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The article is published in Russian in the journal.
The English text is given in the author's version.
IMPROVED SYNTHESIS, SPECTRAL CHARACTERISTICS AND SPACE STRUCTURE OF ETHYL 2-HYDROXY-8-METHYL-4-OXO-4H-PYRIDO[1,2-a]PYRIMIDINE-3-CARBOXYLATE
I.V. Ukrainets1, N.L. Bereznyakova1, K.A. Taran1, A.A. Davidenko2
1National University of Pharmacy
61002, Kharkiv, 53 Pushkinska str. E-mail:
2N. I. Pirogov Vinnitsa National Medical University
21018, Vinnitsa, 56 Pirogov str.
Key words: heterocyclic tricarbonylmethane derivatives, 2-aminopyridines, esters, 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acids.
The improved method for obtaining of ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate being of interest as a base for synthesis of antiviral medicines has been suggested. The method involves a gradual addition of the solution of 2-amino-4-methylpyridine in triethylmethanetricarboxylate used as an acylating and condensing agent, as well as a high boiling heating agent simultaneously in the excess of triethylmethanetricarboxylate preheated to 150 °С. This modification allows not only to reduce considerably regeneration of triethylmethanetricarboxylate taken in excess, but practically to avoid completely the undesirable formation of by-product – 2-hydroxy-8-methyl-N-(4-methypyridin-2-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide. It has been found by X-ray diffraction analysis that in the crystal the ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate synthesized exists in the zwitterionic form with localization of the positive charge at the protonated nitrogen atom and the negative charge at the carbon atom in position 3 of the pyridopyrimidine ring. Based on the study of NMR 1Н and 13С spectra the assumption that the test compound exits as an equilibrium mixture of two tautomeric forms in solution has been expressed.
Increased interest in the 4-oxo-4H-pyrido [1,2-a] pyrimidines and their derivatives from researchers of different scientific disciplines primarily caused wide spectrum of their biological activity. Even a cursory view of various kinds of information sources on this subject reveals a lot of data. For example, based on molecular systems that synthesized highly effective anti-malarial drugs [1, 2]. 2-Methyl-substituted 4-oxo-4H-pyrido[1,2-a]pyrimidines are enhanced pharmacological testing as potential anticancer agents [3, 4]. Aryl substituents in the 2-position of pyrido[1,2-a]pyrimidine cycle impart antioxidant properties of a molecule [5], and the presence of tetrazole in position 3 - antiallergics [6]. With the introduction of ester or urea groups there is an ability to actively inhibit the growth of human immunodeficiency virus [7], herpes simplex [8] and West Nile pathogen [9]. Pyrido[1,2-a]pyrimidines as promising as antimicrobial agents [10, 11], cardioprotectors [12], and anticoagulants [13]. Considering these facts, it becomes clear desire chemists not only offer effective methods of synthesis of pyrido[1,2-a]pyrimidines [10, 14, 15], but also to study in detail their structure [16-22].
Previously we have developed a method of obtaining of ethyl 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylates by reacting the corresponding 2-aminopyridines with a twofold excess of triethylmethanetricarboxylate in a boiling xylene [15]. Now been found that the best results can be achieved using as the acylating triethylmethanetricarboxylate and a condensing agent and a high boiling heat transfer medium at a time, which not only considerably simplify its regeneration, but almost completely avoid formation of undesired 2-hydroxy-4-oxo-N-(pyridin-2-yl)-4H-pyrido[1,2-a]pyrimidine-3-carboxamides. To suppress the side reactions is also important and the order of introduction of the starting materials in the reaction: instead of the usual gradual warming of the reaction mixture, followed by boiling it, contributing to the formation triamides of methanetricarboxylic acid [23], it has to add hot triethylmethanetricarboxylate solution of aminopyridine in triethylmethanetricarboxylate. In example the synthesis of ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1) shows that such a simple modification to the design allows to obtain the target product with higher yield and purity..
According to the X-ray analysis conducted by us (Figure. 1 and 2, Table 1 and 2), the ester 1 is in the crystal exists as a hydrate of 2:3. In the unit cell independent of the two molecules revealed that compound (А and В), that differ in the orientation of the ethyl ester substituent group, and three water molecules.
