research communications\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Volume 71| Part 8| August 2015| Pages 883-885
https://doi.org/10.1107/S2056989015012256

Crystal structures of vortioxetine and its methanol monosolvate

Xin-Bo Zhou,a Jian-Ming Gu,b Meng-ying Sun,a Xiu-Rong Huc* and Su-Xiang Wua

aCollege of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, People's Republic of China, bCenter of Analysis and Measurement, Zhejiang University, Hangzhou, Zhejiang 310028, People's Republic of China, and cChemistry Department, Zhejiang University, Hangzhou, Zhejiang 310028, People's Republic of China
*Correspondence e-mail: huxiurong@zju.edu.cn

Edited by W. T. A. Harrison, University of Aberdeen, Scotland (Received 2 April 2015; accepted 26 June 2015; online 4 July 2015)

Vortioxetine, C18H22N2S, (1), systematic name 1-{2-[(2,4-di­methyl­phen­yl)sulfan­yl]phen­yl}piperazine, a new drug used to treat patients with major depressive disorder, has been crystallized as the free base and its methanol monosolvate, C18H22N2S·CH3OH, (2). In both structures, the vortioxetine mol­ecules have similar conformations: in (1), the dihedral angle between the aromatic rings is 80.04 (16)° and in (2) it is 84.94 (13)°. The C—S—C bond angle in (1) is 102.76 (14)° and the corresponding angle in (2) is 103.41 (11)°. The piperazine ring adopts a chair conformation with the exocyclic N—C bond in a pseudo-equatorial orientation in both structures. No directional inter­actions beyond normal van der Waals contacts could be identified in the crystal of (1), whereas in (2), the vortioxetine and methanol mol­ecules are linked by N—H⋯O and O—H⋯N hydrogen bonds, generating [001] chains.

CCDC references: 1408949; 1408948

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1. Chemical context

Major depressive disorder (MDD) is a disabling mental illness responsible for almost 66 million disability-adjusted life-years globally (Bidzan et al., 2012[Bidzan, L., Mahableshwarkar, A. R., Jacobsen, P., Yan, M. J. & Sheehan, D. V. (2012). Eur. Neuropsychopharmacol. 22, 847-857.]). The medications most often prescribed for depression include the selective serotonin reuptake inhibitors (SSRIs) and the serotonin norepinephrine reuptake inhibitors (SNRIs). As several neurotransmitter pathways may be involved in MDD, anti­depressants possessing two or more complementary modes of action (i.e. multi-modal) have been a focus of MDD therapy for some time (Richelson, 2013[Richelson, E. (2013). Int. J. Neuropsychopharm. 16, 1433-1442.]). One such anti­depressant is vortioxetine.

[Scheme 1]

Vortioxetine is an investigational multi-modal anti­depressant that is believed to work through a combination of two pharmacological modes of action: serotonin (5-HT) reuptake inhibition and 5-HT receptor activity (du Jardin et al., 2014[Jardin, K. G. du, Jensen, J. B., Sanchez, C. & Pehrson, A. L. (2014). Eur. Neuropsychopharmacol. 24, 160-171.]; Hussar et al., 2014[Hussar, D. A. & Lye, A. (2014). J. Am. Pharm. Assoc. (2003), 54, 91-94.]). In 2013, vortioxetine hydro­bromide was approved by the US Food and Drug Administration (FDA) for the once-daily treatment of adults with MDD in the USA (Gibb & Deeks, 2014[Gibb, A. & Deeks, E. D. (2014). Drugs, 74, 135-145.]. The patent of Benny et al. (2007[Benny, B. A., Andre, F., Heidi, L. D. D., Arne, M., Rene, H., Bryan, S. T., Munch, R. L. J. M. M., Harold, R. M., Jorgen, B., Morten, R. & Nicholas, M. (2007). World Patent WO2007114005A1.]) discloses crystalline vortioxetine base and a variety of crystalline vortioxetine salts, comprising polymorphs of vortioxetine hydro­bromide as well as a hemihydrate and an ethyl acetate solvate thereof, and crystalline vortioxetine hydro­chloride and a monohydrate thereof. Crystalline vortioxetine mesylate, meso­hydrogentartrate, hydrogenmaleate and hydrogen sulfate are also disclosed. However, there are few reports on the single-crystal X-ray structure of vortioxetine base and its salts. As part of our ongoing structural studies of pharmaceutical compounds, the crystal structures of vortioxetine free base (1), and its methanol solvate (2), have been determined and reported here.

