5-Methyl-N-(1,3-thia­zol-2-yl)isoxazole-4-carboxamide

Abstract

In the title compound, C₈H₇N₃O₂S, the dihedral angle between the thia­zol and isoxazole rings is 34.08 (13)°. In the crystal, the mol­ecules are linked by pairs of N—H⋯N hydrogen bonds, forming inversion dimers, and C—H⋯O inter­actions, resulting in chains along the b-axis direction.

Related literature  

For background to isoxazole-containing drugs, see: Shaw et al. (2011 ▶); Schattenkirchner (2000 ▶); Huang et al. (2003 ▶). For the crystal structure of a related compound, see: Wang et al. (2011 ▶).

Experimental  

Crystal data  

• C₈H₇N₃O₂S

• M _r = 209.23

• Monoclinic,

• a = 8.8460 (18) Å

• b = 10.742 (2) Å

• c = 10.024 (2) Å

• β = 107.27 (3)°

• V = 909.6 (3) ų

• Z = 4

• Mo Kα radiation

• μ = 0.33 mm⁻¹

• T = 293 K

• 0.30 × 0.20 × 0.10 mm

Data collection  

• Enraf–Nonius CAD-4 diffractometer

• Absorption correction: ψ scan (North et al., 1968 ▶) T _min = 0.907, T _max = 0.968

• 3462 measured reflections

• 1676 independent reflections

• 1298 reflections with I > 2σ(I)

• R _int = 0.060

• 3 standard reflections every 200 reflections intensity decay: 1%

Refinement  

• R[F ² > 2σ(F ²)] = 0.051

• wR(F ²) = 0.152

• S = 1.00

• 1676 reflections

• 128 parameters

• H-atom parameters constrained

• Δρ_max = 0.38 e Å⁻³

• Δρ_min = −0.34 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: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: PLATON (Spek, 2009 ▶).

Supplementary Material

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
N2—H2A⋯N1i	0.86	2.14	2.970 (3)	162
C6—H6A⋯O1ii	0.93	2.36	3.287 (4)	171

Symmetry codes: (i) ; (ii) .

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 which exhibit potent immunomodulating effect (Huang et al., 2003). In our previous work, some anolog has been sucessfully sythesized (Wang et al., 2011). A new leflunomide analog, N-5-methyl-N-(thiazol-2-yl)isoxazole-4-carboxamide, was synthesized in our laboratory as a novel and potent immunomodulating drug. In this paper we report its crystal structure.

The bond distances and angles in the title compound (Fig. 1) agree very well with the corresponding bond distances and angles reported in a closely related compound (Wang et al., 2011). The dihedral angle between the C1/C2/N1/C3/S thiazol ring and the C5/C6/N3/O2/C7 isoxazole ring is 34.08 (13) °. In the crystal, the molecules are linked by N—H···N hydrogen bonds forming diamers about inversion centers and C—H···O hydrogen bonding interactions resulting in chains lying along the b-axis (Tab. 1 & Fig. 2).

Experimental

A solution of 5-methylisoxazole-4-carboxylic acid chloride (7.3 g, 0.05 mol) in acetonitrile (20 ml) was added dropwise, while stirring, to thiazol-2-amine (12.9 g, 0.10 mol) dissolved in acetonitrile (150 ml), at room temperature. After stirring for 40 more minutes, the precipitated 5-methyl-N-(thiazol-2-yl)isoxazole-4-carboxamide was filtered off and washed with 100 ml portions of acetonitrile, and the combined filtrates were concentrated under reduced pressure yielded the title compouind as yellow crytalline product(Yield: 8.2 g; 60%). Crystals suitable for X-ray diffraction were obtained by slow evaporation of toluene solution.

Refinement

All H atoms were placed geometrically at the distances of 0.93–0.96 Å for C—H and 0.86 Å for N—H and included in the refinement in riding motion approximation with U_iso(H) = 1.2 or 1.5U_eq of the carrier atom.

Figures

Fig. 1.

The molecular structure of the title compound with the atom numbering scheme. Displacement ellipsoids are drawn at the 35% probability level. H atoms are presented as small spheres of arbitrary radius.

Fig. 2.

A view of the N—H···N and C—H···O hydrogen bonds (dotted lines) in the crystal structure of the title compound. H atoms non-participating in hydrogen-bonding were omitted for clarity.

