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The title salt, C15H18NO2+·Br·H2O, is an analogue of the anti­depressant drug agomelatine. The cation is protonated at the carbonyl O atom of its amide group. The side chain at the 1-position adopts an extended conformation, with all non-H atoms lying in the same plane as the naphthalene ring. This is in contrast with the crystal structures known for three agomelatine polymorphs, and also with two known cocrystals containing agomelatine. The structure displays three types of hydrogen bond, namely C=O—H...O, N—H...Br and O—H...Br, which define a two-dimensional network parallel to the (100) plane. The naphthalene rings inter­digitate in a `zipper-like' fashion between these hydrogen-bonded networks, forming an offset arrangement. Direct face-to-face π–π contacts between naphthalene rings are not present in the structure.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270112029885/bi3043sup1.cif
Contains datablocks 3, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S0108270112029885/bi30433sup2.hkl
Contains datablock 3

cml

Chemical Markup Language (CML) file https://doi.org/10.1107/S0108270112029885/bi30433sup3.cml
Supplementary material

CCDC reference: 899072

Comment top

Agomelatine {N-[2-(7-methoxy-naphthalen-1-yl)ethyl]acetamide}, (1), is an antidepressant developed by the pharmaceutical company Servier. It is classified as a norepinephrine–dopamine disinhibitor (NDDI) due to its antagonism of the 5-HT2C receptor. Agomelatine is also a potent agonist at melatonin receptors (MT1 and MT2 receptors), which makes it the first melatonergic antidepressant (Millan et al., 2003). This overall favourable therapeutic profile makes it a very promising drug. Various crystallization attempts involving agomelatine have been made over recent years, involving multiple high-throughput screenings and conventional bench-top crystallizations. These have resulted in the discovery of at least six polymorphs and two cocrystals (Yous et al., 1992; Coquerel et al., 2007a,b, 2008, 2010; Souvie et al., 2008; Zhu et al., 2009; Zheng et al., 2011). Five crystal structures have been reported so far (Tinant et al., 1994; Zheng et al., 2011).

During the synthesis of agomelatine in our laboratory, we observed that a white solid precipitated out of an agomelatine solution in ethyl acetate when it was titrated with one equivalent of dry HCl or dry HBr in ethyl acetate. Data obtained from elemental analysis suggested the formula to be agomelatine.HX. The solids formed with HCl or HBr were both unstable when stored in an unsealed condition and converted rapidly to the corresponding monohydrate. Further investigation showed that the monohydrate could also be obtained directly by the addition of one equivalent of concentrated aqueous solutions of HCl or HBr. Since agomelatine has an acetamide and a methoxy group but no basic functional group, salt formaton with HX was not immediately expected. To investigate this further, we synthesized the 6-methoxy analogue of agomelatine, N-[2-(6-methoxy-naphthalen-1-yl) ethyl]acetamide, (2). This compound has also been reported as a melatonin receptor agonist (Depreux et al., 1994; Mor et al., 1998). Crystallization of (2) under the same conditions described for agomelatine produced the analogous compound (2).HX.H2O. Single crystals of the title HBr salt, (3), were prepared and the structure is described here; single crystals of the HCl salt were not obtained.

The molecular structure of (3) is shown in Fig. 1. The bond lengths and angles fall within normal ranges. The naphthalene system is planar within experimental error and the methoxy group lies close to the mean plane of the naphthalene ring. The side chain adopts an extended conformation, with all non-H atoms in the same plane as the naphthalene ring [torsion angle C16—C7—C4—C3 = -179.69 (16)°]. Interestingly, this conformation is different from those in all five of the previously reported structures containing agomelatine, including the two cocrystals with acetic acid and ethylene glycol. The corresponding torsion angle is 79.7° in agomelatine form I (Tinant et al., 1994), 79.4° in form II, 78.6° in form III, 90.5° in the cocrystal with acetic acid and 77.2° in the cocrystal with ethylene glycol (Zheng et al., 2011).

As shown in Fig. 1 and Table 1, the carbonyl O atom of the amide group is protonated, forming a CO—H···O hydrogen bond with the water molecule, and the amide group forms an almost linear N—H···Br- hydrogen bond. The Br- ion also accepts O—H···Br- hydrogen bonds from two water molecules (Table 1) so that each anion accepts three hydrogen bonds in total. As shown in Figs. 2 and 3, the hydrogen-bond network is two-dimensional overall, lying parallel to the (100) plane. Between these hydrogen-bonded networks, the naphthalene rings interdigitate in a `zipper-like' fashion. The rings form interfacial distances of 3.44 (1) [symmetry code (-x + 1, -y + 2, -z + 1)] and 3.58 (1) Å [symmetry code (-x + 1, -y + 1, -z + 1)] accompanied by significant lateral displacement [distances between the centroids of neighbouring C7–C11/C16 rings = 4.70 (1) and 5.44 (1) Å, respectively]. Direct face-to-face ππ contacts are not present.