2. Structural commentary

The asymmetric unit of (1) consists of one vortioxetine mol­ecule and that of compound (2) consists of one vortioxetine mol­ecule and one methanol mol­ecule. Views of the asymmetric units of (1) and (2), with atom labelling, are presented in Figs. 1[link] and 2[link], respectively. In both structures, the two benzene rings bridged by the S atom, are almost perpendicular to one another. The dihedral angles between the planes of these benzene rings is 80.04 (16)° in compound (1) and 84.94 (13)° in compound(2). The S atom is nearly coplanar with the benzene rings as indicated by C1—S1—C9—C14 torsion angles of 176.0 (2) for (1) and −176.04 (18)° for (2). The piperazine ring of both structures adopts a chair conformation with the exocyclic N1—C14 bond in a pseudo equatorial orientation. Atoms N1 and N2 deviate from the best fit plane through the remaining four C atoms by 0.683 (1) and 0.637 (1) Å in (1) and by 0.698 (1) and −0.562 Å in (2).

[Figure 1]
Figure 1
The mol­ecular structure of compound (1), showing 50% probability displacement ellipsoids.
[Figure 2]
Figure 2
The mol­ecular structure of compound (2), showing 50% probability displacement ellipsoids.

3. Supra­molecular features

There are no hydrogen bonds or π–π stacking inter­actions linking the mol­ecules in (1), while in (2) the presence of the additional methanol solvent mol­ecule results in the formation of zigzag chains mediated by alternating O1—H1⋯N2 and N2—H2A⋯O1i [symmetry code: (i) x, −y + [{1\over 2}], z + [{1\over 2}]] hydrogen bonds propagating along the c-axis direction (Table 1[link]). a packing diagram for (2) is shown in Fig. 3[link].

Table 1
Hydrogen-bond geometry (Å, °) for (2)[link]

D—H⋯A D—H H⋯A D⋯A D—H⋯A
N2—H2A⋯O1i 0.86 2.15 2.930 (3) 151
O1—H1⋯N2 0.82 1.93 2.744 (3) 171
Symmetry code: (i) [x, -y+{\script{1\over 2}}, z+{\script{1\over 2}}].
[Figure 3]
Figure 3
Part of the crystal packing of compound (2), viewed along the a axis. Hydrogen bonds are shown as dashed lines. H atoms not involved in hydrogen bonding have been omitted for clarity.

4. Synthesis and crystallization

Vortioxetine was supplied by Zhejiang Jingxin Pharmaceutical Co., Ltd. Crystals of (1) and (2) suitable for X-ray diffraction were recrystallized by slow evaporation from aceto­nitrile and methanol–water solutions, respectively, at room temperature over a few days.

5. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2[link]. All H atoms were placed in idealized positions and refined as riding, with C—H = 0.93–0.97, N—H = 0.86 and O—H = 0.82 Å and Uiso(H) = 1.2Ueq or 1.5Ueq(carrier atom).

Table 2
Experimental details

  (1) (2)
Crystal data
Chemical formula C18H22N2S C18H22N2S·CH4O
Mr 298.44 330.48
Crystal system, space group Triclinic, P[\overline{1}] Monoclinic, P21/c
Temperature (K) 296 296
a, b, c (Å) 7.6160 (4), 8.3267 (5), 13.9011 (7) 13.2100 (7), 18.1500 (9), 8.1746 (4)
α, β, γ (°) 84.999 (2), 77.631 (1), 74.347 (2) 90, 104.378 (2), 90
V (Å3) 828.75 (8) 1898.57 (17)
Z 2 4
Radiation type Mo Kα Mo Kα
μ (mm−1) 0.19 0.18
Crystal size (mm) 0.48 × 0.38 × 0.16 0.38 × 0.33 × 0.28
 
Data collection
Diffractometer Rigaku R-AXIS RAPID/ZJUG Rigaku R-AXIS RAPID/ZJUG
Absorption correction Multi-scan (ABSCOR: Higashi, 1995[Higashi, T. (1995). ABSCOR. Rigaku Corporation, Tokyo, Japan.]) Multi-scan (ABSCOR: Higashi, 1995[Higashi, T. (1995). ABSCOR. Rigaku Corporation, Tokyo, Japan.])
Tmin, Tmax 0.904, 0.970 0.928, 0.952
No. of measured, independent and observed [I > 2σ(I)] reflections 8178, 3756, 2072 18365, 4331, 2468
Rint 0.053 0.054
(sin θ/λ)max (Å−1) 0.649 0.648
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.056, 0.185, 1.00 0.052, 0.156, 1.00
No. of reflections 3756 4331
No. of parameters 193 213
H-atom treatment H-atom parameters constrained H-atom parameters constrained
Δρmax, Δρmin (e Å−3) 0.40, −0.37 0.25, −0.25
Computer programs: PROCESS-AUTO and CrystalStructure (Rigaku, 2007[Rigaku (2007). PROCESS-AUTO and CrystalStructure. Rigaku Americas, The Woodlands, Texas, USA.]), SHELXS97 and SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]) and ORTEP-3 for Windows and WinGX (Farrugia, 2012[Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849-854.]).

