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

Abstract

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,

• a = 15.839 (3) Å

• b = 8.3260 (17) Å

• c = 9.4250 (19) Å

• β = 101.29 (3)°

• V = 1218.9 (4) ų

• 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[F ² > 2σ(F ²)] = 0.062

• wR(F ²) = 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

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.

Supplementary Material

Supplementary material file. DOI: 10.1107/S1600536812016467/xu5516Isup3.cml

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
N1—H1A⋯O1i	0.86	2.13	2.855 (3)	142

Symmetry code: (i) .

supplementary crystallographic information

Comment

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).

Experimental

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.

Refinement

H atoms were placed at calculated positions and were treated as riding on the parent C or N atoms with C—H = 0.96 (methyl), 0.97 (methylene) and N—H = 0.86 Å, U_iso(H) = 1.2 or 1.5 U_eq(C,N).

Figures

Fig. 1.

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

Crystal data

C12H9F3N2O2	F(000) = 552
Mr = 270.21	Dx = 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

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

Refinement

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(Fo2) + (0.068P)2] where P = (Fo2 + 2Fc2)/3
2193 reflections	(Δ/σ)max < 0.001
172 parameters	Δρmax = 0.19 e Å−3
0 restraints	Δρmin = −0.19 e Å−3

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
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 (Ų)

	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)

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)

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.