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Acta Crystallogr Sect E Struct Rep Online. 2010 November 1; 66(Pt 11): o2955.
Published online 2010 October 30. doi:  10.1107/S1600536810042753
PMCID: PMC3009102

N-(2-Chloro­pyrimidin-4-yl)-N,2-di­methyl-2H-indazol-6-amine

Abstract

In the title compound, C13H12ClN5, which is a derivative of the anti­tumor agent pazopanib {systematic name: 5-[[4-[(2,3-di­methyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzolsulfonamide}, the indazole and pyrim­idine fragments form a dihedral angle of 62.63 (5)°. In the crystal, pairs of mol­ecules related by twofold rotational symmetry are linked into dimers through π–π inter­actions between the indazole ring systems [centroid–centroid distance = 3.720 (2) Å]. Weak inter­molecular C—H(...)N hydrogen bonds further assemble these dimers into columns propagated in [001].

Related literature

For background to the pharmacokinetics and clinical studies of the anti­tumor agent pazopanib, see: Limvorasak & Posadas (2009 [triangle]); Sloan & Scheinfeld 2008 [triangle]; Sonpavde et al. (2007 [triangle]). For the synthesis of pazopanib, see: Sorbera et al. (2006 [triangle]).

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Object name is e-66-o2955-scheme1.jpg

Experimental

Crystal data

  • C13H12ClN5
  • M r = 273.73
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-66-o2955-efi1.jpg
  • a = 21.432 (4) Å
  • b = 9.836 (2) Å
  • c = 12.542 (3) Å
  • β = 90.25 (3)°
  • V = 2644.1 (9) Å3
  • Z = 8
  • Mo Kα radiation
  • μ = 0.28 mm−1
  • T = 113 K
  • 0.20 × 0.18 × 0.12 mm

Data collection

  • Rigaku Saturn CCD area-detector diffractometer
  • Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2005 [triangle]) T min = 0.946, T max = 0.967
  • 10576 measured reflections
  • 2323 independent reflections
  • 1982 reflections with I > 2σ(I)
  • R int = 0.043

Refinement

  • R[F 2 > 2σ(F 2)] = 0.036
  • wR(F 2) = 0.100
  • S = 1.01
  • 2323 reflections
  • 175 parameters
  • H-atom parameters constrained
  • Δρmax = 0.21 e Å−3
  • Δρmin = −0.25 e Å−3

Data collection: CrystalClear (Rigaku/MSC, 2005 [triangle]); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL (Sheldrick, 2008 [triangle]); software used to prepare material for publication: SHELXTL.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810042753/cv2775sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810042753/cv2775Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

The authors thank Mr Hai-Bin Song of Nankai University and Mr Shuai Mu of Tianjin University for their helpful suggestions.

supplementary crystallographic information

Comment

Pazopanib is an oral, second-generation multi-targeted tyrosine kinase inhibitor that targets VEGFR, platelet-derived growth factor receptor and c-kit, key proteins responsible for tumor growth and survival (Limvorasak et al., 2009; Sloan et al., 2008; Sonpavde et al., 2007). The crystal structure of the title compound (I), a derivative of pazopanib, synthesized through the transformation of pazopanib (Sorbera et al., 2006), is reported here.

In (I) (Fig. 1), the indazole and pyrimidine fragments form a dihedral angle of 62.63 (5)°. In the crystal structure, The π–π contacts between the indazole systems from the adjacent molecules (Table 1) link them into dimers. Weak intermolecular C—H···N hydrogen bonds (Table 2) link further the dimers into columns propagated in direction [001].

Experimental

To a stirred solution of the N-(2-chloropyrimidin-4-yl)-2 -methyl-2H-indazol-6-amine 5 g (0.02 mol) in DMF (30 ml) was added Cs2CO3 9.8 g (0.03 mol) and iodomethane 2.5 ml (5.7 g, 0.04 mol) at room temperature. The mixture was stirred for 5 h. The reaction mixture was then poured into an ice-water bath, and the precipitate was collected via filtration and washed with water. The precipitate was air-dried to get off-white solid as crude product. The solid was dissolved in ethyl acetate 30 ml at 278 k, then white crystals were generated slowly.

