Fenofibrate

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

doi:10.1107/S1600536803008274

Fenofibrate

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

The crystal structure of 1-methylethyl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate, also known as fenofibrate, C₂₀H₂₁ClO₄, has been determined and is presented here. The compound crystallizes in space group P $\overline 1$ and is notable for its lack of hydrogen-bond donors and thus a lack of hydrogen bonding.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536803008274/fl6029sup1.cif Contains datablocks global, I
	Structure factor file (CIF format) https://doi.org/10.1107/S1600536803008274/fl6029Isup2.hkl Contains datablock I

CCDC reference: 214632

checkCIF report

Key indicators

Single-crystal X-ray study
T = 193 K
Mean (C-C) = 0.002 Å
R factor = 0.052
wR factor = 0.147
Data-to-parameter ratio = 18.4

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry


 Alert Level C:



REFLT_03
         From the CIF: _diffrn_reflns_theta_max           28.27
         From the CIF: _reflns_number_total               4225
         TEST2: Reflns within _diffrn_reflns_theta_max
         Count of symmetry unique reflns         4622
         Completeness (_total/calc)             91.41%
          Alert C: < 95% complete


 0 Alert Level A = Potentially serious problem

 0 Alert Level B = Potential problem

 1 Alert Level C = Please check

Comment top

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, 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° (Newkome et al., 1985). The corresponding torsion angle in fenofibrate is 178.0°, making it the most symmetric crystallographically characterized isopropyl ester

Experimental top

Crystals were grown by slow evaporation from an ethanol solution.

Computing details top

Data collection: SMART (Bruker, 2001); cell refinement: SAINT-Plus (Bruker, 1999); data reduction: SAINT-Plus (Bruker 1999); program(s) used to solve structure: SHELXTL (Sheldrick, 2000); program(s) used to refine structure: SHELXTL; molecular graphics: ORTEPII (Johnson, 1976).

Figures top

Fig. 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 top

Crystal data top

C₂₀H₂₁ClO₄	F(000) = 380
M_r = 360.82	D_x = 1.285 Mg m⁻³
Triclinic, P1	Melting point = 80–81 K
a = 8.1605 (16) Å	Mo Kα radiation, λ = 0.71073 Å
b = 8.2664 (16) Å	Cell parameters from 6105 reflections
c = 14.511 (3) Å	θ = 2.5–28.3°
α = 93.951 (3)°	µ = 0.23 mm⁻¹
β = 105.664 (3)°	T = 193 K
γ = 96.002 (3)°	Parallelepiped, colourless
V = 932.5 (3) Å³	0.4 × 0.4 × 0.4 mm
Z = 2

Data collection top

Bruker SMART Apex CCD diffractometer	3694 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	R_int = 0.065
Graphite monochromator	θ_max = 28.3°, θ_min = 2.5°
ω scans	h = −9→10
6105 measured reflections	k = −10→10
4225 independent reflections	l = −19→19

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)] = 0.052	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.147	H-atom parameters constrained
S = 1.06	w = 1/[σ²(F_o²) + (0.1706P)² + 0.7796P] where P = (F_o² + 2F_c²)/3
4225 reflections	(Δ/σ)_max = 0.001
230 parameters	Δρ_max = 0.38 e Å⁻³
0 restraints	Δρ_min = −0.34 e Å⁻³

Crystal data top

C₂₀H₂₁ClO₄	γ = 96.002 (3)°
M_r = 360.82	V = 932.5 (3) Å³
Triclinic, P1	Z = 2
a = 8.1605 (16) Å	Mo Kα radiation
b = 8.2664 (16) Å	µ = 0.23 mm⁻¹
c = 14.511 (3) Å	T = 193 K
α = 93.951 (3)°	0.4 × 0.4 × 0.4 mm
β = 105.664 (3)°

Data collection top

Bruker SMART Apex CCD diffractometer	3694 reflections with I > 2σ(I)
6105 measured reflections	R_int = 0.065
4225 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.052	0 restraints
wR(F²) = 0.147	H-atom parameters constrained
S = 1.06	Δρ_max = 0.38 e Å⁻³
4225 reflections	Δρ_min = −0.34 e Å⁻³
230 parameters

