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

Luo, Jing a Chen, Hui b Wang, Qiao-Feng b Liu, Hai-Jing a * [a ] ShaanXi Institute For Food And Drug Control, Zhuque Road 431, 710061 Xi-An, People’s Republic of China [b ] Department of Chemistry, School of Pharmacy, Fourth Military Medical University, Changle West Road 17, 710032 Xi-An, People’s Republic of China

Abstract

In the title compound, C 18H 17Cl 2NO 4, 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 ); 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 ). e-66-0o538-scheme1.jpg

Experimental

Crystal data

  • C 18H 17Cl 2NO 4

  • M r = 382.23

  • Orthorhombic, e-66-0o538-efi1.jpg

  • a = 14.3179 (6) Å

  • b = 15.5045 (7) Å

  • c = 16.9664 (8) Å

  • V = 3766.4 (3) Å 3

  • 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 ) 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

  • Δρ max = 0.36 e Å −3

  • Δρ min = −0.26 e Å −3

Data collection: APEX2 (Bruker, 2004 ); cell refinement: SAINT-Plus (Bruker, 2001 ); data reduction: SAINT-Plus; 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.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810003235/pk2222sup1.cif

e-66-0o538-sup1.cif

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

e-66-0o538-Isup2.hkl

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

Notes

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

Acknowledgements

We thank the Natural Science Foundation of China (Nos. 30901883, 20972189, 30600163), the Natural Science Foundation of Shannxi Province (No. 2008C 274) and the Administration Traditional Chinese Medicine Foundation of Shannxi Province (No. jc46, zy16) for financial support.

Appendices

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 CHCl 3 and the combined organic layers were dried over Na 2SO4 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.

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

Crystal data

C 18H 17Cl 2NO 4 F(000) = 1584
M r = 382.23 D x = 1.348 Mg m 3
Orthorhombic, P b c a Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2ab Cell parameters from 2869 reflections
a = 14.3179 (6) Å θ = 2.4–20.2°
b = 15.5045 (7) Å µ = 0.37 mm 1
c = 16.9664 (8) Å T = 296 K
V = 3766.4 (3) Å 3 Block, colorless
Z = 8 0.12 × 0.09 × 0.08 mm

Data collection

Bruker APEXII CCD diffractometer 4268 independent reflections
Radiation source: fine-focus sealed tube 2268 reflections with I > 2σ( I)
graphite R int = 0.054
φ and ω scans θ max = 27.5°, θ min = 2.3°
Absorption correction: multi-scan ( SADABS; Bruker, 2001) h = −18→11
T min = 0.957, T max = 0.971 k = −19→18
21810 measured reflections l = −21→21

Refinement

Refinement on F 2 Primary atom site location: structure-invariant direct methods
Least-squares matrix: full Secondary atom site location: difference Fourier map
R[ F 2 > 2σ( F 2)] = 0.056 Hydrogen site location: inferred from neighbouring sites
wR( F 2) = 0.153 H-atom parameters constrained
S = 1.00 w = 1/[σ 2( F o 2) + (0.056 P) 2 + 2.0434 P] where P = ( F o 2 + 2 F c 2)/3
4268 reflections (Δ/σ) max < 0.001
230 parameters Δρ max = 0.36 e Å 3
0 restraints Δρ min = −0.26 e Å 3

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 F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2, conventional R-factors R are based on F, with F set to zero for negative F 2. The threshold expression of F 2 > σ( F 2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 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 (Å 2)

