Dimethyl 2,6-dimethyl-4-{3-[4-(methyl­sulfan­yl)phen­yl]-1H-pyrazol-4-yl}-1,4-dihydro­pyridine-3,5-dicarboxyl­ate monohydrate

Arun M Islor; A M Vijesh; Thomas Gerber; Eric Hosten; Richard Betz

doi:10.1107/S1600536812045333

. 2012 Nov 10;68(Pt 12):o3302–o3303. doi: 10.1107/S1600536812045333

Dimethyl 2,6-dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-1H-pyrazol-4-yl}-1,4-dihydropyridine-3,5-dicarboxylate monohydrate

Arun M Islor ^a, A M Vijesh ^b, Thomas Gerber ^c, Eric Hosten ^c, Richard Betz ^c,^*

PMCID: PMC3588844 PMID: 23468809

Abstract

In the title compound, C₂₁H₂₃N₃O₄S·H₂O, the methylsulfanyl group is disordered over two sets of sites with site-occupancy factors of 0.631 (11) and 0.369 (11). The dihydropyridine ring adopts an E ₄ conformation. In the crystal, classical O—H⋯N, O—H⋯O and N—H⋯O hydrogen bonds, as well as C—H⋯O and C—H⋯S contacts, connect the molecules into a three-dimensional network.

Related literature

For general information about the pharmacological importance of 1,4-dihydropyridine-based drugs, see: Janis & Triggle (1983 ▶); Boecker & Guengerich (1986 ▶); Gordeev et al. (1996 ▶); Buhler & Kiowski (1987 ▶); Vo et al. (1995 ▶). For puckering analysis of cyclic motifs, see: Cremer & Pople (1975 ▶). For graph-set analysis of hydrogen bonds, see: Etter et al. (1990 ▶); Bernstein et al. (1995 ▶).

Experimental

Crystal data

C₂₁H₂₃N₃O₄S·H₂O
M _r = 431.50
Monoclinic,
a = 10.5542 (2) Å
b = 14.7260 (2) Å
c = 14.5377 (2) Å
β = 110.106 (1)°
V = 2121.77 (6) Å³
Z = 4
Mo Kα radiation
μ = 0.19 mm⁻¹
T = 200 K
0.27 × 0.23 × 0.20 mm

Data collection

Bruker APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2008 ▶) T _min = 0.950, T _max = 0.963
20236 measured reflections
5267 independent reflections
4311 reflections with I > 2σ(I)
R _int = 0.019

Refinement

R[F ² > 2σ(F ²)] = 0.040
wR(F ²) = 0.111
S = 1.03
5267 reflections
312 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.30 e Å⁻³
Δρ_min = −0.27 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, 1997 ▶) 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.^{(30.1KB, cif)}

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812045333/rn2110sup1.cif

e-68-o3302-sup1.cif^{(30.1KB, cif)}

Click here for additional data file.^{(3.3KB, cdx)}

Supplementary material file. DOI: 10.1107/S1600536812045333/rn2110Isup2.cdx

Click here for additional data file.^{(257.9KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812045333/rn2110Isup3.hkl

e-68-o3302-Isup3.hkl^{(257.9KB, hkl)}

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

Supplementary material file. DOI: 10.1107/S1600536812045333/rn2110Isup4.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
O8—H8A⋯N22ⁱ	0.83 (3)	2.09 (3)	2.8982 (18)	167 (2)
O8—H8B⋯O4ⁱⁱ	0.84 (3)	2.09 (3)	2.8989 (19)	164 (2)
N21—H21⋯O2ⁱⁱⁱ	0.884 (19)	1.985 (19)	2.8505 (15)	165.9 (17)
N31—H31A⋯O8^iv	0.908 (19)	1.965 (19)	2.8561 (18)	166.6 (17)
C23—H23⋯S1A ^v	0.95	2.79	3.637 (3)	149

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

Acknowledgments

AMI thanks the Board for Research in Nuclear Sciences, Government of India, for a Young Scientist award.

supplementary crystallographic information

Comment

In recent years, considerable attention has been paid to the synthesis of 1,4-dihydropyridines owing to their significant biological activity. 1,4-Dihydropyridine-containing drugs (1,4-DHPs), such as nifedipine, nicardipine, amlodipine, felodipine and others have been found to be useful as calcium channel blockers (Janis & Triggle, 1983; Boecker & Guengerich, 1986; Gordeev et al., 1996) and are used most frequently as cardiovascular agents for the treatment of hypertension (Buhler & Kiowski, 1987). A number of DHP derivatives are employed as potential drug candidates for the treatment of congestive heart failure (Vo et al., 1995). In continuation of our ongoing interest in pharmaceutically active compounds, the title compound was synthesized to study its crystal structure.

The compound is the hydrate of a mixed pyrazole-1,4-dihydropyridine compound. The thiomethyl group is disordered over two positions with site occupancy factors of 0.631 (11) and 0.369 (11). According to a puckering analysis (Cremer & Pople, 1975), the dihydropyridine ring adopts an E₄ conformation with the flap atom on C31 (E_C31). The least-squares planes defined by the carbon atoms of the phenyl group and the intracyclic atoms of the pyrazole ring enclose an angle of 48.42 (8) °. At the same time, the aforementioned planes intersect with the least-squares plane defined by the atoms of the 1,4-dihydropyridine ring at angles of 45.18 (7) ° and 86.12 (7) °, respectively.

In the crystal, classical hydrogen bonds of the O–H···N, O–H···O and N–H..O type can be observed that are supported by all nitrogen- and oxygen-bound hydrogen atoms. The bifurcated C H···O contact may influence the eclipsed ester substituent conformation with respect to this group. Furthermore, an intermolecular C–H···S contact is present falling short by more than 0.2 Å of the sum of van-der-Waals radii of the corresponding atoms. These contacts connect the entities in the crystal structure to a three-dimensional network. In terms of graph-set analysis (Etter et al., 1990; Bernstein et al., 1995), the descriptor for these contacts is S(5)S(5)DDDC¹₁(8)C¹₁(9) on the unary level. The C¹₁(9) descriptor detailing the intermolecular C–H···S contacts is shown in Figure 2. Metrical parameters as well as information about the symmetry of these contacts are summarized in Table 1. The shortest intercentroid distance between two aromatic systems was measured at 5.2965 (8) Å and is apparent between the pyrazole and the phenyl moiety in two neighbouring molecules.

Experimental

3-(4-methylsulfanyl-phenyl)-1H-pyrazole-4-carbaldehyde (0.2 g, 0.9 mmol), methylacetoacetate (0.21 g, 1.8 mmol) and ammonium acetate (0.07 g, 0.9 mmol) in methanol (20 mL) were heated under reflux in an oil bath for 8 h. After completion of the reaction, the reaction mixture was concentrated and poured onto crushed ice. The precipitate was filtered and washed with water. The resulting solid was recrystallized from hot methanol, yield: 0.32 g (84%).