organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890

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

aShaanXi Institute For Food And Drug Control, Zhuque Road 431, 710061 Xi-An, People's Republic of China, and bDepartment of Chemistry, School of Pharmacy, Fourth Military Medical University, Changle West Road 17, 710032 Xi-An, People's Republic of China
*Correspondence e-mail: liuhaijing1@163.com

(Received 16 December 2009; accepted 26 January 2010; online 6 February 2010)

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[Baranda, A. B., Jiménez, R. M. & Alonso, R. M. (2004). J. Chromatogr. A, 1031, 275-280.]); Che et al. (2004[Che, D., Guntoori, B. R. & Murthy, S. K. (2004). US Patent Appl. 2004/0204604 A1, October 14, 2004.]); Won et al. (2005[Won, D. H., Kim, M. S., Lee, S., Park, J. S. & Hwang, S. J. (2005). Int. J. Pharm. 301, 199-208.]); Xu et al. (1995[Xu, Y. G., Hua, W. Y., Zhao, J. H., Chen, Y. Y. & &Yang, Q. H. (1995). J. Chin. Pharm. Univ. 26, 65-67.]). For felodipine derivatives as calcium channel blockers with vasodilator properties, see: Ferrari et al. (2005[Ferrari, M., Ghezzi, M., Alberelli, C. & &Ambrosini, L. (2005). US Patent Appl. 2005/0240022 A1, October 27, 2005.]); Qin et al. (1995[Qin, X. Z., Joe, D. M. & Dominic, P. I. (1995). J. Chromatogr. A, 707, 245-254.]); Marciniec et al. (2002[Marciniec, B., Jaroszkiewicz, E. & Ogrodowczyk, M. (2002). Int. J. Pharm. 233, 207-215.]).

[Scheme 1]

Experimental

Crystal data
  • C18H17Cl2NO4

  • Mr = 382.23

  • Orthorhombic, P b c a

  • 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[Bruker (2001). SAINT-Plus and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]) Tmin = 0.957, Tmax = 0.971

  • 21810 measured reflections

  • 4268 independent reflections

  • 2268 reflections with I > 2σ(I)

  • Rint = 0.054

Refinement
  • R[F2 > 2σ(F2)] = 0.056

  • wR(F2) = 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

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
C5—H5⋯O1i 0.93 2.55 3.303 (4) 139
C16—H16C⋯O1ii 0.96 2.67 3.328 (5) 126
C17—H17B⋯O4iii 0.97 2.55 3.247 (4) 129
Symmetry codes: (i) [x+{\script{1\over 2}}, y, -z+{\script{1\over 2}}]; (ii) [x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+1]; (iii) [x-{\script{1\over 2}}, y, -z+{\script{1\over 2}}].

Data collection: APEX2 (Bruker, 2004[Bruker (2004). APEX2. Bruker AXS Inc., Madison, Wisconsin, USA.]); cell refinement: SAINT-Plus (Bruker, 2001[Bruker (2001). SAINT-Plus and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]); data reduction: SAINT-Plus; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); software used to prepare material for publication: SHELXTL.

Supporting information


Comment top

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.

Related literature top

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

Experimental top

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 top

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)

