5-Methyl-N-[2-(trifluoro­meth­yl)phen­yl]isoxazole-4-carboxamide

Wang, D.-C.; Qiu, J.-K.; Zhu, H.-X.; Wei, P.; Ou-Yang, P.-K.

doi:10.1107/S1600536812016467

organic compounds

CRYSTALLOGRAPHIC
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ISSN: 2056-9890

Volume 68| Part 5| May 2012| Page o1450

doi:10.1107/S1600536812016467

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5-Methyl-N-[2-(trifluoromethyl)phenyl]isoxazole-4-carboxamide

De-Cai Wang,^a ^* Jiang-Kai Qiu,^a Hai-Xi Zhu,^a Ping Wei ^a and Ping-Kai Ou-Yang ^a

^aState Key Laboratory of Materials-Oriented Chemical Engineering, School of Pharmaceutical Sciences, Nanjing University of Technology, Xinmofan Road No.5 Nanjing, Nanjing 210009, People's Republic of China
^*Correspondence e-mail: dc_wang@hotmail.com

(Received 15 April 2012; accepted 16 April 2012; online 21 April 2012)

In the title compound, C₁₂H₉F₃N₂O₂, the benzene ring is nearly perpendicular to the isoxazole ring, making a dihedral angle of 82.97 (2)°. In the crystal, molecules are linked by N—H⋯O hydrogen bonds into a supramolecular chain running along the c axis.

Related literature

For applications of leflunomide [systematic name: 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide] in the treatment of rheumatoid arthritis, see: Shaw et al. (2011 ); Schattenkirchner (2000 ). For leflunomide analogs, see: Huang et al. (2003 ); Wang et al. (2011 ).

Experimental

Crystal data

C₁₂H₉F₃N₂O₂
M_r = 270.21
Monoclinic, P 2₁ /c
a = 15.839 (3) Å
b = 8.3260 (17) Å
c = 9.4250 (19) Å
β = 101.29 (3)°
V = 1218.9 (4) Å³
Z = 4
Mo Kα radiation
μ = 0.13 mm⁻¹
T = 293 K
0.20 × 0.10 × 0.10 mm

Data collection

Enref–Nonius CAD-4 diffractometer
Absorption correction: ψ scan (North et al., 1968 ) T_min = 0.974, T_max = 0.987
2193 measured reflections
2193 independent reflections
1125 reflections with I > 2σ(I)
3 standard reflections every 200 reflections intensity decay: 1%

Refinement

R[F² > 2σ(F²)] = 0.062
wR(F²) = 0.164
S = 1.00
2193 reflections
172 parameters
H-atom parameters constrained
Δρ_max = 0.19 e Å⁻³
Δρ_min = −0.19 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1A⋯O1ⁱ	0.86	2.13	2.855 (3)	142
Symmetry code: (i) $[x, -y+{\script{1\over 2}}, z+{\script{1\over 2}}]$ .

Data collection: CAD-4 EXPRESS (Enraf–Nonius, 1994 ); cell refinement: CAD-4 EXPRESS; data reduction: XCAD4 (Harms & Wocadlo,1995 ); program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Supporting information

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536812016467/xu5516sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536812016467/xu5516Isup2.hkl

Supporting information file. DOI: 10.1107/S1600536812016467/xu5516Isup3.cml

checkCIF report

Comment top

Leflunomide is one of the most effective isoxazole-containing disease-modifying drugs for treating rheumatoid arthritis (Shaw et al., 2011; Schattenkirchner, 2000). Many leflunomide analogs have been synthesized and exhibit potent immunomodulating effect (Huang, et al., 2003). In our previous work, some anolog has been sucessfully sythesized (Wang et al., 2011). In this paper, one new leflunomide analog N-(2,4-difluorophenyl)-5-methylisoxazole-4-carboxamide monohydrate, was synthesized as a novel and potent immunomodulating drugs. We report herein its crystal structure.

