Ethyl 5-amino-3-(pyridin-4-yl)-1-(2,4,6-tri­chloro­phen­yl)-1H-pyrazole-4-carb­oxyl­ate dimethyl sulfoxide hemisolvate

Bassam Abu Thaher; Pierre Koch; Dieter Schollmeyer; Stefan Laufer

doi:10.1107/S1600536812008264

. 2012 Feb 29;68(Pt 3):o917–o918. doi: 10.1107/S1600536812008264

Ethyl 5-amino-3-(pyridin-4-yl)-1-(2,4,6-trichlorophenyl)-1H-pyrazole-4-carboxylate dimethyl sulfoxide hemisolvate

Bassam Abu Thaher ^a, Pierre Koch ^b, Dieter Schollmeyer ^c, Stefan Laufer ^b,^*

PMCID: PMC3297958 PMID: 22412761

Abstract

The asymmetric unit of the title compound, C₁₇H₁₃Cl₃N₄O₂·0.5C₂H₆OS, contains two almost identical molecules and one dimethyl sulfoxide (DMSO-d ₆) solvent molecule. The pyrazole ring forms dihedral angles of 54.6 (4) and 80.0 (4)° in one molecule, and dihedral angles of 54.2 (4) and 81.2 (4)° in the other molecule, with the directly attached pyridine and trichlorophenyl rings, respectively. The dihedral angles of the pyridine and trichlorophenyl rings are 51.2 (4) and 52.0 (4)°, respectively. The crystal packing is characterized by intra- and intermolecular hydrogen bonds. The crystal is a nonmerohedral twin with a contribution of 0.488 (1) for the minor twin component. The terminal ethyl group of one molecule and the S atom of DMSO are disordered over two sites.

Related literature

For pyridinyl-substituted five-membered heterocycles as p38α MAP kinase inhibitors, see: Abu Thaher et al. (2009 ▶); Peifer et al. (2006 ▶). For inhibitory activity and preparation of the title compound, see: Abu Thaher, Arnsmann et al. (2012 ▶). For related structures, see: Abu Thaher, Koch et al. (2012a ▶,b ▶).

Experimental

Crystal data

C₁₇H₁₃Cl₃N₄O₂·0.5C₂H₆OS
M _r = 450.73
Monoclinic,
a = 13.501 (2) Å
b = 10.3222 (15) Å
c = 14.889 (2) Å
β = 100.453 (5)°
V = 2040.5 (5) Å³
Z = 4
Mo Kα radiation
μ = 0.53 mm⁻¹
T = 173 K
0.40 × 0.20 × 0.05 mm

Data collection

Bruker APEXII diffractometer
Absorption correction: multi-scan (TWINABS; Sheldrick, 2008b ▶) T _min = 0.818, T _max = 0.974
9562 measured reflections
9562 independent reflections
5575 reflections with I > 2σ(I)

Refinement

R[F ² > 2σ(F ²)] = 0.068
wR(F ²) = 0.133
S = 0.98
9562 reflections
526 parameters
19 restraints
H-atom parameters constrained
Δρ_max = 0.39 e Å⁻³
Δρ_min = −0.39 e Å⁻³
Absolute structure: Flack (1983 ▶), 4289 Friedel pairs
Flack parameter: 0.61 (10)

Data collection: APEX2 (Bruker, 2006 ▶); cell refinement: SAINT (Bruker, 2006 ▶); data reduction: SAINT; program(s) used to solve structure: SIR97 (Altomare et al., 1999 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008a ▶); molecular graphics: PLATON (Spek, 2009 ▶); software used to prepare material for publication: PLATON.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812008264/bt5829sup1.cif

e-68-0o917-sup1.cif^{(54KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812008264/bt5829Isup2.hkl

e-68-0o917-Isup2.hkl^{(467.7KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812008264/bt5829Isup3.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
N12A—H12A⋯O15A	0.88	2.34	2.767 (8)	110
N12A—H12A⋯O14Bⁱ	0.88	2.10	2.957 (8)	164
N12A—H12B⋯N21Aⁱⁱ	0.94	2.15	2.906 (9)	137
N12B—H12C⋯O15B	0.88	2.13	2.778 (8)	130
N12B—H12C⋯O14Aⁱⁱⁱ	0.88	2.24	2.983 (8)	142
N12B—H12D⋯N21Bⁱⁱ	0.88	2.02	2.901 (9)	176

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

Acknowledgments

BAT thanks the Alexander von Humboldt Foundation for funding.

supplementary crystallographic information

Comment

Pyridin-4-yl substituted five-membered heterocycles have been considered to be potential p38α MAP kinase inhibitors (Abu Thaher et al. 2009; Peifer et al. 2006). We showed that the regioisomeric switch from 3-(4-fluorophenyl)-4-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine to 4-(4-fluorophenyl)-3-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine completely changed the inhibitory profile from p38α MAP kinase to kinases releant in cancer (Abu Thaher, Arnsmann et al. 2012). Recently, we reported similar crystal structures (Abu Thaher, Koch et al. 2012a,b).

The asymmetric unit of the title compound contains two almost identical molecules and DMSO-d6 (Fig. 1). In molecule A the pyrazole ring forms dihedral angles of 54.6 (4)° and 80.0 (4)° with the directly attached pyridine and trichlorophenyl rings, respectively. In molecule B the pyrazole ring forms dihedral angels of 54.2 (4)° and 81.2 (4)° with the pyridine and trichlorophenyl rings, respectively. The dihedral angle of the pyridine and trichlorophenyl rings in molecules A and B are 51.1 (4)° and 52.0 (4)°, respectively.

The crystal packing (Fig. 2) shows that the amino function (N12) acts as a hydrogen bond donor forming an intramolecular hydrogen bond to the oxygen atom (O15) and two intermolecular hydrogen bonds to the nitrogen atom of the pyridine ring (N21) (A—A/B—B) and to the carbonyl oxygen atom (O14) of the ester moiety of two different molecules (A—B/B—A) resulting in a double chain along the b axis.

Experimental

4 mmol of N-(2,4,6-trichlorophenyl)-4-pyridinecarbohydrazonoyl chloride and 1.5 equiv. of ethyl cyanoacetate were dissolved in 20 ml dry ethanol and cooled to 273 K in an ice bath. 2.0 equiv. of sodium ethoxide solution (21% ethanol) was added dropwise and the reaction was stirred over night. The precipitate was filtered from the reaction mixture, washed with water and recrystallized from hot ethanol. Yield: 56%. Suitable crystals for X-ray were taken from the NMR-tube in DMSO-d₆.