The packing arrangement in (3) differs considerably from that found in the five previously known crystal structures containing agomelatine. In agomelatine forms I–III, no solvent molecule is present, and the agomelatine molecules are linked by intermolecular hydrogen bonding between the amide N atom and the carbonyl O atom to form one-dimensional chains. The different polymorphs result mainly from different packing arrangements of these one-dimensional chains. In the cocrystal with acetic acid, the latter molecule is inserted into the one-dimensional chain of the agomelatine molecules. In the cocrystal with ethylene glycol, a two-dimensional chiral sheet is formed.

Related literature top

For related literature, see: Coquerel et al. (2007a, 2007b, 2008, 2010); Depreux et al. (1994); Millan et al. (2003); Mor et al. (1998); Souvie et al. (2008); Tang & Chen (2008); Tinant et al. (1994); Yous et al. (1992); Zheng et al. (2011); Zhu et al. (2009).

Experimental top

The synthesis of N-[2-(6-methoxynaphthalen-1-yl)ethyl]acetamide, (2), was carried out according to the previously reported method for the preparation of agomelatine (Tang & Chen, 2008). The product was isolated in 31% yield (purity determined by high-performance liquid chromatography 99%) and identified as (2) from MS, IR and NMR analyses. The compound was kept at 298 K in a sealed container.

For the preparation of (3), a solution of (2) [How much?] in ethyl acetate [How much?] was cooled in an ice bath. To the mixture was added aqueous HBr (40%) [How much?] dropwise over a period of 30 min. After stirring for 1 h, the crystallized product was collected by filtration, washed with ethyl acetate and dried in vacuo at 313 K to obtain a white powder, viz. (3) (yield 90%). Slow evaporation of a solution of (3) in methanol at room temperature gave single crystals suitable for X-ray diffraction analysis.

Refinement top

H atoms bound to C atoms were placed in geometically idealized positions and constrained to ride on their parent atoms, with C—H = 0.93 (aromatic), 0.96 (methyl) or 0.97 Å (methylene), and with Uiso(H) = 1.5Ueq(C) for methyl H atoms or 1.2Ueq(C) otherwise. Atoms H2 and H5 and the H atoms of the water molecule were located in a difference Fourier map, and refined with isotropic displacement parameters and bond-distance restraints of N—H = 0.86 (1) Å and O—H = 0.82 (1) Å. The H1W···H2W distance was also restrained to 1.34 (1) Å.