As illustrated in Fig. 1, the molecular structure of the title compound is not planar. The C1-C6 benzene and the C9-C11/N2/O2 isoxazole ring is almost perpendicular to each other with the dihedral angle of 82.97 (2) °. The central nitrogen atom (N1) and carbon atom (C8) are nearly coplanar with the benzene ring and the isoxazole rings [N1-C5-C6-C1 torsion angles = -176.7 (3) ° and C8-C9-C10-O2 torsion angles = -177.9 (3) °], respectively. The length of the C11=N2 double bond is 1.295 (5) Å, slightly longer than standard 1.28 Å value of a C=N double bond. The crystal structure is stabilized by N—H···O hydrogen bonds(Table 1).

Related literature top

For applications of leflunomide [systematic name: 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide] in the treatment of rheumatoid arthritis, see: Shaw et al. (2011); Schattenkirchner (2000). For leflunomide analogs, see: Huang et al. (2003); Wang et al. (2011).

Experimental top

A solution of 0.05 mole of 5-methylisoxazole-4-carboxylic acid chloride (7.3 g) in 20 ml of acetonitrile is added drop-wise, while stirring, to 0.1 mole of 2-(trifluoromethyl)aniline (16.1g),dissolved in 150 ml of acetonitrile at room temperature.After stirring for 40 minutes, the precipitated 2-(trifluoromethyl)aniline hydrochloride is filtered off and washed with 100 ml portions of acetonitrile, and the combined filtrates are concentrated under reduced pressure.9.6g(69.51% of theory) of white crystalline 5-methyl-N-(2-(trifluoromethyl)phenyl)isoxazole-4- carboxamide are thus obtained. Crystals of (I) suitable for X-ray diffraction were obtained by slow evaporation of an methylbenzene solution.

Computing details top

Data collection: CAD-4 EXPRESS (Enraf–Nonius, 1994); cell refinement: CAD-4 EXPRESS (Enraf–Nonius, 1994); data reduction: XCAD4 (Harms & Wocadlo,1995); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top

Fig. 1. The structure of the title compound, showing the atomic numbering scheme. Non-H atoms are shown with 30% probability displacement ellipsoids.

5-Methyl-N-[2-(trifluoromethyl)phenyl]isoxazole-4-carboxamide top

Crystal data top

C₁₂H₉F₃N₂O₂	F(000) = 552
M_r = 270.21	D_x = 1.472 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 25 reflections
a = 15.839 (3) Å	θ = 9–13°
b = 8.3260 (17) Å	µ = 0.13 mm⁻¹
c = 9.4250 (19) Å	T = 293 K
β = 101.29 (3)°	Block, colorless
V = 1218.9 (4) Å³	0.20 × 0.10 × 0.10 mm
Z = 4

Data collection top

Enref–Nonius CAD-4 diffractometer	1125 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	R_int = 0.000
Graphite monochromator	θ_max = 25.2°, θ_min = 1.3°
ω/2θ scans	h = −18→18
Absorption correction: ψ scan (North et al., 1968)	k = 0→9
T_min = 0.974, T_max = 0.987	l = 0→11
2193 measured reflections	3 standard reflections every 200 reflections
2193 independent reflections	intensity decay: 1%

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)] = 0.062	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.164	H-atom parameters constrained
S = 1.00	w = 1/[σ²(F_o²) + (0.068P)²] where P = (F_o² + 2F_c²)/3
2193 reflections	(Δ/σ)_max < 0.001
172 parameters	Δρ_max = 0.19 e Å⁻³
0 restraints	Δρ_min = −0.19 e Å⁻³

Crystal data top

C₁₂H₉F₃N₂O₂	V = 1218.9 (4) Å³
M_r = 270.21	Z = 4
Monoclinic, P2₁/c	Mo Kα radiation
a = 15.839 (3) Å	µ = 0.13 mm⁻¹
b = 8.3260 (17) Å	T = 293 K
c = 9.4250 (19) Å	0.20 × 0.10 × 0.10 mm
β = 101.29 (3)°

Data collection top

Enref–Nonius CAD-4 diffractometer	1125 reflections with I > 2σ(I)
Absorption correction: ψ scan (North et al., 1968)	R_int = 0.000
T_min = 0.974, T_max = 0.987	3 standard reflections every 200 reflections
2193 measured reflections	intensity decay: 1%
2193 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.062	0 restraints
wR(F²) = 0.164	H-atom parameters constrained
S = 1.00	Δρ_max = 0.19 e Å⁻³
2193 reflections	Δρ_min = −0.19 e Å⁻³
172 parameters

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.

