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

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.

In the title compound, C 12 H 15 NO 4 , the dihedral angle between the acetamide group and the ring is 29.6 (2)(su?) . In the crystal molecules are linked through N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds, thereby forming corrugated sheets propagating in the ac plane. These sheets are composed of R 4 4 (28) graph-set motifs.

Benavides 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 hydrogenbond pattern, the N-H···O and O-H···O hydrogen bonds are forming corrugated sheets. These sheets are composed of R 4 4 (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 Na 2 SO 4 and partially evaporated under reduced pressure.
The resulting solid was treated with a mixture of THF/MeOH/H 2 O (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 CH 2 Cl 2 (3 x 10 ml), dried with Na 2 SO 4 , filtered, and concentrated in vacuo to give a white solid (m.p. 438 K). Single crystals were obtained from methanol. 1 H NMR data

Figure 1
The molecular structure of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radius. Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.