Refinement

C-bound H atoms were geometrically positioned (C—H 0.95–0.98 Å), and refined as riding with Uiso = 1.2-1.5 Ueq(C).

Figures

Fig. 1.
The molecular structure of (I). Displacement ellipsoids are drawn at the 50% probability level.

Crystal data

C13H12ClN5F(000) = 1136
Mr = 273.73Dx = 1.375 Mg m3
Monoclinic, C2/cMo Kα radiation, λ = 0.71073 Å
a = 21.432 (4) ÅCell parameters from 4286 reflections
b = 9.836 (2) Åθ = 1.9–27.9°
c = 12.542 (3) ŵ = 0.28 mm1
β = 90.25 (3)°T = 113 K
V = 2644.1 (9) Å3Block, white
Z = 80.20 × 0.18 × 0.12 mm

Data collection

Rigaku Saturn CCD area-detector diffractometer2323 independent reflections
Radiation source: rotating anode1982 reflections with I > 2σ(I)
confocalRint = 0.043
Detector resolution: 7.31 pixels mm-1θmax = 25.0°, θmin = 1.9°
ω and [var phi] scansh = −25→25
Absorption correction: multi-scan (CrystalClear; Rigaku/MSC, 2005)k = −11→11
Tmin = 0.946, Tmax = 0.967l = −14→14
10576 measured reflections

Refinement

Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.036H-atom parameters constrained
wR(F2) = 0.100w = 1/[σ2(Fo2) + (0.070P)2] where P = (Fo2 + 2Fc2)/3
S = 1.01(Δ/σ)max = 0.001
2323 reflectionsΔρmax = 0.21 e Å3
175 parametersΔρmin = −0.25 e Å3
0 restraintsExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.0191 (14)

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 (Å2)

