5-Methyl­isoxazole-4-carboxylic acid

Wang, D.-C.; Xu, W.; Wu, W.-Y.

doi:10.1107/S1600536809048636

organic compounds

CRYSTALLOGRAPHIC
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ISSN: 2056-9890

Volume 65| Part 12| December 2009| Page o3140

doi:10.1107/S1600536809048636

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5-Methylisoxazole-4-carboxylic acid

De-Cai Wang,^a ^* Wei Xu ^a and Wen-Yuan Wu ^b

^aState Key Laboratory of Materials-Oriented Chemical Engineering, College of Pharmaceutical Sciences, Nanjing University of Technology, Xinmofan Road No. 5 Nanjing, Nanjing 210009, People's Republic of China, and ^bDepartment of Applied Chemistry, College of Science, Nanjing University of Technology, Xinmofan Road No. 5 Nanjing, Nanjing 210009, People's Republic of China
^*Correspondence e-mail: dcwang@njut.edu.cn

(Received 10 October 2009; accepted 16 November 2009; online 21 November 2009)

In the title compound, C₅H₅NO₃, the molecule lies on a crystallographic mirror plane with one half-molecule in the asymmetric unit. An intramolecular C—H⋯O interaction is present. In the crystal, strong intermolecular O—H⋯N hydrogen bonds result in the formation of a linear chain structure along [100], and there are also weak C—H⋯O hydrogen bonds between the chains which help to stabilize the crystal packing.

Related literature

The title compound is an intermediate (Kotchekov et al., 1985 ) for the synthesis of Leflunomide (Ree, 1998 ), an important antirheumatoid arthritis drug. For a related structure, see: Lee et al. (2002 ).

Experimental

Crystal data

C₅H₅NO₃
M_r = 127.10
Orthorhombic, P n m a
a = 7.2540 (15) Å
b = 6.4700 (13) Å
c = 12.273 (3) Å
V = 576.0 (2) Å³
Z = 4
Mo Kα radiation
μ = 0.12 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 = 0.964, T_max = 0.988
1096 measured reflections
574 independent reflections
504 reflections with I > 2σ(I)
R_int = 0.042
3 standard reflections every 200 reflections intensity decay: none

Refinement

R[F² > 2σ(F²)] = 0.040
wR(F²) = 0.098
S = 1.00
574 reflections
63 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.26 e Å⁻³
Δρ_min = −0.16 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯N1ⁱ	0.85	1.95	2.760 (3)	160
C4—H4⋯O2ⁱⁱ	0.93	2.33	3.217 (3)	159
C5—H3⋯O1	0.92 (2)	2.44 (5)	3.032 (4)	126 (5)
Symmetry codes: (i) x-1, y, z; (ii) $[x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+{\script{3\over 2}}]$ .

Data collection: CAD-4 Software (Enraf–Nonius, 1989 ); cell refinement: CAD-4 Software; 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 global, I. DOI: 10.1107/S1600536809048636/fl2281sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536809048636/fl2281Isup2.hkl

checkCIF report

Comment top

The title compound, (I), is a good organic intermediate (Kotchekov et al., 1985) for the synthesis of Leflunomide (Ree, 1998), an important antirheumatoid arthritis drug. Here we report its crystal structure.

In the molecule of (I), (Fig. 1), the bond lengths and angles are within normal ranges. There is a mirror plane through all atoms except for two H atoms of the methyl group which are related by the mirror image - one above and one below the symmetry plane while the third methyly H atom lies in the mirror plane. An intramolecular C—H···O hydrogen bond helps to establish the molecular conformation. The molecule is similar to 3-Methylisoxazole-4-carboxylic acid methyl ester (Lee et al. (2002)).

Strong intermolecular hydrogen bonds are found between the H atom of carboxylic group and the N atom of the isoxazole ring (Table 1), which link the molecules into a one-dimensional supramolecular structure along the a axis. There are also weak C—H···O hydrogen bonds between adjacent two linear structures in the same symmetry plane (Fig. 2), which makes the linear structure two molecules wide.

Related literature top

The title compound is an intermediate (Kotchekov et al., 1985) for the synthesis of Leflunomide (Ree, 1998), an important antirheumatoid arthritis drug. For a related structure, see:: Lee et al. (2002).

Experimental top

A 500 ml solution of hydroxylamine hydrochloride (190 g, 2.7 mol) and sodium acetate trihydrate (370 g, 2.7 mol) was added to another 500 ml ethanol solution containing (E)-ethyl 2- (ethoxymethylene)-3-oxobutanoate. The mixture was stirred for 2 h and kept overnight at 273 K. Then the product of 5-methylisoxazole-4-carboxylate (II) (340–350 g) was extracted by dichloromethane (1200 ml).

