N-Cyclo­propyl-N-[2-(2,4-difluoro­phen­yl)-2-hy­droxy-1-(1H-1,2,4-triazol-1-yl)prop­yl]-2-(5-methyl-2,4-dioxo-1,2,3,4-tetra­hydro­pyrimidin-1-yl)acetamide dichloro­methane 0.62-solvate

Nan Wang; Huan-Mei Guo; Gui-Ge Hou; Xin-Yue Hu; Qing-Guo Meng

doi:10.1107/S1600536811034295

. 2011 Aug 27;67(Pt 9):o2464. doi: 10.1107/S1600536811034295

N-Cyclopropyl-N-[2-(2,4-difluorophenyl)-2-hydroxy-1-(1H-1,2,4-triazol-1-yl)propyl]-2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)acetamide dichloromethane 0.62-solvate

Nan Wang ^a, Huan-Mei Guo ^b, Gui-Ge Hou ^c, Xin-Yue Hu ^a, Qing-Guo Meng ^a,^*

PMCID: PMC3200716 PMID: 22059025

Abstract

In the title compound, C₂₁H₂₂F₂N₆O₄·0.62CH₂Cl₂, the difluoro-substituted benzene ring forms dihedral angles of 54.6 (3)° with the mean plane of the thymine ring and 50.9 (2)° with the triazole ring. The dihedral angle between the thymine and triazole rings is 7.4 (3)°. In the crystal, intermolecular N—H⋯N and O—H⋯O hydrogen bonds link the main molecules into chains along [10 Inline graphic ]. The CH₂Cl₂ solvent molecule was refined as partial occupancy over two sets of sites with refined occupancies of 0.308 (9) and 0.310 (8).

Related literature

For the applications of azole and triazole compounds as antifungal agents, see: Singh (2001 ▶); Richardson (2005 ▶); Hobson (2003 ▶); Slavin et al. (2002 ▶); Wingard & Leather (2004 ▶); Fridkin & Jarvis (1996 ▶); Gallis et al. (1990 ▶); Sheehan et al. (1999 ▶); Denning (2002 ▶); Aoyama et al. (1984 ▶); Lamb et al. (1999 ▶).

Experimental

Crystal data

C₂₁H₂₂F₂N₆O₄·0.62CH₂Cl₂
M _r = 512.93
Triclinic,
a = 8.474 (2) Å
b = 12.464 (3) Å
c = 13.410 (4) Å
α = 62.942 (4)°
β = 73.187 (4)°
γ = 83.746 (4)°
V = 1207.1 (6) Å³
Z = 2
Mo Kα radiation
μ = 0.24 mm⁻¹
T = 298 K
0.30 × 0.16 × 0.14 mm

Data collection

Bruker SMART APEX diffractometer
6058 measured reflections
4162 independent reflections
3053 reflections with I > 2σ(I)
R _int = 0.022

Refinement

R[F ² > 2σ(F ²)] = 0.092
wR(F ²) = 0.209
S = 1.16
4162 reflections
356 parameters
42 restraints
H-atom parameters constrained
Δρ_max = 0.50 e Å⁻³
Δρ_min = −0.34 e Å⁻³

Data collection: SMART (Bruker, 1997 ▶); cell refinement: SAINT (Bruker, 1997 ▶); data reduction: SAINT; 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.

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536811034295/lh5302sup1.cif

e-67-o2464-sup1.cif^{(24.8KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811034295/lh5302Isup2.hkl

e-67-o2464-Isup2.hkl^{(203.9KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811034295/lh5302Isup3.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
N6—H6⋯N2ⁱ	0.80	2.11	2.893 (5)	167
O1—H1A⋯O2ⁱⁱ	0.82	2.13	2.903 (4)	158

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

Acknowledgments

The authors thank Mr Lian-dong Liu (College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University, Jinan, China) for his invaluable support in the X-ray data collection. The authors also thank the National Natural Science Foundation of China for a research grant (No. 81072534).

supplementary crystallographic information

Comment

In recent years, fungal infections are prevalent diseases from which a large proportion of the human population suffers (Singh, 2001; Richardson, 2005; Hobson, 2003; Slavin et al., 2002). The increased emergence of both superficial and systemic fungal infections has led to the massive increase in the rate of mortality, especially in immunocompromised individuals i.e. those suffering from tuberculosis, cancer or AIDS (Wingard & Leather, 2004; Fridkin & Jarvis, 1996). There are very few antifungal agents that can be used for life-threatening fungal infections. Several clinical drugs, such as amphotericin B,5-fluorocytosine, azoles (such as fluconazole and itraconazole) and echinocandins (such as caspofungin and micafungin) have been developed to reduce the impact of fungal diseases (Gallis et al., 1990; Sheehan et al., 1999; Denning, 2002). Among those, azoles, especially triazole antifungal agents, are used widely and efficiently. For over a decade, azoles have been a mainstay of the antifungal armamentarium. They act by competitive inhibition of the lanosterol 1410 which is the key enzyme in sterol biosynthesis of fungi (Aoyama et al., 1984). Selective inhibition of CYP51 would cause depletion of ergosterol and accumulation of lanosterol and other 14-methyl sterols resulting in the growth inhibition of fungal cells (Lamb et al., 1999). We have attempted to prepare some potential antifungal agents with improved activity and broader spectrum, by sythesizing a series of 1-(1H-1,2,4-triazole-1-yl)-(2,4-difluorophenyl)-3-[N-n-alkyl-N-(1-thyminyl)acetyl]-2-propanol compounds. Herein, we report the crystal structure of the title compound (I).

The molecular structure of the title compound is shown in Fig. 1. The difluoro-substituted benzene ring forms dihedral angles of 54.6 (3)° with the mean plane of the thymine ring and 50.9 (2)° with the triazole ring. The dihedral angle between the thymine and triazole rings is 7.4 (3)°. In the crystal, intermolecular N—H···N and O—H···O hydrogen bonds link the main molecules into one-dimensional chains (Fig. 2) along [101].

Experimental

The synthesis of thymin-1-yl acetic acid: To a solution of thymine (30.00 g, 237.89 mmol) in water (150 ml) was added potassium hydroxide (51.25 g, 903.79 mmol). The solution was heated to 313 K, and then bromoacetic acid (49.58 g, 356.83 mmol) was added dropwise. The resulting solution was allowed to stir for 2 h at the same temperature. The solution was then brought to pH 5 with 36% HCl at 273 K. The white precipitate was filtered off and discarded. Then the filtrate was brought to pH 1 with 36% HCl. Solid was filtered off and dried and obtained in 83.5% yield, m.p 528–530 K.

The synthesis of the title compound: To a solution of 1-(1H-1,2,4-triazole)-2,2-[oxiranyl-(2,4-difluorophenyl)]ethane mesylate (16.75 g, 50 mmol) in ethanol (240 ml) was added triethylamine (16 ml, 110 mmol) and cyclopropylamine (6.93 ml, 100 mmol). The resulting solution was raised to 318 K and stirred for 10 h at the same temperature. Once concentrated to light yellow oil under vacuum, the residue was taken off with ethyl acetate and was treated with 1 M HCl. The aqueous phase was then brought to pH 8 with sodium carbonate and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. A light yellow oil was obtained in 67.6% yield. A solution of the title compound (9.2 mg,0.02 mmol) in dichloromethane and methanol (4 ml, 1:1, v/v) was kept at room temperature. Upon slow evaporation of the solvent over about 10 d, colourless block-shaped crystals suitable for X-ray measurements were obtained.