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Acta Cryst. (2009). E65, o550    [ doi:10.1107/S1600536809005182 ]

2-[6,8-Dibromo-3-(4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazolin-2-yl]-6-methoxyphenol

Z.-G. Wang, R. Wang, Y. Zhang, F. Zhi and Y.-L. Yang

Abstract top

The title compound, C21H24Br2N2O3, was synthesized by the condensation reaction of 3-methoxysalicylaldehyde with 4-(2-amino-3,5-dibromobenzylamino)cyclohexanol in a methanol solution. The dihedral angle between the two benzene rings is 76.4 (3)°. The cyclohexyl ring adopts a chair configuration. There is an intramolecular O-H...N hydrogen bond which affects the solid state conformation of the molecule. The crystal structure is stabilized by intermolecular O-H...O hydrogen bonds, forming chains running along the b axis.

Comment top

Ambroxol, 4-(2-amino-3,5-dibromobenzylamino)cyclohexanol, is an expectorant agent which leads to bronchial secretion due to its mucolytic properties (Felix et al., 2008; Gaida et al., 2005; Lee et al., 2004). In this paper, the crystal structure of the new title compound, (I), derived from the condensation reaction of 3-methoxysalicylaldehyde with 4-(2-amino-3,5-dibromobenzylamino)cyclohexanol in a methanol solution, is reported.

In (I), Fig. 1, the dihedral angle between the two benzene rings is 76.4 (3)°. The cyclohexyl ring adopts a chair configuration. All the bond lengths are within normal ranges (Allen et al., 1987). There is an intramolecular O2—H2···N2 hydrogen bond which affects the solid state conformation of the molecule. The crystal structure is stabilized by intermolecular O—H···O hydrogen bonds (Table 1), forming chains running along the b axis (Fig. 2).

Related literature top

For details of the pharmaceutical uses of the closely related compound ambroxol, systematic name 4-(2-amino-3,5-dibromobenzylamino)cyclohexanol, see: Felix et al. (2008); Gaida et al. (2005); Lee et al. (2004). For bond length data, see: Allen et al. (1987).

Experimental top

3-Methoxysalicylaldehyde (1.0 mol, 152.1 mg) and 4-(2-amino-3,5-dibromobenzylamino)cyclohexanol (1.0 mmol, 378.1 mg) were dissolved in a methanol solution (10 ml). The mixture was stirred at room temperature to give a clear colorless solution. Crystals of the title compound were formed by gradual evaporation of the solvent for a week at room temperature.

Refinement top

H atoms were constrained to ideal geometries, with C–H = 0.93–0.97 Å, O–H = 0.82 Å, and with Uiso(H) set to 1.2Ueq(C) and 1.5Ueq(O and C21).

