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

Shao, H.; Zhao, G.; Liu, W.; Wang, Y.; Xu, W.

doi:10.1107/S1600536809047151

organic compounds

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Volume 65| Part 12| December 2009| Page o3071

doi:10.1107/S1600536809047151

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

Hua Shao,^a Guilong Zhao,^a ^* Wei Liu,^a Yuli Wang ^a and Weiren Xu ^a

^aTianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, People's Republic of China
^*Correspondence e-mail: zhao_guilong@126.com

(Received 31 October 2009; accepted 8 November 2009; online 14 November 2009)

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 ). For reference structural data, see Allen et al. (1987 ).

Experimental

Crystal data

C₁₅H₁₂BrClO₂
M_r = 339.61
Orthorhombic, P b c a
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 ) 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[F² > 2σ(F²)] = 0.032
wR(F²) = 0.083
S = 1.09
2460 reflections
174 parameters
H-atom parameters constrained
Δρ_max = 0.56 e Å⁻³
Δρ_min = −0.63 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C10—H10⋯O1ⁱ	0.93	2.50	3.369 (3)	156
Symmetry code: (i) $[-x+{\script{3\over 2}}, y-{\script{1\over 2}}, z]$ .

Data collection: XSCANS (Bruker, 1999); cell refinement: XSCANS; data reduction: XSCANS; 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.

Supporting information

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

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

checkCIF report

Comment top

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.

Related literature top

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

Experimental top

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).

Computing details top

Data collection: XSCANS (Bruker, 1999); cell refinement: XSCANS (Bruker, 1999); data reduction: XSCANS (Bruker, 1999); 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

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

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

Crystal data top

C₁₅H₁₂BrClO₂	F(000) = 1360
M_r = 339.61	D_x = 1.616 Mg m⁻³
Orthorhombic, Pbca	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2ab	Cell parameters from 7090 reflections
a = 9.5979 (19) Å	θ = 2.6–27.9°
b = 12.951 (3) Å	µ = 3.13 mm⁻¹
c = 22.457 (5) Å	T = 153 K
V = 2791.3 (10) Å³	Block, colourless
Z = 8	0.22 × 0.18 × 0.12 mm

Data collection top

Bruker P4 diffractometer	2460 independent reflections
Radiation source: sealed tube	2127 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.043
ω scans	θ_max = 25.0°, θ_min = 2.8°
Absorption correction: gaussian (XSCANS; Bruker, 1999)	h = −11→10
T_min = 0.546, T_max = 0.705	k = −15→12
17640 measured reflections	l = −26→23

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.032	H-atom parameters constrained
wR(F²) = 0.083	w = 1/[σ²(F_o²) + (0.0488P)² + 0.2837P] where P = (F_o² + 2F_c²)/3
S = 1.09	(Δ/σ)_max = 0.001
2460 reflections	Δρ_max = 0.56 e Å⁻³
174 parameters	Δρ_min = −0.63 e Å⁻³
0 restraints	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0024 (4)

Crystal data top

C₁₅H₁₂BrClO₂	V = 2791.3 (10) Å³
M_r = 339.61	Z = 8
Orthorhombic, Pbca	Mo Kα radiation
a = 9.5979 (19) Å	µ = 3.13 mm⁻¹
b = 12.951 (3) Å	T = 153 K
c = 22.457 (5) Å	0.22 × 0.18 × 0.12 mm

Data collection top

Bruker P4 diffractometer	2460 independent reflections
Absorption correction: gaussian (XSCANS; Bruker, 1999)	2127 reflections with I > 2σ(I)
T_min = 0.546, T_max = 0.705	R_int = 0.043
17640 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.032	0 restraints
wR(F²) = 0.083	H-atom parameters constrained
S = 1.09	Δρ_max = 0.56 e Å⁻³
2460 reflections	Δρ_min = −0.63 e Å⁻³
174 parameters

