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

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aV. N. Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv 61077, Ukraine, bSSI `Institute for Single Crystals', National Academy of Sciences of Ukraine, 60 Nauky Ave., Kharkiv 61001, Ukraine, and cNational University of Pharmacy, 4 Valentinivska St., Kharkiv 61168, Ukraine
*Correspondence e-mail: swhtlover@gmail.com

Edited by H. Stoeckli-Evans, University of Neuchâtel, Switzerland (Received 13 April 2017; accepted 19 April 2017; online 28 April 2017)

The title compound, C11H14O3, 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 −43.7°. In the crystal, bifurcated O—H⋯(O,O) hydrogen bonds, enclosing R12(5) ring motifs, lead to the formation of chains propagating along the c-axis direction. Inversion-related chains are linked by the C—H⋯O hydrogen bonds, forming undulating layers lying parallel to the bc plane.

1. 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[European Pharmacopoeia Supplement (2016). pp. 5801-5803. Strasbourg: Council of Europe.]). The title compound is used as the pharmacopoeia reference standard for the determining the level of impurities in Pregabalin (European Pharmacopoeia Supplement, 2016[European Pharmacopoeia Supplement (2017). pp. 733-736. Strasbourg: Council of Europe.]). This drug, sold under the trade mark `Lyrica' (Silverman, 2016[Silverman, R. B. (2016). Technol. Innov. 17, 153-158.]) is used for the treatment of epilepsy and diabetic neuropathic pains. Until now, its mol­ecular and crystal structure were unknown.

[Scheme 1]

2. Structural commentary

The mol­ecular structure of the title compound is shown in Fig. 1[link]. The hydroxyl group is situated in the -sc position relative to the C1—C6 endocyclic bond; torsion angle C1—C6—C7—O1 being −46.2 (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 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 −43.7°.

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

3. Supra­molecular features

In the crystal, mol­ecules are linked by bifurcated O—H⋯(O,O) hydrogen bonds, forming chains propagating along [001] and enclosing R12(5) ring motifs (Fig. 2[link] and Table 1[link]). Neighbouring chains are linked by C—H⋯O hydrogen bonds, forming undulating layers lying parallel to the bc plane (Table 1[link] and Fig. 3[link]).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
O1—H1O⋯O1i 0.83 (6) 2.12 (5) 2.903 (2) 158 (5)
O1—H1O⋯O2i 0.83 (6) 2.38 (6) 2.930 (5) 124 (5)
C9—H9⋯O2ii 1.00 2.53 3.379 (7) 142
Symmetry codes: (i) [x, -y+{\script{1\over 2}}, z+{\script{1\over 2}}]; (ii) -x+2, -y+1, -z.
[Figure 2]
Figure 2
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[link]). For clarity, only H atoms H1O and H9 have been included.
[Figure 3]
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[link]). For clarity, only H atoms H1O and H9 have been included.

4. Database survey

A search in the Cambridge Structural Database (Version 5.38, update February 2017; Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]) for substructure isopropyl 2-hy­droxy-2-phenyl­acetate yielded three hits, viz. isopropyl 2,2-bis­(4-bromo­phen­yl)-2-hy­droxy­acetate (EFAFEY; Smith, 2012[Smith, G. (2012). Acta Cryst. E68, o3276.]), 1-isopropyl 4-methyl 2-hy­droxy-2-{2-[(meth­oxy­carbon­yl)amino]­phen­yl} succinate (MAZJAA; Suárez-Castillo et al., 2012[Suárez-Castillo, R., Bautista-Hernández, C. I., Sánchez-Zavala, M., Meléndez-Rodríguez, M., Sierra-Zenteno, A., Morales-Ríos, M. S. & Joseph-Nathan, P. (2012). Heterocycles, 85, 2147-2171.]) and syn-isopropyl 2,3-dihy­droxy-4-methyl-2-phenyl­penta­noate (MERRIL; Scholtis et al., 2006[Scholtis, S., Ide, A. & Mahrwald, R. (2006). Org. Lett. 8, 5353-5355.]). In the crystals of these three compounds, mol­ecules are linked by pairs of O—H⋯O hydrogen bonds, forming inversion dimers.

5. 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 H2SO4, and the mixture was refluxed for 5 h (Fig. 4[link]). The excess of propan-2-ol was removed in vacuo. The reaction mixture was diluted with cold water and Na2CO3 was added to adjust the pH to 8. The solution was extract with CH2Cl2 (3 × 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).

[Figure 4]
Figure 4
Reaction scheme

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2[link]. All of the H atoms could all be located from difference-Fourier maps. The hydroxyl H atom was refined with Uiso(H) = 1.5Ueq(O). The C-bound H atoms were included in calculated positions and treated as riding: C—H = 0.93–0.97 Å, with Uiso(H) = 1.5Ueq(C-meth­yl) and 1.2Ueq(C) for other H atoms.