Computing details top

Data collection: SMART (Bruker, 2002); cell refinement: SAINT (Bruker, 2002); data reduction: SAINT (Bruker, 2002); 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 structure of (I) at the 30% probability level. The intramolecular O–H···N hydrogen bond is shown as a dashed line.
[Figure 2] Fig. 2. Molecular packing of (I), viewed along the a axis. Intermolecular hydrogen bonds are shown as dashed lines.
(I) top
Crystal data top
C21H24Br2N2O3Z = 2
Mr = 512.24F(000) = 516
Triclinic, P1Dx = 1.655 Mg m−3
Hall symbol: -P 1Mo Kα radiation, λ = 0.71073 Å
a = 8.695 (2) ÅCell parameters from 2079 reflections
b = 11.124 (3) Åθ = 2.3–24.6°
c = 12.090 (2) ŵ = 3.97 mm−1
α = 73.870 (3)°T = 298 K
β = 78.226 (3)°Block, colorless
γ = 67.031 (2)°0.30 × 0.30 × 0.30 mm
V = 1028.2 (4) Å3
Data collection top
Bruker SMART CCD area detector
diffractometer		4305 independent reflections
Radiation source: fine-focus sealed tube3035 reflections with I > 2σ(I)
graphiteRint = 0.032
ω scansθmax = 27.0°, θmin = 1.8°
Absorption correction: multi-scan
(SADABS; Sheldrick, 1996)		h = −11→10
Tmin = 0.382, Tmax = 0.382k = −14→14
8514 measured reflectionsl = −15→15
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)] = 0.042Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.096H-atom parameters constrained
S = 1.02 w = 1/[σ2(Fo2) + (0.0423P)2 + 0.0168P]
where P = (Fo2 + 2Fc2)/3
4305 reflections(Δ/σ)max = 0.001
256 parametersΔρmax = 0.51 e Å−3
0 restraintsΔρmin = −0.41 e Å−3
Crystal data top
C21H24Br2N2O3γ = 67.031 (2)°
Mr = 512.24V = 1028.2 (4) Å3
Triclinic, P1Z = 2
a = 8.695 (2) ÅMo Kα radiation
b = 11.124 (3) ŵ = 3.97 mm−1
c = 12.090 (2) ÅT = 298 K
α = 73.870 (3)°0.30 × 0.30 × 0.30 mm
β = 78.226 (3)°
Data collection top
Bruker SMART CCD area detector
diffractometer		4305 independent reflections
Absorption correction: multi-scan
(SADABS; Sheldrick, 1996)		3035 reflections with I > 2σ(I)
Tmin = 0.382, Tmax = 0.382Rint = 0.032
8514 measured reflectionsθmax = 27.0°
Refinement top
R[F2 > 2σ(F2)] = 0.042H-atom parameters constrained
wR(F2) = 0.096Δρmax = 0.51 e Å−3
S = 1.02Δρmin = −0.41 e Å−3
4305 reflectionsAbsolute structure: ?
256 parametersFlack parameter: ?
0 restraintsRogers parameter: ?
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
Br11.17738 (5)0.24247 (4)0.32321 (4)0.04726 (14)
Br21.28346 (5)0.54977 (4)0.58131 (3)0.04402 (14)
O10.2331 (3)0.9422 (3)0.3052 (2)0.0418 (7)
H10.15810.98830.26350.063*
O20.9413 (3)0.8807 (3)−0.1082 (2)0.0430 (7)
H20.89610.8692−0.04160.065*
O31.1435 (4)0.9116 (3)−0.2940 (2)0.0510 (7)
N11.0518 (4)0.5182 (3)0.1542 (2)0.0305 (7)
H1A1.05270.44320.14690.037*
N20.9133 (3)0.7617 (3)0.1103 (2)0.0249 (6)
C11.1053 (4)0.6460 (3)0.2638 (3)0.0265 (8)
C21.1080 (4)0.5243 (3)0.2507 (3)0.0263 (7)
C31.1674 (4)0.4110 (3)0.3381 (3)0.0287 (8)
C41.2199 (4)0.4172 (3)0.4357 (3)0.0317 (8)
H41.25860.34050.49310.038*
C51.2143 (4)0.5386 (4)0.4468 (3)0.0302 (8)
C61.1591 (4)0.6523 (3)0.3620 (3)0.0306 (8)
H61.15760.73340.37020.037*
C71.0414 (4)0.7698 (3)0.1692 (3)0.0259 (7)
H7A0.99290.84810.20270.031*
H7B1.13490.77990.11280.031*
C80.7481 (4)0.7705 (3)0.1797 (3)0.0269 (8)
H80.75600.68120.22630.032*
C90.6954 (4)0.8659 (4)0.2601 (3)0.0377 (9)
H9A0.69770.95250.21560.045*
H9B0.77510.83240.31680.045*
