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Acta Crystallogr Sect E Struct Rep Online. 2010 March 1; 66(Pt 3): o538.
Published online 2010 February 6. doi:  10.1107/S1600536810003235
PMCID: PMC2983690

3-Ethyl 5-methyl 4-(2,3-dichloro­phen­yl)-2,6-dimethyl­pyridine-3,5-dicarboxyl­ate

Abstract

In the title compound, C18H17Cl2NO4, an oxidation product of felodipine, the dihedral angle between the benzene and pyridine rings is 75.3 (4)°. The crystal structure is stabilized by intermolecular C—H(...)O interactions.

Related literature

For related structures, see: Baranda et al. (2004 [triangle]); Che et al. (2004 [triangle]); Won et al. (2005 [triangle]); Xu et al. (1995 [triangle]). For felodipine derivatives as calcium channel blockers with vasodilator properties, see: Ferrari et al. (2005 [triangle]); Qin et al. (1995 [triangle]); Marciniec et al. (2002 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-66-0o538-scheme1.jpg

Experimental

Crystal data

  • C18H17Cl2NO4
  • M r = 382.23
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is e-66-0o538-efi1.jpg
  • a = 14.3179 (6) Å
  • b = 15.5045 (7) Å
  • c = 16.9664 (8) Å
  • V = 3766.4 (3) Å3
  • Z = 8
  • Mo Kα radiation
  • μ = 0.37 mm−1
  • T = 296 K
  • 0.12 × 0.09 × 0.08 mm

Data collection

  • Bruker APEXII CCD diffractometer
  • Absorption correction: multi-scan (SADABS; Bruker, 2001 [triangle]) T min = 0.957, T max = 0.971
  • 21810 measured reflections
  • 4268 independent reflections
  • 2268 reflections with I > 2σ(I)
  • R int = 0.054

Refinement

  • R[F 2 > 2σ(F 2)] = 0.056
  • wR(F 2) = 0.153
  • S = 1.00
  • 4268 reflections
  • 230 parameters
  • H-atom parameters constrained
  • Δρmax = 0.36 e Å−3
  • Δρmin = −0.26 e Å−3

Data collection: APEX2 (Bruker, 2004 [triangle]); cell refinement: SAINT-Plus (Bruker, 2001 [triangle]); data reduction: SAINT-Plus; 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/S1600536810003235/pk2222sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810003235/pk2222Isup2.hkl

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

Acknowledgments

We thank the Natural Science Foundation of China (Nos. 30901883, 20972189, 30600163), the Natural Science Foundation of Shannxi Province (No. 2008C274) and the Administration Traditional Chinese Medicine Foundation of Shannxi Province (No. jc46, zy16) for financial support.

supplementary crystallographic information

Comment

Felodipine is a calcium channel blocker with vasodilator properties. It is used in several commercial preparations for treatment of hypertension (Marciniec et al., 2002). It has been the subject of many analytical chemical investigations. Regulations on the purity profile of bulk drug substances require determination of levels of impurities such as the title compound, which is an oxidation product of felodipine.

The molecular structure is shown in Fig 1. The dihedral angle between the phenyl ring and the pyridine ring is 75.3 (4)°. The crystal structure is stabilized by van der Waals interactions.

Experimental

A mixture of 5 g felodipine and 50 mL 50% sulfuric acid (50%, v/v) was heated under reflux for 30 min, then cooled to room temperature and saturated sodium hydroxide was added slowly until the solution was neutral. The mixture was then extracted with 3×100 ml CHCl3 and the combined organic layers were dried over Na2SO4 before solvent removal. The product was purified by chromatography on silica gel with 1:1 EtOAc / hexanes as eluent.

Refinement

H-atoms were included in calculated positions and treated as riding atoms: C-H = 0.92—0.97 Å with Uiso(H) = 1.2—1.5 Ueq(C)

Figures

Fig. 1.
Molecular structure of the title compound (I). Displacement ellipsoids are drawn at the 30% probability level.

