Structure of Bromopride

ANALYTICAL SCIENCES 2004, VOL. 20 x79 2004 © The Japan Society for Analytical Chemistry

X-ray Structure Analysis Online

Rumiko TANAKA and Noriaki HIRAYAMA†

Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Boseidai, Isehara, Kanagawa 259-1193, Japan

− The title compound, C14H22BrN3O2, is an antiemetic agent. The crystal belongs to space group P1 with the cell dimensions a = 7.5711(6), b = 8.7500(9), c = 13.601(2)Å, α = 93.214(6), β = 99.940(4) and γ = 115.448(3)û. The final R value is 0.054. The molecule does not take a fully extended conformation owing to a weak but measurable intramolecular hydrogen bond.

(Received March 29, 2004; Accepted May 11,2004; Published on Web June 17, 2004)

Bromopride (4-amino-5-bromo-N-[2-(diethylamino)ethyl]-2- antiemetic properties.1 Bromopride is used to treat a variety of methoxybenzamide) (Fig.1) is the bromo-analogue of gastrointestinal disorders, including nausea and vomiting, and metoclopramide; both are benzamide derivatives. Like motility disorders. The main action of bromopride is related to metoclopramide, bromopride stimulates motility of the blockade of dopamine-2 receptors in the central nervous system gastrointestinal tract, enhances gastric empyting rate, and has and gastrointestinal tract. Similar to other benzamide derivatives, gastrointestinal tract stimulation by bromopride appears to be mediated at least in part by indirect cholinergic activity. The X-ray analysis of bromopride was undertaken to disclose its inherent three-dimensional structure to understand the molecular mechanism of the drug action. Single crystals were grown from methanol/acetonitrile solution. A colorless crystal with the size of 0.25 × 0.10 × 0.08 mm was mounted on a glass fiber and used for data collection. The structure was solved by heavy-atom Patterson methods2 and Fig. 1 Chemical structure of bromopride. refined by a full-matrix least squares method. Non-H atoms were refined with anisotropic temperature factors. All H-atoms

Table 1 Crystal and experimental data Table 2 Atomic coordinates and equivalent isotropic thermal

Formula: C14H22BrN3O2 parameters (Beq) Formula weight = 344.25 Atom x y z Beq Crystal system: triclinic Space group: P1ø Z = 2 a = 7.5711(6)Å α = 93.214(6)û b = 8.7500(9)Å β = 99.940(4)û c = 13.601(2)Å γ = 115.448(3)û V = 792.8(1)Å3 3 Dx = 1.442 g/cm No. of observations (I > 2.00σ (I)) = 1878 θ max = 67.5û with Cu Kα R(I > 2.00σ (I)) = 0.054 (/)∆σ max = 0.007 3 (∆ρ)max = 0.71 e/Å 3 (∆ρ)min = Ð 0.65 e/Å Measurement: Rigaku RAXIS-RAPID Program system: CrystalStructure 3.5.13 Structure determination: Patterson Methods (DIRDIF99)2 Refinement: full-matrix

† 2 2 2 2 To whom correspondence should be addressed. Beq = (8/3)π (U11(aa*) + U22(bb*) + U33(cc*) + 2U12(aa*bb*)cos γ βα E-mail: [email protected] + 2U13(aa*cc*)cos + 2U23(bb*cc*)cos ) x80 ANALYTICAL SCIENCES 2004, VOL. 20

atoms (N2áááO1 = 2.688(8), N2ÐH = 0.72(1), HáááO1 = 2.13(2)Å, ∠N2ÐHáááO1=135(1)û), the amide N atom points towards the methoxy oxygen atom. N1, Br1, O1, C7, C8, O2, N2, C9 and C10 atoms are almost on the plane of the phenyl ring. The maximum deviation from the plane is 0.297(8)Å for the C9 atom. The torsion angle N2ÐC9ÐC10ÐN3 of 69(1)û shows that this part takes a gauche conformation. This conformation appears to be stabilized by a weak but measurable intramolecular hydrogen bond between N2 and N3 atoms (N2áááN3 = 3.021(9), N2ÐH = 0.72(14), HáááN3 = 2.8(1)Å, ∠N2ÐHáááN3 = 101(11)û). In metclopramide, the pertinent part Fig. 2 Molecular structure of bromopride along with the labeling of the molecule takes a very similar conformation to the present atoms. Thermal ellipsoids of non-H atoms are drawn at the 50% one and two nitrogen atoms may be hydrogen-bonded in the probability level. molecule (NáááN = 3.03, HáááN = 2.7Å, ∠NÐHáááN = 104û0).5 The torsion angle of NÐCÐCÐN is 71.1û. Therefore this intramolecular NáááN hydrogen bond would be weak but important in determining the folded conformation of the Table 3 Selected bond lengths (Å), bond angles(û) and torsion structures of bromopride and metclopramide. There are two angles(û) intermolecular hydrogen bonds, as follows: N1ÐHáááO2 (Ð1 + x, Ð1 + y, z): N1áááO2 = 2.929(8)Å, N1ÐH = 0.91(8)Å, HáááO2 = 2.09(8)Å, ∠N1ÐHáááO2 = 152(7)û; C7ÐHáááO2(1 Ð x, Ðy, Ðz): C7áááO2 = 3.366(10)Å, C7ÐH = 0.952(11)Å, HáááO2 = 2.558(10)Å, ∠C7ÐHáááO2 = 142.9(8)û. Neither of these hydrogen bonds exert any effect on the conformations of the (diethylamino)ethyl moiety.

Acknowledgements

This work was supported by Grants for the Key Technology Research Promotion Program of New Energy and Industrial Technology Development Organization (NEDO) of Japan, and also by the Research and Study Program of Tokai University Educational System General Research Organization.

References

1. F. Roila, V. Minotti, and E. Ballatori, Tumori, 1985, 71, 455. were found from difference Fourier maps. H-atoms of amide, 2. CrystalStructure, version 3.5.1, 2000Ð2003, Crystal amine and phenyl groups were refined with isotropic Structure Analysis Package, Rigaku and Rigaku/MSC. temperature factors. Other H-atoms were refined with the 3. DIRDIF99, P. T. Beurskens, G. Admiraal, G. Beurskens, riding-model. The crystal and experimental data are shown in W. P. Bosman, S. Garcia-Granda, R. O. Gould, J. M. M. Table 1. Atomic parameters of non-H atoms are shown in Table Smits, and C. Smykalla, 1992, The DIRDIF program 2. system, Technical Report of the Crystallography The molecular structure drawn by ORTEP-III4 is shown in Laboratory, University of Nijmegen, The Netherlands. Fig. 2. Selected bond lengths, bond angles and torsion angles 4. ORTEP III, L. J. Farrugia, J. Appl. Cryst., 1997, 22, 389. are listed in Table 3. Bond lengths and bond angles are all 5. W. Shin, T. S. Chang and C. H. Koo, Bull. Korean Chem. within the expected ranges. Soc., 1983, 4, 123. Due to the intramolecular hydrogen bond between N2 and O1