C100.5210 (5)0.8823 (4)0.3222 (3)0.0410 (10)
H10A0.52130.79730.37220.049*
H10B0.49080.94640.37050.049*
C110.3920 (4)0.9293 (3)0.2392 (3)0.0322 (8)
H110.38801.01750.19180.039*
C120.4406 (4)0.8330 (4)0.1607 (3)0.0414 (10)
H12A0.36000.86620.10450.050*
H12B0.43800.74680.20620.050*
C130.6155 (4)0.8160 (4)0.0976 (3)0.0378 (9)
H13A0.64520.75090.05040.045*
H13B0.61430.90060.04630.045*
C140.9912 (4)0.6381 (3)0.0655 (3)0.0255 (7)
H140.90300.62890.03290.031*
C151.1251 (4)0.6565 (4)−0.0355 (3)0.0296 (8)
C161.0875 (4)0.7752 (4)−0.1185 (3)0.0298 (8)
C171.1986 (5)0.7917 (4)−0.2178 (3)0.0367 (9)
C181.3514 (5)0.6900 (5)−0.2301 (3)0.0454 (11)
H181.42740.7007−0.29510.055*
C191.3921 (5)0.5718 (4)−0.1457 (4)0.0476 (11)
H191.49540.5038−0.15410.057*
C201.2793 (4)0.5554 (4)−0.0496 (3)0.0368 (9)
H201.30680.47590.00630.044*
C211.2282 (7)0.9219 (5)−0.4076 (3)0.0797 (17)
H21A1.34180.9132−0.40480.120*
H21B1.17151.0074−0.45490.120*
H21C1.22880.8521−0.44000.120*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Br10.0577 (3)0.0246 (2)0.0575 (3)−0.00942 (19)−0.0134 (2)−0.00831 (19)
Br20.0490 (3)0.0547 (3)0.0320 (2)−0.0205 (2)−0.01256 (18)−0.00628 (18)
O10.0277 (14)0.0408 (16)0.0439 (16)−0.0053 (13)0.0025 (12)−0.0038 (13)
O20.0370 (16)0.0440 (16)0.0302 (14)−0.0040 (13)0.0040 (12)−0.0011 (12)
O30.0602 (19)0.0570 (18)0.0303 (15)−0.0259 (16)0.0092 (13)−0.0038 (14)
N10.0405 (18)0.0227 (15)0.0294 (16)−0.0106 (14)−0.0055 (14)−0.0073 (13)
N20.0216 (15)0.0262 (15)0.0263 (15)−0.0077 (12)−0.0019 (12)−0.0068 (12)
C10.0208 (18)0.0288 (19)0.0291 (18)−0.0088 (15)−0.0031 (15)−0.0048 (15)
C20.0186 (18)0.0276 (18)0.0313 (19)−0.0066 (15)0.0006 (14)−0.0094 (15)
C30.028 (2)0.0219 (18)0.036 (2)−0.0074 (16)−0.0032 (16)−0.0082 (16)
C40.027 (2)0.029 (2)0.031 (2)−0.0038 (17)−0.0074 (16)−0.0005 (16)
C50.0239 (19)0.039 (2)0.0297 (19)−0.0106 (17)−0.0051 (15)−0.0097 (17)
C60.0249 (19)0.032 (2)0.037 (2)−0.0127 (16)0.0005 (16)−0.0098 (17)
C70.0232 (18)0.0268 (18)0.0297 (18)−0.0096 (15)−0.0042 (15)−0.0073 (15)
C80.0257 (19)0.0221 (17)0.0311 (19)−0.0081 (15)−0.0016 (15)−0.0047 (15)
C90.030 (2)0.048 (2)0.035 (2)−0.0078 (18)−0.0039 (17)−0.0168 (18)
C100.036 (2)0.048 (2)0.032 (2)−0.0031 (19)−0.0032 (18)−0.0155 (18)
C110.028 (2)0.0266 (19)0.036 (2)−0.0076 (16)0.0033 (16)−0.0049 (16)
C120.027 (2)0.050 (2)0.050 (2)−0.0111 (19)−0.0040 (18)−0.018 (2)
C130.027 (2)0.054 (3)0.039 (2)−0.0119 (19)−0.0026 (17)−0.0247 (19)
C140.0221 (18)0.0295 (19)0.0270 (18)−0.0080 (15)−0.0046 (14)−0.0098 (15)
C150.027 (2)0.039 (2)0.0253 (18)−0.0134 (17)−0.0032 (15)−0.0096 (16)
C160.025 (2)0.037 (2)0.0259 (18)−0.0096 (17)−0.0037 (15)−0.0072 (16)
C170.038 (2)0.049 (2)0.028 (2)−0.020 (2)0.0007 (17)−0.0109 (18)
C180.035 (2)0.073 (3)0.037 (2)−0.026 (2)0.0066 (19)−0.024 (2)
C190.026 (2)0.062 (3)0.054 (3)−0.003 (2)−0.001 (2)−0.032 (2)
C200.026 (2)0.042 (2)0.041 (2)−0.0053 (18)−0.0057 (17)−0.0149 (18)
C210.131 (5)0.086 (4)0.029 (2)−0.063 (4)0.027 (3)−0.013 (2)
Geometric parameters (Å, °) top
Br1—C31.900 (3)C9—C101.514 (5)
Br2—C51.895 (3)C9—H9A0.9700
O1—C111.423 (4)C9—H9B0.9700
O1—H10.8200C10—C111.499 (5)
O2—C161.364 (4)C10—H10A0.9700
O2—H20.8200C10—H10B0.9700
O3—C171.363 (4)C11—C121.509 (5)
O3—C211.416 (4)C11—H110.9800
N1—C21.381 (4)C12—C131.520 (5)
N1—C141.448 (4)C12—H12A0.9700
N1—H1A0.8600C12—H12B0.9700
N2—C141.476 (4)C13—H13A0.9700
