4,5-Bis(4-fluoro­phen­yl)-5-hy­droxy-3-(2-methyl­propano­yl)-1-phenyl­pyrrolidin-2-one

Jian-Ying Huang; Fengyan Zhou

doi:10.1107/S1600536811008786

. 2011 Mar 12;67(Pt 4):o873–o874. doi: 10.1107/S1600536811008786

4,5-Bis(4-fluorophenyl)-5-hydroxy-3-(2-methylpropanoyl)-1-phenylpyrrolidin-2-one

Jian-Ying Huang ^a,^*, Fengyan Zhou ^b

PMCID: PMC3099992 PMID: 21754151

Abstract

The title compound, C₂₆H₂₃F₂NO₃, was synthesized by the reaction of 2-(4-fluorobenzylidene)-4-methyl-3-oxo-N-phenylpentanamide and 4-fluorobenzaldehyde. The dihedral angles between the mean plane through the pyrrolidine ring (nearly planar; maximum deviation of 0.145 Å for the C atom bearing the hydroxy group) with the phenyl and benzene rings are 37.22 (7), 51.88 (7) and 87.64 (9)°, respectively. The pyyolidine ring is near coplaner, with max offset of 0.145 A for C19 atom.\uff09 In the crystal, molecules are linked by pairs of O—H⋯O hydrogen bonds into inversion dimers, which are further assembled into chains parallel to the b axis by weak C—H⋯O hydrogen bonds.

Related literature

The title compound is an impurity in the preparation of an intermediate in the synthesis of atorvastatin {systematic name [R-(R ^*,R ^*)]-2-(4-fluorophenyl)-ρ,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptenoic acid}, see: Baumann et al. (1992 ▶); Sagyam et al. (2007 ▶). For the use of atorvastatin as a hypolipidemic and hypocholesterolemic agent, see: Lea & McTavish, (1997 ▶). For bond-length data, see: Allen et al. (1987 ▶).

Experimental

Crystal data

C₂₆H₂₃F₂NO₃
M _r = 435.45
Monoclinic,
a = 24.506 (4) Å
b = 10.2180 (15) Å
c = 20.554 (3) Å
β = 121.963 (2)°
V = 4366.5 (11) Å³
Z = 8
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 153 K
0.15 × 0.15 × 0.10 mm

Data collection

Bruker SMART CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2005 ▶) T _min = 0.986, T _max = 0.990
10716 measured reflections
4091 independent reflections
2471 reflections with I > 2σ(I)
R _int = 0.033

Refinement

R[F ² > 2σ(F ²)] = 0.039
wR(F ²) = 0.103
S = 1.02
4091 reflections
293 parameters
H-atom parameters constrained
Δρ_max = 0.15 e Å⁻³
Δρ_min = −0.18 e Å⁻³

Data collection: SMART (Bruker, 2005 ▶); cell refinement: SAINT (Bruker, 2005 ▶); data reduction: SAINT; 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: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536811008786/rz2536sup1.cif

e-67-0o873-sup1.cif^{(23.4KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536811008786/rz2536Isup2.hkl

e-67-0o873-Isup2.hkl^{(200.6KB, hkl)}

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
C10—H10⋯O1ⁱ	0.95	2.59	3.489 (3)	157
O2—H2⋯O1ⁱⁱ	0.84	1.93	2.7625 (18)	174

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

Acknowledgments

This work was supported by the Education Department of Zhejiang Province (No. Y200906515) and Zhejiang Gong Shang University (No. X-106).

supplementary crystallographic information

Comment

Atorvastatin, {[R-(R^*,R^*)]-2-(4-fluorophenyl)-ρ,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptenoic acid}, is a selective and competitive inhibitor of the enzyme hydroxyl-methylglutaryl coenzyme-A reductase (HMG-CoA-R), which plays a key role in the biosynthesis of cholesterol. By virtue of that activity atorvastatin is useful as a hypolipidemic and hypocholesterolemic agent (Lea & McTavish, 1997). The synthesis of atorvastatin is carried out via the critical intermediate 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide (Sagyam et al., 20077; Baumann et al., 1992). The process for preparing this intermediate is particularly sensitive and vulnerable to the formation of some impurities which may cause product rejection and decreased yields. We report here the crystal structure of one of these impurities.

In the title compound (Fig. 1) bond lengths and angles are within normal ranges (Allen et al., 1987). The five atoms of the pyrrolidine ring are not coplanar, with deviations from the planarity ranging from -0.124 (2) to 0.163 (2) Å. The dihedral angles between the mean plane through the pyrrolidine ring with the C13–C18 phenyl ring and the C1–C6, C7–C12 benzene rings are 37.22 (7), 51.88 (7)° and 87.64 (9)°, respectively. In the crystal structure, the molecules are linked by intermolecular O—H···O hydrogen bonds into dinuclear units (Table 1). The dinuclear units are further assembled into one–dimensional chains along the [010] direction by C–H···O hydrogen bonds.

Experimental

A mixture of 2-(4-fluorobenzylidene)-4-methyl-3-oxo-N-phenylpentanamide (5.10 g, 16.4 mmol), ethyl hydroxyethylmethyl thiazolium bromide (0.60 g, 2.38 mmol), 4-fluorobenzaldehyde (2.16 g, 17.4 mmol) and triethylamine (1.20 g, 11.9 mmol) was heated with stirring to 338 K. The reaction mixture was allowed to stand for 24 h at this temperature. Then 2-propanol (6.0 ml) was added and the mixture was heated to about 373 K. Deionized water (6.0 ml) was dropwise added to the reaction mixture over 30 min while maintaining the temperature at 338 K. After it was gradually cooled to 273 K, a white solid was isolated on a filter and washed with 2-propanol. The solid was recrystallized from ethyl acetate/hexane (1:1 v/v) and dried under vacuum at 323 K to give the title product as a white solid (2.28 g, yield 32%). Colourless crystals were obtained by vapor diffusion of pentane into an acetone solution over a period of 5 d.