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

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.

Key indicators

• Single-crystal X-ray study
• T = 296 K
• Mean [sigma](C-C) = 0.004 Å
• R factor = 0.056
• wR factor = 0.153
• Data-to-parameter ratio = 18.6

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT242_ALERT_2_C Check Low       Ueq as Compared to Neighbors for        C13
PLAT480_ALERT_4_C Long H...A H-Bond Reported H16C   ..  O1      ..       2.67 Ang.
PLAT912_ALERT_4_C Missing # of FCF Reflections Above STh/L=  0.600         52

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   3 ALERT level C = Check and explain
   0 ALERT level G = General alerts; check

   0 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   1 ALERT type 2 Indicator that the structure model may be wrong or deficient
   0 ALERT type 3 Indicator that the structure quality may be low
   2 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. 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.

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).

S2. 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.

S3. 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)

Computing details

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

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

Crystal data

C18H17Cl2NO4	F(000) = 1584
Mr = 382.23	Dx = 1.348 Mg m^−3
Orthorhombic, Pbca	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 monochromator	Rint = 0.054
ϕ and ω scans	θmax = 27.5°, θmin = 2.3°
Absorption correction: multi-scan (SADABS; Bruker, 2001)	h = −18→11
Tmin = 0.957, Tmax = 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(Fo^2) + (0.056P)^2 + 2.0434P] where P = (Fo^2 + 2Fc^2)/3
4268 reflections	(Δ/σ)max < 0.001
230 parameters	Δρmax = 0.36 e Å^−3
0 restraints	Δρmin = −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 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 (Ų)

	x	y	z	Uiso*/Ueq
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 (Ų)

	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, º)

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, º)

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.