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Acta Crystallogr Sect E Struct Rep Online. 2009 December 1; 65(Pt 12): o3071.
Published online 2009 November 14. doi:  10.1107/S1600536809047151
PMCID: PMC2971929

(5-Bromo-2-chloro­phen­yl)(4-ethoxy­phen­yl)methanone

Abstract

In the title mol­ecule, C15H12BrClO2, the two benzene rings form a dihedral angle of 69.30 (3)°. In the crystal structure, weak inter­molecular C—H(...)O hydrogen bonds link mol­ecules into chains propagating along the b axis.

Related literature

The title compound is an inter­mediate in the synthesis of Dapagliflozin, which exhibits strong biological activity, see Meng et al. (2008 [triangle]). For reference structural data, see Allen et al. (1987 [triangle]).

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Object name is e-65-o3071-scheme1.jpg

Experimental

Crystal data

  • C15H12BrClO2
  • M r = 339.61
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is e-65-o3071-efi1.jpg
  • a = 9.5979 (19) Å
  • b = 12.951 (3) Å
  • c = 22.457 (5) Å
  • V = 2791.3 (10) Å3
  • Z = 8
  • Mo Kα radiation
  • μ = 3.13 mm−1
  • T = 153 K
  • 0.22 × 0.18 × 0.12 mm

Data collection

  • Bruker P4 diffractometer
  • Absorption correction: gaussian (XSCANS; Bruker, 1999 [triangle]) T min = 0.546, T max = 0.705
  • 17640 measured reflections
  • 2460 independent reflections
  • 2127 reflections with I > 2σ(I)
  • R int = 0.043

Refinement

  • R[F 2 > 2σ(F 2)] = 0.032
  • wR(F 2) = 0.083
  • S = 1.09
  • 2460 reflections
  • 174 parameters
  • H-atom parameters constrained
  • Δρmax = 0.56 e Å−3
  • Δρmin = −0.63 e Å−3

Data collection: XSCANS (Bruker, 1999 [triangle]); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL (Sheldrick, 2008 [triangle]); software used to prepare material for publication: SHELXTL.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809047151/cv2652sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809047151/cv2652Isup2.hkl

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

supplementary crystallographic information

Comment

Dapagliflozin is an anti-diabetic agent through the inhibition of renal SGLT2, which is developed by Bristol-Myers Squibb Company, and now it is in the phase III clinical trial (Meng et al., 2008). During the development of our own SGLT2 inhibitors as anti-diabetic agents, Dapagliflozin was synthesized as the positive control in the bioactivity screening, and the title compound, (I), was prepared as an intermediate. The crystallographic analysis of (I) confirms the molecular structures of the title compound and Dapagliflozin.

In (I) (Fig. 1), all bond lengths are normal and in a good agreement with those reported previously (Allen et al., 1987). Two benzene rings (C1—C6 and C8—C13) form a dihedral angle of 69.30 (3) °. In the crystal structure, weak intermolecular C—H···O hydrogen bonds (Table 1) link molecules into chains along axis b.

Experimental

A round-bottomed flask was charged with 2.36 g (10 mmol) of 5-bromo-2-chlorobenoic acid, 1 drop of DMF, 1.27 g (10 mmol) of oxalyl chloride and 3 ml of dried dichloromethane, and the mixture was stirred at room temperature over night until a clear solution formed. The reaction mixture was evaporated on a rotary evaporator to give crude 5-bromo-2-chlorobenzoic acid, which was dissolved in 15 ml of dried dichloromethane. The solution thus obtained was stirred while being cooled with an ice-salt mixture, and 1.22 g (10 mmol) of phenetole was added followed by addition of 1.60 g (12 mmol) of anhydrous aluminium chloride in a portionwise manner. The resulting mixture was stirred at this temperature for 1 h and poured into 150 ml of ice-water. The mixture thus formed was exacted with three 50-ml portions of dichloromethane, and the combined exacts were washed with saturated brine, dried over sodium sulfate and evaporated on a rotary evaporator to afford the crude title compound. Pure title compound was obtained by column chromatography (2.86 g 84.2%). Crystals suitable for X-ray diffraction were obtained through slow evaporation of a solution of the pure title compound in dichloromethane/ethyl acetate/petroleum ether (2/1/3 by volume).