Special details top

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 F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) 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) top

	x	y	z	U_iso*/U_eq
Cl1	0.56390 (7)	0.29037 (8)	0.42848 (4)	0.0691 (2)
O3	1.84131 (12)	0.41642 (12)	0.83905 (8)	0.0326 (2)
O1	1.78245 (16)	0.68641 (14)	0.93170 (8)	0.0408 (3)
O4	1.16190 (15)	−0.07372 (13)	0.71558 (9)	0.0411 (3)
O2	1.78000 (19)	0.82642 (14)	0.80542 (10)	0.0498 (3)
C1	1.18172 (19)	0.06097 (17)	0.68797 (10)	0.0320 (3)
C2	1.67663 (17)	0.34356 (16)	0.79862 (10)	0.0284 (3)
C3	1.53632 (18)	0.42282 (16)	0.75832 (11)	0.0314 (3)
H3	1.5499	0.5356	0.7565	0.038*
C4	1.65445 (19)	0.17488 (17)	0.80155 (11)	0.0318 (3)
H4	1.7481	0.1218	0.8290	0.038*
C5	0.9039 (2)	0.2710 (2)	0.48911 (11)	0.0411 (4)
H5	0.9138	0.3349	0.4401	0.049*
C6	1.37547 (18)	0.33229 (17)	0.72069 (11)	0.0320 (3)
H6	1.2816	0.3856	0.6940	0.038*
C15	1.81198 (17)	0.71001 (16)	0.84840 (10)	0.0294 (3)
C7	1.0477 (2)	0.22088 (19)	0.54899 (11)	0.0365 (3)
H7	1.1552	0.2519	0.5406	0.044*
C8	1.03302 (19)	0.12374 (17)	0.62217 (10)	0.0322 (3)
C9	1.35218 (18)	0.16340 (17)	0.72222 (10)	0.0299 (3)
C10	0.8701 (2)	0.07593 (19)	0.63247 (11)	0.0374 (3)
H10	0.8584	0.0083	0.6795	0.045*
C16	1.89999 (18)	0.57282 (16)	0.81342 (11)	0.0310 (3)
C11	1.49490 (19)	0.08644 (16)	0.76405 (11)	0.0328 (3)
H11	1.4817	−0.0262	0.7665	0.039*
C12	1.8796 (2)	0.56876 (19)	0.70608 (12)	0.0403 (4)
H12A	1.9370	0.4826	0.6864	0.060*
H12B	1.9290	0.6716	0.6922	0.060*
H12C	1.7599	0.5495	0.6718	0.060*
C13	0.7452 (2)	0.2253 (2)	0.50278 (12)	0.0421 (4)
C14	0.7265 (2)	0.1278 (2)	0.57366 (12)	0.0425 (4)
H14	0.6186	0.0976	0.5817	0.051*
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) top

	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) top

Cl1—C13	1.7397 (18)	C9—C11	1.399 (2)
O3—C2	1.3672 (17)	C10—C14	1.379 (2)
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)

C2—O3—C16	121.03 (11)	C17—C16—C15	106.81 (12)
C15—O1—C18	117.62 (12)	C4—C11—C9	120.92 (13)
O4—C1—C9	119.93 (14)	C4—C11—H11	119.5
O4—C1—C8	119.46 (13)	C9—C11—H11	119.5
C9—C1—C8	120.58 (12)	C16—C12—H12A	109.5
O3—C2—C3	125.97 (12)	C16—C12—H12B	109.5
O3—C2—C4	114.29 (12)	H12A—C12—H12B	109.5
C3—C2—C4	119.73 (13)	C16—C12—H12C	109.5
C2—C3—C6	119.49 (13)	H12A—C12—H12C	109.5
C2—C3—H3	120.3	H12B—C12—H12C	109.5
C6—C3—H3	120.3	C14—C13—C5	121.57 (16)
C11—C4—C2	120.33 (13)	C14—C13—Cl1	119.01 (14)
C11—C4—H4	119.8	C5—C13—Cl1	119.42 (13)
C2—C4—H4	119.8	C10—C14—C13	119.05 (15)
C7—C5—C13	119.23 (15)	C10—C14—H14	120.5
C7—C5—H5	120.4	C13—C14—H14	120.5
C13—C5—H5	120.4	C16—C17—H17A	109.5
C3—C6—C9	121.26 (13)	C16—C17—H17B	109.5
C3—C6—H6	119.4	H17A—C17—H17B	109.5
C9—C6—H6	119.4	C16—C17—H17C	109.5
O2—C15—O1	124.98 (13)	H17A—C17—H17C	109.5
O2—C15—C16	122.90 (13)	H17B—C17—H17C	109.5
O1—C15—C16	112.08 (12)	O1—C18—C19	107.64 (15)
C5—C7—C8	120.50 (15)	O1—C18—C20	106.31 (17)
C5—C7—H7	119.8	C19—C18—C20	111.6 (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