(II) was then refluxed together with acetic acid (300 ml), water (300 ml), and concentrated HCl (300 ml) for 10 h, and crude sample of the title compound (260–270 g) was obtained. Pure compound (I) suitable for X-ray diffraction was collected by recrystallization from ethanol.

Computing details top

Data collection: CAD-4 Software (Enraf–Nonius, 1989); cell refinement: CAD-4 Software (Enraf–Nonius, 1989); 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 molecular structure of (I), showing the atom-numbering scheme and displacement ellipsoids at the 30% probability level.
	Fig. 2. A packing diagram of (I). The intermolecular hydrogen bonds are shown as dashed lines.

5-Methylisoxazole-4-carboxylic acid top

Crystal data top

C₅H₅NO₃	F(000) = 264
M_r = 127.10	D_x = 1.466 Mg m⁻³
Orthorhombic, Pnma	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2n	Cell parameters from 25 reflections
a = 7.2540 (15) Å	θ = 9–13°
b = 6.4700 (13) Å	µ = 0.12 mm⁻¹
c = 12.273 (3) Å	T = 293 K
V = 576.0 (2) Å³	Block, colourless
Z = 4	0.30 × 0.20 × 0.10 mm

Data collection top

Enraf–Nonius CAD-4 diffractometer	504 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	R_int = 0.042
Graphite monochromator	θ_max = 25.3°, θ_min = 3.3°
ω/2θ scans	h = −8→8
Absorption correction: ψ scan (North et al., 1968)	k = 0→7
T_min = 0.964, T_max = 0.988	l = 0→14
1096 measured reflections	3 standard reflections every 200 reflections
574 independent reflections	intensity decay: none

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)] = 0.040	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.098	w = 1/[σ²(F_o²) + (0.0214P)² + 0.509P] where P = (F_o² + 2F_c²)/3
S = 1.00	(Δ/σ)_max < 0.001
574 reflections	Δρ_max = 0.26 e Å⁻³
63 parameters	Δρ_min = −0.16 e Å⁻³
0 restraints	Extinction correction: SHELXTL (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.108 (6)

Crystal data top

C₅H₅NO₃	V = 576.0 (2) Å³
M_r = 127.10	Z = 4
Orthorhombic, Pnma	Mo Kα radiation
a = 7.2540 (15) Å	µ = 0.12 mm⁻¹
b = 6.4700 (13) Å	T = 293 K
c = 12.273 (3) Å	0.30 × 0.20 × 0.10 mm

Data collection top

Enraf–Nonius CAD-4 diffractometer	504 reflections with I > 2σ(I)
Absorption correction: ψ scan (North et al., 1968)	R_int = 0.042
T_min = 0.964, T_max = 0.988	3 standard reflections every 200 reflections
1096 measured reflections	intensity decay: none
574 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.040	0 restraints
wR(F²) = 0.098	H atoms treated by a mixture of independent and constrained refinement
S = 1.00	Δρ_max = 0.26 e Å⁻³
574 reflections	Δρ_min = −0.16 e Å⁻³
63 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 > 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
C1	0.5625 (4)	0.2500	0.5646 (2)	0.0402 (7)
C2	0.7524 (3)	0.2500	0.52268 (19)	0.0340 (7)
C3	0.8152 (3)	0.2500	0.4188 (2)	0.0399 (7)
C4	0.9135 (3)	0.2500	0.5867 (2)	0.0396 (7)
H4	0.9130	0.2500	0.6625	0.048*
C5	0.7282 (5)	0.2500	0.3096 (3)	0.0687 (12)
H2	0.770 (4)	0.139 (4)	0.269 (2)	0.139 (15)*
H3	0.601 (3)	0.2500	0.314 (4)	0.131 (19)*
N1	1.0626 (3)	0.2500	0.52849 (19)	0.0442 (7)
O1	0.4365 (2)	0.2500	0.48671 (16)	0.0493 (6)
H1	0.3301	0.2500	0.5157	0.074*
O2	0.5268 (3)	0.2500	0.65992 (16)	0.0684 (8)
O3	1.0006 (2)	0.2500	0.41956 (14)	0.0446 (6)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0255 (14)	0.0539 (16)	0.0412 (15)	0.000	0.0037 (11)	0.000
C2	0.0212 (13)	0.0449 (14)	0.0359 (13)	0.000	−0.0005 (10)	0.000
C3	0.0203 (12)	0.0577 (18)	0.0416 (14)	0.000	0.0015 (11)	0.000
C4	0.0258 (13)	0.0530 (16)	0.0400 (14)	0.000	−0.0027 (11)	0.000
C5	0.0402 (18)	0.130 (4)	0.0357 (17)	0.000	−0.0017 (14)	0.000
N1	0.0224 (11)	0.0600 (16)	0.0503 (14)	0.000	−0.0049 (10)	0.000
O1	0.0183 (9)	0.0770 (15)	0.0525 (12)	0.000	0.0002 (8)	0.000
O2	0.0395 (12)	0.124 (2)	0.0412 (12)	0.000	0.0123 (9)	0.000
O3	0.0213 (10)	0.0677 (13)	0.0448 (11)	0.000	0.0048 (8)	0.000

