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

Wang, D.-C.; Sun, X.; Su, P.; Ou-Yang, P.-K.

doi:10.1107/S1600536813012105

organic compounds

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 69| Part 6| June 2013| Page o853

doi:10.1107/S1600536813012105

Open

access

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

De-Cai Wang,^a ^* Xiang Sun,^a Peng Su ^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: dcwang@njut.edu.cn

(Received 22 April 2013; accepted 3 May 2013; online 11 May 2013)

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, P 2₁ /c
a = 8.8460 (18) Å
b = 10.742 (2) Å
c = 10.024 (2) Å
β = 107.27 (3)°
V = 909.6 (3) Å³
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[F² > 2σ(F²)] = 0.051
wR(F²) = 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

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) -x+1, -y, -z+1; (ii) $[-x+1, y-{\script{1\over 2}}, -z+{\script{1\over 2}}]$ .

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: 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 ).

Supporting information

Crystal structure: contains datablocks I, New_Global_Publ_Block. DOI: 10.1107/S1600536813012105/pv2631sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536813012105/pv2631Isup2.hkl

Supporting information file. DOI: 10.1107/S1600536813012105/pv2631Isup3.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 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).

Related literature top

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 top

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.

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: 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).

Figures top

	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.

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

Crystal data top

C₈H₇N₃O₂S	F(000) = 432
M_r = 209.23	D_x = 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 top

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

Refinement top

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(F_o²) + (0.1P)² + 0.180P] where P = (F_o² + 2F_c²)/3
S = 1.00	(Δ/σ)_max < 0.001
1676 reflections	Δρ_max = 0.38 e Å⁻³
128 parameters	Δρ_min = −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)

Crystal data top

C₈H₇N₃O₂S	V = 909.6 (3) Å³
M_r = 209.23	Z = 4
Monoclinic, P2₁/c	Mo Kα radiation
a = 8.8460 (18) Å	µ = 0.33 mm⁻¹
b = 10.742 (2) Å	T = 293 K
c = 10.024 (2) Å	0.30 × 0.20 × 0.10 mm
β = 107.27 (3)°

Data collection top

Enraf–Nonius CAD-4 diffractometer	1298 reflections with I > 2σ(I)
Absorption correction: ψ scan (North et al., 1968)	R_int = 0.060
T_min = 0.907, T_max = 0.968	3 standard reflections every 200 reflections
3462 measured reflections	intensity decay: 1%
1676 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.051	0 restraints
wR(F²) = 0.152	H-atom parameters constrained
S = 1.00	Δρ_max = 0.38 e Å⁻³
1676 reflections	Δρ_min = −0.34 e Å⁻³
128 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
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 (Å²) top

	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) top

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) top

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.

Experimental details

Crystal data
Chemical formula	C₈H₇N₃O₂S
M_r	209.23
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	293
a, b, c (Å)	8.8460 (18), 10.742 (2), 10.024 (2)
β (°)	107.27 (3)
V (Å³)	909.6 (3)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.33
Crystal size (mm)	0.30 × 0.20 × 0.10

Data collection
Diffractometer	Enraf–Nonius CAD-4 diffractometer
Absorption correction	ψ scan (North et al., 1968)
T_min, T_max	0.907, 0.968
No. of measured, independent and observed [I > 2σ(I)] reflections	3462, 1676, 1298
R_int	0.060
(sin θ/λ)_max (Å⁻¹)	0.604

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.051, 0.152, 1.00
No. of reflections	1676
No. of parameters	128
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.38, −0.34

Computer programs: CAD-4 EXPRESS (Enraf–Nonius,1994), XCAD4 (Harms & Wocadlo,1995), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008), PLATON (Spek, 2009).

Hydrogen-bond geometry (Å, º) top

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.

References

Enraf–Nonius (1994). CAD-4 Software. 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
Spek, A. L. (2009). Acta Cryst. D65, 148–155. Web of Science CrossRef CAS IUCr Journals Google Scholar
Wang, D.-C., Huang, L.-C., Liu, H.-Q., Peng, Y.-R. & Song, J.-S. (2011). Acta Cryst. E67, o3207. Web of Science CSD CrossRef IUCr Journals Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 69| Part 6| June 2013| Page o853

doi:10.1107/S1600536813012105

Open

access