Crystal structure of 2-(6-chloro-4-P-tolylamino)pyrido[3,2-d]pyrimidin-1-ium-1-yl)acetate oxonium bromide

Article abstract of DOI:10.1007/s10947-010-0060-9

The crystals of 2-(6-chloro-4-(p-tolylamino)pyrido[3,2-d]pyrimidin-1-ium-1-yl)acetate (zwitterionic form) oxonium bromide, C₁₆H₁₃ClN₄O₂·Br^-·H₃O⁺ (I) were prepared and studied by

Full text of DOI:10.1007/s10947-010-0060-9

Journal of Structural Chemistry. Vol. 51, No. 2, pp. 398-400, 2010
Original Russian Text Copyright © 2010 by L. Shen and F. L. Zhang
CRYSTAL STRUCTURE OF 2-(6-CHLORO-4-
(P-TOLYLAMINO)PYRIDO[3,2-d]PYRIMIDIN-1-
IUM-1-YL)ACETATE OXONIUM BROMIDE
L. Shen and F. L. Zhang
UDC 548.737;544.142.4
The crystals of 2-(6-chloro-4-(p-tolylamino)pyrido[3,2-d]pyrimidin-1-ium-1-yl)acetate (zwitterionic form)
oxonium bromide, C16H13ClN4O24Br–4H3O+ (I) were prepared and studied by single-crystal X-ray
diffraction method. The compound crystallizes in the triclinic space group P-1 with a = 8.3121(8) Å,
b = 9.3885(8) Å, c = 13.2903(12) Å, ꢀ = 106.788(2)ꢁ, ꢂ = 95.204(3)ꢁ, ꢃ = 110.871(2)ꢁ, V = 905.81(14) Å3,
Z = 2; final R = 0.053, wR2 = 0.150. It is interesting that methylene C in the BrCH2COOH molecule binds
to the N1 of the pyrimidine ring. In the crystal studied, two neighboring organic molecules are connected
by hydrogen bonds through carboxylate oxygen, oxonium and bromide ions to form a dimer.
Keywords: Pyridopyrimidine derivatives, quaternary ammonium salts, crystal structure, hydrogen bond.
Pyridopyrimidine derivatives have been intensively investigated due to analgesic, antiinflammatory and central
nervous system depressing activities [1, 2]. In particular, their potent activities as anticancer agents are of great interest. The
pyridopyrimidine derivatives were included in anticancer selective kinase inhibitors acting as ATP binding site. The recent
development of anticancer agents led to some pyridopyrimidines analogues such as PD166285 [3, 4] and PD173074 [5],
which were described as very promising PDGF kinase inhibitors. Pyridopyrimidinium derivatives also exhibit antibacterial
and fungicidal activities [6, 7]. A few crystal structures of protonated pyridinium and pyrimidinium derivatives were reported
in the literature [8-10]. In this work, we report on the preparation and a crystal structure study of a new pyridopyrimidine
derivative.
Experimental. Synthesis. 4,6-dichloropyrido[3,2-d]pyrimidine was prepared as reported elsewhere [11]. 6-Chloro-
4-(p-tolylamino)pyrido[3,2-d]pyrimidine was synthesized by the reaction of 4,6-dichloropyrido[3,2-d]pyrimidine and 4-
methylaniline in 2-propanol in a molar ratio of 1:1.25 and was confirmed by the means of elemental analysis, IR, NMR and
MS. The title compound I (2-(6-chloro-4-(p-tolylamino)pyrido[3,2-d]pyrimidin-1-ium-1-yl)acetate (zwitterionic form)
oxonium bromide) was obtained as a yellow product by mixing 6-chloro-4-(p-tolylamino)pyrido[3,2-d]pyrimidine and
bromoacetic acid (1:1.1) in ethanol/water at room temperature. Single crystals were grown by slow evaporation of the
reaction solution.
X-Ray diffraction analysis. For X-ray data collection, a single crystal with dimensions 0.32ꢄ0.20ꢄ0.11 mm was
mounted on a Rigaku RAXIS-RAPID diffractometer with MoKꢀ radiation source (0.71073 Å). The crystal structure was
solved by direct methods using SHELXS-97 [12]. The refinement method involved the full-matrix least-squares procedure on
F2. All non-hydrogen atoms were refined anisotropically. The hydrogen atoms were treated as riding atoms but included in
College of Material Chemistry and Chemical Engineering, Key Laboratory of Organosilicon Chemistry and Material
Technology, Ministry of Education, Hangzhou Normal University, Hangzhou 310036, P. R. China; shenchem@hotmail.com.
The text was submitted by the authors in English. Zhurnal Strukturnoi Khimii, Vol. 51, No. 2, pp. 410-412, March-April,
2010. Original article submitted June 15, 2009.
398
0022-4766/10/5102-0398 © 2010 Springer Science+Business Media, Inc.

