4-(7-Acet­oxy-6-meth­oxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl acetate

Hao Jiang; Peng Xia; Qian Zhang

doi:10.1107/S1600536808012890

. 2008 Jun 7;64(Pt 7):o1230. doi: 10.1107/S1600536808012890

4-(7-Acetoxy-6-methoxy-4-methyl-2-oxo-2H-chromen-3-yl)phenyl acetate

Hao Jiang ^a, Peng Xia ^a, Qian Zhang ^a,^*

PMCID: PMC2961866 PMID: 21202867

Abstract

The title compound, C₂₁H₁₈O₇, is an important intermediate in the synthesis of 3-(4-hydroxyphenyl)-4-methyl-6-methoxy-7-hydroxycoumarin, which is a nonsteroidal analogue of 2-methoxyestradiol (2-ME). The substituent benzene ring is not in the same plane as the coumarin ring system, with a dihedral angle of 66.88 (10)°. There are some weak intermolecular C—H⋯O interactions. One carbonyl O atom is disordered over two sites, with occupancies of 0.6 and 0.4.

Related literature

For related literature, see: Gibanananda et al. (2006 ▶); Sutherland et al. (2007 ▶).

Experimental

Crystal data

C₂₁H₁₈O₇
M _r = 382.35
Triclinic,
a = 8.142 (3) Å
b = 11.167 (4) Å
c = 11.756 (4) Å
α = 65.130 (4)°
β = 75.392 (4)°
γ = 79.055 (4)°
V = 934.1 (5) Å³
Z = 2
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 293 (2) K
0.15 × 0.12 × 0.04 mm

Data collection

Bruker SMART APEX CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 1996 ▶) T _min = 0.985, T _max = 0.996
3893 measured reflections
3245 independent reflections
2279 reflections with I > 2σ(I)
R _int = 0.031

Refinement

R[F ² > 2σ(F ²)] = 0.074
wR(F ²) = 0.254
S = 1.09
3245 reflections
266 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.28 e Å⁻³
Δρ_min = −0.50 e Å⁻³

Data collection: SMART (Bruker, 2000 ▶); cell refinement: SMART; data reduction: SAINT (Bruker, 2000 ▶); 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 datablocks I, global. DOI: 10.1107/S1600536808012890/cf2199sup1.cif

e-64-o1230-sup1.cif^{(21KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808012890/cf2199Isup2.hkl

e-64-o1230-Isup2.hkl^{(159.2KB, hkl)}

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
C20—H20B⋯O2ⁱ	0.96	2.47	3.362 (4)	154
C20—H20C⋯O4Bⁱ	0.96	2.55	3.297 (9)	134
C11—H11B⋯O7ⁱⁱ	0.96	2.74	3.349 (4)	122
C13—H13⋯O2ⁱⁱⁱ	0.93	2.74	3.331 (4)	122
C19—H19A⋯O7ⁱⁱⁱ	0.96	2.50	3.392 (5)	154
C17—H17⋯O2^iv	0.93	2.66	3.246 (3)	122

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

Acknowledgments

This work was financed by the National Natural Science Foundation of China (grant No. 30500631, awarded to Qian Zhang) and the Postgraduate Innovative Research Foundation of Fudan University (grant awarded to Hao Jiang). The authors acknowledge Professor Minqin Chen, Center of Analysis and Measurement, Fudan University, for his kind help with the data analysis and his professional advice.

supplementary crystallographic information

Comment

2-ME, an endogenous metabolite of estrogen, was proved to be a potent antitumor and antiangiogenic compound (Gibanananda et al., 2006). Currently 2-ME is in phase I–III clinical trials for treating a variety of solid cancers, especially breast cancer, prostate cancer and multiple myeloma (Sutherland et al., 2007). Based on the structure and the bioactivity of 2-ME, 3-(p-hydroxyphenyl)-4-methyl-6-methoxyl-7-hydroxycoumarin, an non-steroidal analog of 2-ME, was designed, synthesized and evaluated on Human Umbilical Vein Endothelial Cells (HUVEC). The compound showed higher activity and much lower toxicity (EC₅₀ = 5.69 µM; TI = 45.01) than 2-ME (EC₅₀ = 8.59 µM; TI = 8.25) in the biological assay. Here we report the crystal structure of 3-(p-acetoxyphenyl)-4-methyl-6-methoxyl-7-acetoxycoumarin, which is an important intermediate in the synthesis of 3-(p-hydroxyphenyl)-4-methyl-6-methoxyl-7-hydroxycoumarin. The molecular structure of (I) is illustrated in Fig.1. The coumarin ring system (C1—C10) is essentially planar, with a mean deviation of 0.0153 Å from the least-squares plane defined by the ten constituent atoms. The coumarin ring system and the 3-aryl ring make a dihedral angle of 66.88 (10)°. The fact that the of C3—C12 bond [length 1.480 (4) Å] is a single bond also confirms that the coumarin ring system and the 3-substituent are not conjugated. The molecular packing (Fig. 2) is stabilized by weak intermolecular C—H···O hydrogen bonds.

Experimental

A mixture of 1-(2,4-dihydroxyl-5-methoxyphenyl)ethanone (300 mg, 1.65 mmol), 4-hydroxyphenylacetic acid (501 mg, 3.29 mmol), Et₃N (6 ml) and Ac₂O (10 ml) was refluxed for 10 h. After cooling, the mixture was poured into 2 N HCl (20 ml) and extracted with acetyl acetate. The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a yellow oil, which was purified via chromatography on silica gel column with petroleum ether/acetone (10:3) as eluent. The title compound was recrystallized from acetyl acetate to give colorless crystals for the single-crystal X-ray diffraction analysis.