Crystal data

C18H17Cl2NO4F(000) = 1584
Mr = 382.23Dx = 1.348 Mg m3
Orthorhombic, PbcaMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2abCell parameters from 2869 reflections
a = 14.3179 (6) Åθ = 2.4–20.2°
b = 15.5045 (7) ŵ = 0.37 mm1
c = 16.9664 (8) ÅT = 296 K
V = 3766.4 (3) Å3Block, colorless
Z = 80.12 × 0.09 × 0.08 mm

Data collection

Bruker APEXII CCD diffractometer4268 independent reflections
Radiation source: fine-focus sealed tube2268 reflections with I > 2σ(I)
graphiteRint = 0.054
[var phi] and ω scansθmax = 27.5°, θmin = 2.3°
Absorption correction: multi-scan (SADABS; Bruker, 2001)h = −18→11
Tmin = 0.957, Tmax = 0.971k = −19→18
21810 measured reflectionsl = −21→21

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.056Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.153H-atom parameters constrained
S = 1.00w = 1/[σ2(Fo2) + (0.056P)2 + 2.0434P] where P = (Fo2 + 2Fc2)/3
4268 reflections(Δ/σ)max < 0.001
230 parametersΔρmax = 0.36 e Å3
0 restraintsΔρmin = −0.26 e Å3

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
C10.6713 (2)0.16190 (18)0.34902 (17)0.0502 (7)
C20.6979 (2)0.08675 (19)0.30988 (19)0.0616 (8)
C30.7775 (3)0.0859 (2)0.2636 (2)0.0718 (10)
H30.79550.03570.23780.086*
C40.8295 (2)0.1596 (2)0.2559 (2)0.0715 (9)
H40.88320.15910.22510.086*
C50.8034 (2)0.2339 (2)0.29326 (18)0.0584 (8)
H50.83930.28340.28720.070*
C60.72405 (18)0.23629 (18)0.33994 (16)0.0462 (7)
C70.69755 (18)0.31818 (17)0.38064 (16)0.0448 (6)
C80.74662 (19)0.34553 (19)0.44663 (16)0.0504 (7)
C90.7225 (2)0.4235 (2)0.48194 (18)0.0608 (8)
C100.6020 (2)0.44520 (19)0.39427 (18)0.0542 (7)
C110.62486 (18)0.37031 (18)0.35304 (16)0.0460 (7)
C120.5729 (2)0.34657 (18)0.28006 (18)0.0519 (7)
C130.8256 (2)0.2937 (2)0.47870 (17)0.0594 (8)
C140.5231 (2)0.5037 (2)0.3710 (2)0.0731 (10)
H14A0.48070.50980.41450.110*
H14B0.49070.47960.32670.110*
H14C0.54760.55930.35700.110*
C150.7767 (3)0.4590 (3)0.5511 (2)0.0977 (13)
H15A0.81210.50840.53440.147*
H15B0.81830.41550.57070.147*
H15C0.73400.47570.59200.147*
C160.8683 (3)0.1748 (3)0.5567 (3)0.1154 (17)
H16A0.90220.14370.51700.173*
H16B0.83880.13470.59190.173*
H16C0.91060.21070.58580.173*
C170.5886 (3)0.3220 (3)0.1420 (2)0.0806 (11)
H17A0.62310.34850.09920.097*
