3-(2-Fluoro­phen­yl)-6-(phenoxy­meth­yl)-1,2,4-triazolo[3,4-b][1,3,4]thia­diazole

Melanie Holm; Dieter Schollmeyer; Stefan Laufer

doi:10.1107/S1600536808003917

. 2008 Mar 12;64(Pt 4):o700. doi: 10.1107/S1600536808003917

3-(2-Fluorophenyl)-6-(phenoxymethyl)-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole

Melanie Holm ^a, Dieter Schollmeyer ^b, Stefan Laufer ^a,^*

PMCID: PMC2961052 PMID: 21202091

Abstract

The crystal structure of the title compound, C₁₆H₁₁FN₄OS, was synthesized in the course of our studies on 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles as inhibitors of p38 mitogen-activated protein kinase (MAPK). The three-dimensional data obtained were used to generate a three-dimensional pharmacophore model for in silico database screening. The dihedral angles between the central heterocylic system and the fluorophenyl and phenyl rings are 20.21 (3) and 5.43 (1)°, respectively; the dihedral angle between the two benzene rings is 15.80 (4)°.

Related literature

Protein kinases (PK) are favoured targets for the development of new drugs (Hopkins & Groon, 2002 ▶) because the reversible protein-phosphorylation by PK is an important control mechanism in the signal pathways of a cell (Laufer et al., 2005 ▶). The [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole nucleus is associated with diverse biological activities (Malhotra et al., 2003 ▶). For the preparation of the title compound, see: Invidiata et al. (1997 ▶); Malhotra et al. (2003 ▶).

Experimental

Crystal data

C₁₆H₁₁FN₄OS
M _r = 326.35
Monoclinic,
a = 10.8551 (6) Å
b = 12.1899 (3) Å
c = 11.6667 (6) Å
β = 110.857 (5)°
V = 1442.61 (11) Å³
Z = 4
Cu Kα radiation
μ = 2.19 mm⁻¹
T = 193 (2) K
0.58 × 0.51 × 0.26 mm

Data collection

Enraf–Nonius CAD-4 diffractometer
Absorption correction: ψ scan (CORINC; Dräger & Gattow, 1971 ▶) T _min = 0.61, T _max = 0.99 (expected range = 0.348–0.565)
2883 measured reflections
2736 independent reflections
2583 reflections with I > 2σ(I)
R _int = 0.037
3 standard reflections frequency: 60 min intensity decay: 4%

Refinement

R[F ² > 2σ(F ²)] = 0.048
wR(F ²) = 0.135
S = 1.06
2736 reflections
209 parameters
H-atom parameters constrained
Δρ_max = 0.43 e Å⁻³
Δρ_min = −0.43 e Å⁻³

Data collection: CAD-4 Software (Enraf–Nonius, 1989 ▶); cell refinement: CAD-4 Software; data reduction: CORINC (Dräger & Gattow, 1971 ▶); program(s) used to solve structure: SIR92 (Altomare et al., 1994 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2003 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536808003917/bt2678sup1.cif

e-64-0o700-sup1.cif^{(18.9KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808003917/bt2678Isup2.hkl

e-64-0o700-Isup2.hkl^{(134.4KB, hkl)}

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

Acknowledgments

We are grateful to BERGHOF Products & Instruments GmbH, Eningen, Germany for the BR-25 high pressure reactor and for technical support.

supplementary crystallographic information

Comment

Continued interest in development of small molecule inhibitors of p38 mitogen-activated protein (MAP) kinase is based on the central role of this enzyme in inflammatory cell signalling. Activation of p38 leads to an increase production of pro-inflammatory cytokines such as TNF-alpha and IL-1beta. Many different diseases have their seeds in an overactive immune response. Prominent examples like psoriasis, rheumatoid arthritis and inflammatory bowel disease turn it into a still prominent target for antiinflammatory drug discovery. 3-(2-chlorophenyl)-6-((4-methoxyphenoxy)methyl)-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazole was identified as potential hit in a virtual screening and the [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole core therefore chosen as starting point for a medicinal chemistry program. To gain more information about structure-activity relationship, a series of compounds were synthesized and tested.

The synthesis of 1 (Figure 1) was started from the substituted hydrazide, which was treated with carbon disulfide. Cyclization followed by reaction with hydrazine. The final product 2 was synthesized by reaction of 1 with 2-phenoxyacetic acid in presence of phosphorus oxychloride.

Of special interest was the proposed binding mode of disubstituted compound and a crystal structure of compound 2 was prepared (Figure 2).

Experimental

The synthesis of 3-(2-fluorophenyl)-6-(phenoxymethyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole was started from 2-fluorobenzohydrazide. Carbon disulfide (55.0 mmol) was added slowly to a solution of the hydrazide (36.0 mmol) in absolute ethanol (70 ml) containing potassium hydroxid (55.0 mmol). The resulting mixture was stirred over night at room temperature, then cooled and diluted with ether (100 ml). Potassium 2-(2-fluorobenzoyl)hydrazinecarbodithioate precipitated and was collected by filtration, washed with diethyl ether and dried.

A mixture containing potassium dithiocarbazinate (16.0 mmol) suspended in water (2 ml) and hydrazine hydrate (99%, 32.0 mmol) was heated under gentle reflux for 2 h. It was cooled to room temperature and diluted with water (80 ml) and acidified with concentrated hydrochloric acid. Thick white solid mass separated out. It was collected by filtration, washed with water and recrystallized from ethanol to get 4-amino-5-(2-fluorophenyl)-4H-1,2,4-triazole-3-thiol 1. (Invidiata et al., 1997)

For the preparation of the title compound, a mixture of 1 (5.0 mmol), 2-phenoxyacetic acid (1.0 mmol) and phosphorus oxychloride (10 ml) was refluxed for 6 h, cooled to room temperature and poured onto crushed ice. The solid product separated out and was collected by filtration, washed with aqueous NaOH solution (20 ml, 2 M) and then with water, dried and recrystallized from ethanol 2. (Malhotra et al., 2003)

Crystals of 2 for X-ray analysis precipitated slowly as brown platelets from ethanol at room temperature.