Fenofibrate

Acta Cryst.(2003). E59, o699±o700 DOI: 10.1107/S1600536803008274 R. F. Henryet al. C₂₀H₂₁ClO₄

o699

organic papers

Acta Crystallographica Section E

Structure Reports Online

ISSN 1600-5368

Fenofibrate

R. F. Henry,a_{* G. Z. Zhang,}b Y. Gaoc_{and I. S. Buckner}d

a_{Abbott Laboratories, Global Pharmaceuticals}

Division, Department 418, Building AP9, 100 Abbott Park Road, Abbott Park, IL 60064, USA,

b_{Abbott Laboratories, Global Pharmaceuticals}

Division, Department R4P3, Building AP9, 100 Abbott Park Road, Abbott Park, IL 60064, USA,

c_{Abbott Laboratories, Global Pharmaceuticals}

Division, Department D4P#, Building AP9, 100 Abbott Park Road, Abbott Park, IL 60064, USA, andd_{Abbott Laboratories, Global}

Pharmaceuticals Division, Department D4P3, Building AP9, 100 Abbott Park Road, Abbott Park, IL 60064, USA

Correspondence e-mail: [email protected]

Key indicators

Single-crystal X-ray study

T= 193 K

Mean(C±C) = 0.002 AÊ

Rfactor = 0.052

wRfactor = 0.147

Data-to-parameter ratio = 18.4

For details of how these key indicators were automatically derived from the article, see http://journals.iucr.org/e.

#2003 International Union of Crystallography Printed in Great Britain ± all rights reserved

The crystal structure of 1-methylethyl 2-[4-(4-chlorobenzoyl)-phenoxy]-2-methylpropanoate, also known as feno®brate, C20H21ClO4, has been determined and is presented here.

The compound crystallizes in space group P1 and is notable for its lack of hydrogen-bond donors and thus a lack of hydrogen bonding.

Comment

Feno®brate belongs to a class of compounds, ®bric acid derivatives, which are used to treat hypercholesterolemia or mixed dyslipidemia (Kloer, 1987). The physicochemical properties of feno®brate, including solubility, hygroscopicity, distribution coef®cient, and solid-state characterization, have been studied in detail (Shoji et al., 1995). Recently, a meta-stable polymorph was reported (Di Martinoet al.2000); in that paper the original polymorph and the newly discovered polymorph were designated forms I and II, respectively. In this paper, we report the molecular structure of feno®brate form I.

Feno®brate form I (see Scheme) crystallizes in the

centro-symmetric triclinic space group P1. The molecule lacks

hydrogen-bond donating groups, making it impossible for the structure to contain any type of hydrogen bonding. In the absence of hydrogen-bonding interactions, the molecules are arranged head-to-head and tail-to-tail, producing aliphatic and aromatic layers. These layers are perpendicular to thec

axis. An interesting feature of the conformation of the mol-ecule is the symmetrical nature of the isopropyl ester. A survey of the CSD (Allen, 2002) found 115 structures containing isopropyl esters. These 115 structures contained a total of 171 isopropyl ester fragments. The symmetry of the isopropyl ester was measured as the torsion angle between the carbonyl carbon, estericsp3_{oxygen, isopropyl methine carbon}

and the centroid of the two methyl groups. Values near zero or

180 _{would indicate a highly symmetric orientation of the}

isopropyl group. In this orientation, the isopropyl group's bisecting mirror plane coincides with the plane of the two O atoms and one carbon of the carbonyl group. The mean value found for this torsion angle was 150.7_{. The value nearest 180}

was 174.6_{(Newkomeet al., 1985). The corresponding torsion}

angle in feno®brate is 178.0_{, making it the most symmetric}

crystallographically characterized isopropyl ester.

Experimental

Crystals were grown by slow evaporation of an ethanol solution.

Crystal data

C20H21ClO4

Mr= 360.82

Triclinic,P1

a= 8.1605 (16) AÊ

b= 8.2664 (16) AÊ

c= 14.511 (3) AÊ = 93.951 (3)

= 105.664 (3)

= 96.002 (3)

V= 932.5 (3) AÊ3

Z= 2

Dx= 1.285 Mg mÿ3

MoKradiation Cell parameters from 6105

re¯ections = 2.5±28.3

= 0.23 mmÿ1

T= 193 K

Parallelepiped, colourless 0.40.40.4 mm

Data collection

Bruker SMART Apex CCD diffractometer

!scans

Absorption correction: none 6105 measured re¯ections 4225 independent re¯ections

3694 re¯ections withI> 2(I)