Refinement

All C-bound H atoms were placed in calculated positions, with C—H = 0.93–0.97 Å, and included in the final cycles of refinement using a riding model, with Uiso(H) = 1.2Ueq(C) for the aryl and methylene H atoms and 1.5Ueq(C) for the methyl H atoms.

Figures

Fig. 1.
View of the title compound, with displacement ellipsoids drawn at the 40% probability level.

Crystal data

C15H12BrClO2F(000) = 1360
Mr = 339.61Dx = 1.616 Mg m3
Orthorhombic, PbcaMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2abCell parameters from 7090 reflections
a = 9.5979 (19) Åθ = 2.6–27.9°
b = 12.951 (3) ŵ = 3.13 mm1
c = 22.457 (5) ÅT = 153 K
V = 2791.3 (10) Å3Block, colourless
Z = 80.22 × 0.18 × 0.12 mm

Data collection

Bruker P4 diffractometer2460 independent reflections
Radiation source: sealed tube2127 reflections with I > 2σ(I)
graphiteRint = 0.043
ω scansθmax = 25.0°, θmin = 2.8°
Absorption correction: gaussian (XSCANS; Bruker, 1999)h = −11→10
Tmin = 0.546, Tmax = 0.705k = −15→12
17640 measured reflectionsl = −26→23

Refinement

Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.032H-atom parameters constrained
wR(F2) = 0.083w = 1/[σ2(Fo2) + (0.0488P)2 + 0.2837P] where P = (Fo2 + 2Fc2)/3
S = 1.09(Δ/σ)max = 0.001
2460 reflectionsΔρmax = 0.56 e Å3
174 parametersΔρmin = −0.62 e Å3
0 restraintsExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.0024 (4)

Special details

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)