Supporting information

CCDC references: 1408949; 1408948

Crystal structure: contains datablocks 1, 2, global. DOI: https://doi.org/10.1107/S2056989015012256/hb7395sup1.cif

Structure factors: contains datablocks 1, 2. DOI: https://doi.org/10.1107/S2056989015012256/hb73951sup3.hkl

Structure factors: contains datablock 2. DOI: https://doi.org/10.1107/S2056989015012256/hb73952sup4.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989015012256/hb73951sup4.cml

Supporting information file. DOI: https://doi.org/10.1107/S2056989015012256/hb73952sup5.cml

checkCIF report


Computing details top

For both compounds, data collection: PROCESS-AUTO (Rigaku, 2007); cell refinement: PROCESS-AUTO (Rigaku, 2007); data reduction: CrystalStructure (Rigaku, 2007); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: WinGX (Farrugia, 2012).

(1) 1-{2-[(2,4-Dimethylphenyl)sulfanyl]phenyl}piperazine top
Crystal data top
C18H22N2SZ = 2
Mr = 298.44F(000) = 320
Triclinic, P1Dx = 1.196 Mg m−3
Hall symbol: -P 1Mo Kα radiation, λ = 0.71073 Å
a = 7.6160 (4) ÅCell parameters from 5189 reflections
b = 8.3267 (5) Åθ = 3.0–27.4°
c = 13.9011 (7) ŵ = 0.19 mm−1
α = 84.999 (2)°T = 296 K
β = 77.631 (1)°Chunk, colorless
γ = 74.347 (2)°0.48 × 0.38 × 0.16 mm
V = 828.75 (8) Å3
Data collection top
Rigaku R-AXIS RAPID/ZJUG
diffractometer		3756 independent reflections
Radiation source: rotating anode2072 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.053
Detector resolution: 10.00 pixels mm-1θmax = 27.5°, θmin = 3.0°
ω scansh = −9→9
Absorption correction: multi-scan
(ABSCOR: Higashi, 1995)		k = −10→10
Tmin = 0.904, Tmax = 0.970l = −18→17
8178 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.056H-atom parameters constrained
wR(F2) = 0.185 w = 1/[σ2(Fo2) + (0.0622P)2 + 0.7569P]
where P = (Fo2 + 2Fc2)/3
S = 1.00(Δ/σ)max < 0.001
3756 reflectionsΔρmax = 0.40 e Å−3
193 parametersΔρmin = −0.37 e Å−3
0 restraintsExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.072 (7)
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C10.6391 (4)0.3576 (4)0.1355 (2)0.0428 (7)
C20.6226 (5)0.1944 (5)0.1467 (3)0.0549 (8)
H20.56980.15590.20790.066*
C30.6828 (5)0.0891 (5)0.0688 (3)0.0641 (10)
H30.6711−0.01980.07810.077*
C40.7608 (5)0.1436 (5)−0.0235 (3)0.0575 (9)
C50.7753 (4)0.3054 (5)−0.0349 (2)0.0520 (8)
H50.82650.3428−0.09690.062*
C60.7165 (4)0.4163 (4)0.0425 (2)0.0446 (7)
C70.8231 (6)0.0284 (6)−0.1104 (3)0.0894 (14)
H7A0.87910.0843−0.16730.134*
H7B0.7174−0.0007−0.12410.134*
H7C0.9121−0.0710−0.09480.134*
C80.7350 (5)0.5916 (4)0.0254 (3)0.0573 (9)
H8A0.82680.60610.05920.086*
H8B0.61750.66800.04980.086*
H8C0.77270.6130−0.04400.086*
C90.7492 (4)0.5017 (4)0.2771 (2)0.0429 (7)
C100.9282 (4)0.4087 (4)0.2382 (2)0.0478 (8)
H100.94730.33880.18620.057*
C111.0770 (4)0.4193 (4)0.2761 (2)0.0526 (8)
H111.19580.35630.24960.063*
C121.0515 (4)0.5228 (5)0.3533 (2)0.0568 (9)
H121.15250.52930.37890.068*
C130.8738 (4)0.6169 (4)0.3921 (2)0.0523 (8)
H130.85650.68690.44380.063*
C140.7213 (4)0.6081 (4)0.3550 (2)0.0420 (7)
C150.4781 (5)0.8573 (4)0.3382 (2)0.0542 (8)
H15A0.50810.83760.26810.065*
H15B0.54500.93500.35040.065*
C160.2704 (5)0.9311 (5)0.3705 (3)0.0643 (10)