Computing details top

Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT (Bruker, 2009); 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 (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. The molecular structure of (3). Displacement ellipsoids are drawn at the 50% probability level.
[Figure 2] Fig. 2. A view of the structure of (3), along the b axis. Dashed lines represent hydrogen bonds. The two-dimensional hydrogen-bond network lies in the (100) plane (horizontal).
[Figure 3] Fig. 3. A view of the structure of (3), along the a axis. Dashed lines represent hydrogen bonds.
(1-{[2-(6-Methoxynaphthalen-1-yl)ethyl]amino}ethylidene)oxidanium bromide monohydrate top
Crystal data top
C15H18NO2+·Br·H2OF(000) = 704
Mr = 342.23Dx = 1.459 Mg m3
Monoclinic, P21/cCu Kα radiation, λ = 1.54178 Å
Hall symbol: -P 2ybcCell parameters from 3863 reflections
a = 11.9376 (1) Åθ = 3.8–67.5°
b = 7.3761 (1) ŵ = 3.66 mm1
c = 18.1618 (2) ÅT = 296 K
β = 102.979 (1)°Block, colourless
V = 1558.34 (3) Å30.10 × 0.10 × 0.10 mm
Z = 4
Data collection top
Bruker SMART APEXII area-detector
diffractometer
2613 independent reflections
Radiation source: fine-focus sealed tube2486 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.014
ϕ and ω scansθmax = 66.5°, θmin = 3.8°
Absorption correction: multi-scan
(SADABS; Bruker, 2009)
h = 1413
Tmin = 0.711, Tmax = 0.711k = 68
5359 measured reflectionsl = 2119
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.026Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.071H atoms treated by a mixture of independent and constrained refinement
S = 1.08 w = 1/[σ2(Fo2) + (0.0368P)2 + 0.593P]
where P = (Fo2 + 2Fc2)/3
2613 reflections(Δ/σ)max = 0.001
199 parametersΔρmax = 0.31 e Å3
5 restraintsΔρmin = 0.26 e Å3
Crystal data top
C15H18NO2+·Br·H2OV = 1558.34 (3) Å3
Mr = 342.23Z = 4
Monoclinic, P21/cCu Kα radiation
a = 11.9376 (1) ŵ = 3.66 mm1
b = 7.3761 (1) ÅT = 296 K
c = 18.1618 (2) Å0.10 × 0.10 × 0.10 mm
β = 102.979 (1)°
Data collection top
Bruker SMART APEXII area-detector
diffractometer
2613 independent reflections
Absorption correction: multi-scan
(SADABS; Bruker, 2009)
2486 reflections with I > 2σ(I)
Tmin = 0.711, Tmax = 0.711Rint = 0.014
5359 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0265 restraints
wR(F2) = 0.071H atoms treated by a mixture of independent and constrained refinement
S = 1.08Δρmax = 0.31 e Å3
2613 reflectionsΔρmin = 0.26 e Å3
199 parameters
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds 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
Br10.047030 (18)0.82862 (3)0.374825 (12)0.05309 (11)
C10.18049 (16)0.6564 (2)0.59156 (11)0.0396 (4)
N20.23448 (14)0.7093 (2)0.54133 (9)0.0405 (4)
H20.1960 (19)0.755 (3)0.5004 (9)0.056 (7)*
C30.36006 (15)0.7004 (3)0.55098 (11)0.0399 (4)
H3A0.38670.57760.56330.048*
H3B0.39710.77950.59190.048*
C40.38986 (15)0.7593 (3)0.47803 (11)0.0400 (4)
H4A0.35480.67510.43860.048*
H4B0.35590.87750.46430.048*
O50.24057 (12)0.5884 (2)0.65337 (8)0.0484 (3)
H50.198 (2)0.558 (4)0.6812 (15)0.087 (10)*
C60.05402 (18)0.6761 (3)0.57906 (14)0.0547 (5)
H6A0.02110.56330.59010.082*
H6B0.02270.70870.52740.082*
H6C0.03630.76910.61170.082*
C70.51665 (15)0.7706 (2)0.47987 (10)0.0359 (4)
C80.59920 (17)0.7316 (3)0.54357 (11)0.0428 (4)
H8A0.57700.69480.58720.051*
C90.71684 (17)0.7463 (3)0.54415 (11)0.0486 (5)
H9A0.77120.72170.58830.058*
C100.75204 (16)0.7961 (3)0.48073 (12)0.0453 (4)
H10A0.83020.80330.48180.054*
C110.67075 (16)0.8371 (2)0.41334 (11)0.0368 (4)
C120.70719 (16)0.8917 (3)0.34784 (11)0.0394 (4)
H12A0.78520.89700.34850.047*
C130.62818 (16)0.9367 (3)0.28367 (10)0.0415 (4)
C140.50984 (17)0.9290 (3)0.28244 (11)0.0476 (5)
H14A0.45640.96100.23870.057*
C150.47317 (16)0.8753 (3)0.34453 (11)0.0421 (4)
H15A0.39470.87020.34230.051*
C160.55160 (15)0.8264 (2)0.41291 (10)0.0349 (4)
O170.65468 (12)0.9909 (2)0.21755 (8)0.0536 (4)
C180.77221 (19)1.0213 (3)0.21896 (12)0.0550 (5)
H18A0.77951.06910.17110.082*
H18B0.81350.90900.22850.082*
H18C0.80331.10650.25820.082*
O1W0.12755 (17)0.4503 (3)0.74000 (11)0.0713 (5)
H1W0.076 (2)0.382 (4)0.7181 (18)0.101 (12)*
