Crystal structure of isopropyl 2-hydroxy-2-phenylacetate: a pharmacopoeia reference standard

The title compound is a pharmacopoeia reference standard for determining impurities in the drug Pregabalin, used for the treatment of epilepsy and diabetic neuropathic pain.

The title compound, C 11 H 14 O 3 , is used as a pharmacopoeia reference standard for determining impurities in the drug Pregabalin, used for the treatment of epilepsy and diabetic neuropathic pain. The molecule is far from being planar, with the dihedral angle between the planes of the aromatic ring and the carboxyl fragment (O-C O) being 76.1 (6) . The isopropyl substituent is located in a synperiplanar position relative to the C O bond and is turned so that the C-O-C-H torsion angle is À43.7 . In the crystal, bifurcated O-HÁ Á Á(O,O) hydrogen bonds, enclosing R 1 2 (5) ring motifs, lead to the formation of chains propagating along the c-axis direction. Inversion-related chains are linked by the C-HÁ Á ÁO hydrogen bonds, forming undulating layers lying parallel to the bc plane.

Chemical context
Pharmacopoeia reference standards are used widely for identification and quantitative determination of an active ingredient and undesirable impurity contents in many drug substances (European Pharmacopoeia Supplement, 2017). The title compound is used as the pharmacopoeia reference standard for the determining the level of impurities in Pregabalin (European Pharmacopoeia Supplement, 2016). This drug, sold under the trade mark 'Lyrica' (Silverman, 2016) is used for the treatment of epilepsy and diabetic neuropathic pains. Until now, its molecular and crystal structure were unknown.

Structural commentary
The molecular structure of the title compound is shown in Fig. 1. The hydroxyl group is situated in the -sc position relative to the C1-C6 endocyclic bond; torsion angle C1-C6-C7-O1 being À46.2 (6) ). The ester substituent at atom C7 has a +sc-orientation with respect to bond C1-C6 bond, with torsion angle C1-C6-C7-C8 = 71.2 (6) , and it is turned in such way that the dihedral angle between the planes ISSN 2056-9890 of the aromatic ring (C1-C6) and the carboxyl fragment (O3-C8 O2) is 76.1 (6) . The isopropyl substituent is located in a syn-periplanar position relative to the C8 O2 bond and is turned so that the C8-O3-C9-H9 torsion angle is À43.7 .

Supramolecular features
In the crystal, molecules are linked by bifurcated O-HÁ Á Á(O,O) hydrogen bonds, forming chains propagating along [001] and enclosing R 2 1 (5) ring motifs ( Fig. 2 and Table 1). Neighbouring chains are linked by C-HÁ Á ÁO hydrogen bonds, forming undulating layers lying parallel to the bc plane (Table 1 and Fig. 3).  Scholtis et al., 2006). In the crystals of these three compounds, molecules are linked by pairs of O-HÁ Á ÁO hydrogen bonds, forming inversion dimers.

Synthesis and crystallization
To a solution of (2RS)-2-hydroxy-2-phenylacetic acid (15.22 g, 0.1 mol; racemic mandelic acid) in 50 ml propan-2-ol was added 0.5 ml of concentrated H 2 SO 4 , and the mixture was refluxed for 5 h (Fig. 4). The excess of propan-2-ol was removed in vacuo. The reaction mixture was diluted with cold water and Na 2 CO 3 was added to adjust the pH to 8. The solution was extract with CH 2 Cl 2 (3 Â 30 ml). The organic layers were combined and the solvent extracted by distillation (at reduced pressure at the end). The residue was distilled in vacuo, and a fraction with a boiling point of 361-363 K/4 mm Hg was taken, and then left for several hours in the refrigerator at ca 278 K, giving finally the title compound as colourless needle-like crystals (yield of 17.67 g, 91%; m.p. 306.9-307.3 K). A partial view along the a axis of the crystal packing of the title compound, with the hydrogen bonds shown as dashed lines (see Table 1). For clarity, only H atoms H1O and H9 have been included. Table 1 Hydrogen-bond geometry (Å , ).  (7)  142 Symmetry codes: (i) x; Ày þ 1 2 ; z þ 1 2 ; (ii) Àx þ 2; Ày þ 1; Àz.

Figure 3
A view along the c axis of the crystal packing of the title compound, with the hydrogen bonds shown as dashed lines (see Table 1). For clarity, only H atoms H1O and H9 have been included.

Figure 1
The molecular structure of the title compound, showing the atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

Isopropyl 2-hydroxy-2-phenylacetate
Crystal data where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.30 e Å −3 Δρ min = −0.26 e Å −3 Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.