H16A0.23381.03700.33560.077*
H16B0.20400.85660.35350.077*
C170.2816 (5)0.8026 (5)0.5307 (2)0.0561 (9)
H17A0.21640.72270.51960.067*
H17B0.25160.82380.60060.067*
C180.4901 (4)0.7287 (4)0.4994 (2)0.0485 (8)
H18A0.55680.80490.51400.058*
H18B0.52780.62420.53540.058*
N10.5348 (3)0.7000 (3)0.39293 (16)0.0425 (6)
N20.2190 (4)0.9568 (4)0.4764 (2)0.0692 (9)
H2A0.15971.05060.50300.083*
S10.54672 (10)0.48897 (12)0.23790 (6)0.0524 (3)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0376 (15)0.0479 (18)0.0434 (15)−0.0111 (13)−0.0076 (12)−0.0052 (13)
C20.0553 (19)0.057 (2)0.0552 (19)−0.0189 (16)−0.0121 (16)−0.0012 (16)
C30.069 (2)0.048 (2)0.079 (3)−0.0141 (17)−0.022 (2)−0.0033 (18)
C40.0539 (19)0.058 (2)0.061 (2)−0.0015 (16)−0.0194 (17)−0.0219 (17)
C50.0440 (17)0.067 (2)0.0425 (16)−0.0091 (15)−0.0087 (14)−0.0079 (15)
C60.0372 (15)0.0502 (19)0.0458 (16)−0.0103 (13)−0.0077 (13)−0.0024 (13)
C70.088 (3)0.095 (3)0.086 (3)−0.005 (3)−0.023 (2)−0.048 (3)
C80.055 (2)0.055 (2)0.064 (2)−0.0212 (16)−0.0089 (16)0.0014 (17)
C90.0402 (15)0.0448 (18)0.0375 (14)−0.0075 (13)0.0005 (12)0.0006 (12)
C100.0390 (15)0.056 (2)0.0437 (16)−0.0090 (14)0.0006 (13)−0.0094 (14)
C110.0346 (15)0.066 (2)0.0540 (18)−0.0071 (14)−0.0076 (14)−0.0083 (16)
C120.0426 (17)0.074 (3)0.058 (2)−0.0168 (16)−0.0161 (15)−0.0066 (17)
C130.0475 (18)0.065 (2)0.0488 (17)−0.0172 (15)−0.0110 (15)−0.0141 (15)
C140.0410 (15)0.0452 (18)0.0378 (14)−0.0113 (13)−0.0035 (12)−0.0012 (12)
C150.059 (2)0.048 (2)0.0475 (17)−0.0077 (15)−0.0032 (15)0.0013 (14)
C160.064 (2)0.051 (2)0.065 (2)0.0022 (17)−0.0102 (18)0.0045 (17)
C170.0546 (19)0.061 (2)0.0459 (17)−0.0119 (16)0.0054 (15)−0.0107 (15)
C180.0516 (18)0.057 (2)0.0376 (15)−0.0142 (15)−0.0066 (13)−0.0097 (14)
N10.0423 (13)0.0423 (15)0.0367 (12)−0.0054 (11)−0.0013 (10)−0.0033 (10)
N20.071 (2)0.0517 (19)0.0656 (18)0.0063 (15)0.0048 (16)−0.0124 (15)
S10.0349 (4)0.0732 (6)0.0475 (5)−0.0108 (4)−0.0023 (3)−0.0186 (4)
Geometric parameters (Å, º) top
C1—C21.391 (5)C11—C121.384 (5)
C1—C61.406 (4)C11—H110.9300
C1—S11.773 (3)C12—C131.388 (4)
C2—C31.373 (5)C12—H120.9300
C2—H20.9300C13—C141.389 (4)
C3—C41.386 (5)C13—H130.9300
C3—H30.9300C14—N11.430 (4)
C4—C51.374 (5)C15—N11.464 (4)
C4—C71.522 (5)C15—C161.517 (5)
C5—C61.398 (4)C15—H15A0.9700
C5—H50.9300C15—H15B0.9700
C6—C81.497 (5)C16—N21.459 (4)
C7—H7A0.9600C16—H16A0.9700
C7—H7B0.9600C16—H16B0.9700
C7—H7C0.9600C17—N21.449 (4)
C8—H8A0.9600C17—C181.521 (4)
C8—H8B0.9600C17—H17A0.9700
C8—H8C0.9600C17—H17B0.9700
C9—C101.392 (4)C18—N11.472 (4)
C9—C141.403 (4)C18—H18A0.9700
C9—S11.773 (3)C18—H18B0.9700
C10—C111.373 (4)N2—H2A0.8600
C10—H100.9300
C2—C1—C6119.3 (3)C11—C12—H12120.3
C2—C1—S1118.4 (2)C13—C12—H12120.3
C6—C1—S1122.2 (2)C14—C13—C12121.1 (3)
C3—C2—C1121.2 (3)C14—C13—H13119.5
C3—C2—H2119.4C12—C13—H13119.5
C1—C2—H2119.4C13—C14—C9118.9 (3)
C2—C3—C4120.6 (4)C13—C14—N1123.5 (3)
C2—C3—H3119.7C9—C14—N1117.5 (3)
C4—C3—H3119.7N1—C15—C16109.5 (3)
C5—C4—C3118.3 (3)N1—C15—H15A109.8
C5—C4—C7121.0 (4)C16—C15—H15A109.8
C3—C4—C7120.7 (4)N1—C15—H15B109.8
C4—C5—C6122.9 (3)C16—C15—H15B109.8
C4—C5—H5118.6H15A—C15—H15B108.2
C6—C5—H5118.6N2—C16—C15111.3 (3)
C5—C6—C1117.7 (3)N2—C16—H16A109.4
C5—C6—C8120.4 (3)C15—C16—H16A109.4