H17B0.52410.34090.13830.097*
C180.5928 (3)0.2273 (3)0.1341 (2)0.0997 (14)
H18A0.65570.20810.14290.150*
H18B0.57340.21100.08210.150*
H18C0.55220.20120.17230.150*
Cl10.57453 (6)0.16217 (6)0.40985 (6)0.0735 (3)
Cl20.63272 (8)−0.00639 (6)0.31910 (7)0.0982 (4)
N10.65082 (19)0.47100 (17)0.45730 (15)0.0630 (7)
O10.49233 (15)0.32839 (17)0.27743 (14)0.0830 (8)
O20.62809 (14)0.35000 (15)0.21758 (12)0.0665 (6)
O30.79723 (16)0.22840 (16)0.51927 (17)0.0860 (8)
O40.90563 (18)0.3137 (2)0.47082 (18)0.1162 (12)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
C10.0476 (15)0.0505 (17)0.0526 (17)0.0011 (14)−0.0078 (13)0.0058 (14)
C20.070 (2)0.0493 (18)0.065 (2)0.0015 (16)−0.0240 (17)0.0022 (15)
C30.085 (3)0.067 (2)0.063 (2)0.028 (2)−0.0124 (19)−0.0119 (18)
C40.068 (2)0.086 (3)0.061 (2)0.019 (2)0.0066 (17)−0.0047 (19)
C50.0483 (17)0.066 (2)0.061 (2)0.0025 (15)0.0045 (15)0.0006 (16)
C60.0410 (15)0.0518 (16)0.0458 (16)0.0036 (13)−0.0063 (12)−0.0002 (13)
C70.0410 (15)0.0482 (16)0.0452 (16)−0.0027 (13)0.0025 (12)0.0009 (12)
C80.0471 (15)0.0592 (18)0.0449 (16)−0.0013 (14)−0.0014 (14)0.0008 (14)
C90.069 (2)0.065 (2)0.0484 (18)−0.0016 (17)−0.0028 (15)−0.0051 (15)
C100.0550 (18)0.0545 (18)0.0532 (19)0.0024 (14)0.0056 (14)0.0058 (14)
C110.0452 (15)0.0486 (16)0.0443 (16)−0.0032 (13)0.0005 (12)0.0035 (13)
C120.0454 (17)0.0539 (17)0.0565 (19)0.0012 (14)−0.0054 (14)0.0057 (14)
C130.054 (2)0.079 (2)0.0446 (17)0.0017 (17)−0.0055 (15)−0.0050 (16)
C140.072 (2)0.062 (2)0.085 (3)0.0173 (17)−0.0004 (19)−0.0003 (18)
C150.122 (3)0.098 (3)0.074 (3)0.013 (3)−0.034 (2)−0.033 (2)
C160.099 (3)0.072 (3)0.175 (5)0.014 (2)−0.065 (3)0.022 (3)
C170.088 (3)0.103 (3)0.051 (2)−0.009 (2)−0.0154 (18)−0.0036 (19)
C180.113 (3)0.103 (3)0.083 (3)0.000 (3)−0.019 (2)−0.022 (2)
Cl10.0591 (5)0.0707 (6)0.0907 (6)−0.0108 (4)0.0126 (4)0.0090 (5)
Cl20.1146 (8)0.0497 (5)0.1304 (10)−0.0090 (5)−0.0369 (7)0.0011 (5)
N10.0763 (18)0.0573 (16)0.0555 (17)0.0072 (14)−0.0004 (14)−0.0067 (13)
O10.0480 (13)0.125 (2)0.0764 (17)−0.0154 (14)−0.0082 (11)−0.0051 (15)
O20.0584 (13)0.0900 (17)0.0512 (13)−0.0115 (11)−0.0062 (10)−0.0020 (11)
O30.0682 (15)0.0638 (15)0.126 (2)−0.0021 (12)−0.0318 (15)0.0242 (15)
O40.0533 (16)0.182 (3)0.114 (2)0.0082 (18)−0.0036 (15)0.057 (2)

