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2,4-Di­chloro-7-fluoro­quinazoline

aDepartment of Chinese Traditional Herbs, Agromomy College, Sichuan Agricultural University, Chengdu 611130, People's Republic of China
*Correspondence e-mail: gaofeng@sicau.edu.cn

(Received 13 January 2012; accepted 11 February 2012; online 17 February 2012)

The mol­ecule of the title compound, C8H3Cl2FN2, is essentially planar, with a maximum deviation of 0.018 (2) Å. In the crystal, ππ stacking is observed between parallel quinazoline moieties of adjacent mol­ecules, the centroid–centroid distance being 3.8476 (14) Å.

Related literature

For the synthesis of quinazoline derivatives, see: Roberts et al. (2011[Roberts, B., Liptrot, D., Luker, T., Stocks, M. J., Barber, C., Webb, N., Dods, R. & Martin, B. (2011). Tetrahedron Lett. 52, 3793-3796.]); Gao et al. (2010[Gao, J., He, L.-N., Miao, C.-X. & Chanfreau, S. B. (2010). Tetrahedron, 66, 4063-4067.]); Li et al. (2009[Li, J.-R., Chen, X., Shi, D.-X., Ma, S.-L., Li, Q., Zhang, Q. & Tang, J.-H. (2009). Org. Lett. 11, 1193-1196.]); Connolly et al. (2005[Connolly, T. J., McGarry, P. & Sukhtankar, S. (2005). Green Chem. 7, 586-589.]). For the pharmacological properties of quinazoline analogues, see: Koller et al. (2011[Koller, M., Lingenhoehl, K., Schmutz, M., Vranesic, I.-T., Kallen, J., Auberson, Y. P., Carcache, D. A., Mattes, H., Ofner, S., Orain, D. & Urwyler, S. (2011). Bioorg. Med. Chem. Lett. 21, 3358-3361.]); Garofalo et al. (2011[Garofalo, A., Goossens, L., Six, P., Lemoine, A., Ravez, S., Farce, A. & Depreux, P. (2011). Bioorg. Med. Chem. Lett. 21, 2106-2112.]); Yang et al. (2011[Yang, S. H., Khadka, D. B., Cho, S. H., Ju, H. K., Lee, Y. K., Han, J. H., Lee, K. T. & Cho, W. J. (2011). Bioorg. Med. Chem. 19, 968-977.]). For related structures, see: Jia et al. (2011[Jia, J., Wang, G. & Lu, D. (2011). Acta Cryst. E67, o229.]); Ouahrouch et al. (2011[Ouahrouch, A., Lazrek, H. B., Taourirte, M., El Azhari, M., Saadi, M. & El Ammari, L. (2011). Acta Cryst. E67, o2029-o2030.]).

[Scheme 1]

Experimental

Crystal data
  • C8H3Cl2FN2

  • Mr = 217.02

  • Monoclinic, P 21 /n

  • a = 3.8257 (3) Å

  • b = 15.0664 (9) Å

  • c = 14.3453 (6) Å

  • β = 95.102 (5)°

  • V = 823.59 (9) Å3

  • Z = 4

  • Mo Kα radiation

  • μ = 0.75 mm−1

  • T = 293 K

  • 0.35 × 0.30 × 0.25 mm

Data collection
  • Agilent Xcalibur Eos diffractometer

  • Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2010[Agilent (2010). CrysAlis PRO. Agilent Technologies, Yarnton, Oxfordshire, England.]) Tmin = 0.780, Tmax = 0.835

  • 3156 measured reflections

  • 1452 independent reflections

  • 1120 reflections with I > 2σ(I)

  • Rint = 0.025

Refinement
  • R[F2 > 2σ(F2)] = 0.038

  • wR(F2) = 0.095

  • S = 1.07

  • 1452 reflections

  • 118 parameters

  • H-atom parameters constrained

  • Δρmax = 0.20 e Å−3

  • Δρmin = −0.23 e Å−3

Data collection: CrysAlis PRO (Agilent, 2010[Agilent (2010). CrysAlis PRO. Agilent Technologies, Yarnton, Oxfordshire, England.]); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; 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

As the important six-membered heterocycles, quinazoline derivatives have always drawn the attention of organic and medicinal chemists for their various biological activities and significant synthetic materials. Several quinazoline-containing compounds have been approved by FDA, such as EGFR inhibitors Iressa and Tarceva used in the treatment of cancer, as well as alpha adrenergic receptor antagonists Praosin and Alfuzosine, which have been used for anti-hypertensive drugs in clinic. In addition, quinazoline derivatives also have been reported as anti-inflammatory, antibacterial or anticonvulsant agents. Most recently, quinazoline analogues have been found as selective VEGFR-2 receptor tyrosine kinase inhibitors, novel heat shock protein 90 inhibitors, EGFR Tyrosine kinase inhibitors, as well as glucocerebrosidase inhibitors.