C1—C6—C8121.9 (3)N2—C16—H16B109.4
C4—C7—H7A109.5C15—C16—H16B109.4
C4—C7—H7B109.5H16A—C16—H16B108.0
H7A—C7—H7B109.5N2—C17—C18111.5 (3)
C4—C7—H7C109.5N2—C17—H17A109.3
H7A—C7—H7C109.5C18—C17—H17A109.3
H7B—C7—H7C109.5N2—C17—H17B109.3
C6—C8—H8A109.5C18—C17—H17B109.3
C6—C8—H8B109.5H17A—C17—H17B108.0
H8A—C8—H8B109.5N1—C18—C17108.9 (3)
C6—C8—H8C109.5N1—C18—H18A109.9
H8A—C8—H8C109.5C17—C18—H18A109.9
H8B—C8—H8C109.5N1—C18—H18B109.9
C10—C9—C14119.6 (3)C17—C18—H18B109.9
C10—C9—S1124.1 (2)H18A—C18—H18B108.3
C14—C9—S1116.3 (2)C14—N1—C15112.9 (2)
C11—C10—C9120.5 (3)C14—N1—C18115.5 (2)
C11—C10—H10119.7C15—N1—C18110.2 (2)
C9—C10—H10119.7C17—N2—C16110.8 (3)
C10—C11—C12120.6 (3)C17—N2—H2A124.6
C10—C11—H11119.7C16—N2—H2A124.6
C12—C11—H11119.7C9—S1—C1102.76 (14)
C11—C12—C13119.3 (3)
C6—C1—C2—C30.9 (5)C10—C9—C14—C13−0.6 (4)
S1—C1—C2—C3176.7 (3)S1—C9—C14—C13176.8 (2)
C1—C2—C3—C4−0.4 (5)C10—C9—C14—N1−179.5 (3)
C2—C3—C4—C5−0.3 (5)S1—C9—C14—N1−2.1 (3)
C2—C3—C4—C7−178.4 (3)N1—C15—C16—N257.3 (4)
C3—C4—C5—C60.6 (5)N2—C17—C18—N1−57.9 (4)
C7—C4—C5—C6178.7 (3)C13—C14—N1—C1595.2 (4)
C4—C5—C6—C1−0.1 (5)C9—C14—N1—C15−85.9 (3)
C4—C5—C6—C8−179.7 (3)C13—C14—N1—C18−32.8 (4)
C2—C1—C6—C5−0.6 (4)C9—C14—N1—C18146.1 (3)
S1—C1—C6—C5−176.2 (2)C16—C15—N1—C14169.7 (3)
C2—C1—C6—C8178.9 (3)C16—C15—N1—C18−59.5 (4)
S1—C1—C6—C83.3 (4)C17—C18—N1—C14−171.1 (3)
C14—C9—C10—C110.6 (5)C17—C18—N1—C1559.5 (3)
S1—C9—C10—C11−176.6 (2)C18—C17—N2—C1656.1 (4)
C9—C10—C11—C12−0.1 (5)C15—C16—N2—C17−55.7 (4)
C10—C11—C12—C13−0.3 (5)C10—C9—S1—C1−6.7 (3)
C11—C12—C13—C140.3 (5)C14—C9—S1—C1176.0 (2)
C12—C13—C14—C90.1 (5)C2—C1—S1—C9106.2 (3)
C12—C13—C14—N1179.0 (3)C6—C1—S1—C9−78.2 (3)
(2) 1-{2-[(2,4-Dimethylphenyl)sulfanyl]phenyl}piperazine methanol monosolvate top
Crystal data top
C18H22N2S·CH4OF(000) = 712
Mr = 330.48Dx = 1.156 Mg m−3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybcCell parameters from 10380 reflections
a = 13.2100 (7) Åθ = 3.2–27.4°
b = 18.1500 (9) ŵ = 0.18 mm−1
c = 8.1746 (4) ÅT = 296 K
β = 104.378 (2)°Chunk, colorless
V = 1898.57 (17) Å30.38 × 0.33 × 0.28 mm
Z = 4
Data collection top
Rigaku R-AXIS RAPID/ZJUG
diffractometer		4331 independent reflections
Radiation source: rotating anode2468 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.054
Detector resolution: 10.00 pixels mm-1θmax = 27.4°, θmin = 3.2°
ω scansh = −16→17
Absorption correction: multi-scan
(ABSCOR: Higashi, 1995)		k = −23→23
Tmin = 0.928, Tmax = 0.952l = −10→10
18365 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.052H-atom parameters constrained
wR(F2) = 0.156 w = 1/[σ2(Fo2) + (0.0598P)2 + 0.7465P]
where P = (Fo2 + 2Fc2)/3
S = 1.00(Δ/σ)max = 0.001
4331 reflectionsΔρmax = 0.25 e Å−3
213 parametersΔρmin = −0.25 e Å−3
0 restraintsExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.032 (3)
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C160.7959 (2)0.35981 (14)0.6308 (3)0.0631 (7)
H16A0.74460.33220.67260.076*
H16B0.78100.35210.50970.076*
C150.78325 (19)0.44056 (13)0.6641 (3)0.0590 (6)
H15A0.71480.45730.60180.071*
H15B0.78920.44840.78350.071*
C180.96814 (19)0.45883 (14)0.7082 (3)0.0604 (6)
H18A0.97440.46670.82770.073*
H18B1.02190.48750.67540.073*
C170.9822 (2)0.37770 (14)0.6748 (3)0.0628 (7)