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

	x	y	z	U_iso*/U_eq
Br1	1.01219 (3)	0.15934 (2)	0.193829 (13)	0.03274 (14)
Cl1	0.65219 (8)	0.50193 (5)	0.32750 (3)	0.0359 (2)
O1	0.9357 (2)	0.46850 (12)	0.39989 (8)	0.0332 (5)
O2	0.8726 (2)	0.06639 (12)	0.55900 (7)	0.0302 (4)
C1	0.7603 (3)	0.41473 (16)	0.29098 (12)	0.0241 (6)
C2	0.7414 (3)	0.39945 (17)	0.23067 (12)	0.0270 (6)
H2	0.6765	0.4389	0.2100	0.032*
C3	0.8190 (3)	0.32545 (18)	0.20097 (11)	0.0265 (6)
H3	0.8088	0.3162	0.1601	0.032*
C4	0.9117 (3)	0.26556 (17)	0.23294 (10)	0.0252 (6)
C5	0.9313 (3)	0.28109 (17)	0.29345 (10)	0.0243 (6)
H5	0.9940	0.2399	0.3143	0.029*
C6	0.8577 (3)	0.35790 (17)	0.32320 (11)	0.0234 (6)
C7	0.8941 (3)	0.38177 (18)	0.38710 (11)	0.0253 (6)
C8	0.8846 (3)	0.29806 (17)	0.43151 (10)	0.0227 (6)
C9	0.8050 (3)	0.20985 (17)	0.42111 (11)	0.0226 (6)
H9	0.7571	0.2037	0.3853	0.027*
C10	0.7954 (3)	0.13140 (17)	0.46257 (11)	0.0232 (6)
H10	0.7399	0.0739	0.4552	0.028*
C11	0.8703 (3)	0.13978 (17)	0.51571 (10)	0.0240 (6)
C12	0.9505 (3)	0.22788 (19)	0.52704 (11)	0.0285 (6)
H12	1.0000	0.2335	0.5625	0.034*
C13	0.9559 (3)	0.30605 (19)	0.48567 (11)	0.0273 (6)
H13	1.0077	0.3651	0.4938	0.033*
C14	0.7954 (3)	−0.02766 (17)	0.54863 (12)	0.0298 (6)
H14A	0.8222	−0.0581	0.5109	0.036*
H14B	0.6962	−0.0135	0.5477	0.036*
C15	0.8293 (3)	−0.1000 (2)	0.59905 (12)	0.0348 (7)
H15A	0.9277	−0.1135	0.5994	0.052*
H15B	0.7796	−0.1636	0.5938	0.052*
H15C	0.8025	−0.0689	0.6361	0.052*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Br1	0.0368 (2)	0.0330 (2)	0.0284 (2)	0.00518 (11)	0.01330 (12)	−0.00036 (11)
Cl1	0.0359 (5)	0.0346 (4)	0.0371 (4)	0.0117 (3)	−0.0049 (3)	−0.0100 (3)
O1	0.0377 (13)	0.0273 (9)	0.0347 (11)	−0.0038 (8)	−0.0067 (9)	−0.0030 (8)
O2	0.0342 (12)	0.0340 (9)	0.0223 (9)	−0.0072 (8)	−0.0035 (8)	0.0017 (8)
C1	0.0223 (15)	0.0195 (12)	0.0306 (14)	−0.0020 (10)	0.0034 (11)	−0.0013 (10)
C2	0.0260 (16)	0.0262 (13)	0.0290 (14)	−0.0026 (11)	−0.0032 (11)	0.0038 (11)
C3	0.0326 (17)	0.0286 (13)	0.0183 (13)	−0.0058 (11)	0.0038 (11)	−0.0002 (10)
C4	0.0243 (16)	0.0258 (12)	0.0256 (13)	−0.0031 (11)	0.0086 (12)	−0.0005 (10)
C5	0.0210 (16)	0.0251 (13)	0.0269 (13)	0.0006 (11)	0.0015 (11)	0.0045 (10)
C6	0.0212 (15)	0.0227 (12)	0.0263 (13)	−0.0030 (10)	0.0020 (11)	0.0016 (10)
C7	0.0180 (15)	0.0274 (13)	0.0304 (14)	0.0000 (11)	0.0007 (12)	−0.0044 (11)
C8	0.0186 (15)	0.0261 (12)	0.0234 (13)	0.0031 (10)	0.0011 (11)	−0.0052 (10)
C9	0.0189 (15)	0.0277 (13)	0.0212 (13)	0.0021 (10)	−0.0011 (10)	−0.0073 (10)
C10	0.0209 (15)	0.0263 (12)	0.0224 (13)	−0.0034 (10)	0.0005 (11)	−0.0044 (10)
C11	0.0214 (16)	0.0327 (13)	0.0181 (13)	0.0016 (11)	0.0024 (11)	−0.0019 (11)
C12	0.0279 (16)	0.0370 (15)	0.0206 (13)	−0.0014 (12)	−0.0035 (12)	−0.0070 (11)
C13	0.0247 (16)	0.0301 (13)	0.0271 (14)	−0.0033 (11)	−0.0008 (12)	−0.0049 (11)
C14	0.0249 (17)	0.0320 (13)	0.0324 (15)	−0.0038 (11)	−0.0002 (12)	0.0001 (11)
C15	0.0309 (18)	0.0382 (15)	0.0353 (16)	−0.0014 (12)	0.0028 (13)	0.0028 (12)

Geometric parameters (Å, º) top

Br1—C4	1.896 (2)	C8—C9	1.394 (3)
Cl1—C1	1.739 (2)	C8—C13	1.399 (3)
O1—C7	1.226 (3)	C9—C10	1.381 (3)
O2—C11	1.360 (3)	C9—H9	0.9300
O2—C14	1.444 (3)	C10—C11	1.397 (3)
C1—C2	1.381 (4)	C10—H10	0.9300
C1—C6	1.392 (4)	C11—C12	1.400 (3)
C2—C3	1.385 (4)	C12—C13	1.375 (4)
C2—H2	0.9300	C12—H12	0.9300
C3—C4	1.382 (4)	C13—H13	0.9300
C3—H3	0.9300	C14—C15	1.505 (3)
C4—C5	1.386 (3)	C14—H14A	0.9700
C5—C6	1.391 (3)	C14—H14B	0.9700
C5—H5	0.9300	C15—H15A	0.9600
C6—C7	1.509 (3)	C15—H15B	0.9600
C7—C8	1.476 (3)	C15—H15C	0.9600