xyzUiso*/Ueq
Br11.01219 (3)0.15934 (2)0.193829 (13)0.03274 (14)
Cl10.65219 (8)0.50193 (5)0.32750 (3)0.0359 (2)
O10.9357 (2)0.46850 (12)0.39989 (8)0.0332 (5)
O20.8726 (2)0.06639 (12)0.55900 (7)0.0302 (4)
C10.7603 (3)0.41473 (16)0.29098 (12)0.0241 (6)
C20.7414 (3)0.39945 (17)0.23067 (12)0.0270 (6)
H20.67650.43890.21000.032*
C30.8190 (3)0.32545 (18)0.20097 (11)0.0265 (6)
H30.80880.31620.16010.032*
C40.9117 (3)0.26556 (17)0.23294 (10)0.0252 (6)
C50.9313 (3)0.28109 (17)0.29345 (10)0.0243 (6)
H50.99400.23990.31430.029*
C60.8577 (3)0.35790 (17)0.32320 (11)0.0234 (6)
C70.8941 (3)0.38177 (18)0.38710 (11)0.0253 (6)
C80.8846 (3)0.29806 (17)0.43151 (10)0.0227 (6)
C90.8050 (3)0.20985 (17)0.42111 (11)0.0226 (6)
H90.75710.20370.38530.027*
C100.7954 (3)0.13140 (17)0.46257 (11)0.0232 (6)
H100.73990.07390.45520.028*
C110.8703 (3)0.13978 (17)0.51571 (10)0.0240 (6)
C120.9505 (3)0.22788 (19)0.52704 (11)0.0285 (6)
H121.00000.23350.56250.034*
C130.9559 (3)0.30605 (19)0.48567 (11)0.0273 (6)
H131.00770.36510.49380.033*
C140.7954 (3)−0.02766 (17)0.54863 (12)0.0298 (6)
H14A0.8222−0.05810.51090.036*
H14B0.6962−0.01350.54770.036*
C150.8293 (3)−0.1000 (2)0.59905 (12)0.0348 (7)
H15A0.9277−0.11350.59940.052*
H15B0.7796−0.16360.59380.052*
H15C0.8025−0.06890.63610.052*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
Br10.0368 (2)0.0330 (2)0.0284 (2)0.00518 (11)0.01330 (12)−0.00036 (11)
Cl10.0359 (5)0.0346 (4)0.0371 (4)0.0117 (3)−0.0049 (3)−0.0100 (3)
O10.0377 (13)0.0273 (9)0.0347 (11)−0.0038 (8)−0.0067 (9)−0.0030 (8)
O20.0342 (12)0.0340 (9)0.0223 (9)−0.0072 (8)−0.0035 (8)0.0017 (8)
C10.0223 (15)0.0195 (12)0.0306 (14)−0.0020 (10)0.0034 (11)−0.0013 (10)
C20.0260 (16)0.0262 (13)0.0290 (14)−0.0026 (11)−0.0032 (11)0.0038 (11)
C30.0326 (17)0.0286 (13)0.0183 (13)−0.0058 (11)0.0038 (11)−0.0002 (10)
C40.0243 (16)0.0258 (12)0.0256 (13)−0.0031 (11)0.0086 (12)−0.0005 (10)
C50.0210 (16)0.0251 (13)0.0269 (13)0.0006 (11)0.0015 (11)0.0045 (10)
C60.0212 (15)0.0227 (12)0.0263 (13)−0.0030 (10)0.0020 (11)0.0016 (10)
C70.0180 (15)0.0274 (13)0.0304 (14)0.0000 (11)0.0007 (12)−0.0044 (11)
C80.0186 (15)0.0261 (12)0.0234 (13)0.0031 (10)0.0011 (11)−0.0052 (10)
C90.0189 (15)0.0277 (13)0.0212 (13)0.0021 (10)−0.0011 (10)−0.0073 (10)
C100.0209 (15)0.0263 (12)0.0224 (13)−0.0034 (10)0.0005 (11)−0.0044 (10)
C110.0214 (16)0.0327 (13)0.0181 (13)0.0016 (11)0.0024 (11)−0.0019 (11)
C120.0279 (16)0.0370 (15)0.0206 (13)−0.0014 (12)−0.0035 (12)−0.0070 (11)
C130.0247 (16)0.0301 (13)0.0271 (14)−0.0033 (11)−0.0008 (12)−0.0049 (11)
C140.0249 (17)0.0320 (13)0.0324 (15)−0.0038 (11)−0.0002 (12)0.0001 (11)
C150.0309 (18)0.0382 (15)0.0353 (16)−0.0014 (12)0.0028 (13)0.0028 (12)

Geometric parameters (Å, °)

