N-(4-{4-[2-(Trifluoro­meth­oxy)phen­yl]piperazin-1-yl}but­yl)thio­phene-2-carboxamide dihydrate

Jin Cai

doi:10.1107/S160053681005155X

. 2010 Dec 15;67(Pt 1):o125. doi: 10.1107/S160053681005155X

N-(4-{4-[2-(Trifluoromethoxy)phenyl]piperazin-1-yl}butyl)thiophene-2-carboxamide dihydrate

Jin Cai ^a,^*

PMCID: PMC3050331 PMID: 21522636

Abstract

In the title compound, C₂₀H₂₄F₃N₃O₂S·2H₂O, a dopamine D3 ligand, the piperazine ring adopts a chair conformation while the piperazine and benzene rings form a dihedral angle of 47.71 (6)°. In the crystal, molecules are linked by intermolecular N—H⋯O and O—H⋯O hydrogen bonds. In the molecular structure, the F atoms of the trifluoromethyl group are disordered over two sites with occupancies of 0.69 (11) and 0.31 (11).

Related literature

For the synthesis of the title compound and its derivatives, see: Leopoldo et al. (2002 ▶); Robarge et al. (2001 ▶). For the pharmacological activity of the dopamine D3 ligand, see: Pilla et al. (1999 ▶); Garcia-Ladona & Cox (2003 ▶); Wood et al. (2000 ▶); Luedtke & Mach (2003 ▶). For structure–activity relationships for the dopamine D3 receptor, see: Bettinetti et al. (2002) ▶; Leopoldo et al. (2002 ▶); Dutta et al., (2004 ▶).

Experimental

Crystal data

C₂₀H₂₄F₃N₃O₂S·2H₂O
M _r = 463.51
Orthorhombic,
a = 9.361 (2) Å
b = 35.966 (9) Å
c = 6.9102 (17) Å
V = 2326.5 (10) Å³
Z = 4
Mo Kα radiation
μ = 0.19 mm⁻¹
T = 298 K
0.53 × 0.49 × 0.47 mm

Data collection

Bruker SMART CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 1999 ▶) T _min = 0.905, T _max = 0.915
11753 measured reflections
2234 independent reflections
1588 reflections with I > 2σ(I)
R _int = 0.051

Refinement

R[F ² > 2σ(F ²)] = 0.056
wR(F ²) = 0.173
S = 1.05
2234 reflections
308 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.28 e Å⁻³
Δρ_min = −0.34 e Å⁻³

Data collection: SMART (Bruker, 1999 ▶); cell refinement: SAINT (Bruker, 1999 ▶); data reduction: SAINT; 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

Crystal structure: contains datablocks I, global. DOI: 10.1107/S160053681005155X/bg2379sup1.cif

e-67-0o125-sup1.cif^{(22.3KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S160053681005155X/bg2379Isup2.hkl

e-67-0o125-Isup2.hkl^{(109.8KB, 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—H1⋯O3ⁱ	0.86	2.17	2.929 (5)	148
O3—H21⋯N2ⁱⁱ	0.85	2.02	2.835 (4)	160
O3—H22⋯O1ⁱⁱⁱ	0.85	1.98	2.822 (5)	171
O4—H23⋯O1^iv	0.85	2.09	2.830 (7)	146
O4—H24⋯O3^v	0.85	2.07	2.831 (6)	150

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

Acknowledgments

We are grateful to the National Natural Science Foundation of China (project No. 30701052) for financial support.

supplementary crystallographic information

Comment

The title compound was designed as a dopamine D3 ligand. The dopamine D3 receptor is recognized as a potential therapeutic target for the treatment of various neurological and psychiatric disorders, such as schizophrenia, Parkinson's disease and drug abuse (Pilla et al., 1999; Garcia-Ladona et al., 2003; Wood et al., 2000; Luedtke et al., 2003). Study of structure-activity relationships for dopamine D3 receptor are helpfull to rationalize the discovery of super-potent and highly selective dopamine D3 receptor antagonists and partial agonists (Bettinetti et al., 2002; Leopoldo et al., 2002; Dutta et al., 2004). We report here the crystal structure of the title compound, which was synthesized by the two-component reaction of 4-(4-(2-(trifluoromethoxy) phenyl) piperazin-1-yl)butan-1-amine and thiophene-2-carbonyl chloride. In the title compound, the piperazine ring (C10/C11/C12/C13/N2/N3) adopts a chair conformation, atoms C10, C11, C12 and C13 are coplanar, with atoms N2 and N3 deviating from the plane by -0.661 (5) and 0.679 (5) Å, respectively (Fig. 1).The dihedral angle between the C10/C11/C12/C13 plane and the C15/C16/C17/C18/C19/C20 plane is 47.71 (6) °.The molecules are linked by N1–H1···O3 intermolecular hydrogen bonds (Table 1, Fig. 2). In the molecular structure, the fluorine atoms of trifluoromethyl group is disordered over two sites with occupancies of 0.69 (11) and 0.31 (11).

Experimental

All chemicals used(reagent grade) were commercially available. 4-(4-(2-(trifluoromethoxy)phenyl)piperazin-1-yl)butan-1-amine 0.64 g (2mmol) was dissovled by 20 mL dichloromethane, then K₂CO₃ 2 g (15mmol) and thiophene-2-carbonyl chloride 0.29 g (2mmol) were added under ice-cooling and stirred for 30 min. The mixture was filtered, and evaporated the dissolvent.Purification of the crude product by a column chramotagraphy (v:v chloroform: methanol = 40:1) afforded the title compound (0.56g, 65.2%) Crystals suitable for X-ray diffraction were obtained by slow evaporation of an ethanol solution at room temperature. m.p. 358–359 K;¹H-NMR(CDCl₃, 300MHz), δ(ppm): 1.63-1.69(m, 4H), 2.47(t, 2H, J=6.93Hz), 2.61(t, 4H, J=4.74Hz), 3.09(t, 4H, J=4.82Hz), 3.47(q, 2H, J=6.26Hz), 6.36(br, 1H), 6.98-7.07(m, 3H), 7.18-7.26(m, 2H), 7.43-7.51(m, 2H); ¹³C-NMR(CDCl₃, 300MHz), δ(ppm): 24.3, 27.6, 27.7, 40.0, 50.7, 50.8, 50.9, 53.4, 58.0, 119.9, 122.0, 122.3, 122.4, 122.5, 122.6, 127.5, 127.5, 127.9, 129.5, 139.2, 142.4, 145.1, 162.0; ESI-MS m/z: 428.2[M+H]⁺; Anal. calcd for C₂₀H₂₄F₃N₃O₂S(%): C 56.19, H 5.66, N 9.83; Found: C 56.25, H 5.70, N 9.83.