Geometric parameters (Å, º) top

C1—O2	1.198 (3)	C4—N1	1.296 (3)
C1—O1	1.323 (3)	C4—H4	0.9300
C1—C2	1.470 (3)	C5—H2	0.923 (18)
C2—C3	1.353 (4)	C5—H3	0.92 (2)
C2—C4	1.408 (3)	N1—O3	1.410 (3)
C3—O3	1.345 (3)	O1—H1	0.8500
C3—C5	1.482 (4)

O2—C1—O1	123.8 (3)	N1—C4—C2	112.7 (2)
O2—C1—C2	122.9 (2)	N1—C4—H4	123.7
O1—C1—C2	113.3 (2)	C2—C4—H4	123.7
C3—C2—C4	104.2 (2)	C3—C5—H2	110 (2)
C3—C2—C1	130.2 (2)	C3—C5—H3	112 (3)
C4—C2—C1	125.6 (2)	H2—C5—H3	111 (3)
O3—C3—C2	109.3 (2)	C4—N1—O3	104.8 (2)
O3—C3—C5	115.6 (2)	C1—O1—H1	108.9
C2—C3—C5	135.1 (2)	C3—O3—N1	108.97 (19)

O2—C1—C2—C3	180.0	C1—C2—C3—C5	0.0
O1—C1—C2—C3	0.0	C3—C2—C4—N1	0.0
O2—C1—C2—C4	0.0	C1—C2—C4—N1	180.0
O1—C1—C2—C4	180.0	C2—C4—N1—O3	0.0
C4—C2—C3—O3	0.0	C2—C3—O3—N1	0.0
C1—C2—C3—O3	180.0	C5—C3—O3—N1	180.0
C4—C2—C3—C5	180.0	C4—N1—O3—C3	0.0

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···N1ⁱ	0.85	1.95	2.760 (3)	160
C4—H4···O2ⁱⁱ	0.93	2.33	3.217 (3)	159
C5—H3···O1	0.92 (2)	2.44 (5)	3.032 (4)	126 (5)

Symmetry codes: (i) x−1, y, z; (ii) x+1/2, −y+1/2, −z+3/2.

Experimental details

Crystal data
Chemical formula	C₅H₅NO₃
M_r	127.10
Crystal system, space group	Orthorhombic, Pnma
Temperature (K)	293
a, b, c (Å)	7.2540 (15), 6.4700 (13), 12.273 (3)
V (Å³)	576.0 (2)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.12
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	0.964, 0.988
No. of measured, independent and observed [I > 2σ(I)] reflections	1096, 574, 504
R_int	0.042
(sin θ/λ)_max (Å⁻¹)	0.601

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.040, 0.098, 1.00
No. of reflections	574
No. of parameters	63
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.26, −0.16

Computer programs: CAD-4 Software (Enraf–Nonius, 1989), 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
O1—H1···N1ⁱ	0.85	1.95	2.760 (3)	160
C4—H4···O2ⁱⁱ	0.93	2.33	3.217 (3)	159
C5—H3···O1	0.92 (2)	2.44 (5)	3.032 (4)	126 (5)

Symmetry codes: (i) x−1, y, z; (ii) x+1/2, −y+1/2, −z+3/2.

Acknowledgements

The authors thank the Center of Testing and Analysis, Nanjing University, for support.

References

Enraf–Nonius (1989). CAD-4 Software. Enraf–Nonius, Delft, The Netherlands. Google Scholar
Harms, K. & Wocadlo, S. (1995). XCAD4. University of Marburg, Germany. Google Scholar
Kotchekov, N. K., Khomutova, E. D. & Bazilevskii, M. W. (1985). Zh. Ohshch. Khim. 28, 2736–2745. Google Scholar
Lee, C. K. Y., Easton, C. J., Gebara-Coghlan, M., Random, L., Scott, A. P., Simpson, G. W. & Willis, A. C. (2002). J. Chem. Soc. Perkin Trans. 2, p. 2031–2038. CrossRef 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
Ree, N. N. (1998). Drugs Future, 23, 827–837. Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar