organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

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ISSN: 2056-9890

5-Methyl­isoxazole-4-carboxylic acid

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[Kotchekov, N. K., Khomutova, E. D. & Bazilevskii, M. W. (1985). Zh. Ohshch. Khim. 28, 2736-2745.]) for the synthesis of Leflunomide (Ree, 1998[Ree, N. N. (1998). Drugs Future, 23, 827-837.]), an important anti­rheumatoid arthritis drug. For a related structure, see: Lee et al. (2002[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.]).

[Scheme 1]

Experimental

Crystal data
  • C5H5NO3

  • Mr = 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[North, A. C. T., Phillips, D. C. & Mathews, F. S. (1968). Acta Cryst. A24, 351-359.]) Tmin = 0.964, Tmax = 0.988

  • 1096 measured reflections

  • 574 independent reflections

  • 504 reflections with I > 2σ(I)

  • Rint = 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

  • Δρmax = 0.26 e Å−3

  • Δρmin = −0.16 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA 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[Enraf-Nonius (1989). CAD-4 Software. Enraf-Nonius, Delft, The Netherlands.]); cell refinement: CAD-4 Software; data reduction: XCAD4 (Harms & Wocadlo, 1995[Harms, K. & Wocadlo, S. (1995). XCAD4. University of Marburg, Germany.]); program(s) used to solve structure: SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Supporting information


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.

Refinement top

H atoms of methyl group were located in a difference map and refined freely. Then the other H atoms were positioned geometrically [O—H = 0.85 Å and C—H = 0.93 Å for aromatic H atoms] and constrained to ride on their parent atoms, with Uiso(H) = xUeq(C,O), wherex = 1.2 for aromatic and x = 1.5 for hydroxyl H atoms.

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
[Figure 1] Fig. 1. The molecular structure of (I), showing the atom-numbering scheme and displacement ellipsoids at the 30% probability level.
[Figure 2] 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
C5H5NO3F(000) = 264
Mr = 127.10Dx = 1.466 Mg m3
Orthorhombic, PnmaMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2nCell parameters from 25 reflections
a = 7.2540 (15) Åθ = 9–13°
b = 6.4700 (13) ŵ = 0.12 mm1
c = 12.273 (3) ÅT = 293 K
V = 576.0 (2) Å3Block, colourless
Z = 40.30 × 0.20 × 0.10 mm
Data collection top
Enraf–Nonius CAD-4
diffractometer
504 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.042
Graphite monochromatorθmax = 25.3°, θmin = 3.3°
ω/2θ scansh = 88
Absorption correction: ψ scan
(North et al., 1968)
k = 07
Tmin = 0.964, Tmax = 0.988l = 014
1096 measured reflections3 standard reflections every 200 reflections
574 independent reflections intensity decay: none
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.040H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.098 w = 1/[σ2(Fo2) + (0.0214P)2 + 0.509P]
where P = (Fo2 + 2Fc2)/3
S = 1.00(Δ/σ)max < 0.001
574 reflectionsΔρmax = 0.26 e Å3
63 parametersΔρmin = 0.16 e Å3
0 restraintsExtinction correction: SHELXTL (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.108 (6)
Crystal data top
C5H5NO3V = 576.0 (2) Å3
Mr = 127.10Z = 4
Orthorhombic, PnmaMo Kα radiation
a = 7.2540 (15) ŵ = 0.12 mm1
b = 6.4700 (13) ÅT = 293 K
c = 12.273 (3) Å0.30 × 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)
Rint = 0.042
Tmin = 0.964, Tmax = 0.9883 standard reflections every 200 reflections
1096 measured reflections intensity decay: none
574 independent reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0400 restraints
wR(F2) = 0.098H atoms treated by a mixture of independent and constrained refinement
S = 1.00Δρmax = 0.26 e Å3
574 reflectionsΔρmin = 0.16 e Å3
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
xyzUiso*/Ueq
C10.5625 (4)0.25000.5646 (2)0.0402 (7)
C20.7524 (3)0.25000.52268 (19)0.0340 (7)
C30.8152 (3)0.25000.4188 (2)0.0399 (7)
C40.9135 (3)0.25000.5867 (2)0.0396 (7)
H40.91300.25000.66250.048*
C50.7282 (5)0.25000.3096 (3)0.0687 (12)
H20.770 (4)0.139 (4)0.269 (2)0.139 (15)*
H30.601 (3)0.25000.314 (4)0.131 (19)*
N11.0626 (3)0.25000.52849 (19)0.0442 (7)
O10.4365 (2)0.25000.48671 (16)0.0493 (6)
H10.33010.25000.51570.074*
O20.5268 (3)0.25000.65992 (16)0.0684 (8)
O31.0006 (2)0.25000.41956 (14)0.0446 (6)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0255 (14)0.0539 (16)0.0412 (15)0.0000.0037 (11)0.000
C20.0212 (13)0.0449 (14)0.0359 (13)0.0000.0005 (10)0.000
C30.0203 (12)0.0577 (18)0.0416 (14)0.0000.0015 (11)0.000
C40.0258 (13)0.0530 (16)0.0400 (14)0.0000.0027 (11)0.000
C50.0402 (18)0.130 (4)0.0357 (17)0.0000.0017 (14)0.000
N10.0224 (11)0.0600 (16)0.0503 (14)0.0000.0049 (10)0.000
O10.0183 (9)0.0770 (15)0.0525 (12)0.0000.0002 (8)0.000
O20.0395 (12)0.124 (2)0.0412 (12)0.0000.0123 (9)0.000
O30.0213 (10)0.0677 (13)0.0448 (11)0.0000.0048 (8)0.000
Geometric parameters (Å, º) top
C1—O21.198 (3)C4—N11.296 (3)
C1—O11.323 (3)C4—H40.9300
C1—C21.470 (3)C5—H20.923 (18)
C2—C31.353 (4)C5—H30.92 (2)
C2—C41.408 (3)N1—O31.410 (3)
C3—O31.345 (3)O1—H10.8500
C3—C51.482 (4)
O2—C1—O1123.8 (3)N1—C4—C2112.7 (2)
O2—C1—C2122.9 (2)N1—C4—H4123.7
O1—C1—C2113.3 (2)C2—C4—H4123.7
C3—C2—C4104.2 (2)C3—C5—H2110 (2)
C3—C2—C1130.2 (2)C3—C5—H3112 (3)
C4—C2—C1125.6 (2)H2—C5—H3111 (3)
O3—C3—C2109.3 (2)C4—N1—O3104.8 (2)
O3—C3—C5115.6 (2)C1—O1—H1108.9
C2—C3—C5135.1 (2)C3—O3—N1108.97 (19)
O2—C1—C2—C3180.0C1—C2—C3—C50.0
O1—C1—C2—C30.0C3—C2—C4—N10.0
O2—C1—C2—C40.0C1—C2—C4—N1180.0
O1—C1—C2—C4180.0C2—C4—N1—O30.0
C4—C2—C3—O30.0C2—C3—O3—N10.0
C1—C2—C3—O3180.0C5—C3—O3—N1180.0
C4—C2—C3—C5180.0C4—N1—O3—C30.0
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1···N1i0.851.952.760 (3)160
C4—H4···O2ii0.932.333.217 (3)159
C5—H3···O10.92 (2)2.44 (5)3.032 (4)126 (5)
Symmetry codes: (i) x1, y, z; (ii) x+1/2, y+1/2, z+3/2.