Related literature top

For the synthesis of quinazoline derivatives, see: Roberts et al. (2011); Gao et al. (2010); Li et al. (2009); Connolly et al. (2005). For the pharmacological properties of quinazoline analogues, see: Koller et al. (2011); Garofalo et al. (2011); Yang et al. (2011). For related structures, see: Jia et al. (2011); Ouahrouch et al. (2011).

Experimental top

2,4-Dichloro-7-fluoroquinazoline was synthesized presently through two steps reactions implying 2-amino-4-fluorobenzoic acid as the starting material: 1. Acetic acid (80 ml) was added to a suspension of 2-amino-4-fluorobenzoic acid (100 g, 0.645 mol) in water (2L), a solution of NaOCN (105 g, 1.616 mol) in water (800 ml) was added dropwise under vigorous stirring with a mechanical stirrer. The reaction mixture was stirred at room temperature for 30 min, and NaOH (480 g, 12 mol) was added in small portions, and the mixture was cooled to room temperature. Then concentrated HCl (~1.2L) was added dropwise to the reaction mixture to attain pH ~4 (strong foaming!). The formed precipitate was separated by filtration, washed with water, and air-dried to give compound 7-fluoroquinazoline-2,4(1H,3H)-dione (yield 82%, 95 g). It was used in the next step without any purification. 2. A mixture of compound 7-fluoroquinazoline-2,4(1H,3H)-dione (150 g, 0.83 mol), N,N-diethylaniline (125 g, 0.84 mol), and POCl3 (500 ml) was refluxed for overnight. Most of POCl3 was removed by rotary vapor. The residue was poured into the mixture water/ice (~4L), and the formed precipitate was separated by filtration, washed with water, and vacuum-dried to give compound 2,4-dichloro-7-fluoroquinazoline (yield 94%, 170 g). Single crystals of 2,4-dichloro-7-fluoroquinazoline, C8H3Cl2FN2, were recrystallized from acetone, mounted in inert oil and transferred to the cold gas stream of the diffractometer.

Refinement top

H atoms were placed in calculated positions and treated as riding atoms [C—H = 0.93–0.96 Å], with Uiso(H) = 1.5Ueq(C) for methyl H atoms and 1.2Ueq(C) for others.