H17A0.98410.37170.55770.075*
H17B1.04900.36150.74460.075*
C140.84554 (18)0.55978 (12)0.5953 (3)0.0500 (5)
C130.89399 (19)0.61073 (14)0.7155 (3)0.0579 (6)
H130.94190.59480.81260.069*
C120.8721 (2)0.68494 (14)0.6929 (3)0.0644 (7)
H120.90490.71860.77470.077*
C110.8017 (2)0.70901 (14)0.5493 (3)0.0645 (7)
H110.78650.75900.53480.077*
C100.7535 (2)0.65945 (13)0.4267 (3)0.0600 (6)
H100.70560.67610.33020.072*
C90.77610 (18)0.58456 (12)0.4466 (3)0.0520 (6)
C10.6514 (2)0.56877 (13)0.1194 (3)0.0560 (6)
C60.5482 (2)0.58898 (14)0.1102 (3)0.0612 (6)
C50.4947 (2)0.62711 (16)−0.0328 (4)0.0738 (8)
H50.42610.6413−0.04010.089*
C40.5387 (2)0.64500 (16)−0.1649 (3)0.0723 (8)
C30.6398 (2)0.62274 (17)−0.1533 (3)0.0743 (8)
H30.67080.6328−0.24130.089*
C20.6953 (2)0.58576 (15)−0.0131 (3)0.0650 (7)
H20.76380.5718−0.00700.078*
C80.4960 (3)0.5711 (2)0.2494 (4)0.0946 (10)
H8A0.42800.59350.22520.142*
H8B0.53760.58970.35460.142*
H8C0.48900.51860.25710.142*
C70.4764 (3)0.6864 (2)−0.3175 (5)0.1267 (15)
H7A0.52320.7121−0.37040.190*
H7B0.43110.7212−0.28250.190*
H7C0.43510.6523−0.39620.190*
C190.8246 (3)0.1517 (2)0.6374 (5)0.1043 (11)
H19A0.86280.14740.75340.156*
H19B0.81530.10360.58660.156*
H19C0.75760.17340.63170.156*
N10.86499 (14)0.48236 (10)0.6108 (2)0.0520 (5)
N20.89994 (17)0.33031 (11)0.7085 (2)0.0601 (5)
H2A0.91600.32960.81710.090*
O10.87917 (19)0.19532 (11)0.5525 (2)0.0848 (6)
H10.89250.23490.60170.127*
S10.72717 (6)0.51680 (4)0.29023 (9)0.0699 (3)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C160.0652 (16)0.0537 (14)0.0744 (16)−0.0033 (12)0.0246 (13)0.0061 (12)
C150.0560 (15)0.0559 (15)0.0708 (15)0.0007 (11)0.0263 (12)0.0091 (12)
C180.0550 (15)0.0564 (15)0.0679 (15)0.0030 (12)0.0117 (12)0.0056 (12)
C170.0605 (15)0.0587 (16)0.0700 (15)0.0089 (12)0.0179 (12)0.0051 (12)
C140.0514 (13)0.0455 (13)0.0583 (13)0.0004 (10)0.0232 (10)0.0031 (10)
C130.0568 (15)0.0582 (15)0.0588 (14)−0.0015 (12)0.0149 (11)−0.0027 (11)
C120.0692 (17)0.0522 (15)0.0726 (16)−0.0061 (13)0.0193 (13)−0.0104 (12)
C110.0738 (17)0.0441 (13)0.0795 (17)0.0015 (12)0.0265 (14)−0.0004 (12)
C100.0660 (16)0.0479 (14)0.0657 (15)0.0032 (12)0.0158 (12)0.0040 (11)
C90.0538 (14)0.0469 (13)0.0585 (13)0.0014 (11)0.0197 (11)0.0017 (10)
C10.0587 (15)0.0494 (13)0.0603 (14)−0.0020 (11)0.0154 (11)−0.0061 (10)
C60.0576 (15)0.0588 (15)0.0684 (15)−0.0071 (12)0.0183 (12)−0.0078 (12)
C50.0520 (15)0.0746 (19)0.087 (2)0.0034 (13)0.0023 (14)−0.0083 (15)
C40.076 (2)0.0682 (18)0.0647 (16)−0.0061 (15)0.0024 (14)0.0004 (13)
C30.079 (2)0.084 (2)0.0612 (16)−0.0154 (16)0.0194 (14)−0.0003 (14)
C20.0552 (15)0.0723 (18)0.0686 (16)−0.0039 (13)0.0173 (12)−0.0070 (13)
C80.089 (2)0.106 (3)0.102 (2)−0.012 (2)0.0492 (19)−0.0035 (19)
C70.138 (4)0.125 (3)0.094 (3)0.014 (3)−0.014 (2)0.026 (2)
C190.111 (3)0.101 (3)0.113 (3)−0.031 (2)0.049 (2)−0.009 (2)
N10.0503 (11)0.0459 (11)0.0609 (11)0.0022 (9)0.0158 (9)0.0081 (8)
N20.0708 (14)0.0516 (12)0.0599 (12)0.0050 (10)0.0201 (10)0.0058 (9)
O10.1255 (18)0.0678 (13)0.0686 (12)−0.0129 (12)0.0384 (12)−0.0116 (9)
S10.0871 (5)0.0482 (4)0.0669 (4)0.0070 (3)0.0050 (3)−0.0044 (3)
Geometric parameters (Å, º) top
C16—N21.465 (3)C9—S11.776 (2)
C16—C151.507 (4)C1—C21.384 (3)