Experimental details

Crystal data
Chemical formulaC5H5NO3
Mr127.10
Crystal system, space groupOrthorhombic, Pnma
Temperature (K)293
a, b, c (Å)7.2540 (15), 6.4700 (13), 12.273 (3)
V3)576.0 (2)
Z4
Radiation typeMo Kα
µ (mm1)0.12
Crystal size (mm)0.30 × 0.20 × 0.10
Data collection
DiffractometerEnraf–Nonius CAD-4
diffractometer
Absorption correctionψ scan
(North et al., 1968)
Tmin, Tmax0.964, 0.988
No. of measured, independent and
observed [I > 2σ(I)] reflections
1096, 574, 504
Rint0.042
(sin θ/λ)max1)0.601
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.040, 0.098, 1.00
No. of reflections574
No. of parameters63
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)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···AD—HH···AD···AD—H···A
O1—H1···N1i0.851.952.760 (3)160
C4—H4···O2ii0.932.333.217 (3)159
C5—H3···O10.92 (2)2.44 (5)3.032 (4)126 (5)
Symmetry codes: (i) x1, 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

First citationEnraf–Nonius (1989). CAD-4 Software. Enraf–Nonius, Delft, The Netherlands.  Google Scholar
First citationHarms, K. & Wocadlo, S. (1995). XCAD4. University of Marburg, Germany.  Google Scholar
First citationKotchekov, N. K., Khomutova, E. D. & Bazilevskii, M. W. (1985). Zh. Ohshch. Khim. 28, 2736–2745.  Google Scholar
First citationLee, 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
First citationNorth, A. C. T., Phillips, D. C. & Mathews, F. S. (1968). Acta Cryst. A24, 351–359.  CrossRef IUCr Journals Web of Science Google Scholar
First citationRee, N. N. (1998). Drugs Future, 23, 827–837.  Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar

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ISSN: 2056-9890
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