xyzUiso*/Ueq
Cl10.227613 (19)0.06867 (4)0.79285 (3)0.0308 (2)
N10.13815 (6)0.18363 (13)0.68576 (10)0.0268 (4)
N20.18239 (6)0.30697 (12)0.83256 (10)0.0206 (3)
N30.14793 (6)0.52060 (13)0.88097 (10)0.0206 (3)
N4−0.06548 (6)0.69175 (13)0.92048 (10)0.0223 (3)
N5−0.08472 (6)0.82333 (13)0.91397 (10)0.0218 (3)
C10.17633 (7)0.20335 (15)0.76669 (12)0.0211 (4)
C20.10043 (8)0.29266 (17)0.66821 (13)0.0284 (4)
H20.07200.28800.61010.034*
C30.10066 (8)0.40761 (16)0.72803 (12)0.0235 (4)
H30.07360.48150.71240.028*
C40.14298 (7)0.41252 (15)0.81461 (12)0.0189 (4)
C50.19380 (7)0.52028 (18)0.96815 (13)0.0295 (4)
H5A0.17760.46711.02800.044*
H5B0.20160.61390.99150.044*
H5C0.23290.47970.94320.044*
C60.10170 (7)0.62570 (16)0.88222 (11)0.0194 (4)
C70.12160 (7)0.76193 (16)0.86613 (13)0.0252 (4)
H70.16440.78010.85290.030*
C80.07992 (7)0.86753 (17)0.86940 (13)0.0267 (4)
H80.09350.95850.85920.032*
C90.01641 (7)0.83811 (15)0.88831 (12)0.0209 (4)
C10−0.00297 (7)0.70070 (15)0.90426 (11)0.0188 (4)
C110.04067 (7)0.59365 (15)0.90219 (12)0.0195 (4)
H110.02820.50230.91420.023*
C12−0.03903 (7)0.91238 (17)0.89500 (12)0.0246 (4)
H12−0.04341.00800.88750.030*
C13−0.15098 (7)0.85326 (18)0.92276 (13)0.0286 (4)
H13A−0.15730.95190.92010.043*
H13B−0.16670.81790.99060.043*
H13C−0.17350.81020.86360.043*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
Cl10.0287 (3)0.0271 (3)0.0365 (3)0.00976 (17)−0.00266 (19)−0.00407 (17)
N10.0329 (8)0.0226 (8)0.0250 (8)0.0042 (6)−0.0049 (6)−0.0020 (6)
N20.0177 (7)0.0222 (8)0.0220 (7)0.0014 (6)0.0025 (5)0.0001 (6)
N30.0176 (7)0.0228 (7)0.0214 (7)0.0028 (6)−0.0009 (5)−0.0045 (6)
N40.0207 (7)0.0194 (8)0.0267 (8)0.0035 (6)0.0006 (6)0.0018 (5)
N50.0223 (7)0.0204 (7)0.0226 (7)0.0049 (6)−0.0011 (5)0.0004 (6)
C10.0205 (8)0.0200 (9)0.0228 (9)0.0009 (7)0.0050 (7)0.0024 (7)
C20.0344 (9)0.0284 (10)0.0225 (9)0.0018 (8)−0.0080 (7)0.0005 (7)
C30.0274 (9)0.0220 (9)0.0210 (8)0.0041 (7)−0.0025 (7)0.0036 (7)
C40.0181 (8)0.0203 (9)0.0184 (8)−0.0010 (6)0.0052 (6)0.0028 (6)
C50.0229 (9)0.0349 (10)0.0307 (10)0.0057 (8)−0.0078 (7)−0.0107 (8)
C60.0206 (8)0.0214 (9)0.0163 (8)0.0019 (7)−0.0011 (6)−0.0024 (6)
C70.0212 (8)0.0254 (9)0.0290 (9)−0.0040 (7)0.0022 (7)−0.0015 (7)
C80.0278 (9)0.0194 (9)0.0328 (10)−0.0036 (7)0.0007 (7)0.0011 (7)
C90.0239 (8)0.0188 (8)0.0200 (8)−0.0002 (7)−0.0013 (6)0.0001 (6)
C100.0201 (8)0.0199 (8)0.0164 (8)−0.0004 (6)−0.0025 (6)−0.0002 (6)
C110.0225 (8)0.0176 (8)0.0185 (8)−0.0005 (6)−0.0001 (6)−0.0003 (6)
C120.0303 (10)0.0180 (8)0.0255 (9)0.0009 (7)−0.0013 (7)0.0003 (7)
C130.0223 (9)0.0308 (10)0.0328 (10)0.0082 (7)0.0023 (7)0.0053 (7)

Geometric parameters (Å, °)