C16—H16A0.9700C1—C61.395 (4)
C16—H16B0.9700C1—S11.774 (2)
C15—N11.471 (3)C6—C51.391 (4)
C15—H15A0.9700C6—C81.506 (4)
C15—H15B0.9700C5—C41.386 (4)
C18—N11.461 (3)C5—H50.9300
C18—C171.517 (3)C4—C31.376 (4)
C18—H18A0.9700C4—C71.513 (4)
C18—H18B0.9700C3—C21.373 (4)
C17—N21.464 (3)C3—H30.9300
C17—H17A0.9700C2—H20.9300
C17—H17B0.9700C8—H8A0.9600
C14—C131.385 (3)C8—H8B0.9600
C14—C91.403 (3)C8—H8C0.9600
C14—N11.428 (3)C7—H7A0.9600
C13—C121.380 (3)C7—H7B0.9600
C13—H130.9300C7—H7C0.9600
C12—C111.375 (4)C19—O11.370 (4)
C12—H120.9300C19—H19A0.9600
C11—C101.379 (3)C19—H19B0.9600
C11—H110.9300C19—H19C0.9600
C10—C91.393 (3)N2—H2A0.8598
C10—H100.9300O1—H10.8200
N2—C16—C15114.3 (2)C2—C1—S1118.1 (2)
N2—C16—H16A108.7C6—C1—S1122.3 (2)
C15—C16—H16A108.7C5—C6—C1117.5 (2)
N2—C16—H16B108.7C5—C6—C8120.7 (3)
C15—C16—H16B108.7C1—C6—C8121.8 (3)
H16A—C16—H16B107.6C4—C5—C6123.2 (3)
N1—C15—C16109.0 (2)C4—C5—H5118.4
N1—C15—H15A109.9C6—C5—H5118.4
C16—C15—H15A109.9C3—C4—C5117.7 (3)
N1—C15—H15B109.9C3—C4—C7121.5 (3)
C16—C15—H15B109.9C5—C4—C7120.8 (3)
H15A—C15—H15B108.3C2—C3—C4120.6 (3)
N1—C18—C17109.0 (2)C2—C3—H3119.7
N1—C18—H18A109.9C4—C3—H3119.7
C17—C18—H18A109.9C3—C2—C1121.5 (3)
N1—C18—H18B109.9C3—C2—H2119.3
C17—C18—H18B109.9C1—C2—H2119.3
H18A—C18—H18B108.3C6—C8—H8A109.5
N2—C17—C18114.0 (2)C6—C8—H8B109.5
N2—C17—H17A108.8H8A—C8—H8B109.5
C18—C17—H17A108.8C6—C8—H8C109.5
N2—C17—H17B108.8H8A—C8—H8C109.5
C18—C17—H17B108.8H8B—C8—H8C109.5
H17A—C17—H17B107.7C4—C7—H7A109.5
C13—C14—C9119.2 (2)C4—C7—H7B109.5
C13—C14—N1123.6 (2)H7A—C7—H7B109.5
C9—C14—N1117.2 (2)C4—C7—H7C109.5
C12—C13—C14120.8 (2)H7A—C7—H7C109.5
C12—C13—H13119.6H7B—C7—H7C109.5
C14—C13—H13119.6O1—C19—H19A109.5
C11—C12—C13120.0 (2)O1—C19—H19B109.5
C11—C12—H12120.0H19A—C19—H19B109.5
C13—C12—H12120.0O1—C19—H19C109.5
C12—C11—C10120.4 (2)H19A—C19—H19C109.5
C12—C11—H11119.8H19B—C19—H19C109.5
C10—C11—H11119.8C14—N1—C18117.31 (19)
C11—C10—C9120.3 (2)C14—N1—C15113.85 (18)
C11—C10—H10119.9C18—N1—C15109.97 (18)
C9—C10—H10119.9C17—N2—C16111.36 (19)
C10—C9—C14119.3 (2)C17—N2—H2A101.4
C10—C9—S1124.22 (18)C16—N2—H2A114.7
C14—C9—S1116.39 (17)C19—O1—H1109.5
C2—C1—C6119.5 (2)C1—S1—C9103.41 (11)
N2—C16—C15—N154.9 (3)C6—C5—C4—C7179.9 (3)
N1—C18—C17—N2−55.2 (3)C5—C4—C3—C2−1.6 (4)
C9—C14—C13—C122.2 (4)C7—C4—C3—C2179.4 (3)
N1—C14—C13—C12179.8 (2)C4—C3—C2—C10.9 (4)
C14—C13—C12—C11−0.3 (4)C6—C1—C2—C30.6 (4)
C13—C12—C11—C10−0.6 (4)S1—C1—C2—C3176.9 (2)
C12—C11—C10—C9−0.4 (4)C13—C14—N1—C18−28.7 (3)
C11—C10—C9—C142.3 (4)C9—C14—N1—C18149.0 (2)
C11—C10—C9—S1−174.67 (19)C13—C14—N1—C15101.7 (3)
C13—C14—C9—C10−3.1 (3)C9—C14—N1—C15−80.6 (3)
N1—C14—C9—C10179.1 (2)C17—C18—N1—C14−166.5 (2)
C13—C14—C9—S1174.04 (18)C17—C18—N1—C1561.3 (3)
N1—C14—C9—S1−3.7 (3)C16—C15—N1—C14164.7 (2)
C2—C1—C6—C5−1.3 (4)C16—C15—N1—C18−61.3 (3)
S1—C1—C6—C5−177.42 (19)C18—C17—N2—C1648.1 (3)
C2—C1—C6—C8179.2 (3)C15—C16—N2—C17−48.2 (3)
S1—C1—C6—C83.0 (4)C2—C1—S1—C9100.2 (2)
C1—C6—C5—C40.6 (4)C6—C1—S1—C9−83.6 (2)
C8—C6—C5—C4−179.9 (3)C10—C9—S1—C11.0 (2)
C6—C5—C4—C30.9 (4)C14—C9—S1—C1−176.04 (18)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N2—H2A···O1i0.862.152.930 (3)151
O1—H1···N20.821.932.744 (3)171
Symmetry code: (i) x, −y+1/2, z+1/2.
 

