STOE IPDS 2 diffractometer
Absorption correction: integration (X-RED32; Stoe & Cie, 2002 ▶) T _min = 0.945, T _max = 0.981
13273 measured reflections
4861 independent reflections
3479 reflections with I > 2σ(I)
R _int = 0.029

Refinement

R[F ² > 2σ(F ²)] = 0.036
wR(F ²) = 0.091
S = 1.03
4861 reflections
316 parameters
H-atom parameters constrained
Δρ_max = 0.12 e Å⁻³
Δρ_min = −0.14 e Å⁻³

Data collection: X-AREA (Stoe & Cie, 2002 ▶); cell refinement: X-AREA; data reduction: X-RED32 (Stoe & Cie, 2002 ▶); program(s) used to solve structure: SIR97 (Altomare et al., 1999 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶); software used to prepare material for publication: WinGX (Farrugia, 1999 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536811005071/ez2227sup1.cif

e-67-0o666-sup1.cif^{(30.6KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536811005071/ez2227Isup2.hkl

e-67-0o666-Isup2.hkl^{(238.1KB, hkl)}

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

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

Cg2, Cg4 and Cg5 are the centroids of the N1/N2/C7–C10, C1–C6 and C21–C26 rings, respectively.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C11—H11B⋯O3ⁱ	0.97	2.41	3.3306 (18)	159
C5—H5⋯Cg5ⁱⁱ	0.93	2.86	3.4941 (18)	127
C13—H13B⋯Cg4ⁱ	0.97	2.92	3.7395 (19)	143
C18—H18A⋯Cg2ⁱⁱⁱ	0.97	2.73	3.5079 (16)	138

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

Acknowledgments

The authors acknowledge the Faculty of Arts and Sciences, Ondokuz Mayıs University, Turkey, for the use of the Stoe IPDS 2 diffractometer (purchased under grant F.279 of the University Research Fund).

supplementary crystallographic information

Comment

In recent years, the 3(2H)-pyridazinone system has aroused a great deal of attention due to its structural relationship to pyrazolone derivatives such as aminopyrine and dipyrone in view of the ring enlargement of pyrazolone to pyridazinone. These drugs possess analgesic and anti-inflammatory activities although they have limitations for their clinical use due to serious side effects such as blood dyscrasias (Şüküroğlu et al., 2006; Brogden, 1986).

A series of 6-morpholino-4-aryl-3(2H)-pyridazinone alkanoic acids, their ester and amide derivatives were prepared and tested for their in vivo analgesic activity by using the p-benzoquinone-induced writhing test. The title compound, C₂₆H₂₈FN₅O₃, generally showed higher activity but caused gastric ulceration in the animals (Şüküroğlu et al., 2006).

In the title molecule (I), Fig. 1, the morpholine ring (N3/O2/C11–C14) adopts a chair conformation. The piperazine ring (N4/N5/C17–C20) is puckered. The conformation of this ring is described by three puckering parameters: Q_T = 0.5437 (15) Å, θ = 8.89 (15) ° and, φ = 357.2 (11) ° (Cremer & Pople, 1975). The 1,6-dihydropyridazine ring (N1/N2/C7–C10) makes dihedral angles of 28.03 (7) and 77.46 (7) ° with the C1–C6 phenyl and C21–C26 benzene rings, respectively. The phenyl and benzene rings make a dihedral angle of 50.17 (8) ° with each other. In the crystal structure, molecules are linked along the c-axis direction and are flattened parallel to the plane containing the a and c axes. Furthermore, C–H···π interactions contribute to the stability of the structure (Table 1). Fig. 2 shows the packing diagram of (I) down the b axis.

Theoretical calculations were carried out using the semiempirical quantum-mechanical CNDO/2 (Complete Neglect of Differential Overlap) method (Pople and Beveridge, 1970). The spatial view of the single molecule calculated as closed-shell in a vacuum is shown in Fig. 3 with atomic labels. The calculated dipole moment of (I) is about 2.795 Debye. The HOMO and LUMO energy levels are -10.013 and 0.832 eV, respectively.

According to the theoretical CNDO/2 and experimental X-ray structural results, the values of the geometric parameters of (I) are almost comparable within the experimental error interval (Allen et al., 1987).

The 1,6-dihydropyridazine ring (N1/N2/C7–C10) forms dihedral angles of 2.24 and 60.48° with the C1–C6 phenyl and C21–C26 benzene rings, respectively. The dihedral angle between the phenyl and benzene rings is 62.62°. The orientations of the planes of the rings are however, slightly different in the CNDO/2 and X-ray results. That is, intermolecular interactions play an important role in determining the crystal state conformation of (I).

Experimental

A reaction mixture containing 2-[4-phenyl-6-(morpholin-4-yl)-3(2H)- pyridazinone-2-yl]acetic acid (0.01 mole) and triethylamine (0.011 mole) in 20 ml dichloromethane at 273 K (ice-bath) was treated with ethyl chloroformate (0,01 mole). After stirring the reaction mixture at 273 K for 15 min, 0.011 mole of 4-(4-fluorophenyl)-piperazine derivative was added to this solution. The final mixture was stirred at room temperature for 24 h and evaporated to dryness and then acetone was added. All undissolved salts were filtered off, the filtrate was evaporated to dryness and the residue was recrystallized from acetone-water (1:1) to yield 62%, [m.p.: 457 K].

¹H-NMR (CDCl₃), δ 7.75 (m, 2H, phenyl-H2, H6), 7.43 (m, 3H, phenyl-H3, H4, H5), 7.23 (s, 1H, pyridazinone-H5), 6.99 (m, 4H, 4-fluorophenyl-H2, H3, H5, H6), 4.98 (s, 2H, N—CH₂—CO), 3.82 (m, 6H, morpholine-H2, H6, piperazine- H2(6)), 3.71 (m, 2H, piperazine-H6(2)), 3.31 (t, 8H, morpholine-H3, H5), 3.15 (m, 4H, piperazine-H3, H5) p.p.m.. IR v_max cm^-1 (KBr): 2845, 1661, 1643. Anal. C, H, N (C₂₆H₂₈FN₅O₃) (Şüküroğlu et al., 2006). Elemental analysis: C₂₆H₂₈FN₅O₃, Calc.(%) / Found (%): C: 65.39/65.54, H: 5.91/5.49, N: 14.67/14.28.