Geometric parameters (Å, °)

C1—C61.387 (4)C12—O11.188 (3)
C1—C21.394 (4)C12—O21.323 (3)
C1—Cl11.728 (3)C13—O41.194 (4)
C2—C31.384 (5)C13—O31.290 (4)
C2—Cl21.726 (3)C14—H14A0.9602
C3—C41.371 (5)C14—H14B0.9602
C3—H30.9300C14—H14C0.9602
C4—C51.367 (4)C15—H15A0.9601
C4—H40.9300C15—H15B0.9601
C5—C61.385 (4)C15—H15C0.9601
C5—H50.9300C16—O31.459 (4)
C6—C71.494 (4)C16—H16A0.9600
C7—C111.398 (4)C16—H16B0.9600
C7—C81.388 (4)C16—H16C0.9600
C8—C91.393 (4)C17—O21.467 (4)
C8—C131.490 (4)C17—C181.476 (5)
C9—N11.331 (4)C17—H17A0.9700
C9—C151.510 (4)C17—H17B0.9700
C10—N11.339 (4)C18—H18A0.9600
C10—C111.395 (4)C18—H18B0.9600
C10—C141.501 (4)C18—H18C0.9600
C11—C121.491 (4)
C6—C1—C2119.6 (3)O4—C13—O3124.5 (3)
C6—C1—Cl1120.1 (2)O4—C13—C8123.2 (3)
C2—C1—Cl1120.4 (2)O3—C13—C8112.2 (3)
C3—C2—C1120.2 (3)C10—C14—H14A109.5
C3—C2—Cl2119.2 (3)C10—C14—H14B109.5
C1—C2—Cl2120.6 (3)H14A—C14—H14B109.5
C4—C3—C2119.6 (3)C10—C14—H14C109.5
C4—C3—H3120.2H14A—C14—H14C109.5
C2—C3—H3120.2H14B—C14—H14C109.5
C3—C4—C5120.6 (3)C9—C15—H15A109.5
C3—C4—H4119.7C9—C15—H15B109.5
C5—C4—H4119.7H15A—C15—H15B109.5
C4—C5—C6120.8 (3)C9—C15—H15C109.5
C4—C5—H5119.6H15A—C15—H15C109.5
C6—C5—H5119.6H15B—C15—H15C109.5
C5—C6—C1119.2 (3)O3—C16—H16A109.5
C5—C6—C7119.7 (3)O3—C16—H16B109.5
C1—C6—C7121.1 (2)H16A—C16—H16B109.5
C11—C7—C8118.1 (3)O3—C16—H16C109.5
C11—C7—C6121.7 (2)H16A—C16—H16C109.5
C8—C7—C6120.2 (2)H16B—C16—H16C109.5
C9—C8—C7119.1 (3)O2—C17—C18110.9 (3)
C9—C8—C13119.9 (3)O2—C17—H17A109.5
C7—C8—C13120.9 (3)C18—C17—H17A109.5
N1—C9—C8122.4 (3)O2—C17—H17B109.5
N1—C9—C15116.0 (3)C18—C17—H17B109.4
C8—C9—C15121.5 (3)H17A—C17—H17B108.0
N1—C10—C11121.8 (3)C17—C18—H18A109.5
N1—C10—C14114.9 (3)C17—C18—H18B109.5
C11—C10—C14123.3 (3)H18A—C18—H18B109.5
C7—C11—C10119.2 (3)C17—C18—H18C109.5
C7—C11—C12120.5 (3)H18A—C18—H18C109.5
C10—C11—C12120.3 (3)H18B—C18—H18C109.5
O1—C12—O2124.0 (3)C9—N1—C10119.3 (3)
O1—C12—C11125.1 (3)C12—O2—C17117.3 (2)
O2—C12—C11110.9 (2)C13—O3—C16117.4 (3)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
C5—H5···O1i0.932.553.303 (4)139
C16—H16C···O1ii0.962.673.328 (5)126
C17—H17B···O4iii0.972.553.247 (4)129

Symmetry codes: (i) x+1/2, y, −z+1/2; (ii) x+1/2, −y+1/2, −z+1; (iii) x−1/2, y, −z+1/2.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: PK2222).

References

  • Baranda, A. B., Jiménez, R. M. & Alonso, R. M. (2004). J. Chromatogr. A, 1031, 275–280. [PubMed]
  • Bruker (2001). SAINT-Plus and SADABS Bruker AXS Inc., Madison, Wisconsin, USA.
  • Bruker (2004). APEX2 Bruker AXS Inc., Madison, Wisconsin, USA.
  • Che, D., Guntoori, B. R. & Murthy, S. K. (2004). US Patent Appl. 2004/0204604 A1, October 14, 2004.
  • Ferrari, M., Ghezzi, M., Alberelli, C. & &Ambrosini, L. (2005). US Patent Appl. 2005/0240022 A1, October 27, 2005.
  • Marciniec, B., Jaroszkiewicz, E. & Ogrodowczyk, M. (2002). Int. J. Pharm.233, 207–215. [PubMed]
  • Qin, X. Z., Joe, D. M. & Dominic, P. I. (1995). J. Chromatogr. A, 707, 245–254.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Won, D. H., Kim, M. S., Lee, S., Park, J. S. & Hwang, S. J. (2005). Int. J. Pharm.301, 199–208. [PubMed]
  • Xu, Y. G., Hua, W. Y., Zhao, J. H., Chen, Y. Y. & &Yang, Q. H. (1995). J. Chin. Pharm. Univ.26, 65–67.

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