Acknowledgements

The project was supported by the Analysis and Measurement Foundation of Zhejiang Provincial, China (grant No. 2014 C37055).

References

First citationBenny, B. A., Andre, F., Heidi, L. D. D., Arne, M., Rene, H., Bryan, S. T., Munch, R. L. J. M. M., Harold, R. M., Jorgen, B., Morten, R. & Nicholas, M. (2007). World Patent WO2007114005A1.  Google Scholar
 First citationBidzan, L., Mahableshwarkar, A. R., Jacobsen, P., Yan, M. J. & Sheehan, D. V. (2012). Eur. Neuropsychopharmacol. 22, 847–857.  Web of Science CrossRef CAS PubMed Google Scholar
 First citationFarrugia, L. J. (2012). J. Appl. Cryst. 45, 849–854.  Web of Science CrossRef CAS IUCr Journals Google Scholar
 First citationGibb, A. & Deeks, E. D. (2014). Drugs, 74, 135–145.  Web of Science CrossRef CAS PubMed Google Scholar
 First citationHigashi, T. (1995). ABSCOR. Rigaku Corporation, Tokyo, Japan.  Google Scholar
 First citationHussar, D. A. & Lye, A. (2014). J. Am. Pharm. Assoc. (2003), 54, 91–94.  Web of Science CrossRef PubMed Google Scholar
 First citationJardin, K. G. du, Jensen, J. B., Sanchez, C. & Pehrson, A. L. (2014). Eur. Neuropsychopharmacol. 24, 160–171.  Web of Science PubMed Google Scholar
 First citationRichelson, E. (2013). Int. J. Neuropsychopharm. 16, 1433–1442.  Web of Science CrossRef CAS Google Scholar
 First citationRigaku (2007). PROCESS-AUTO and CrystalStructure. Rigaku Americas, The Woodlands, Texas, USA.  Google Scholar
 First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar

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
Volume 71| Part 8| August 2015| Pages 883-885
https://doi.org/10.1107/S2056989015012256
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