C11—O2—C14	117.77 (19)	C10—C9—H9	119.1
C2—C1—C6	121.5 (2)	C8—C9—H9	119.1
C2—C1—Cl1	118.49 (19)	C9—C10—C11	119.0 (2)
C6—C1—Cl1	119.9 (2)	C9—C10—H10	120.5
C1—C2—C3	120.1 (2)	C11—C10—H10	120.5
C1—C2—H2	120.0	O2—C11—C10	124.4 (2)
C3—C2—H2	120.0	O2—C11—C12	115.5 (2)
C4—C3—C2	119.0 (2)	C10—C11—C12	120.1 (2)
C4—C3—H3	120.5	C13—C12—C11	119.9 (2)
C2—C3—H3	120.5	C13—C12—H12	120.1
C3—C4—C5	121.0 (2)	C11—C12—H12	120.1
C3—C4—Br1	119.63 (18)	C12—C13—C8	121.0 (2)
C5—C4—Br1	119.37 (19)	C12—C13—H13	119.5
C4—C5—C6	120.4 (2)	C8—C13—H13	119.5
C4—C5—H5	119.8	O2—C14—C15	107.0 (2)
C6—C5—H5	119.8	O2—C14—H14A	110.3
C5—C6—C1	118.0 (2)	C15—C14—H14A	110.3
C5—C6—C7	119.1 (2)	O2—C14—H14B	110.3
C1—C6—C7	122.8 (2)	C15—C14—H14B	110.3
O1—C7—C8	122.3 (2)	H14A—C14—H14B	108.6
O1—C7—C6	119.1 (2)	C14—C15—H15A	109.5
C8—C7—C6	118.6 (2)	C14—C15—H15B	109.5
C9—C8—C13	118.3 (2)	H15A—C15—H15B	109.5
C9—C8—C7	121.5 (2)	C14—C15—H15C	109.5
C13—C8—C7	120.2 (2)	H15A—C15—H15C	109.5
C10—C9—C8	121.8 (2)	H15B—C15—H15C	109.5

C6—C1—C2—C3	0.7 (4)	O1—C7—C8—C9	163.0 (2)
Cl1—C1—C2—C3	−175.51 (19)	C6—C7—C8—C9	−20.0 (4)
C1—C2—C3—C4	2.0 (4)	O1—C7—C8—C13	−16.7 (4)
C2—C3—C4—C5	−2.3 (4)	C6—C7—C8—C13	160.3 (2)
C2—C3—C4—Br1	176.92 (19)	C13—C8—C9—C10	0.0 (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—C1	2.9 (4)	C14—O2—C11—C10	1.7 (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—C5	173.05 (19)	C9—C10—C11—C12	1.7 (4)
C2—C1—C6—C7	171.9 (2)	O2—C11—C12—C13	179.4 (2)
Cl1—C1—C6—C7	−11.8 (3)	C10—C11—C12—C13	−0.2 (4)
C5—C6—C7—O1	118.6 (3)	C11—C12—C13—C8	−1.4 (4)
C1—C6—C7—O1	−56.4 (4)	C9—C8—C13—C12	1.6 (4)
C5—C6—C7—C8	−58.5 (3)	C7—C8—C13—C12	−178.7 (2)
C1—C6—C7—C8	126.5 (3)	C11—O2—C14—C15	173.1 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C10—H10···O1ⁱ	0.93	2.50	3.369 (3)	156

Symmetry code: (i) −x+3/2, y−1/2, z.

Experimental details

Crystal data
Chemical formula	C₁₅H₁₂BrClO₂
M_r	339.61
Crystal system, space group	Orthorhombic, Pbca
Temperature (K)	153
a, b, c (Å)	9.5979 (19), 12.951 (3), 22.457 (5)
V (Å³)	2791.3 (10)
Z	8
Radiation type	Mo Kα
µ (mm⁻¹)	3.13
Crystal size (mm)	0.22 × 0.18 × 0.12

Data collection
Diffractometer	Bruker P4 diffractometer
Absorption correction	Gaussian (XSCANS; Bruker, 1999)
T_min, T_max	0.546, 0.705
No. of measured, independent and observed [I > 2σ(I)] reflections	17640, 2460, 2127
R_int	0.043
(sin θ/λ)_max (Å⁻¹)	0.595

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.032, 0.083, 1.09
No. of reflections	2460
No. of parameters	174
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.56, −0.63

Computer programs: XSCANS (Bruker, 1999), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C10—H10···O1ⁱ	0.93	2.50	3.369 (3)	155.7

Symmetry code: (i) −x+3/2, y−1/2, z.

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. CrossRef Web of Science Google Scholar
Bruker (1999). XSCANS. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
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. Web of Science CrossRef PubMed CAS Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar

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doi:10.1107/S1600536809047151

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