TABLE 1. Selected Bond Lengths (Å) in the Title Compound
Cl(1)—C(1)
O(1)–C(16)
O(2)–C(16)
N(1)–C(4)
N(1)–C(5)
N(1)–C(15)
1.727(5)
1.299(6)
1.224(7)
1.385(6)
1.330(5)
1.465(6)
N(2)—C(5)
N(2)–C(6)
N(3)–C(1)
N(3)–C(7)
N(4)–C(6)
N(4)–C(8)
1.309(6)
1.337(6)
1.311(5)
1.346(6)
1.325(5)
1.428(5)
C(1)—C(2)
C(2)–C(3)
C(3)–C(4)
C(4)–C(7)
C(6)–C(7)
C(8)–C(9)
1.391(7)
1.352(7)
1.402(6)
1.390(6)
1.451(5)
1.379(6)
C(8)—C(13)
C(9)–C(10)
C(10)–C(11)
C(11)–C(12)
C(11)–C(14)
C(12)–C(13)
1.383(6)
1.386(6)
1.373(7)
1.381(7)
1.510(6)
1.381(6)
TABLE 2. Hydrogen Bonds Found in the Title Compound: Bond Lengths (Å) and Angles (deg)
D–H---A
D–H
H---A
D---A
D–H---A
O(3)–H(301)---O(1)
O(3)–H(302)---Br(1)i
N(4)–H(4)---N(3)
0.82
0.82
0.82
1.72
2.58
2.30
2.505(8)
3.280(6)
2.718(7)
159
144
110
Symmetry code i: –x, –y + 1, –z + 2.
Fig. 1. Asymmetric unit of C16H13ClN4O24Br–4H3O+ with atom
numbering scheme (50% probability displacement ellipsoids).
the structure factor calculations. Crystal data for I: C16H16BrClN4O3, M = 427.69, triclinic, P-1, a = 8.3121(8) Å,
b = 9.3885(8) Å, c = 13.2903(12) Å, ꢀ = 106.788(2)ꢁ, ꢂ = 95.204(3)ꢁ, ꢃ = 110.871(2)ꢁ, V = 905.81(14) Å3, Z = 2.7949
reflections were measured with ꢅ-scans, in the range of 3.1ꢁ
ꢆ
27.4ꢁ (–10
h
10, –11
k
10, –16
l
16) to yield
3567 independent reflections (Rint = 0.031). Final R1 = 0.053, wR2 = 0.150 [I > 2ꢇ(I)], and the goodness-of-fit on F2 was
1.001.
Selected bond lengths for the title compound are given in Table 1. The parameters of hydrogen bonds are listed in
Table 2. The CIF file with complete information about the structure was deposited with CCDC (Deposition no. 737932),
from which it is available free of charge on request at www.ccdc.cam.ac.uk/data_request/cif.
Results and discussion. As shown in Fig. 1, the main molecule of I is flat; it comprises connected through NH-
group pyrimidine and benzene moieties as well as side substituent groups. Presumably, the main molecule is in zwitterionic
form with a positive charge on N1 and negative charge on the C16O1O2 group. The ring atoms in the pyridopyrimidine ring
are co-planar within ꢈ0.004 Å and the bonded to it Cl1, C15 and N4 atoms are in the same plane within 0.000 Å, 0.037 Å,
and 0.014 Å, respectively. The atoms of the benzene ring are co-planar within ꢈ0.001 Å and the bonded to it N4 and C14
399

Fig. 2. View of a dimer formed by hydrogen bonds in the crystal
studied (the two halves are related by centrosymmetry).
atoms are in the same plane within 0.046 Å and 0.065 Å, respectively. The dihedral angle between the two planes is 7.9ꢁ. It is
interesting that methylene C in the BrCH2COOH molecule bonds to the N1 atom of the pyrimidine ring (N1–C15 bond). The
N1–C15 distance of 1.465(6) Å is longer than the N1–C4 and N1–C5 distances of 1.385(6) Å and 1.330(5) Å, respectively. A
similar feature is also observed in 4-aminopyridinium-N-acetate [13]. The dihedral angle between the planes of pyrido-
pyrimidine ring and carboxymethylene fragment is 84.7ꢁ.
Hydrogen bonding interactions (Table 2) play an important role in the crystal structure. As shown in Fig. 2, two
adjacent molecules are linked by intermolecular hydrogen bonds through carboxylate oxygen, oxonium and bromide, with
O1---O3 (2.505(8) Å) and O3---Br1(–x, –y+1, –z+2) (3.280(6) Å) contacts. There also exist an intramolecular hydrogen bond
between pyridine N3 atom and amine N4 atom.
REFERENCES
1. E. J. E. Freyne, M. Willems, P. Storck, et al., WO Pat. No. 2005058913 (2005).
2. S. D. Jonghe, E. Dolusic, L. J. Gao, et al., WO Pat. No. 2006069805 (2006).
3. C. J. Dimitroff, W. Klohs, A. Sharma, et al., Investigational New Drugs, 17, No. 2, 121 (1999).
4. P. Furet, G. Caravatti, V. Guagnano, et al., Bioorg. Med. Chem. Lett., 18, No. 3, 897 (2008).
5. S. D. Skaper, W. J. Kee, L. Facci, et al., J. Neurochem., 75, No. 4, 1520 (2000).
6. W. Sliwa and B. Mianowska, Heterocycles, 29, No. 3, 557 (1989).
7. T. Zhao, G. H. Wang, and G. Sun, CN Pat. No. 1973625 (2007).
8. Z. M. Jin, Z. G. Li, M. C. Li, et al., Acta Crystallogr., E59, o903 (2003).
9. S. R. Jebas, A. Sinthiya, B. R. D. Nayagam, et al., ibid., C65, o361 (2009).
10. K. Thanigaimani, A. Subashini, P. T. Muthiah, et al., ibid., o42.
11. G. W. Rewcastle, B. D. Palmer, A. M. Thompson, et al., J. Med. Chem., 39, No. 9, 1823 (1996).
12. G. M. Sheldrick, SHELXS-97 and SHELXL-97, Univ. Gotingen, Germany (1997).
13. G. Liu, Acta Crystallogr., E65, o857 (2009).
400