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

Isaiev, I.; Shishkina, S.; Ukrainets, I.; Bevz, E.

doi:10.1107/S2056989017005862

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ISSN: 2056-9890

Volume 73| Part 5| May 2017| Pages 771-773

https://doi.org/10.1107/S2056989017005862

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

Ivan Isaiev,^a ^* Svitlana Shishkina,^b Igor Ukrainets ^c and Elena Bevz ^c

^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.

Keywords: crystal structure; pharmacopoeia reference standard; hydrogen bonding..

CCDC reference: 1544853

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 ). 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.

2. 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 −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
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 and Table 1). Neighbouring chains are linked by C—H⋯O hydrogen bonds, forming undulating layers lying parallel to the bc plane (Table 1 and Fig. 3).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	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
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.

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.

4. Database survey

A search in the Cambridge Structural Database (Version 5.38, update February 2017; Groom et al., 2016 ) for substructure isopropyl 2-hydroxy-2-phenylacetate yielded three hits, viz. isopropyl 2,2-bis(4-bromophenyl)-2-hydroxyacetate (EFAFEY; Smith, 2012 ), 1-isopropyl 4-methyl 2-hydroxy-2-{2-[(methoxycarbonyl)amino]phenyl} succinate (MAZJAA; Suárez-Castillo et al., 2012 ) and syn-isopropyl 2,3-dihydroxy-4-methyl-2-phenylpentanoate (MERRIL; Scholtis et al., 2006 ). 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). 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
Reaction scheme

6. Refinement

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

Table 2
Experimental details

Crystal data
Chemical formula	C₁₁H₁₄O₃
M_r	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)
V (Å³)	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 )
T_min, T_max	0.357, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	5292, 1761, 922
R_int	0.101
(sin θ/λ)_max (Å⁻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
Δρ_max, Δρ_min (e Å⁻³)	0.30, −0.26
Computer programs: CrysAlis CCD and CrysAlis RED (Agilent, 2012), SHELXS2014 (Sheldrick, 2008 ), SHELXL2014 (Sheldrick, 2015 ), ORTEP-3 for Windows (Farrugia, 2012 ), Mercury (Macrae et al., 2008 ), PLATON (Spek, 2009 ) and publCIF (Westrip, 2010 ).

Supporting information

CCDC reference: 1544853

Crystal structure: contains datablocks I, Global. DOI: https://doi.org/10.1107/S2056989017005862/su5365sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989017005862/su5365Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989017005862/su5365Isup3.cml

checkCIF report

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

C₁₁H₁₄O₃	F(000) = 416
M_r = 194.22	D_x = 1.278 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 11.872 (3) Å	Cell parameters from 403 reflections
b = 15.165 (4) Å	θ = 4.3–21.1°
c = 5.6079 (11) Å	µ = 0.09 mm⁻¹
β = 91.41 (2)°	T = 100 K
V = 1009.3 (4) Å³	Needle, colourless
Z = 4	0.20 × 0.08 × 0.06 mm

Data collection top

Agilent Xcalibur Sapphire3 diffractometer	1761 independent reflections
Radiation source: Enhance (Mo) X-ray Source	922 reflections with I > 2σ(I)
Detector resolution: 16.1827 pixels mm^-1	R_int = 0.101
ω–scan	θ_max = 25.0°, θ_min = 3.2°
Absorption correction: multi-scan (CrysAlis RED; Agilent, 2012)	h = −14→13
T_min = 0.357, T_max = 1.000	k = −17→18
5292 measured reflections	l = −5→6

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.090	Hydrogen site location: difference Fourier map
wR(F²) = 0.255	H atoms treated by a mixture of independent and constrained refinement
S = 1.03	w = 1/[σ²(F_o²) + (0.1022P)²] where P = (F_o² + 2F_c²)/3
1761 reflections	(Δ/σ)_max < 0.001
132 parameters	Δρ_max = 0.30 e Å⁻³
0 restraints	Δρ_min = −0.26 e Å⁻³