x y z U iso*/ U eq
C1 0.6713 (2) 0.16190 (18) 0.34902 (17) 0.0502 (7)
C2 0.6979 (2) 0.08675 (19) 0.30988 (19) 0.0616 (8)
C3 0.7775 (3) 0.0859 (2) 0.2636 (2) 0.0718 (10)
H3 0.7955 0.0357 0.2378 0.086*
C4 0.8295 (2) 0.1596 (2) 0.2559 (2) 0.0715 (9)
H4 0.8832 0.1591 0.2251 0.086*
C5 0.8034 (2) 0.2339 (2) 0.29326 (18) 0.0584 (8)
H5 0.8393 0.2834 0.2872 0.070*
C6 0.72405 (18) 0.23629 (18) 0.33994 (16) 0.0462 (7)
C7 0.69755 (18) 0.31818 (17) 0.38064 (16) 0.0448 (6)
C8 0.74662 (19) 0.34553 (19) 0.44663 (16) 0.0504 (7)
C9 0.7225 (2) 0.4235 (2) 0.48194 (18) 0.0608 (8)
C10 0.6020 (2) 0.44520 (19) 0.39427 (18) 0.0542 (7)
C11 0.62486 (18) 0.37031 (18) 0.35304 (16) 0.0460 (7)
C12 0.5729 (2) 0.34657 (18) 0.28006 (18) 0.0519 (7)
C13 0.8256 (2) 0.2937 (2) 0.47870 (17) 0.0594 (8)
C14 0.5231 (2) 0.5037 (2) 0.3710 (2) 0.0731 (10)
H14A 0.4807 0.5098 0.4145 0.110*
H14B 0.4907 0.4796 0.3267 0.110*
H14C 0.5476 0.5593 0.3570 0.110*
C15 0.7767 (3) 0.4590 (3) 0.5511 (2) 0.0977 (13)
H15A 0.8121 0.5084 0.5344 0.147*
H15B 0.8183 0.4155 0.5707 0.147*
H15C 0.7340 0.4757 0.5920 0.147*
C16 0.8683 (3) 0.1748 (3) 0.5567 (3) 0.1154 (17)
H16A 0.9022 0.1437 0.5170 0.173*
H16B 0.8388 0.1347 0.5919 0.173*
H16C 0.9106 0.2107 0.5858 0.173*
C17 0.5886 (3) 0.3220 (3) 0.1420 (2) 0.0806 (11)
H17A 0.6231 0.3485 0.0992 0.097*
H17B 0.5241 0.3409 0.1383 0.097*
C18 0.5928 (3) 0.2273 (3) 0.1341 (2) 0.0997 (14)
H18A 0.6557 0.2081 0.1429 0.150*
H18B 0.5734 0.2110 0.0821 0.150*
H18C 0.5522 0.2012 0.1723 0.150*
Cl1 0.57453 (6) 0.16217 (6) 0.40985 (6) 0.0735 (3)
Cl2 0.63272 (8) −0.00639 (6) 0.31910 (7) 0.0982 (4)
N1 0.65082 (19) 0.47100 (17) 0.45730 (15) 0.0630 (7)
O1 0.49233 (15) 0.32839 (17) 0.27743 (14) 0.0830 (8)
O2 0.62809 (14) 0.35000 (15) 0.21758 (12) 0.0665 (6)
O3 0.79723 (16) 0.22840 (16) 0.51927 (17) 0.0860 (8)
O4 0.90563 (18) 0.3137 (2) 0.47082 (18) 0.1162 (12)

Atomic displacement parameters (Å 2)