Cl1—C11.7515 (16)C5—H5B0.9800
N1—C11.315 (2)C5—H5C0.9800
N1—C21.360 (2)C6—C111.370 (2)
N2—C11.3182 (19)C6—C71.421 (2)
N2—C41.3564 (19)C7—C81.371 (2)
N3—C41.3540 (19)C7—H70.9500
N3—C61.4321 (19)C8—C91.413 (2)
N3—C51.467 (2)C8—H80.9500
N4—C101.3586 (19)C9—C121.398 (2)
N4—N51.3607 (17)C9—C101.428 (2)
N5—C121.336 (2)C10—C111.409 (2)
N5—C131.4551 (19)C11—H110.9500
C2—C31.357 (2)C12—H120.9500
C2—H20.9500C13—H13A0.9800
C3—C41.413 (2)C13—H13B0.9800
C3—H30.9500C13—H13C0.9800
C5—H5A0.9800
Cg1···Cg2i3.720 (2)
C1—N1—C2112.08 (13)C11—C6—C7122.04 (14)
C1—N2—C4115.36 (12)C11—C6—N3119.81 (14)
C4—N3—C6121.42 (12)C7—C6—N3118.11 (13)
C4—N3—C5120.45 (13)C8—C7—C6120.96 (15)
C6—N3—C5117.04 (12)C8—C7—H7119.5
C10—N4—N5103.19 (12)C6—C7—H7119.5
C12—N5—N4114.34 (13)C7—C8—C9118.58 (15)
C12—N5—C13126.67 (14)C7—C8—H8120.7
N4—N5—C13118.92 (13)C9—C8—H8120.7
N1—C1—N2131.07 (14)C12—C9—C8136.31 (15)
N1—C1—Cl1114.88 (12)C12—C9—C10103.78 (14)
N2—C1—Cl1114.05 (11)C8—C9—C10119.90 (14)
C3—C2—N1124.52 (14)N4—C10—C11127.55 (14)
C3—C2—H2117.7N4—C10—C9111.71 (13)
N1—C2—H2117.7C11—C10—C9120.74 (14)
C2—C3—C4117.01 (15)C6—C11—C10117.78 (14)
C2—C3—H3121.5C6—C11—H11121.1
C4—C3—H3121.5C10—C11—H11121.1
N3—C4—N2116.87 (13)N5—C12—C9106.98 (14)
N3—C4—C3123.20 (14)N5—C12—H12126.5
N2—C4—C3119.91 (14)C9—C12—H12126.5
N3—C5—H5A109.5N5—C13—H13A109.5
N3—C5—H5B109.5N5—C13—H13B109.5
H5A—C5—H5B109.5H13A—C13—H13B109.5
N3—C5—H5C109.5N5—C13—H13C109.5
H5A—C5—H5C109.5H13A—C13—H13C109.5
H5B—C5—H5C109.5H13B—C13—H13C109.5
C10—N4—N5—C120.03 (17)C11—C6—C7—C8−0.4 (2)
C10—N4—N5—C13177.21 (12)N3—C6—C7—C8−178.15 (13)
C2—N1—C1—N21.9 (2)C6—C7—C8—C9−0.5 (2)
C2—N1—C1—Cl1−178.80 (12)C7—C8—C9—C12−178.16 (16)
C4—N2—C1—N1−0.3 (2)C7—C8—C9—C100.4 (2)
C4—N2—C1—Cl1−179.62 (10)N5—N4—C10—C11−179.72 (13)
C1—N1—C2—C3−1.4 (2)N5—N4—C10—C90.32 (16)
N1—C2—C3—C4−0.4 (3)C12—C9—C10—N4−0.53 (17)
C6—N3—C4—N2−168.27 (13)C8—C9—C10—N4−179.54 (12)
C5—N3—C4—N2−0.5 (2)C12—C9—C10—C11179.50 (13)
C6—N3—C4—C313.5 (2)C8—C9—C10—C110.5 (2)
C5—N3—C4—C3−178.74 (15)C7—C6—C11—C101.3 (2)
C1—N2—C4—N3179.92 (13)N3—C6—C11—C10179.02 (12)
C1—N2—C4—C3−1.8 (2)N4—C10—C11—C6178.69 (14)
C2—C3—C4—N3−179.73 (15)C9—C10—C11—C6−1.3 (2)
C2—C3—C4—N22.1 (2)N4—N5—C12—C9−0.37 (18)
C4—N3—C6—C1157.33 (19)C13—N5—C12—C9−177.29 (13)
C5—N3—C6—C11−110.80 (17)C8—C9—C12—N5179.28 (16)
C4—N3—C6—C7−124.86 (16)C10—C9—C12—N50.52 (16)
C5—N3—C6—C767.01 (18)

Symmetry codes: (i) −x, y, −z+3/2.

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
C13—H13B···N2ii0.982.563.517 (2)166

Symmetry codes: (ii) −x, −y+1, −z+2.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: CV2775).

References

  • Limvorasak, S. & Posadas, E. M. (2009). Expert Opin. Pharmacother.10, 3091–3102. [PubMed]
  • Rigaku/MSC (2005). CrystalClear Rigaku/MSC Inc., The Woodlands, Texas, USA.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Sloan, B. & Scheinfeld, N. S. (2008). Curr. Opin. Investig. Drugs, 9, 1324–1335. [PubMed]
  • Sonpavde, G. M. D., Hutson, T. E. D. O. & Pharm, D. (2007). Curr. Oncol. Rep.9, 115–119. [PubMed]
  • Sorbera, L. A., Bolos, J. & Serradell, N. (2006). Drugs. Fut.31, 585–589.

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