H2W0.102 (2)0.514 (4)0.7696 (15)0.095 (11)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Br10.04511 (16)0.06130 (17)0.05232 (16)0.00216 (9)0.00980 (10)0.00548 (9)
C10.0350 (10)0.0361 (9)0.0471 (10)0.0004 (7)0.0080 (8)0.0060 (8)
N20.0332 (8)0.0404 (8)0.0469 (9)0.0010 (6)0.0070 (7)0.0030 (7)
C30.0315 (9)0.0377 (9)0.0500 (10)0.0003 (7)0.0083 (8)0.0011 (8)
C40.0329 (9)0.0407 (10)0.0450 (10)0.0019 (7)0.0060 (7)0.0027 (8)
O50.0383 (7)0.0608 (9)0.0454 (8)0.0019 (6)0.0081 (6)0.0053 (7)
C60.0361 (11)0.0663 (14)0.0621 (13)0.0045 (9)0.0122 (9)0.0041 (10)
C70.0331 (9)0.0293 (8)0.0441 (9)0.0003 (7)0.0063 (7)0.0002 (7)
C80.0414 (10)0.0431 (10)0.0434 (10)0.0024 (8)0.0084 (8)0.0070 (8)
C90.0360 (10)0.0598 (12)0.0450 (10)0.0058 (9)0.0015 (8)0.0127 (10)
C100.0297 (9)0.0526 (11)0.0512 (11)0.0067 (8)0.0041 (8)0.0084 (9)
C110.0331 (9)0.0339 (9)0.0419 (10)0.0043 (7)0.0051 (7)0.0003 (7)
C120.0332 (9)0.0404 (9)0.0448 (10)0.0035 (7)0.0088 (7)0.0005 (8)
C130.0440 (10)0.0415 (10)0.0380 (9)0.0006 (8)0.0072 (8)0.0004 (8)
C140.0405 (10)0.0569 (12)0.0393 (10)0.0018 (9)0.0039 (8)0.0037 (9)
C150.0297 (9)0.0466 (10)0.0459 (10)0.0026 (8)0.0004 (7)0.0007 (8)
C160.0315 (9)0.0306 (9)0.0405 (9)0.0002 (6)0.0038 (7)0.0014 (7)
O170.0510 (8)0.0700 (10)0.0391 (7)0.0006 (7)0.0088 (6)0.0066 (7)
C180.0567 (13)0.0648 (13)0.0464 (11)0.0033 (11)0.0177 (9)0.0033 (10)
O1W0.0847 (13)0.0761 (12)0.0615 (10)0.0166 (10)0.0338 (10)0.0112 (9)
Geometric parameters (Å, º) top
C1—N21.290 (3)C9—H9A0.930
C1—O51.290 (2)C10—C111.413 (3)
C1—C61.483 (3)C10—H10A0.930
N2—C31.471 (2)C11—C121.414 (3)
N2—H20.85 (1)C11—C161.423 (3)
C3—C41.511 (3)C12—C131.366 (3)
C3—H3A0.970C12—H12A0.930
C3—H3B0.970C13—O171.368 (2)
C4—C71.509 (2)C13—C141.409 (3)
C4—H4A0.970C14—C151.357 (3)
C4—H4B0.970C14—H14A0.930
O5—H50.82 (1)C15—C161.424 (3)
C6—H6A0.960C15—H15A0.930
C6—H6B0.960O17—C181.415 (3)
C6—H6C0.960C18—H18A0.960
C7—C81.371 (3)C18—H18B0.960
C7—C161.432 (3)C18—H18C0.960
C8—C91.406 (3)O1W—H1W0.83 (1)
C8—H8A0.930O1W—H2W0.82 (1)
C9—C101.362 (3)
N2—C1—O5117.68 (17)C10—C9—H9A119.6
N2—C1—C6121.02 (18)C8—C9—H9A119.6
O5—C1—C6121.29 (18)C9—C10—C11120.51 (18)
C1—N2—C3124.05 (17)C9—C10—H10A119.7
C1—N2—H2118.7 (18)C11—C10—H10A119.7
C3—N2—H2117.3 (18)C10—C11—C12120.55 (17)
N2—C3—C4108.49 (15)C10—C11—C16118.95 (17)
N2—C3—H3A110.0C12—C11—C16120.49 (17)
C4—C3—H3A110.0C13—C12—C11120.22 (17)
N2—C3—H3B110.0C13—C12—H12A119.9
C4—C3—H3B110.0C11—C12—H12A119.9
H3A—C3—H3B108.4C12—C13—O17124.65 (17)
C7—C4—C3115.41 (15)C12—C13—C14120.11 (17)
C7—C4—H4A108.4O17—C13—C14115.25 (16)
C3—C4—H4A108.4C15—C14—C13120.52 (17)
C7—C4—H4B108.4C15—C14—H14A119.7
C3—C4—H4B108.4C13—C14—H14A119.7
H4A—C4—H4B107.5C14—C15—C16121.82 (17)
C1—O5—H5110 (2)C14—C15—H15A119.1
C1—C6—H6A109.5C16—C15—H15A119.1
C1—C6—H6B109.5C11—C16—C15116.84 (17)
H6A—C6—H6B109.5C11—C16—C7119.53 (16)
C1—C6—H6C109.5C15—C16—C7123.63 (17)
H6A—C6—H6C109.5C13—O17—C18117.00 (15)
H6B—C6—H6C109.5O17—C18—H18A109.5
C8—C7—C16119.06 (17)O17—C18—H18B109.5
C8—C7—C4122.30 (16)H18A—C18—H18B109.5
C16—C7—C4118.63 (16)O17—C18—H18C109.5
C7—C8—C9121.16 (18)H18A—C18—H18C109.5
C7—C8—H8A119.4H18B—C18—H18C109.5
C9—C8—H8A119.4H1W—O1W—H2W108.3 (16)
C10—C9—C8120.77 (18)
O5—C1—N2—C31.4 (3)C12—C13—C14—C150.7 (3)
C6—C1—N2—C3177.58 (18)O17—C13—C14—C15179.34 (19)
C1—N2—C3—C4175.27 (17)C13—C14—C15—C160.5 (3)
N2—C3—C4—C7175.96 (15)C10—C11—C16—C15177.77 (17)
C3—C4—C7—C80.6 (3)C12—C11—C16—C150.8 (3)
C3—C4—C7—C16179.69 (16)C10—C11—C16—C71.4 (3)
C16—C7—C8—C90.3 (3)C12—C11—C16—C7179.94 (16)
C4—C7—C8—C9178.85 (19)C14—C15—C16—C110.2 (3)
C7—C8—C9—C101.4 (3)C14—C15—C16—C7179.41 (19)
C8—C9—C10—C111.1 (3)C8—C7—C16—C111.1 (3)
C9—C10—C11—C12179.0 (2)C4—C7—C16—C11179.73 (16)
C9—C10—C11—C160.3 (3)C8—C7—C16—C15178.01 (18)
C10—C11—C12—C13177.87 (19)C4—C7—C16—C151.1 (3)
C16—C11—C12—C130.7 (3)C12—C13—O17—C187.3 (3)
C11—C12—C13—O17179.96 (18)C14—C13—O17—C18172.68 (19)
C11—C12—C13—C140.0 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N2—H2···Br10.85 (1)2.62 (1)3.4478 (16)167 (2)
O5—H5···O1W0.82 (1)1.70 (1)2.507 (2)167 (3)
O1W—H1W···Br1i0.83 (1)2.51 (1)3.312 (2)164 (3)
O1W—H2W···Br1ii0.82 (1)2.45 (1)3.2614 (19)170 (3)
Symmetry codes: (i) x, y+1, z+1; (ii) x, y+3/2, z+1/2.