U 11 U 22 U 33 U 12 U 13 U 23
C1 0.0476 (15) 0.0505 (17) 0.0526 (17) 0.0011 (14) −0.0078 (13) 0.0058 (14)
C2 0.070 (2) 0.0493 (18) 0.065 (2) 0.0015 (16) −0.0240 (17) 0.0022 (15)
C3 0.085 (3) 0.067 (2) 0.063 (2) 0.028 (2) −0.0124 (19) −0.0119 (18)
C4 0.068 (2) 0.086 (3) 0.061 (2) 0.019 (2) 0.0066 (17) −0.0047 (19)
C5 0.0483 (17) 0.066 (2) 0.061 (2) 0.0025 (15) 0.0045 (15) 0.0006 (16)
C6 0.0410 (15) 0.0518 (16) 0.0458 (16) 0.0036 (13) −0.0063 (12) −0.0002 (13)
C7 0.0410 (15) 0.0482 (16) 0.0452 (16) −0.0027 (13) 0.0025 (12) 0.0009 (12)
C8 0.0471 (15) 0.0592 (18) 0.0449 (16) −0.0013 (14) −0.0014 (14) 0.0008 (14)
C9 0.069 (2) 0.065 (2) 0.0484 (18) −0.0016 (17) −0.0028 (15) −0.0051 (15)
C10 0.0550 (18) 0.0545 (18) 0.0532 (19) 0.0024 (14) 0.0056 (14) 0.0058 (14)
C11 0.0452 (15) 0.0486 (16) 0.0443 (16) −0.0032 (13) 0.0005 (12) 0.0035 (13)
C12 0.0454 (17) 0.0539 (17) 0.0565 (19) 0.0012 (14) −0.0054 (14) 0.0057 (14)
C13 0.054 (2) 0.079 (2) 0.0446 (17) 0.0017 (17) −0.0055 (15) −0.0050 (16)
C14 0.072 (2) 0.062 (2) 0.085 (3) 0.0173 (17) −0.0004 (19) −0.0003 (18)
C15 0.122 (3) 0.098 (3) 0.074 (3) 0.013 (3) −0.034 (2) −0.033 (2)
C16 0.099 (3) 0.072 (3) 0.175 (5) 0.014 (2) −0.065 (3) 0.022 (3)
C17 0.088 (3) 0.103 (3) 0.051 (2) −0.009 (2) −0.0154 (18) −0.0036 (19)
C18 0.113 (3) 0.103 (3) 0.083 (3) 0.000 (3) −0.019 (2) −0.022 (2)
Cl1 0.0591 (5) 0.0707 (6) 0.0907 (6) −0.0108 (4) 0.0126 (4) 0.0090 (5)
Cl2 0.1146 (8) 0.0497 (5) 0.1304 (10) −0.0090 (5) −0.0369 (7) 0.0011 (5)
N1 0.0763 (18) 0.0573 (16) 0.0555 (17) 0.0072 (14) −0.0004 (14) −0.0067 (13)
O1 0.0480 (13) 0.125 (2) 0.0764 (17) −0.0154 (14) −0.0082 (11) −0.0051 (15)
O2 0.0584 (13) 0.0900 (17) 0.0512 (13) −0.0115 (11) −0.0062 (10) −0.0020 (11)
O3 0.0682 (15) 0.0638 (15) 0.126 (2) −0.0021 (12) −0.0318 (15) 0.0242 (15)
O4 0.0533 (16) 0.182 (3) 0.114 (2) 0.0082 (18) −0.0036 (15) 0.057 (2)

Geometric parameters (Å, °)

C1—C6 1.387 (4) C12—O1 1.188 (3)
C1—C2 1.394 (4) C12—O2 1.323 (3)
C1—Cl1 1.728 (3) C13—O4 1.194 (4)
C2—C3 1.384 (5) C13—O3 1.290 (4)
C2—Cl2 1.726 (3) C14—H14A 0.9602
C3—C4 1.371 (5) C14—H14B 0.9602
C3—H3 0.9300 C14—H14C 0.9602
C4—C5 1.367 (4) C15—H15A 0.9601
C4—H4 0.9300 C15—H15B 0.9601
C5—C6 1.385 (4) C15—H15C 0.9601
C5—H5 0.9300 C16—O3 1.459 (4)
C6—C7 1.494 (4) C16—H16A 0.9600
C7—C11 1.398 (4) C16—H16B 0.9600
C7—C8 1.388 (4) C16—H16C 0.9600
C8—C9 1.393 (4) C17—O2 1.467 (4)
C8—C13 1.490 (4) C17—C18 1.476 (5)
C9—N1 1.331 (4) C17—H17A 0.9700
C9—C15 1.510 (4) C17—H17B 0.9700
C10—N1 1.339 (4) C18—H18A 0.9600
C10—C11 1.395 (4) C18—H18B 0.9600
C10—C14 1.501 (4) C18—H18C 0.9600
C11—C12 1.491 (4)
C6—C1—C2 119.6 (3) O4—C13—O3 124.5 (3)
C6—C1—Cl1 120.1 (2) O4—C13—C8 123.2 (3)
C2—C1—Cl1 120.4 (2) O3—C13—C8 112.2 (3)
C3—C2—C1 120.2 (3) C10—C14—H14A 109.5
C3—C2—Cl2 119.2 (3) C10—C14—H14B 109.5
C1—C2—Cl2 120.6 (3) H14A—C14—H14B 109.5
C4—C3—C2 119.6 (3) C10—C14—H14C 109.5
C4—C3—H3 120.2 H14A—C14—H14C 109.5
C2—C3—H3 120.2 H14B—C14—H14C 109.5
C3—C4—C5 120.6 (3) C9—C15—H15A 109.5
C3—C4—H4 119.7 C9—C15—H15B 109.5
C5—C4—H4 119.7 H15A—C15—H15B 109.5
C4—C5—C6 120.8 (3) C9—C15—H15C 109.5
C4—C5—H5 119.6 H15A—C15—H15C 109.5
C6—C5—H5 119.6 H15B—C15—H15C 109.5
C5—C6—C1 119.2 (3) O3—C16—H16A 109.5
C5—C6—C7 119.7 (3) O3—C16—H16B 109.5
C1—C6—C7 121.1 (2) H16A—C16—H16B 109.5
C11—C7—C8 118.1 (3) O3—C16—H16C 109.5
C11—C7—C6 121.7 (2) H16A—C16—H16C 109.5
C8—C7—C6 120.2 (2) H16B—C16—H16C 109.5
C9—C8—C7 119.1 (3) O2—C17—C18 110.9 (3)
C9—C8—C13 119.9 (3) O2—C17—H17A 109.5
C7—C8—C13 120.9 (3) C18—C17—H17A 109.5
N1—C9—C8 122.4 (3) O2—C17—H17B 109.5
N1—C9—C15 116.0 (3) C18—C17—H17B 109.4
C8—C9—C15 121.5 (3) H17A—C17—H17B 108.0
N1—C10—C11 121.8 (3) C17—C18—H18A 109.5
N1—C10—C14 114.9 (3) C17—C18—H18B 109.5
C11—C10—C14 123.3 (3) H18A—C18—H18B 109.5
C7—C11—C10 119.2 (3) C17—C18—H18C 109.5
C7—C11—C12 120.5 (3) H18A—C18—H18C 109.5
C10—C11—C12 120.3 (3) H18B—C18—H18C 109.5
O1—C12—O2 124.0 (3) C9—N1—C10 119.3 (3)
O1—C12—C11 125.1 (3) C12—O2—C17 117.3 (2)
O2—C12—C11 110.9 (2) C13—O3—C16 117.4 (3)