Table 2
Experimental details

Crystal data
Chemical formula C11H14O3
Mr 194.22
Crystal system, space group Monoclinic, P21/c
Temperature (K) 100
a, b, c (Å) 11.872 (3), 15.165 (4), 5.6079 (11)
β (°) 91.41 (2)
V3) 1009.3 (4)
Z 4
Radiation type Mo Kα
μ (mm−1) 0.09
Crystal size (mm) 0.20 × 0.08 × 0.06
 
Data collection
Diffractometer Agilent Xcalibur Sapphire3
Absorption correction Multi-scan (CrysAlis RED; Agilent, 2012[Agilent (2012). CrysAlis PRO. Agilent Technologies, Yarnton, England.])
Tmin, Tmax 0.357, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections 5292, 1761, 922
Rint 0.101
(sin θ/λ)max−1) 0.594
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.090, 0.255, 1.03
No. of reflections 1761
No. of parameters 132
H-atom treatment H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3) 0.30, −0.26
Computer programs: CrysAlis CCD and CrysAlis RED (Agilent, 2012[Agilent (2012). CrysAlis PRO. Agilent Technologies, Yarnton, England.]), SHELXS2014 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]), SHELXL2014 (Sheldrick, 2015[Sheldrick, G. M. (2015). Acta Cryst. C71, 3-8.]), ORTEP-3 for Windows (Farrugia, 2012[Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849-854.]), Mercury (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]), PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]) and publCIF (Westrip, 2010[Westrip, S. P. (2010). J. Appl. Cryst. 43, 920-925.]).

Supporting information


Computing details top

Data collection: CrysAlis CCD (Agilent, 2012); cell refinement: CrysAlis CCD (Agilent, 2012); data reduction: CrysAlis RED (Agilent, 2012); program(s) used to solve structure: SHELXS2014 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015), PLATON (Spek, 2009) and publCIF (Westrip, 2010).