Computing details top

Data collection: CrysAlis PRO (Agilent, 2010); cell refinement: CrysAlis PRO (Agilent, 2010); data reduction: CrysAlis PRO (Agilent, 2010); 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. Molecular structure of showing 30% probability displacement ellipsoids.
[Figure 2] Fig. 2. The packing viewed along c axis with π···π interactions, indicating the dimer.
2,4-Dichloro-7-fluoroquinazoline top
Crystal data top
C8H3Cl2FN2F(000) = 432
Mr = 217.02Dx = 1.750 Mg m3
Monoclinic, P21/nMo Kα radiation, λ = 0.71073 Å
a = 3.8257 (3) ÅCell parameters from 1033 reflections
b = 15.0664 (9) Åθ = 3.0–25.0°
c = 14.3453 (6) ŵ = 0.75 mm1
β = 95.102 (5)°T = 293 K
V = 823.59 (9) Å3Block, brown
Z = 40.35 × 0.30 × 0.25 mm
Data collection top
Agilent Xcalibur Eos
diffractometer
1452 independent reflections
Radiation source: Enhance (Mo) X-ray Source1120 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.025
Detector resolution: 10.0 pixels mm-1θmax = 25.0°, θmin = 3.1°
ω scansh = 44
Absorption correction: multi-scan
(CrysAlis PRO; Agilent, 2010)
k = 1517
Tmin = 0.780, Tmax = 0.835l = 1616
3156 measured reflections
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.038Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.095H-atom parameters constrained
S = 1.07 w = 1/[σ2(Fo2) + (0.0389P)2]
where P = (Fo2 + 2Fc2)/3
1452 reflections(Δ/σ)max < 0.001
118 parametersΔρmax = 0.20 e Å3
0 restraintsΔρmin = 0.23 e Å3
Crystal data top
C8H3Cl2FN2V = 823.59 (9) Å3
Mr = 217.02Z = 4
Monoclinic, P21/nMo Kα radiation
a = 3.8257 (3) ŵ = 0.75 mm1
b = 15.0664 (9) ÅT = 293 K
c = 14.3453 (6) Å0.35 × 0.30 × 0.25 mm
β = 95.102 (5)°
Data collection top
Agilent Xcalibur Eos
diffractometer
1452 independent reflections
Absorption correction: multi-scan
(CrysAlis PRO; Agilent, 2010)
1120 reflections with I > 2σ(I)
Tmin = 0.780, Tmax = 0.835Rint = 0.025
3156 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0380 restraints
wR(F2) = 0.095H-atom parameters constrained
S = 1.07Δρmax = 0.20 e Å3
1452 reflectionsΔρmin = 0.23 e Å3
118 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
xyzUiso*/Ueq
Cl10.18763 (19)0.24582 (4)0.86579 (4)0.0500 (3)
Cl20.2734 (2)0.09054 (5)0.54819 (5)0.0628 (3)
F10.8584 (4)0.55046 (10)0.60324 (11)0.0652 (5)
N10.2491 (5)0.17987 (14)0.70176 (14)0.0416 (5)
N20.4812 (5)0.25290 (13)0.57255 (14)0.0389 (5)
C10.3448 (6)0.18701 (17)0.61375 (17)0.0392 (6)
C20.3050 (6)0.25134 (16)0.75263 (17)0.0360 (6)
C30.4494 (6)0.33043 (16)0.72000 (16)0.0331 (6)
C40.5323 (6)0.32793 (16)0.62626 (16)0.0327 (6)
C50.6758 (7)0.40354 (16)0.58670 (16)0.0389 (6)
H50.73650.40300.52530.047*
C60.7228 (7)0.47677 (17)0.64004 (19)0.0428 (7)
C70.6403 (7)0.48233 (17)0.73259 (19)0.0455 (7)
H70.67830.53460.76650.055*
C80.5030 (7)0.40973 (16)0.77230 (17)0.0426 (7)
H80.44430.41220.83380.051*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.0595 (5)0.0612 (5)0.0313 (4)0.0047 (4)0.0158 (3)0.0092 (3)
Cl20.0870 (6)0.0476 (5)0.0541 (5)0.0111 (4)0.0086 (4)0.0150 (4)
F10.0783 (13)0.0466 (10)0.0717 (12)0.0159 (9)0.0123 (10)0.0132 (9)
N10.0454 (14)0.0428 (13)0.0367 (12)0.0035 (11)0.0043 (10)0.0014 (11)
N20.0455 (13)0.0404 (13)0.0314 (11)0.0004 (11)0.0074 (10)0.0032 (10)
C10.0433 (16)0.0373 (15)0.0369 (14)0.0015 (13)0.0029 (12)0.0033 (12)
C20.0330 (14)0.0469 (16)0.0285 (12)0.0071 (12)0.0045 (11)0.0052 (12)
C30.0320 (14)0.0385 (14)0.0286 (12)0.0057 (12)0.0022 (11)0.0039 (11)
C40.0301 (14)0.0365 (14)0.0315 (13)0.0033 (12)0.0019 (11)0.0037 (11)
C50.0427 (16)0.0437 (16)0.0311 (13)0.0022 (13)0.0074 (12)0.0037 (12)
C60.0389 (15)0.0397 (16)0.0493 (16)0.0033 (13)0.0008 (13)0.0123 (14)
C70.0504 (17)0.0370 (15)0.0485 (16)0.0004 (13)0.0013 (13)0.0069 (13)
C80.0469 (17)0.0478 (16)0.0336 (14)0.0060 (14)0.0066 (12)0.0037 (13)
Geometric parameters (Å, º) top
Cl1—C21.724 (2)C3—C81.416 (3)
Cl2—C11.739 (3)C4—C51.406 (3)
F1—C61.352 (3)C5—C61.346 (3)
N1—C21.308 (3)C5—H50.9300
N1—C11.350 (3)C6—C71.394 (4)
N2—C11.289 (3)C7—C81.360 (3)
N2—C41.372 (3)C7—H70.9300
C2—C31.411 (3)C8—H80.9300
C3—C41.409 (3)
C2—N1—C1114.3 (2)C5—C4—C3119.5 (2)
C1—N2—C4114.9 (2)C6—C5—C4118.2 (2)
N2—C1—N1130.1 (2)C6—C5—H5120.9
N2—C1—Cl2116.50 (18)C4—C5—H5120.9
N1—C1—Cl2113.36 (19)C5—C6—F1119.2 (2)
N1—C2—C3124.0 (2)C5—C6—C7124.1 (2)
N1—C2—Cl1116.25 (18)F1—C6—C7116.7 (2)
C3—C2—Cl1119.70 (18)C8—C7—C6118.6 (2)
C4—C3—C2115.0 (2)C8—C7—H7120.7
C4—C3—C8119.6 (2)C6—C7—H7120.7
C2—C3—C8125.4 (2)C7—C8—C3120.0 (2)
N2—C4—C5118.8 (2)C7—C8—H8120.0
N2—C4—C3121.7 (2)C3—C8—H8120.0