Crystal data

C8H7N3O2S	F(000) = 432
Mr = 209.23	Dx = 1.528 Mg m−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 25 reflections
a = 8.8460 (18) Å	θ = 10–13°
b = 10.742 (2) Å	µ = 0.33 mm−1
c = 10.024 (2) Å	T = 293 K
β = 107.27 (3)°	Block, yellow
V = 909.6 (3) Å3	0.30 × 0.20 × 0.10 mm
Z = 4

Data collection

Enraf–Nonius CAD-4 diffractometer	1298 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.060
Graphite monochromator	θmax = 25.4°, θmin = 2.4°
ω/2θ scans	h = 0→10
Absorption correction: ψ scan (North et al., 1968)	k = −12→12
Tmin = 0.907, Tmax = 0.968	l = −12→11
3462 measured reflections	3 standard reflections every 200 reflections
1676 independent reflections	intensity decay: 1%

Refinement

Refinement on F2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.051	H-atom parameters constrained
wR(F2) = 0.152	w = 1/[σ2(Fo2) + (0.1P)2 + 0.180P] where P = (Fo2 + 2Fc2)/3
S = 1.00	(Δ/σ)max < 0.001
1676 reflections	Δρmax = 0.38 e Å−3
128 parameters	Δρmin = −0.34 e Å−3
0 restraints	Extinction correction: SHELXL, Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.021 (5)

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 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 (Ų)

	x	y	z	Uiso*/Ueq
S	0.27245 (9)	0.30807 (7)	0.46506 (9)	0.0578 (3)
O1	0.5024 (2)	0.36916 (17)	0.3546 (2)	0.0517 (6)
N1	0.3255 (3)	0.0745 (2)	0.5154 (2)	0.0463 (6)
C1	0.1512 (4)	0.2266 (3)	0.5378 (4)	0.0629 (9)
H1A	0.0654	0.2605	0.5607	0.075*
O2	0.8730 (2)	0.2660 (2)	0.1941 (2)	0.0532 (6)
N2	0.5011 (2)	0.16438 (19)	0.4088 (2)	0.0390 (5)
H2A	0.5475	0.0938	0.4106	0.047*
C2	0.1958 (3)	0.1078 (3)	0.5573 (3)	0.0558 (8)
H2B	0.1426	0.0507	0.5969	0.067*
N3	0.8148 (3)	0.1439 (3)	0.1552 (3)	0.0569 (7)
C3	0.3761 (3)	0.1719 (2)	0.4640 (3)	0.0371 (6)
C4	0.5547 (3)	0.2644 (2)	0.3512 (3)	0.0358 (5)
C5	0.6762 (3)	0.2373 (2)	0.2825 (2)	0.0349 (5)
C6	0.6993 (3)	0.1306 (3)	0.2088 (3)	0.0459 (6)
H6A	0.6384	0.0587	0.1998	0.055*
C7	0.7873 (3)	0.3192 (2)	0.2679 (3)	0.0395 (6)
C8	0.8309 (4)	0.4479 (3)	0.3178 (3)	0.0546 (7)
H8A	0.9169	0.4761	0.2855	0.082*
H8B	0.8626	0.4493	0.4180	0.082*
H8C	0.7413	0.5018	0.2821	0.082*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
S	0.0540 (5)	0.0548 (5)	0.0796 (6)	0.0179 (3)	0.0427 (4)	0.0136 (4)
O1	0.0510 (12)	0.0391 (10)	0.0740 (14)	0.0077 (8)	0.0325 (10)	0.0069 (9)
N1	0.0408 (12)	0.0511 (13)	0.0544 (13)	0.0009 (10)	0.0255 (10)	0.0066 (11)
C1	0.0458 (17)	0.081 (2)	0.076 (2)	0.0194 (16)	0.0384 (16)	0.0196 (18)
O2	0.0447 (11)	0.0687 (13)	0.0561 (12)	−0.0065 (9)	0.0302 (9)	−0.0037 (10)
N2	0.0395 (11)	0.0359 (10)	0.0499 (12)	0.0032 (9)	0.0260 (10)	0.0014 (9)
C2	0.0403 (15)	0.076 (2)	0.0595 (17)	0.0020 (14)	0.0282 (13)	0.0169 (15)
N3	0.0598 (15)	0.0630 (15)	0.0570 (15)	0.0005 (13)	0.0312 (12)	−0.0131 (12)
C3	0.0320 (12)	0.0434 (14)	0.0378 (13)	0.0024 (10)	0.0133 (10)	−0.0014 (10)
C4	0.0314 (12)	0.0372 (12)	0.0410 (13)	0.0014 (10)	0.0144 (10)	−0.0008 (10)
C5	0.0329 (12)	0.0382 (13)	0.0356 (12)	0.0004 (10)	0.0132 (10)	0.0014 (10)
C6	0.0498 (15)	0.0436 (14)	0.0482 (15)	−0.0031 (12)	0.0207 (12)	−0.0060 (12)
C7	0.0358 (13)	0.0501 (15)	0.0351 (13)	0.0006 (11)	0.0143 (11)	0.0039 (10)
C8	0.0531 (17)	0.0512 (16)	0.0616 (18)	−0.0123 (13)	0.0203 (14)	0.0034 (14)