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 > 2sigma(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
N1	0.73554 (18)	0.2300 (3)	0.9712 (3)	0.0540 (8)
H1A	0.7386	0.2533	1.0610	0.065*
O1	0.67807 (16)	0.2925 (3)	0.7394 (2)	0.0647 (8)
F1	0.9108 (2)	0.3541 (4)	1.0116 (3)	0.1322 (13)
C1	0.9018 (3)	−0.0106 (6)	0.8447 (4)	0.0732 (12)
H1B	0.9526	0.0039	0.8108	0.088*
O2	0.55089 (19)	0.6534 (3)	0.9342 (3)	0.0782 (9)
N2	0.6083 (3)	0.6480 (4)	1.0694 (4)	0.0790 (11)
F2	0.97802 (18)	0.2773 (4)	0.8551 (4)	0.1233 (11)
C2	0.8701 (3)	−0.1615 (6)	0.8525 (5)	0.0844 (14)
H2B	0.8989	−0.2489	0.8232	0.101*
F3	0.85728 (19)	0.3827 (3)	0.7915 (3)	0.1128 (10)
C3	0.7957 (3)	−0.1853 (5)	0.9035 (5)	0.0805 (13)
H3A	0.7746	−0.2886	0.9103	0.097*
C4	0.7526 (3)	−0.0551 (5)	0.9447 (4)	0.0650 (11)
H4A	0.7023	−0.0707	0.9797	0.078*
C5	0.7837 (2)	0.0983 (4)	0.9344 (3)	0.0512 (9)
C6	0.8601 (2)	0.1205 (5)	0.8858 (4)	0.0574 (10)
C7	0.9005 (3)	0.2832 (5)	0.8849 (5)	0.0680 (11)
C8	0.6852 (2)	0.3198 (4)	0.8696 (4)	0.0486 (9)
C9	0.6396 (2)	0.4541 (4)	0.9236 (4)	0.0488 (9)
C10	0.5722 (3)	0.5371 (5)	0.8487 (4)	0.0589 (10)
C11	0.6589 (3)	0.5281 (5)	1.0597 (4)	0.0641 (11)
H11A	0.7029	0.4948	1.1343	0.077*
C12	0.5197 (3)	0.5268 (5)	0.7026 (4)	0.0761 (12)
H12A	0.4770	0.6101	0.6897	0.114*
H12B	0.4919	0.4240	0.6897	0.114*
H12C	0.5559	0.5397	0.6327	0.114*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.066 (2)	0.0617 (19)	0.0402 (15)	0.0153 (17)	0.0235 (14)	0.0065 (15)
O1	0.0783 (18)	0.0810 (19)	0.0400 (13)	0.0171 (15)	0.0239 (12)	−0.0014 (13)
F1	0.172 (3)	0.127 (3)	0.112 (2)	−0.071 (2)	0.062 (2)	−0.0454 (19)
C1	0.064 (3)	0.081 (3)	0.083 (3)	0.013 (2)	0.035 (2)	0.003 (2)
O2	0.093 (2)	0.0569 (17)	0.094 (2)	0.0188 (16)	0.0402 (19)	0.0020 (16)
N2	0.111 (3)	0.063 (2)	0.069 (2)	0.010 (2)	0.035 (2)	−0.0060 (19)
F2	0.0791 (18)	0.124 (2)	0.182 (3)	−0.0192 (18)	0.0619 (19)	0.010 (2)
C2	0.091 (3)	0.071 (3)	0.100 (4)	0.022 (3)	0.040 (3)	0.003 (3)
F3	0.108 (2)	0.087 (2)	0.135 (3)	−0.0171 (17)	0.0032 (18)	0.0453 (18)
C3	0.097 (3)	0.049 (3)	0.102 (3)	0.003 (2)	0.034 (3)	0.014 (2)
C4	0.065 (3)	0.068 (3)	0.070 (3)	−0.001 (2)	0.033 (2)	0.015 (2)
C5	0.059 (2)	0.054 (2)	0.045 (2)	0.0066 (19)	0.0234 (18)	0.0067 (16)
C6	0.058 (2)	0.069 (3)	0.050 (2)	0.006 (2)	0.0218 (18)	0.0051 (19)
C7	0.065 (3)	0.075 (3)	0.071 (3)	0.000 (2)	0.033 (2)	0.004 (2)
C8	0.050 (2)	0.049 (2)	0.052 (2)	0.0024 (18)	0.0254 (17)	0.0047 (17)
C9	0.061 (2)	0.044 (2)	0.0470 (19)	−0.0004 (18)	0.0261 (17)	0.0010 (17)
C10	0.064 (3)	0.049 (2)	0.070 (2)	−0.004 (2)	0.030 (2)	0.004 (2)
C11	0.091 (3)	0.056 (2)	0.051 (2)	0.003 (2)	0.026 (2)	0.0006 (19)
C12	0.076 (3)	0.072 (3)	0.081 (3)	−0.001 (2)	0.017 (2)	0.015 (2)

Geometric parameters (Å, º) top

N1—C8	1.346 (4)	C3—C4	1.377 (5)
N1—C5	1.417 (4)	C3—H3A	0.9300
N1—H1A	0.8600	C4—C5	1.379 (5)
O1—C8	1.231 (4)	C4—H4A	0.9300
F1—C7	1.314 (4)	C5—C6	1.387 (4)
C1—C2	1.361 (6)	C6—C7	1.499 (5)
C1—C6	1.370 (5)	C8—C9	1.475 (4)
C1—H1B	0.9300	C9—C10	1.350 (5)
O2—C10	1.345 (4)	C9—C11	1.401 (5)
O2—N2	1.415 (4)	C10—C12	1.465 (5)
N2—C11	1.295 (5)	C11—H11A	0.9300
F2—C7	1.312 (4)	C12—H12A	0.9600
C2—C3	1.370 (6)	C12—H12B	0.9600
C2—H2B	0.9300	C12—H12C	0.9600
F3—C7	1.302 (5)

C8—N1—C5	121.8 (3)	F3—C7—F1	106.5 (4)
C8—N1—H1A	119.1	F2—C7—F1	104.9 (4)
C5—N1—H1A	119.1	F3—C7—C6	114.2 (4)
C2—C1—C6	121.1 (4)	F2—C7—C6	112.7 (4)
C2—C1—H1B	119.5	F1—C7—C6	112.2 (3)
C6—C1—H1B	119.5	O1—C8—N1	122.2 (3)
C10—O2—N2	108.9 (3)	O1—C8—C9	121.8 (3)
C11—N2—O2	105.0 (3)	N1—C8—C9	115.9 (3)
C1—C2—C3	120.3 (4)	C10—C9—C11	105.2 (3)
C1—C2—H2B	119.9	C10—C9—C8	126.8 (3)
C3—C2—H2B	119.9	C11—C9—C8	128.0 (4)
C2—C3—C4	119.5 (4)	O2—C10—C9	108.7 (3)
C2—C3—H3A	120.3	O2—C10—C12	116.3 (4)
C4—C3—H3A	120.3	C9—C10—C12	135.0 (4)
C3—C4—C5	120.4 (3)	N2—C11—C9	112.2 (4)
C3—C4—H4A	119.8	N2—C11—H11A	123.9
C5—C4—H4A	119.8	C9—C11—H11A	123.9
C4—C5—C6	119.5 (3)	C10—C12—H12A	109.5
C4—C5—N1	118.9 (3)	C10—C12—H12B	109.5
C6—C5—N1	121.6 (3)	H12A—C12—H12B	109.5
C1—C6—C5	119.2 (4)	C10—C12—H12C	109.5
C1—C6—C7	119.2 (3)	H12A—C12—H12C	109.5
C5—C6—C7	121.6 (3)	H12B—C12—H12C	109.5
F3—C7—F2	105.6 (3)

