2-(4-Acetamido­phen­oxy)-2-methyl­propanoic acid

Gabriel Navarrete-Vázquez; Blanca Colín-Lozano; Hugo Tlahuext; Antonio R Tapia-Benavides

doi:10.1107/S1600536813004856

. 2013 Feb 28;69(Pt 3):o443. doi: 10.1107/S1600536813004856

2-(4-Acetamidophenoxy)-2-methylpropanoic acid

Gabriel Navarrete-Vázquez ^a, Blanca Colín-Lozano ^a, Hugo Tlahuext ^b,^*, Antonio R Tapia-Benavides ^c

PMCID: PMC3588439 PMID: 23476612

Abstract

In the title compound, C₁₂H₁₅NO₄, the dihedral angle between the acetamide group and the ring is 29.6 (2)(su?)°. In the crystal molecules are linked through N—H⋯O and O—H⋯O hydrogen bonds, thereby forming corrugated sheets propagating in the ac plane. These sheets are composed of R ₄ ⁴(28) graph-set motifs.

Related literature

For related literature on analogous structures with analgesic and antidyslipidemic activities, see: Kis et al. (2005 ▶); Navarrete-Vázquez et al. (2008 ▶, 2011 ▶); Thorp & Waring (1962 ▶); Miller & Spence (1998 ▶); Forcheron et al. (2002 ▶). For information on hydrogen bonding, see: Bernstein et al. (1995 ▶); Jeffrey (1997 ▶); Desiraju (1996 ▶).

Experimental

Crystal data

C₁₂H₁₅NO₄
M _r = 237.25
Monoclinic,
a = 8.3184 (4) Å
b = 13.1554 (6) Å
c = 12.0452 (5) Å
β = 109.959 (5)°
V = 1238.96 (10) Å³
Z = 4
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 293 K
0.19 × 0.14 × 0.13 mm

Data collection

Agilent Xcalibur Atlas Gemini diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011 ▶) T _min = 0.982, T _max = 0.988
34747 measured reflections
2179 independent reflections
1738 reflections with I > 2σ(I)
R _int = 0.045

Refinement

R[F ² > 2σ(F ²)] = 0.037
wR(F ²) = 0.098
S = 1.04
2179 reflections
161 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.20 e Å⁻³
Δρ_min = −0.18 e Å⁻³

Data collection: CrysAlis PRO (Agilent, 2011 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; 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: PLATON (Spek, 2009 ▶) and DIAMOND (Crystal Impact, 2006 ▶).

Supplementary Material

Click here for additional data file.^{(21.2KB, cif)}

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536813004856/gw2131sup1.cif

e-69-0o443-sup1.cif^{(21.2KB, cif)}

Click here for additional data file.^{(107.2KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536813004856/gw2131Isup2.hkl

e-69-0o443-Isup2.hkl^{(107.2KB, hkl)}

Click here for additional data file.^{(4.7KB, cml)}

Supplementary material file. DOI: 10.1107/S1600536813004856/gw2131Isup3.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
N1—H1⋯O2ⁱ	0.87 (2)	2.21 (2)	3.081 (2)	174 (2)
O2—H2⋯O4ⁱⁱ	0.82	1.76	2.572 (2)	172
C2—H2A⋯O1ⁱⁱⁱ	0.93	2.63	3.536	166
C5—H5⋯O3^iv	0.93	2.69	3.333	127

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

Acknowledgments

This work was supported by the Consejo Nacional de Ciencia y Tecnología (CONACyT) under grant No. 100608.

supplementary crystallographic information

Comment

Fibrates, such as bezafibrate, clofibrate and fenofibrate, which are ligands for the nuclear receptor PPAR α (Peroxisome Proliferator-Activated Receptor), are used as therapeutic agents in the treatment of dyslipidemia, heart disease and diabetic complications in humans (Forcheron et al.,2002). The fibrate pharmacophore has been of interest to medicinal chemists, and it is a widely used class of lipid-modifying agents that decrease plasma triglycerides (Thorp & Waring, 1962; Miller & Spence, 1998). On the other hand, paracetamol is broadly used as over-the-counter analgesic and antipyretic agent (Kis et al., 2005). In order to assist our knowledge about the stereo electronic requirements from these kinds of molecules to shown antihyperlipidemic activity, we have synthesized and determined the crystal structure of a closed-related nitrofibrate analogue (Navarrete-Vázquez et al., 2008), as well as the compound ethyl 2-[4-(acetylamino)phenoxy]-2-methylpropanoate, which is a bioisoster of clofibrate, with an acetamide group instead of chlorine atom (Navarrete-Vázquez et al.,2011). The last structure resembles to paracetamol, a well known analgesic and antipyretic agent. In this case, the hydrolysis product was obtained in order to find a new biologically active chemical entity.

In (I), all bond lengths and angles show normal values.

In the crystal structure, neighboring molecules are linked through N—H···O, O—H···O hydrogen bonds (Jeffrey, 1997) and weak C—H···O hydrogen bonds (Desiraju, 1996) forming a three dimensional network, Table 1. In the hydrogen-bond pattern, the N—H···O and O—H···O hydrogen bonds are forming corrugated sheets. These sheets are composed of R₄⁴(28) graph set motifs (Bernstein, et al., 1995), (Fig. 2, Table 1). Neighboring sheets are further linked by weak C—H···O hydrogen bonds, generating the three dimensional network.

Experimental

Paracetamol (1 g, 0.0066 mol) and potassium carbonate (2 g, 0.014 mol) were dissolved in the minimum amount of dimethyl sulfoxide and were heated at 40 °C. After 20 minutes, the ethyl 2-bromo-2-methylpropionate (1.45 ml, 0.0099 mol) was added dropwise and the reaction mixture was heated to reflux (80 °C) and monitored by TLC. After the reaction completion (15 h), the reaction mixture was filtered and solid residue was washed off with acetone (10 ml). The total mother liquors were concentrated under reduced pressure and then poured into water and extracted with ethyl acetate (3 x 15 ml). The organic layer was dried over anhydrous Na₂SO₄ and partially evaporated under reduced pressure.

The resulting solid was treated with a mixture of THF/MeOH/H₂O (3:2:1,v/v/v, 6 ml/mmol), and LiOH was added (3 equiv). The mixture stirred at room temperature for 3 h. Then, HCl solution (10% v/v) was added, and most of the organic solvents removed in vacuo. The partly solid residue was extracted with CH₂Cl₂ (3 x 10 ml), dried with Na₂SO₄, filtered, and concentrated in vacuo to give a white solid (m.p. 438 K). Single crystals were obtained from methanol. ¹H NMR data (200 MHz; DMSO-d₆; Me₄Si) δ: 1.46 (6H, s, H-9 and H-10), 2.10 (3H, s, CH₃CO), 6.78 (2H, d, J = 8.7, H-2 and H-6), 7.44 (2H, d, J = 8.7, H-3 and H-5), 9.83 (1H, bs, N—H). ¹³C NMR (50 MHz, DMSO-d₆) δ: 23.8 (CH₃CO), 25.1 (gem-di CH₃), 78.7 (C-7), 119.5 (C-2, C-6), 120.2 (C-3, C-5), 133.9 (C-4), 161.8 (C-1), 167.9 (CONH), 175.2 (COOH). EI—MS: m/z (rel. int.) 237 (M⁺, 25%).