Geometric parameters (Å, º)

S—C1	1.707 (3)	N2—H2A	0.8600
S—C3	1.729 (2)	C2—H2B	0.9300
O1—C4	1.222 (3)	N3—C6	1.296 (4)
N1—C3	1.303 (3)	C4—C5	1.468 (3)
N1—C2	1.381 (3)	C5—C7	1.358 (4)
C1—C2	1.332 (5)	C5—C6	1.411 (4)
C1—H1A	0.9300	C6—H6A	0.9300
O2—C7	1.334 (3)	C7—C8	1.483 (4)
O2—N3	1.420 (3)	C8—H8A	0.9600
N2—C4	1.369 (3)	C8—H8B	0.9600
N2—C3	1.377 (3)	C8—H8C	0.9600
C1—S—C3	88.31 (14)	O1—C4—C5	122.1 (2)
C3—N1—C2	109.1 (2)	N2—C4—C5	115.9 (2)
C2—C1—S	111.0 (2)	C7—C5—C6	104.4 (2)
C2—C1—H1A	124.5	C7—C5—C4	125.2 (2)
S—C1—H1A	124.5	C6—C5—C4	130.3 (2)
C7—O2—N3	109.2 (2)	N3—C6—C5	112.4 (3)
C4—N2—C3	122.9 (2)	N3—C6—H6A	123.8
C4—N2—H2A	118.5	C5—C6—H6A	123.8
C3—N2—H2A	118.5	O2—C7—C5	109.3 (2)
C1—C2—N1	116.1 (3)	O2—C7—C8	117.0 (2)
C1—C2—H2B	122.0	C5—C7—C8	133.7 (3)
N1—C2—H2B	122.0	C7—C8—H8A	109.5
C6—N3—O2	104.7 (2)	C7—C8—H8B	109.5
N1—C3—N2	121.6 (2)	H8A—C8—H8B	109.5
N1—C3—S	115.55 (19)	C7—C8—H8C	109.5
N2—C3—S	122.86 (19)	H8A—C8—H8C	109.5
O1—C4—N2	122.0 (2)	H8B—C8—H8C	109.5
C3—S—C1—C2	0.8 (3)	N2—C4—C5—C7	−152.8 (2)
S—C1—C2—N1	−0.6 (4)	O1—C4—C5—C6	−145.8 (3)
C3—N1—C2—C1	−0.1 (4)	N2—C4—C5—C6	32.8 (4)
C7—O2—N3—C6	−0.6 (3)	O2—N3—C6—C5	−0.1 (3)
C2—N1—C3—N2	−177.4 (2)	C7—C5—C6—N3	0.8 (3)
C2—N1—C3—S	0.7 (3)	C4—C5—C6—N3	176.1 (3)
C4—N2—C3—N1	178.5 (2)	N3—O2—C7—C5	1.2 (3)
C4—N2—C3—S	0.6 (3)	N3—O2—C7—C8	−179.9 (2)
C1—S—C3—N1	−0.9 (2)	C6—C5—C7—O2	−1.2 (3)
C1—S—C3—N2	177.2 (2)	C4—C5—C7—O2	−176.7 (2)
C3—N2—C4—O1	5.7 (4)	C6—C5—C7—C8	−179.8 (3)
C3—N2—C4—C5	−173.0 (2)	C4—C5—C7—C8	4.6 (5)
O1—C4—C5—C7	28.5 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2A···N1i	0.86	2.14	2.970 (3)	162
C6—H6A···O1ii	0.93	2.36	3.287 (4)	171

Symmetry codes: (i) −x+1, −y, −z+1; (ii) −x+1, y−1/2, −z+1/2.