N2—C71.482 (4)C13—H13B0.9700
N2—C81.490 (4)C14—C151.535 (4)
C1—C61.389 (4)C14—H140.9800
C1—C21.396 (4)C15—C161.385 (5)
C1—C71.517 (4)C15—C201.388 (5)
C2—C31.395 (5)C16—C171.397 (5)
C3—C41.376 (4)C17—C181.381 (5)
C4—C51.376 (5)C18—C191.391 (6)
C4—H40.9300C18—H180.9300
C5—C61.374 (5)C19—C201.379 (5)
C6—H60.9300C19—H190.9300
C7—H7A0.9700C20—H200.9300
C7—H7B0.9700C21—H21A0.9600
C8—C91.513 (5)C21—H21B0.9600
C8—C131.518 (4)C21—H21C0.9600
C8—H80.9800
C11—O1—H1109.5H10A—C10—H10B107.9
C16—O2—H2109.5O1—C11—C10107.9 (3)
C17—O3—C21117.3 (3)O1—C11—C12112.8 (3)
C2—N1—C14120.0 (3)C10—C11—C12109.8 (3)
C2—N1—H1A120.0O1—C11—H11108.8
C14—N1—H1A120.0C10—C11—H11108.8
C14—N2—C7107.0 (2)C12—C11—H11108.8
C14—N2—C8112.1 (2)C11—C12—C13110.9 (3)
C7—N2—C8116.3 (2)C11—C12—H12A109.5
C6—C1—C2120.2 (3)C13—C12—H12A109.5
C6—C1—C7121.4 (3)C11—C12—H12B109.5
C2—C1—C7118.4 (3)C13—C12—H12B109.5
N1—C2—C3121.7 (3)H12A—C12—H12B108.1
N1—C2—C1120.4 (3)C8—C13—C12112.7 (3)
C3—C2—C1118.0 (3)C8—C13—H13A109.1
C4—C3—C2121.9 (3)C12—C13—H13A109.1
C4—C3—Br1118.5 (3)C8—C13—H13B109.1
C2—C3—Br1119.6 (3)C12—C13—H13B109.1
C5—C4—C3118.9 (3)H13A—C13—H13B107.8
C5—C4—H4120.6N1—C14—N2113.6 (3)
C3—C4—H4120.6N1—C14—C15113.8 (3)
C6—C5—C4121.1 (3)N2—C14—C15109.0 (3)
C6—C5—Br2119.3 (3)N1—C14—H14106.7
C4—C5—Br2119.6 (3)N2—C14—H14106.7
C5—C6—C1119.9 (3)C15—C14—H14106.7
C5—C6—H6120.0C16—C15—C20118.9 (3)
C1—C6—H6120.0C16—C15—C14118.9 (3)
N2—C7—C1111.6 (3)C20—C15—C14122.1 (3)
N2—C7—H7A109.3O2—C16—C15122.2 (3)
C1—C7—H7A109.3O2—C16—C17116.8 (3)
N2—C7—H7B109.3C15—C16—C17121.0 (3)
C1—C7—H7B109.3O3—C17—C18126.0 (3)
H7A—C7—H7B108.0O3—C17—C16114.9 (3)
N2—C8—C9112.9 (3)C18—C17—C16119.1 (4)
N2—C8—C13108.8 (3)C17—C18—C19120.2 (4)
C9—C8—C13109.3 (3)C17—C18—H18119.9
N2—C8—H8108.6C19—C18—H18119.9
C9—C8—H8108.6C20—C19—C18120.1 (4)
C13—C8—H8108.6C20—C19—H19120.0
C8—C9—C10112.0 (3)C18—C19—H19120.0
C8—C9—H9A109.2C19—C20—C15120.6 (4)
C10—C9—H9A109.2C19—C20—H20119.7
C8—C9—H9B109.2C15—C20—H20119.7
C10—C9—H9B109.2O3—C21—H21A109.5
H9A—C9—H9B107.9O3—C21—H21B109.5
C11—C10—C9112.0 (3)H21A—C21—H21B109.5
C11—C10—H10A109.2O3—C21—H21C109.5
C9—C10—H10A109.2H21A—C21—H21C109.5
C11—C10—H10B109.2H21B—C21—H21C109.5
C9—C10—H10B109.2
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O2—H2···N20.821.892.614 (3)147
O1—H1···O3i0.822.413.048 (4)135
O1—H1···O2i0.822.132.897 (4)155
Symmetry codes: (i) −x+1, −y+2, −z.
Table 1
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
O2—H2···N20.821.892.614 (3)147
O1—H1···O3i0.822.413.048 (4)135
O1—H1···O2i0.822.132.897 (4)155
Symmetry codes: (i) −x+1, −y+2, −z.
Acknowledgements top

Financial support from the Third Affiliated Hospital of Soochow University is acknowledged.

references
References top

Allen, F. H., Kennard, O., Watson, D. G., Brammer, L., Orpen, A. G. & Taylor, R. (1987). J. Chem. Soc. Perkin Trans. 2, pp. S1–19.

Bruker (2002). SAINT and SMART. Bruker AXS Inc., Madison, Wisconsin, USA.

Felix, F. S., Brett, C. M. A. & Angnes, L. (2008). Talanta, 76, 128–133.

Gaida, W., Klinder, K., Arndt, K. & Weiser, T. (2005). Neuropharmacology, 49, 1220–1227.

Lee, H. J., Joung, S. K., Kim, Y. G., Yoo, J.-Y. & Han, S. B. (2004). Pharm. Res. 49, 93–98.

Sheldrick, G. M. (1996). SADABS. University of Göttingen, Germany.

Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.