Rint= 0.065 max= 28.3

h=ÿ9!10

k=ÿ10!10

l=ÿ19!19

Re®nement

Re®nement onF2

R[F2_{> 2(F}2_{)] = 0.052}

wR(F2_{) = 0.147}

S= 1.06 4225 re¯ections 230 parameters

H-atom parameters constrained

w= 1/[2_(F

o2) + (0.1706P)2

+ 0.7796P]

whereP= (Fo2+ 2Fc2)/3

(/)max= 0.001 max= 0.38 e AÊÿ3 min=ÿ0.34 e AÊÿ3

H atoms were treated as riding atoms (CÐH = 0.93 and 0.97 AÊ).

Uisovalues for H atoms were ®xed at 1.2 timesUeqof the parent atom.

Data collection:SMART(Bruker, 2001); cell re®nement: SAINT-Plus (Bruker, 1999); data reduction: SAINT-Plus (Bruker, 1999); program(s) used to solve structure: SHELXTL (Sheldrick, 2000); program(s) used to re®ne structure:SHELXTL; molecular graphics:

ORTEPII (Johnson, 1976).

References

Allen, F. H. (2002).Acta Cryst.B58, 380±388.

Bruker (1999). SAINT-Plus. Version 6.02. Bruker AXS Inc., Madison, Wisconsin, USA.

Bruker (2001).SMART. Version 5.624. Bruker AXS Inc., Madison, Wisconsin, USA.

Di Martino, P., Palmieri, G. F. & Martelli S. (2000).Pharmazie,55, 625±626. Johnson, C. K. (1976).ORTEPII. Report ORNL-5138. Oak Ridge National

Laboratory, Tennessee. USA.

Kloer, H. U. (1987).Am. J. Med.83(suppl 5B), 3±8.

Newkome, G. R., Puckett, W. E., Kiefer, G. E., Gupta, V. K., Fronczek, F. R., Pantaleo, D. C., McClure, G. L., Simpson, J. B. & Deutsch, W. A. (1985).

Inorg. Chem.24, 811.

Sheldrick, G. M. (2000).SHELXTL.Version 6.10. Bruker AXS Inc., Madison, Wisconsin, USA.

Shoji, R., Watanabe, T., Tashiro, S. & Shi, S. (1995).Iyakuhin Kenkyu,26, 386± 397.

Figure 1

supporting information

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supporting information

Acta Cryst. (2003). E59, o699–o700 [doi:10.1107/S1600536803008274]

Fenofibrate

R. F. Henry, G. Z. Zhang, Y. Gao and I. S. Buckner

S1. Comment

Fenofibrate belongs to a class of compounds, fibric acid derivatives, which are used to treat hypercholesterolemia or

mixed dyslipidemia (Kloer 1987). The physicochemical properties of fenofibrate, that include solubility, hygroscopicity,

distribution coefficient, and solid-state characterization, have been studied in detail (Shoji et al., 1995). Recently, a

metastable polymorph was reported (DiMartino et al.. 2000), in which the original polymorph and the newly discovered

polymorph were designated Forms I and II, respectively. In this paper, we report the molecular structure of fenofibrate

Form I.

Fenofibrate Form I (see Scheme) crystallizes in the centrosymmetric triclinic space group P1. The molecule lacks

hydrogen bond donating groups making it impossible for the structure to contain any type of hydrogen bonding. In the

absence of hydrogen-bonding interactions, the molecules have arranged themselves head-to-head and tail-to-tail

producing aliphatic and aromatic layers. These layers are perpendicular to the c axis. An interesting feature of the

conformation of the molecule is the symmetrical nature of the isopropyl ester. A survey of the CCDC (Allen 2002) found

115 structures containing isopropyl esters. These 115 structures contained a total of 171 isopropyl ester fragments. The

symmetry of the isopropyl ester was measured as the torsion angle between the carbonyl carbon, esteric sp3 _oxygen,

iso-propyl methine carbon and the centroid of the two methyl groups. Values near zero or 180° would indicate a highly

symmetric orientation of the isopropyl group. In this orientation, the isopropyl group's bisecting mirror plane coincides

with the plane of the two O atoms and one carbon of the carbonyl group. The mean value found for this torsion angle was

150.7°. The value nearest 180° was 174.6° (Newkome et al., 1985). The corresponding torsion angle in fenofibrate is

178.0°, making it the most symmetric crystallographically characterized isopropyl ester

S2. Experimental

Crystals were grown by slow evaporation from an ethanol solution.