Experimental details

Crystal data
Chemical formulaC8H3Cl2FN2
Mr217.02
Crystal system, space groupMonoclinic, P21/n
Temperature (K)293
a, b, c (Å)3.8257 (3), 15.0664 (9), 14.3453 (6)
β (°) 95.102 (5)
V3)823.59 (9)
Z4
Radiation typeMo Kα
µ (mm1)0.75
Crystal size (mm)0.35 × 0.30 × 0.25
Data collection
DiffractometerAgilent Xcalibur Eos
diffractometer
Absorption correctionMulti-scan
(CrysAlis PRO; Agilent, 2010)
Tmin, Tmax0.780, 0.835
No. of measured, independent and
observed [I > 2σ(I)] reflections
3156, 1452, 1120
Rint0.025
(sin θ/λ)max1)0.594
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.038, 0.095, 1.07
No. of reflections1452
No. of parameters118
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.20, 0.23

Computer programs: CrysAlis PRO (Agilent, 2010), SHELXTL (Sheldrick, 2008).

 

Acknowledgements

This project was supported by the NSFC (grant No. 81001383) and the Doctoral Foundation of the Ministry of Education, China (grant No. 20105103120009).

References

First citationAgilent (2010). CrysAlis PRO. Agilent Technologies, Yarnton, Oxfordshire, England.  Google Scholar
First citationConnolly, T. J., McGarry, P. & Sukhtankar, S. (2005). Green Chem. 7, 586–589.  Web of Science CrossRef CAS Google Scholar
First citationGao, J., He, L.-N., Miao, C.-X. & Chanfreau, S. B. (2010). Tetrahedron, 66, 4063–4067.  Web of Science CrossRef CAS Google Scholar
First citationGarofalo, A., Goossens, L., Six, P., Lemoine, A., Ravez, S., Farce, A. & Depreux, P. (2011). Bioorg. Med. Chem. Lett. 21, 2106–2112.  Web of Science CrossRef CAS PubMed Google Scholar
First citationJia, J., Wang, G. & Lu, D. (2011). Acta Cryst. E67, o229.  Web of Science CSD CrossRef IUCr Journals Google Scholar
First citationKoller, M., Lingenhoehl, K., Schmutz, M., Vranesic, I.-T., Kallen, J., Auberson, Y. P., Carcache, D. A., Mattes, H., Ofner, S., Orain, D. & Urwyler, S. (2011). Bioorg. Med. Chem. Lett. 21, 3358–3361.  Web of Science CrossRef CAS PubMed Google Scholar
First citationLi, J.-R., Chen, X., Shi, D.-X., Ma, S.-L., Li, Q., Zhang, Q. & Tang, J.-H. (2009). Org. Lett. 11, 1193–1196.  Web of Science PubMed CAS Google Scholar
First citationOuahrouch, A., Lazrek, H. B., Taourirte, M., El Azhari, M., Saadi, M. & El Ammari, L. (2011). Acta Cryst. E67, o2029–o2030.  Web of Science CSD CrossRef IUCr Journals Google Scholar
First citationRoberts, B., Liptrot, D., Luker, T., Stocks, M. J., Barber, C., Webb, N., Dods, R. & Martin, B. (2011). Tetrahedron Lett. 52, 3793–3796.  Web of Science CrossRef CAS Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationYang, S. H., Khadka, D. B., Cho, S. H., Ju, H. K., Lee, Y. K., Han, J. H., Lee, K. T. & Cho, W. J. (2011). Bioorg. Med. Chem. 19, 968–977.  Web of Science CrossRef CAS PubMed Google Scholar

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