Br1—C41.896 (2)C8—C91.394 (3)
Cl1—C11.739 (2)C8—C131.399 (3)
O1—C71.226 (3)C9—C101.381 (3)
O2—C111.360 (3)C9—H90.9300
O2—C141.444 (3)C10—C111.397 (3)
C1—C21.381 (4)C10—H100.9300
C1—C61.392 (4)C11—C121.400 (3)
C2—C31.385 (4)C12—C131.375 (4)
C2—H20.9300C12—H120.9300
C3—C41.382 (4)C13—H130.9300
C3—H30.9300C14—C151.505 (3)
C4—C51.386 (3)C14—H14A0.9700
C5—C61.391 (3)C14—H14B0.9700
C5—H50.9300C15—H15A0.9600
C6—C71.509 (3)C15—H15B0.9600
C7—C81.476 (3)C15—H15C0.9600
C11—O2—C14117.77 (19)C10—C9—H9119.1
C2—C1—C6121.5 (2)C8—C9—H9119.1
C2—C1—Cl1118.49 (19)C9—C10—C11119.0 (2)
C6—C1—Cl1119.9 (2)C9—C10—H10120.5
C1—C2—C3120.1 (2)C11—C10—H10120.5
C1—C2—H2120.0O2—C11—C10124.4 (2)
C3—C2—H2120.0O2—C11—C12115.5 (2)
C4—C3—C2119.0 (2)C10—C11—C12120.1 (2)
C4—C3—H3120.5C13—C12—C11119.9 (2)
C2—C3—H3120.5C13—C12—H12120.1
C3—C4—C5121.0 (2)C11—C12—H12120.1
C3—C4—Br1119.63 (18)C12—C13—C8121.0 (2)
C5—C4—Br1119.37 (19)C12—C13—H13119.5
C4—C5—C6120.4 (2)C8—C13—H13119.5
C4—C5—H5119.8O2—C14—C15107.0 (2)
C6—C5—H5119.8O2—C14—H14A110.3
C5—C6—C1118.0 (2)C15—C14—H14A110.3
C5—C6—C7119.1 (2)O2—C14—H14B110.3
C1—C6—C7122.8 (2)C15—C14—H14B110.3
O1—C7—C8122.3 (2)H14A—C14—H14B108.6
O1—C7—C6119.1 (2)C14—C15—H15A109.5
C8—C7—C6118.6 (2)C14—C15—H15B109.5
C9—C8—C13118.3 (2)H15A—C15—H15B109.5
C9—C8—C7121.5 (2)C14—C15—H15C109.5
C13—C8—C7120.2 (2)H15A—C15—H15C109.5
C10—C9—C8121.8 (2)H15B—C15—H15C109.5
C6—C1—C2—C30.7 (4)O1—C7—C8—C9163.0 (2)
Cl1—C1—C2—C3−175.51 (19)C6—C7—C8—C9−20.0 (4)
C1—C2—C3—C42.0 (4)O1—C7—C8—C13−16.7 (4)
C2—C3—C4—C5−2.3 (4)C6—C7—C8—C13160.3 (2)
C2—C3—C4—Br1176.92 (19)C13—C8—C9—C100.0 (4)
C3—C4—C5—C6−0.2 (4)C7—C8—C9—C10−179.8 (2)
Br1—C4—C5—C6−179.38 (19)C8—C9—C10—C11−1.6 (4)
C4—C5—C6—C12.9 (4)C14—O2—C11—C101.7 (4)
C4—C5—C6—C7−172.4 (2)C14—O2—C11—C12−177.9 (2)
C2—C1—C6—C5−3.2 (4)C9—C10—C11—O2−177.9 (2)
Cl1—C1—C6—C5173.05 (19)C9—C10—C11—C121.7 (4)
C2—C1—C6—C7171.9 (2)O2—C11—C12—C13179.4 (2)
Cl1—C1—C6—C7−11.8 (3)C10—C11—C12—C13−0.2 (4)
C5—C6—C7—O1118.6 (3)C11—C12—C13—C8−1.4 (4)
C1—C6—C7—O1−56.4 (4)C9—C8—C13—C121.6 (4)
C5—C6—C7—C8−58.5 (3)C7—C8—C13—C12−178.7 (2)
C1—C6—C7—C8126.5 (3)C11—O2—C14—C15173.1 (2)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
C10—H10···O1i0.932.503.369 (3)156

Symmetry codes: (i) −x+3/2, y−1/2, z.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: CV2652).

References

  • 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 (1999). XSCANS. Bruker AXS Inc., Madison, Wisconsin, USA.
  • Meng, M., Ellsworth, B. A., Nirschl, A. A., McCann, P. J., Patel, M., Girotra, R. N., Wu, G., Sher, P. M., Morrison, E. P., Biller, S. A., Zahler, R., Deshpande, P. P., Pullockaran, A., Hagan, D. L., Morgan, N., Taylor, J. R., Obermeier, M. T., Humphreys, W. G., Khanna, A., Discenza, L., Robertson, J. M., Wang, A., Han, S., Wetterau, J. R., Janovitz, E. B., Flint, O. P., Whaley, J. M. & Washburn, W. N. (2008). J. Med. Chem. 51, 1145–1149.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]

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