C16—O3—C2—C3	−23.4 (2)	C7—C8—C10—C14	−2.1 (2)
C16—O3—C2—C4	157.78 (12)	C1—C8—C10—C14	−179.40 (14)
O3—C2—C3—C6	−179.30 (13)	C2—O3—C16—C12	−57.95 (16)
C4—C2—C3—C6	−0.5 (2)	C2—O3—C16—C17	−177.66 (12)
O3—C2—C4—C11	179.51 (13)	C2—O3—C16—C15	67.52 (16)
C3—C2—C4—C11	0.6 (2)	O2—C15—C16—O3	−146.98 (15)
C2—C3—C6—C9	−0.3 (2)	O1—C15—C16—O3	35.23 (16)
C18—O1—C15—O2	−1.9 (2)	O2—C15—C16—C12	−21.4 (2)
C18—O1—C15—C16	175.86 (13)	O1—C15—C16—C12	160.80 (13)
C13—C5—C7—C8	0.5 (2)	O2—C15—C16—C17	100.00 (18)
C5—C7—C8—C10	1.2 (2)	O1—C15—C16—C17	−77.78 (15)
C5—C7—C8—C1	178.26 (13)	C2—C4—C11—C9	0.1 (2)
O4—C1—C8—C10	32.2 (2)	C6—C9—C11—C4	−0.8 (2)
C9—C1—C8—C10	−146.02 (14)	C1—C9—C11—C4	−176.69 (13)
O4—C1—C8—C7	−144.93 (15)	C7—C5—C13—C14	−1.3 (3)
C9—C1—C8—C7	36.9 (2)	C7—C5—C13—Cl1	179.17 (12)
C3—C6—C9—C11	0.9 (2)	C8—C10—C14—C13	1.4 (2)
C3—C6—C9—C1	176.51 (13)	C5—C13—C14—C10	0.4 (3)
O4—C1—C9—C6	−158.87 (14)	Cl1—C13—C14—C10	179.89 (13)
C8—C1—C9—C6	19.3 (2)	C15—O1—C18—C19	−117.82 (18)
O4—C1—C9—C11	16.7 (2)	C15—O1—C18—C20	122.5 (2)
C8—C1—C9—C11	−165.05 (13)

Experimental details

Crystal data
Chemical formula	C₂₀H₂₁ClO₄
M_r	360.82
Crystal system, space group	Triclinic, P1
Temperature (K)	193
a, b, c (Å)	8.1605 (16), 8.2664 (16), 14.511 (3)
α, β, γ (°)	93.951 (3), 105.664 (3), 96.002 (3)
V (Å³)	932.5 (3)
Z	2
Radiation type	Mo Kα
µ (mm⁻¹)	0.23
Crystal size (mm)	0.4 × 0.4 × 0.4

Data collection
Diffractometer	Bruker SMART Apex CCD diffractometer
Absorption correction	–
No. of measured, independent and observed [I > 2σ(I)] reflections	6105, 4225, 3694
R_int	0.065
(sin θ/λ)_max (Å⁻¹)	0.666

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.052, 0.147, 1.06
No. of reflections	4225
No. of parameters	230
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.38, −0.34

Computer programs: SMART (Bruker, 2001), SAINT-Plus (Bruker, 1999), SAINT-Plus (Bruker 1999), SHELXTL (Sheldrick, 2000), SHELXTL, ORTEPII (Johnson, 1976).

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