S3. Refinement

Molecule crystallized in the triclinic system; space group P1. H atoms were treated as riding atoms (C—H = 0.93 and

Figure 1

A view of fenofibrate with the atomic numbering scheme. Displacement ellipsoids are drawn at the 30% probability level.

1-methylethyl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate

Crystal data C20H21ClO4 Mr = 360.82

Triclinic, P1 a = 8.1605 (16) Å b = 8.2664 (16) Å c = 14.511 (3) Å α = 93.951 (3)° β = 105.664 (3)° γ = 96.002 (3)° V = 932.5 (3) Å3 Z = 2

F(000) = 380 Dx = 1.285 Mg m−3 Melting point = 80–81 K Mo Kα radiation, λ = 0.71073 Å Cell parameters from 6105 reflections θ = 2.5–28.3°

µ = 0.23 mm−1 T = 193 K

Parallelepiped, colourless 0.4 × 0.4 × 0.4 mm

Data collection

Bruker SMART Apex CCD diffractometer

Radiation source: fine-focus sealed tube Graphite monochromator

ω scans

6105 measured reflections 4225 independent reflections

3694 reflections with I > 2σ(I) Rint = 0.065

θmax = 28.3°, θmin = 2.5° h = −9→10

k = −10→10 l = −19→19

Refinement Refinement on F2 Least-squares matrix: full R[F2 _{> 2σ(F}2_{)] = 0.052} wR(F2_{) = 0.147} S = 1.06 4225 reflections

0 restraints

Primary atom site location: structure-invariant direct methods

Secondary atom site location: difference Fourier map

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H-atom parameters constrained w = 1/[σ2_(Fo2_{) + (0.1706P)}2 _{+ 0.7796P]}

where P = (Fo2 _{+ 2Fc}2_)/3

(Δ/σ)max = 0.001 Δρmax = 0.38 e Å−3 Δρmin = −0.34 e Å−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 _{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 F2_{. 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 F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2₎

x y z Uiso*/Ueq

C17 2.0889 (2) 0.6045 (2) 0.87061 (15) 0.0440 (4) H17A 2.0985 0.6038 0.9380 0.066* H17B 2.1381 0.7090 0.8589 0.066* H17C 2.1489 0.5206 0.8509 0.066* C18 1.7095 (2) 0.8146 (2) 0.97655 (12) 0.0446 (4) H18 1.6866 0.9026 0.9347 0.054* C19 1.8357 (3) 0.8783 (3) 1.06991 (17) 0.0686 (6) H19A 1.8565 0.7910 1.1102 0.103* H19B 1.7909 0.9624 1.1012 0.103* H19C 1.9413 0.9228 1.0587 0.103* C20 1.5459 (3) 0.7347 (5) 0.9905 (3) 0.1158 (15) H20A 1.4666 0.6971 0.9289 0.174* H20B 1.4972 0.8123 1.0240 0.174* H20C 1.5691 0.6436 1.0274 0.174*