C10—O2—N2—C11	−1.6 (4)	C1—C6—C7—F1	−123.8 (4)
C6—C1—C2—C3	−0.7 (7)	C5—C6—C7—F1	52.7 (5)
C1—C2—C3—C4	1.0 (7)	C5—N1—C8—O1	0.1 (5)
C2—C3—C4—C5	0.2 (6)	C5—N1—C8—C9	−179.3 (3)
C3—C4—C5—C6	−1.7 (6)	O1—C8—C9—C10	16.6 (5)
C3—C4—C5—N1	177.1 (4)	N1—C8—C9—C10	−163.9 (3)
C8—N1—C5—C4	−100.9 (4)	O1—C8—C9—C11	−160.1 (3)
C8—N1—C5—C6	77.9 (4)	N1—C8—C9—C11	19.4 (5)
C2—C1—C6—C5	−0.8 (6)	N2—O2—C10—C9	1.4 (4)
C2—C1—C6—C7	175.8 (4)	N2—O2—C10—C12	−179.2 (3)
C4—C5—C6—C1	2.0 (5)	C11—C9—C10—O2	−0.7 (4)
N1—C5—C6—C1	−176.7 (3)	C8—C9—C10—O2	−177.9 (3)
C4—C5—C6—C7	−174.5 (4)	C11—C9—C10—C12	−180.0 (4)
N1—C5—C6—C7	6.7 (5)	C8—C9—C10—C12	2.8 (6)
C1—C6—C7—F3	114.9 (4)	O2—N2—C11—C9	1.2 (4)
C5—C6—C7—F3	−68.6 (5)	C10—C9—C11—N2	−0.4 (4)
C1—C6—C7—F2	−5.7 (6)	C8—C9—C11—N2	176.9 (3)
C5—C6—C7—F2	170.9 (4)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1A···O1ⁱ	0.86	2.13	2.855 (3)	142

Symmetry code: (i) x, −y+1/2, z+1/2.

Experimental details

Crystal data
Chemical formula	C₁₂H₉F₃N₂O₂
M_r	270.21
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	293
a, b, c (Å)	15.839 (3), 8.3260 (17), 9.4250 (19)
β (°)	101.29 (3)
V (Å³)	1218.9 (4)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.13
Crystal size (mm)	0.20 × 0.10 × 0.10

Data collection
Diffractometer	Enref–Nonius CAD-4 diffractometer
Absorption correction	ψ scan (North et al., 1968)
T_min, T_max	0.974, 0.987
No. of measured, independent and observed [I > 2σ(I)] reflections	2193, 2193, 1125
R_int	0.000
(sin θ/λ)_max (Å⁻¹)	0.599

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.062, 0.164, 1.00
No. of reflections	2193
No. of parameters	172
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.19, −0.19

Computer programs: CAD-4 EXPRESS (Enraf–Nonius, 1994), XCAD4 (Harms & Wocadlo,1995), SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1A···O1ⁱ	0.86	2.13	2.855 (3)	142.3

Symmetry code: (i) x, −y+1/2, z+1/2.

Acknowledgements

The work was supported by the Center for Testing and Analysis, Nanjing University, China.

References

Enraf–Nonius (1994). CAD-4 EXPRESS. Enraf–Nonius. Delft, The Netherlands. Google Scholar
Harms, K. & Wocadlo, S. (1995). XCAD4. University of Marburg, Germany. Google Scholar
Huang, W. H., Yang, C. L., Lee, A. R. & Chiu, H. F. (2003). Chem. Pharm. Bull. 51, 313–314. CrossRef PubMed CAS Google Scholar
North, A. C. T., Phillips, D. C. & Mathews, F. S. (1968). Acta Cryst. A24, 351–359. CrossRef IUCr Journals Web of Science Google Scholar
Schattenkirchner, M. (2000). Immunopharmacology, 47, 291–298. Web of Science CrossRef PubMed CAS Google Scholar
Shaw, J. J., Chen, B., Wooley, P., Palfey, B., Lee, A. R., Huang, W. H. & Zeng, D. (2011). Am. J. Biomed. Sci. 3, 218–227. CrossRef CAS Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Wang, D.-C., Huang, L.-C., Liu, Z.-Y., Wei, P. & Ou-yang, P.-K. (2011). Acta Cryst. E67, o3332. Web of Science CSD CrossRef IUCr Journals Google Scholar