Diethyl 2,6-dimethyl-4-[5-(4-methyl­phen­yl)-1H-pyrazol-4-yl]-1,4-dihydro­pyridine-3,5-dicarboxyl­ate

Arun M Islor; Shridhar Malladi; Sandeep Telkar; Thomas Gerber; Eric Hosten; Richard Betz

doi:10.1107/S1600536812044649

. 2012 Nov 3;68(Pt 12):o3269–o3270. doi: 10.1107/S1600536812044649

Diethyl 2,6-dimethyl-4-[5-(4-methylphenyl)-1H-pyrazol-4-yl]-1,4-dihydropyridine-3,5-dicarboxylate

Arun M Islor ^a, Shridhar Malladi ^a, Sandeep Telkar ^b, Thomas Gerber ^c, Eric Hosten ^c, Richard Betz ^c,^*

PMCID: PMC3588819 PMID: 23468784

Abstract

In the title compound, C₂₃H₂₇N₃O₄, the dihydropyridine ring adopts a ^1,4 B conformation. Intramolecular C—H⋯O contacts occur. In the crystal, N—H⋯O and N—H⋯N hydrogen bonds and C—H⋯N contacts connect the molecules into strands along the a-axis direction.

Related literature

For background to the biological and pharmaceutical importance of dihydropyridine compounds, see: Stout & Meyers (1982 ▶); Vijesh et al. (2011 ▶); Boecker & Guengerich (1986 ▶); Vo et al. (1995 ▶). For puckering analysis, see: Cremer & Pople (1975 ▶); Boeyens (1978 ▶). For graph-set analysis of hydrogen bonds, see: Etter et al. (1990 ▶); Bernstein et al. (1995 ▶).

Experimental

Crystal data

C₂₃H₂₇N₃O₄
M _r = 409.48
Triclinic,
a = 8.5905 (2) Å
b = 10.8253 (3) Å
c = 11.3702 (3) Å
α = 91.021 (1)°
β = 97.922 (1)°
γ = 93.445 (1)°
V = 1045.02 (5) Å³
Z = 2
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 200 K
0.36 × 0.31 × 0.16 mm

Data collection

Bruker APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2008 ▶) T _min = 0.969, T _max = 0.986
18073 measured reflections
4983 independent reflections
4313 reflections with I > 2σ(I)
R _int = 0.017

Refinement

R[F ² > 2σ(F ²)] = 0.041
wR(F ²) = 0.113
S = 1.05
4983 reflections
284 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.33 e Å⁻³
Δρ_min = −0.21 e Å⁻³

Data collection: APEX2 (Bruker, 2010 ▶); cell refinement: SAINT (Bruker, 2010 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 (Farrugia, 2012 ▶) and Mercury (Macrae et al., 2008 ▶); software used to prepare material for publication: SHELXL97 and PLATON (Spek, 2009 ▶).

Supplementary Material

Click here for additional data file.^{(28.9KB, cif)}

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812044649/hg5264sup1.cif

e-68-o3269-sup1.cif^{(28.9KB, cif)}

Click here for additional data file.^{(3.1KB, cdx)}

Supplementary material file. DOI: 10.1107/S1600536812044649/hg5264Isup2.cdx

Click here for additional data file.^{(244KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812044649/hg5264Isup3.hkl

e-68-o3269-Isup3.hkl^{(244KB, hkl)}

Click here for additional data file.^{(8.5KB, cml)}

Supplementary material file. DOI: 10.1107/S1600536812044649/hg5264Isup4.cml

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

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N11—H11B⋯N21ⁱ	0.890 (17)	2.200 (17)	3.0352 (14)	156.2 (14)
N22—H22⋯O3ⁱⁱ	0.892 (17)	2.066 (17)	2.9580 (13)	178.6 (15)
C2—H2B⋯N21ⁱⁱⁱ	0.98	2.52	3.4223 (16)	153
C36—H36⋯O1	0.95	2.30	3.2428 (17)	173

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Acknowledgments

AMI is thankful to the Board of Research in Nuclear Sciences, Government of India for the Young Scientist award and also thanks the Vision Group on Science & Technology, Government of Karnataka, India for the Best Research Paper award.

supplementary crystallographic information

Comment

The 1,4-dihydropyridine scaffold (DHP) represents a heterocyclic unit of remarkable pharmacological activity (Stout & Meyers, 1982) and is found to exhibit various biological activities (Vijesh et al., 2011). Several DHP-inspired compounds are already used clinically as calcium channel blockers for the treatment of cardiovascular diseases, such as Nifedipine and Nitrendipine – used for the treatment of hypertension and angina pectoris –, Nisoldipine – a potent vasodilator – and Nimodipine – selective agent for targeting cerebral vasculature – to name but a few (Boecker & Guengerich, 1986). A number of DHP derivatives are discussed as potential drugs for the treatment of congestive heart failure (Vo et al., 1995). Motivated by the promising pharmaceutical activities of 1,4-dihydropyridines, the title compound was synthesized to study its crystal structure.

The molecule is a pyrazole derivative featuring a phenyl as well as a dihydropyridine-derived substituent. While the small puckering amplitude precludes a conformational analysis of the five-membered heterocycle, the dihyropyridine ring adopts a ^1,4B (^N11,C11B) conformation (Cremer & Pople, 1975; Boeyens, 1978). The least-squares planes defined by the intracyclic atoms of the phenyl group as well as the five-membered heterocycle, respectively, enclose an angle of 33.03 (7) °. The plane defined by the atoms of the dihydropyridine core is almost planar (r.m.s. of all fitted atoms = 0.1726 Å), with the flap carbon atom and the nitrogen atom deviating most from the plane by 0.270 (1) Å and 0.199 (1) Å, respectively (Fig. 1).

In the crystal, classical intermolecular hydrogen bonds of the N–H···N as well as the N–H···O type are present. Furthermore, C–H···N contacts and C–H···O contacts whose range falls by more than 0.1 Å below the sum of van-der-Waals radii of the corresponding atoms are observed. The C–H···N contacts are supported by one of the hydrogen atoms of a methyl group directly bonded to the dihydropyridine ring and one of the nitrogen atoms of the pyrazole moiety. The intramolecular C–H···O contact is apparent between one of the hydrogen atoms of the phenyl group in ortho position to the pyrazole ring and one of the sp² hybridized oxygen atoms. Metrical parameters as well as information about the symmetry of these contacts are summarized in Table 1. In total, the C–H···N contacts as well as the N–H···O-type hydrogen bonds form antidromic chains of molecules that are extended to strands along the crystallographic a axis by the N–H···N-type hydrogen bonds. In terms of graph-set analysis (Etter et al., 1990; Bernstein et al., 1995), the descriptor for the classical hydrogen bonds is C¹₁(8)R²₂(16) on the unary level. The C–H supported contacts necessitate a S(9)C¹₁(8) descriptor on the same level. The shortest intercentroid distance between two aromatic systems was measured at 4.7738 (8) Å (Fig. 2).

The packing of the title compound in the crystal structure is shown in Figure 3.

Experimental

3-(4-methylphenyl)-1H-pyrazole-4-carbaldehyde(0.187 g, 1.0 mmol), ethylacetoacetate (0.26 g, 2.0 mmol) and ammonium acetate (0.092 g, 1.2 mmol) in ethanol (7 ml) were refluxed in an oil bath for 5 h. After completion of the reaction, the mixture was concentrated and poured into crushed ice. The precipitated product was filtered and washed with water. The resulting solid was recrystallized from ethanol:water (v:v = 1:1), yield: 0.33 g (80.68%).