Isopropyl 2-hydroxy-2-phenylacetate top
Crystal data top
C11H14O3F(000) = 416
Mr = 194.22Dx = 1.278 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
a = 11.872 (3) ÅCell parameters from 403 reflections
b = 15.165 (4) Åθ = 4.3–21.1°
c = 5.6079 (11) ŵ = 0.09 mm1
β = 91.41 (2)°T = 100 K
V = 1009.3 (4) Å3Needle, colourless
Z = 40.20 × 0.08 × 0.06 mm
Data collection top
Agilent Xcalibur Sapphire3
diffractometer
1761 independent reflections
Radiation source: Enhance (Mo) X-ray Source922 reflections with I > 2σ(I)
Detector resolution: 16.1827 pixels mm-1Rint = 0.101
ω–scanθmax = 25.0°, θmin = 3.2°
Absorption correction: multi-scan
(CrysAlis RED; Agilent, 2012)
h = 1413
Tmin = 0.357, Tmax = 1.000k = 1718
5292 measured reflectionsl = 56
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.090Hydrogen site location: difference Fourier map
wR(F2) = 0.255H atoms treated by a mixture of independent and constrained refinement
S = 1.03 w = 1/[σ2(Fo2) + (0.1022P)2]
where P = (Fo2 + 2Fc2)/3
1761 reflections(Δ/σ)max < 0.001
132 parametersΔρmax = 0.30 e Å3
0 restraintsΔρmin = 0.26 e Å3
Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.8289 (3)0.2748 (2)0.4019 (6)0.0456 (10)
H1O0.845 (4)0.252 (4)0.534 (10)0.068*
O20.8740 (3)0.4013 (2)0.0966 (6)0.0476 (11)
O30.8375 (3)0.5068 (2)0.3667 (6)0.0455 (10)
C10.5984 (5)0.3361 (3)0.3003 (9)0.0443 (14)
H10.63140.31080.16380.053*
C20.4827 (5)0.3407 (3)0.3113 (9)0.0479 (14)
H20.43680.31710.18560.057*
C30.4332 (5)0.3801 (3)0.5079 (9)0.0492 (15)
H30.35350.38520.51420.059*
C40.4998 (5)0.4111 (3)0.6910 (9)0.0467 (14)
H40.46580.43670.82620.056*
C50.6154 (5)0.4061 (3)0.6831 (9)0.0419 (13)
H50.66000.42860.81220.050*
C60.6684 (4)0.3679 (3)0.4857 (8)0.0387 (13)
C70.7937 (4)0.3603 (3)0.4744 (8)0.0403 (13)
H70.82830.37430.63430.048*
C80.8399 (4)0.4230 (3)0.2895 (9)0.0416 (13)
C90.8869 (5)0.5744 (3)0.2113 (9)0.0452 (14)
H90.95990.55210.14940.054*
C100.8087 (5)0.5957 (4)0.0050 (9)0.0565 (16)
H10A0.73460.61200.06490.085*
H10B0.80090.54400.09890.085*
H10C0.83940.64510.08560.085*
C110.9094 (5)0.6527 (3)0.3724 (9)0.0528 (15)
H11A0.94890.63290.51830.079*
H11B0.83780.68020.41360.079*
H11C0.95620.69560.28970.079*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.074 (3)0.030 (2)0.0327 (19)0.0060 (18)0.0021 (18)0.0017 (15)
O20.074 (3)0.040 (2)0.0298 (19)0.0036 (18)0.0078 (18)0.0039 (15)
O30.068 (3)0.035 (2)0.0337 (19)0.0031 (18)0.0107 (17)0.0007 (15)
C10.062 (4)0.039 (3)0.031 (3)0.000 (3)0.003 (2)0.003 (2)
C20.064 (4)0.042 (3)0.038 (3)0.001 (3)0.003 (3)0.005 (2)
C30.055 (4)0.046 (3)0.047 (3)0.001 (3)0.001 (3)0.009 (3)
C40.063 (4)0.036 (3)0.041 (3)0.004 (3)0.010 (3)0.001 (2)
C50.065 (4)0.027 (3)0.033 (3)0.004 (3)0.001 (2)0.003 (2)
C60.055 (4)0.033 (3)0.029 (3)0.004 (2)0.003 (2)0.003 (2)
C70.060 (4)0.031 (3)0.030 (3)0.001 (3)0.003 (2)0.004 (2)
C80.055 (4)0.034 (3)0.036 (3)0.002 (3)0.003 (2)0.002 (2)
C90.061 (4)0.038 (3)0.037 (3)0.006 (3)0.012 (2)0.001 (2)
C100.081 (4)0.051 (4)0.038 (3)0.015 (3)0.001 (3)0.010 (3)
C110.074 (4)0.039 (3)0.045 (3)0.008 (3)0.002 (3)0.001 (2)
Geometric parameters (Å, º) top
O1—C71.424 (6)C3—C41.364 (8)
O2—C81.211 (5)C4—C51.376 (8)
O3—C81.343 (6)C5—C61.412 (7)
O3—C91.476 (6)C6—C71.495 (7)
C1—C21.378 (7)C7—C81.519 (7)
C1—C61.401 (7)C9—C101.501 (8)
C2—C31.397 (7)C9—C111.512 (7)
C8—O3—C9117.1 (4)O1—C7—C6112.4 (4)
C2—C1—C6121.6 (5)O1—C7—C8105.2 (4)
C1—C2—C3119.8 (5)C6—C7—C8110.9 (4)
C4—C3—C2119.6 (6)O2—C8—O3123.8 (5)
C3—C4—C5121.1 (5)O2—C8—C7125.0 (4)
C4—C5—C6120.8 (5)O3—C8—C7111.2 (4)
C1—C6—C5117.0 (5)O3—C9—C10111.0 (4)
C1—C6—C7121.0 (5)O3—C9—C11105.0 (4)
C5—C6—C7121.9 (5)C10—C9—C11112.9 (5)
C6—C1—C2—C31.9 (8)C1—C6—C7—C871.2 (6)
C1—C2—C3—C42.1 (8)C5—C6—C7—C8109.5 (5)
C2—C3—C4—C51.4 (8)C9—O3—C8—O24.3 (8)
C3—C4—C5—C60.5 (7)C9—O3—C8—C7176.1 (4)
C2—C1—C6—C50.9 (7)O1—C7—C8—O215.9 (7)
C2—C1—C6—C7178.4 (5)C6—C7—C8—O2105.9 (6)
C4—C5—C6—C10.2 (7)O1—C7—C8—O3164.5 (4)
C4—C5—C6—C7179.1 (4)C6—C7—C8—O373.7 (5)
C1—C6—C7—O146.2 (6)C8—O3—C9—C1076.8 (6)
C5—C6—C7—O1133.0 (5)C8—O3—C9—C11160.9 (5)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1O···O1i0.83 (6)2.12 (5)2.903 (2)158 (5)
O1—H1O···O2i0.83 (6)2.38 (6)2.930 (5)124 (5)
C9—H9···O2ii1.002.533.379 (7)142
Symmetry codes: (i) x, y+1/2, z+1/2; (ii) x+2, y+1, z.
 

References

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