Hydrogen-bond geometry (Å, °)

D—H··· A D—H H··· A D··· A D—H··· A
C5—H5···O1 i 0.93 2.55 3.303 (4) 139
C16—H16C···O1 ii 0.96 2.67 3.328 (5) 126
C17—H17B···O4 iii 0.97 2.55 3.247 (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.

References

1  

Baranda, A. B., Jiménez, R. M. & Alonso, R. M. (2004). J. Chromatogr. A, 1031, 275–280.

2  

Bruker (2001). SAINT-Plus and SADABS Bruker AXS Inc., Madison, Wisconsin, USA.

3  

Bruker (2004). APEX2 Bruker AXS Inc., Madison, Wisconsin, USA.

4  

Che, D., Guntoori, B. R. & Murthy, S. K. (2004). US Patent Appl. 2004/0204604 A1, October 14, 2004.

5  

Ferrari, M., Ghezzi, M., Alberelli, C. & &Ambrosini, L. (2005). US Patent Appl. 2005/0240022 A1, October 27, 2005.

6  

Marciniec, B., Jaroszkiewicz, E. & Ogrodowczyk, M. (2002). Int. J. Pharm. 233, 207–215.

7  

Qin, X. Z., Joe, D. M. & Dominic, P. I. (1995). J. Chromatogr. A, 707, 245–254.

8  

Sheldrick, G. M. (2008). Acta Cryst. A 64, 112–122.

9  

Won, D. H., Kim, M. S., Lee, S., Park, J. S. & Hwang, S. J. (2005). Int. J. Pharm. 301, 199–208.

10  

Xu, Y. G., Hua, W. Y., Zhao, J. H., Chen, Y. Y. & &Yang, Q. H. (1995). J. Chin. Pharm. Univ. 26, 65–67.

Figures and Tables

Table 1

Hydrogen-bond geometry (Å, °)

D—H⋯ A D—H H⋯ A DA D—H⋯ A
C5—H5⋯O1 i 0.93 2.55 3.303 (4) 139
C16—H16 C⋯O1 ii 0.96 2.67 3.328 (5) 126
C17—H17 B⋯O4 iii 0.97 2.55 3.247 (4) 129

Symmetry codes: (i) e-66-0o538-efi2.jpg ; (ii) e-66-0o538-efi3.jpg ; (iii) e-66-0o538-efi4.jpg .