Computing details top

Data collection: APEX2 (Bruker, 2004); cell refinement: SAINT-Plus (Bruker, 2001); data reduction: SAINT-Plus (Bruker, 2001); 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. Molecular structure of the title compound (I). Displacement ellipsoids are drawn at the 30% probability level.
3-Ethyl 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethylpyridine-3,5-dicarboxylate top
Crystal data top
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 top
Bruker APEXII CCD
diffractometer
4268 independent reflections
Radiation source: fine-focus sealed tube2268 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.054
ϕ and ω scansθmax = 27.5°, θmin = 2.3°
Absorption correction: multi-scan
(SADABS; Bruker, 2001)
h = 1811
Tmin = 0.957, Tmax = 0.971k = 1918
21810 measured reflectionsl = 2121
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)] = 0.056Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.153H-atom parameters constrained
S = 1.00 w = 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
Crystal data top
C18H17Cl2NO4V = 3766.4 (3) Å3
Mr = 382.23Z = 8
Orthorhombic, PbcaMo Kα radiation
a = 14.3179 (6) ŵ = 0.37 mm1
b = 15.5045 (7) ÅT = 296 K
c = 16.9664 (8) Å0.12 × 0.09 × 0.08 mm
Data collection top
Bruker APEXII CCD
diffractometer
4268 independent reflections
Absorption correction: multi-scan
(SADABS; Bruker, 2001)
2268 reflections with I > 2σ(I)
Tmin = 0.957, Tmax = 0.971Rint = 0.054
21810 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0560 restraints
wR(F2) = 0.153H-atom parameters constrained
S = 1.00Δρmax = 0.36 e Å3
4268 reflectionsΔρmin = 0.26 e Å3
230 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
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) top
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, º) top
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, º) top
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) x1/2, y, z+1/2.

Experimental details

Crystal data
Chemical formulaC18H17Cl2NO4
Mr382.23
Crystal system, space groupOrthorhombic, Pbca
Temperature (K)296
a, b, c (Å)14.3179 (6), 15.5045 (7), 16.9664 (8)
V3)3766.4 (3)
Z8
Radiation typeMo Kα
µ (mm1)0.37
Crystal size (mm)0.12 × 0.09 × 0.08
Data collection
DiffractometerBruker APEXII CCD
diffractometer
Absorption correctionMulti-scan
(SADABS; Bruker, 2001)
Tmin, Tmax0.957, 0.971
No. of measured, independent and
observed [I > 2σ(I)] reflections
21810, 4268, 2268
Rint0.054
(sin θ/λ)max1)0.650
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.056, 0.153, 1.00
No. of reflections4268
No. of parameters230
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.36, 0.26

Computer programs: APEX2 (Bruker, 2004), SAINT-Plus (Bruker, 2001), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
C5—H5···O1i0.932.553.303 (4)138.5
C16—H16C···O1ii0.962.670003.328 (5)126.00
C17—H17B···O4iii0.972.553.247 (4)129.00
Symmetry codes: (i) x+1/2, y, z+1/2; (ii) x+1/2, y+1/2, z+1; (iii) x1/2, y, z+1/2.
 

Acknowledgements

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.

References

First citationBaranda, A. B., Jiménez, R. M. & Alonso, R. M. (2004). J. Chromatogr. A, 1031, 275–280.  Web of Science CrossRef PubMed CAS Google Scholar
First citationBruker (2001). SAINT-Plus and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.  Google Scholar
First citationBruker (2004). APEX2. Bruker AXS Inc., Madison, Wisconsin, USA.  Google Scholar
First citationChe, D., Guntoori, B. R. & Murthy, S. K. (2004). US Patent Appl. 2004/0204604 A1, October 14, 2004.  Google Scholar
First citationFerrari, M., Ghezzi, M., Alberelli, C. & &Ambrosini, L. (2005). US Patent Appl. 2005/0240022 A1, October 27, 2005.  Google Scholar
First citationMarciniec, B., Jaroszkiewicz, E. & Ogrodowczyk, M. (2002). Int. J. Pharm. 233, 207–215.  Web of Science CrossRef PubMed CAS Google Scholar
First citationQin, X. Z., Joe, D. M. & Dominic, P. I. (1995). J. Chromatogr. A, 707, 245–254.  CrossRef CAS Web of Science Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationWon, D. H., Kim, M. S., Lee, S., Park, J. S. & Hwang, S. J. (2005). Int. J. Pharm. 301, 199–208.  Web of Science CrossRef PubMed CAS Google Scholar
First citationXu, Y. G., Hua, W. Y., Zhao, J. H., Chen, Y. Y. & &Yang, Q. H. (1995). J. Chin. Pharm. Univ. 26, 65–67.  CAS Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Follow Acta Cryst. E
Sign up for e-alerts
Follow Acta Cryst. on Twitter
Follow us on facebook
Sign up for RSS feeds