Experimental details

Crystal data
Chemical formulaC15H18NO2+·Br·H2O
Mr342.23
Crystal system, space groupMonoclinic, P21/c
Temperature (K)296
a, b, c (Å)11.9376 (1), 7.3761 (1), 18.1618 (2)
β (°) 102.979 (1)
V3)1558.34 (3)
Z4
Radiation typeCu Kα
µ (mm1)3.66
Crystal size (mm)0.10 × 0.10 × 0.10
Data collection
DiffractometerBruker SMART APEXII area-detector
diffractometer
Absorption correctionMulti-scan
(SADABS; Bruker, 2009)
Tmin, Tmax0.711, 0.711
No. of measured, independent and
observed [I > 2σ(I)] reflections
5359, 2613, 2486
Rint0.014
(sin θ/λ)max1)0.595
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.026, 0.071, 1.08
No. of reflections2613
No. of parameters199
No. of restraints5
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.31, 0.26

Computer programs: APEX2 (Bruker, 2009), SAINT (Bruker, 2009), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N2—H2···Br10.85 (1)2.62 (1)3.4478 (16)167 (2)
O5—H5···O1W0.82 (1)1.70 (1)2.507 (2)167 (3)
O1W—H1W···Br1i0.83 (1)2.51 (1)3.312 (2)164 (3)
O1W—H2W···Br1ii0.82 (1)2.45 (1)3.2614 (19)170 (3)
Symmetry codes: (i) x, y+1, z+1; (ii) x, y+3/2, z+1/2.
 

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