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

	x	y	z	U_iso*/U_eq
O1	0.8289 (3)	0.2748 (2)	0.4019 (6)	0.0456 (10)
H1O	0.845 (4)	0.252 (4)	0.534 (10)	0.068*
O2	0.8740 (3)	0.4013 (2)	0.0966 (6)	0.0476 (11)
O3	0.8375 (3)	0.5068 (2)	0.3667 (6)	0.0455 (10)
C1	0.5984 (5)	0.3361 (3)	0.3003 (9)	0.0443 (14)
H1	0.6314	0.3108	0.1638	0.053*
C2	0.4827 (5)	0.3407 (3)	0.3113 (9)	0.0479 (14)
H2	0.4368	0.3171	0.1856	0.057*
C3	0.4332 (5)	0.3801 (3)	0.5079 (9)	0.0492 (15)
H3	0.3535	0.3852	0.5142	0.059*
C4	0.4998 (5)	0.4111 (3)	0.6910 (9)	0.0467 (14)
H4	0.4658	0.4367	0.8262	0.056*
C5	0.6154 (5)	0.4061 (3)	0.6831 (9)	0.0419 (13)
H5	0.6600	0.4286	0.8122	0.050*
C6	0.6684 (4)	0.3679 (3)	0.4857 (8)	0.0387 (13)
C7	0.7937 (4)	0.3603 (3)	0.4744 (8)	0.0403 (13)
H7	0.8283	0.3743	0.6343	0.048*
C8	0.8399 (4)	0.4230 (3)	0.2895 (9)	0.0416 (13)
C9	0.8869 (5)	0.5744 (3)	0.2113 (9)	0.0452 (14)
H9	0.9599	0.5521	0.1494	0.054*
C10	0.8087 (5)	0.5957 (4)	0.0050 (9)	0.0565 (16)
H10A	0.7346	0.6120	0.0649	0.085*
H10B	0.8009	0.5440	−0.0989	0.085*
H10C	0.8394	0.6451	−0.0856	0.085*
C11	0.9094 (5)	0.6527 (3)	0.3724 (9)	0.0528 (15)
H11A	0.9489	0.6329	0.5183	0.079*
H11B	0.8378	0.6802	0.4136	0.079*
H11C	0.9562	0.6956	0.2897	0.079*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.074 (3)	0.030 (2)	0.0327 (19)	0.0060 (18)	0.0021 (18)	0.0017 (15)
O2	0.074 (3)	0.040 (2)	0.0298 (19)	−0.0036 (18)	0.0078 (18)	−0.0039 (15)
O3	0.068 (3)	0.035 (2)	0.0337 (19)	−0.0031 (18)	0.0107 (17)	−0.0007 (15)
C1	0.062 (4)	0.039 (3)	0.031 (3)	0.000 (3)	−0.003 (2)	0.003 (2)
C2	0.064 (4)	0.042 (3)	0.038 (3)	−0.001 (3)	−0.003 (3)	0.005 (2)
C3	0.055 (4)	0.046 (3)	0.047 (3)	−0.001 (3)	−0.001 (3)	0.009 (3)
C4	0.063 (4)	0.036 (3)	0.041 (3)	0.004 (3)	0.010 (3)	0.001 (2)
C5	0.065 (4)	0.027 (3)	0.033 (3)	−0.004 (3)	0.001 (2)	0.003 (2)
C6	0.055 (4)	0.033 (3)	0.029 (3)	−0.004 (2)	0.003 (2)	0.003 (2)
C7	0.060 (4)	0.031 (3)	0.030 (3)	−0.001 (3)	0.003 (2)	−0.004 (2)
C8	0.055 (4)	0.034 (3)	0.036 (3)	−0.002 (3)	−0.003 (2)	−0.002 (2)
C9	0.061 (4)	0.038 (3)	0.037 (3)	−0.006 (3)	0.012 (2)	0.001 (2)
C10	0.081 (4)	0.051 (4)	0.038 (3)	−0.015 (3)	0.001 (3)	0.010 (3)
C11	0.074 (4)	0.039 (3)	0.045 (3)	−0.008 (3)	0.002 (3)	−0.001 (2)

Geometric parameters (Å, º) top

O1—C7	1.424 (6)	C3—C4	1.364 (8)
O2—C8	1.211 (5)	C4—C5	1.376 (8)
O3—C8	1.343 (6)	C5—C6	1.412 (7)
O3—C9	1.476 (6)	C6—C7	1.495 (7)
C1—C2	1.378 (7)	C7—C8	1.519 (7)
C1—C6	1.401 (7)	C9—C10	1.501 (8)
C2—C3	1.397 (7)	C9—C11	1.512 (7)

C8—O3—C9	117.1 (4)	O1—C7—C6	112.4 (4)
C2—C1—C6	121.6 (5)	O1—C7—C8	105.2 (4)
C1—C2—C3	119.8 (5)	C6—C7—C8	110.9 (4)
C4—C3—C2	119.6 (6)	O2—C8—O3	123.8 (5)
C3—C4—C5	121.1 (5)	O2—C8—C7	125.0 (4)
C4—C5—C6	120.8 (5)	O3—C8—C7	111.2 (4)
C1—C6—C5	117.0 (5)	O3—C9—C10	111.0 (4)
C1—C6—C7	121.0 (5)	O3—C9—C11	105.0 (4)
C5—C6—C7	121.9 (5)	C10—C9—C11	112.9 (5)

C6—C1—C2—C3	1.9 (8)	C1—C6—C7—C8	71.2 (6)
C1—C2—C3—C4	−2.1 (8)	C5—C6—C7—C8	−109.5 (5)
C2—C3—C4—C5	1.4 (8)	C9—O3—C8—O2	−4.3 (8)
C3—C4—C5—C6	−0.5 (7)	C9—O3—C8—C7	176.1 (4)
C2—C1—C6—C5	−0.9 (7)	O1—C7—C8—O2	15.9 (7)
C2—C1—C6—C7	178.4 (5)	C6—C7—C8—O2	−105.9 (6)
C4—C5—C6—C1	0.2 (7)	O1—C7—C8—O3	−164.5 (4)
C4—C5—C6—C7	−179.1 (4)	C6—C7—C8—O3	73.7 (5)
C1—C6—C7—O1	−46.2 (6)	C8—O3—C9—C10	76.8 (6)
C5—C6—C7—O1	133.0 (5)	C8—O3—C9—C11	−160.9 (5)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	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+1/2, z+1/2; (ii) −x+2, −y+1, −z.

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