Atomic displacement parameters (Å2₎

U11 _U22 _U33 _U12 _U13 _U23

Cl1 0.0578 (3) 0.0836 (4) 0.0622 (3) 0.0194 (3) 0.0023 (2) 0.0244 (3) O3 0.0290 (5) 0.0236 (5) 0.0446 (6) 0.0027 (4) 0.0087 (4) 0.0058 (4) O1 0.0557 (7) 0.0389 (6) 0.0340 (5) 0.0203 (5) 0.0167 (5) 0.0070 (4) O4 0.0435 (6) 0.0311 (6) 0.0460 (6) −0.0064 (4) 0.0113 (5) 0.0067 (5) O2 0.0734 (9) 0.0330 (6) 0.0600 (8) 0.0217 (6) 0.0383 (7) 0.0177 (5) C1 0.0381 (7) 0.0281 (7) 0.0302 (7) −0.0029 (5) 0.0140 (6) −0.0007 (5) C2 0.0298 (6) 0.0243 (6) 0.0325 (7) 0.0016 (5) 0.0120 (5) 0.0024 (5) C3 0.0338 (7) 0.0211 (6) 0.0387 (7) 0.0026 (5) 0.0095 (6) 0.0034 (5) C4 0.0352 (7) 0.0245 (6) 0.0389 (7) 0.0065 (5) 0.0140 (6) 0.0059 (5) C5 0.0545 (9) 0.0375 (8) 0.0293 (7) −0.0017 (7) 0.0112 (7) 0.0034 (6) C6 0.0319 (7) 0.0274 (7) 0.0361 (7) 0.0034 (5) 0.0089 (6) 0.0026 (5) C15 0.0283 (6) 0.0244 (6) 0.0356 (7) 0.0017 (5) 0.0100 (5) 0.0014 (5) C7 0.0430 (8) 0.0356 (7) 0.0308 (7) −0.0059 (6) 0.0149 (6) −0.0002 (6) C8 0.0377 (7) 0.0289 (7) 0.0285 (7) −0.0038 (5) 0.0111 (6) −0.0023 (5) C9 0.0336 (7) 0.0269 (6) 0.0301 (6) −0.0011 (5) 0.0129 (5) 0.0001 (5) C10 0.0402 (8) 0.0372 (8) 0.0348 (7) −0.0040 (6) 0.0136 (6) 0.0043 (6) C16 0.0299 (7) 0.0230 (6) 0.0419 (8) 0.0019 (5) 0.0138 (6) 0.0029 (5) C11 0.0403 (8) 0.0215 (6) 0.0384 (7) 0.0012 (5) 0.0154 (6) 0.0036 (5) C12 0.0492 (9) 0.0320 (7) 0.0462 (9) 0.0025 (6) 0.0258 (7) 0.0020 (6) C13 0.0451 (9) 0.0427 (8) 0.0347 (8) 0.0047 (7) 0.0055 (6) 0.0017 (6) C14 0.0374 (8) 0.0480 (9) 0.0415 (8) −0.0007 (7) 0.0122 (7) 0.0045 (7) C17 0.0288 (7) 0.0337 (8) 0.0681 (11) 0.0024 (6) 0.0120 (7) 0.0037 (7) C18 0.0576 (10) 0.0443 (9) 0.0379 (8) 0.0223 (8) 0.0181 (7) 0.0020 (7) C19 0.0758 (15) 0.0636 (13) 0.0610 (13) 0.0036 (11) 0.0181 (11) −0.0182 (10) C20 0.0498 (13) 0.131 (3) 0.157 (3) −0.0084 (15) 0.0428 (17) −0.080 (3)

Geometric parameters (Å, º)

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O3—C16 1.4395 (16) C10—H10 0.9300 O1—C15 1.3181 (18) C16—C12 1.519 (2) O1—C18 1.4651 (18) C16—C17 1.526 (2) O4—C1 1.2187 (18) C11—H11 0.9300 O2—C15 1.1960 (18) C12—H12A 0.9600 C1—C9 1.490 (2) C12—H12B 0.9600 C1—C8 1.493 (2) C12—H12C 0.9600 C2—C3 1.3894 (19) C13—C14 1.379 (2) C2—C4 1.3922 (19) C14—H14 0.9300 C3—C6 1.390 (2) C17—H17A 0.9600 C3—H3 0.9300 C17—H17B 0.9600 C4—C11 1.375 (2) C17—H17C 0.9600 C4—H4 0.9300 C18—C19 1.486 (3) C5—C7 1.380 (2) C18—C20 1.496 (4) C5—C13 1.381 (3) C18—H18 0.9800 C5—H5 0.9300 C19—H19A 0.9600 C6—C9 1.3917 (19) C19—H19B 0.9600 C6—H6 0.9300 C19—H19C 0.9600 C15—C16 1.5322 (18) C20—H20A 0.9600 C7—C8 1.397 (2) C20—H20B 0.9600 C7—H7 0.9300 C20—H20C 0.9600 C8—C10 1.397 (2)

C8—C7—H7 119.8 O1—C18—H18 110.4 C10—C8—C7 118.85 (14) C19—C18—H18 110.4 C10—C8—C1 117.49 (13) C20—C18—H18 110.4 C7—C8—C1 123.60 (14) C18—C19—H19A 109.5 C6—C9—C11 118.25 (13) C18—C19—H19B 109.5 C6—C9—C1 123.73 (13) H19A—C19—H19B 109.5 C11—C9—C1 117.88 (13) C18—C19—H19C 109.5 C14—C10—C8 120.77 (14) H19A—C19—H19C 109.5 C14—C10—H10 119.6 H19B—C19—H19C 109.5 C8—C10—H10 119.6 C18—C20—H20A 109.5 O3—C16—C12 111.55 (12) C18—C20—H20B 109.5 O3—C16—C17 103.88 (11) H20A—C20—H20B 109.5 C12—C16—C17 111.06 (13) C18—C20—H20C 109.5 O3—C16—C15 111.82 (11) H20A—C20—H20C 109.5 C12—C16—C15 111.38 (12) H20B—C20—H20C 109.5