Bicyclic moiety and atoms О(1), С(9), С(12) in both molecules are in one plane with an accuracy of 0.02 Å. This gives rise to the attractive interaction H(5a)…O(2a) 2.35 Å in molecule А and 2.34 Å in molecule В (the sum of the van der Waals radii [24] is 2.46 Å), which can not be regarded as a hydrogen bond due to too acute angle С-Н…О (99º in А and В). This attractive interaction with one hand and repulsion between spatially close carbonyl groups on the other lead to an increase in valence angle О(2)-С(6)-С(7) to 129.1(1)º in А and to 128.3(1)º in В in as compared with a standard value 120º. As well as in the corresponding previously studied compound [25], the fragment iminopiridinium of the bicyclic a noticeable alternation links: bonds N(1)-C(1) 1.347(2) Å in molecule А and 1.348(2) Å in molecule В, C(2)-C(3) 1.378(2) Å in A and 1.374(2) Å in B, C(4)-C(5) 1.351(2) Å in A and 1.349(2) Å in B by its length closer to the double bonds, and the bond lengths С(1)-С(2) 1.402(2) Å in А and В, С(3)-С(4) 1.425(2) Å in А and 1.424(2) Å in В, N(2)-C(5) 1.387(2) Å in A and 1.383(2) Å in B closer to the average values for single bonds. The lengths of the С(6)-С(7) 1.417(2) Å in А and В, С(7)-С(8) 1.452(2) Å in А and 1.446(2) Å in В, С(7)-С(9) 1.475(2) Å in А and В are close enough to the mean value [26] for Csp2-Csp2 communication (1.455 Å), and the atom С(7) has a planar configuration, suggesting its existence in sp2-hybridization. We should initially note that the hydrogen atom at the nitrogen atom N(1) was revealed objectively in both molecules, and the lengths of the С(8)-О(1) 1.244(2) Å inв А and 1.240(2) Å in В, and С(6)-О(2) 1.235(2) Å in А and 1.238(2) Å in В correspond to the double bonds of С=О (average 1.210 Å). Consequently, it can be assumed that the molecule in the crystal of ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1) is in zwitterionic form 1а with localization of the positive charge at the protonated nitrogen atom and the negative charge at the carbon atom С(7).
Figure 1. Structure of ester 1 with representation of the atoms by thermal vibration ellipsoids of 50% probability.
Table 1
Interatomic Distances (l) in the Structure of Ester 1
Bond / l, Å / Bond / l, ÅN(1A)-C(1A) / 1.347(2) / N(1A)-C(8A) / 1.390(2)
N(2A)-C(1A) / 1.366(2) / N(2A)-C(5A) / 1.387(2)
N(2A)-C(6A) / 1.481(2) / O(1A)-C(8A) / 1.244(2)
O(2A)-C(6A) / 1.235(2) / O(3A)-C(9A) / 1.220(2)
O(4A)-C(9A) / 1.351(2) / O(4A)-C(10A) / 1.452(2)
C(1A)-C(2A) / 1.402(2) / C(2A)-C(3A) / 1.378(2)
C(3A)-C(4A) / 1.425(2) / C(3A)-C(12A) / 1.496(2)
C(4A)-C(5A) / 1.351(2) / C(6A)-C(7A) / 1.417(2)
C(7A)-C(8A) / 1.452(2) / C(7A)-C(9A) / 1.475(2)
C(10A)-C(11A) / 1.485(2) / N(1B)-C(1B) / 1.348(2)
N(1B)-C(8B) / 1.397(2) / N(2B)-C(1B) / 1.364(2)
N(2B)-C(5B) / 1.383(2) / N(2B)-C(6B) / 1.471(2)
O(1B)-C(8B) / 1.240(2) / O(2B)-C(6B) / 1.238(2)
O(3B)-C(9B) / 1.221(2) / O(4B)-C(9B) / 1.352(2)
O(4B)-C(10B) / 1.453(2) / C(1B)-C(2B) / 1.402(2)
C(2B)-C(3B) / 1.374(2) / C(3B)-C(4B) / 1.424(2)
C(3B)-C(12B) / 1.501(2) / C(4B)-C(5B) / 1.349(2)
C(6B)-C(7B) / 1.417(2) / C(7B)-C(8B) / 1.446(2)
C(7B)-C(9B) / 1.475(2) / C(10B)-C(11B) / 1.504(2)
Table 2
Valence Angles (ω) in the Structure of Ester 1
Angle / w, град. / Angle / w, град.C(1A)-N(1A)-C(8A) / 126.3(1) / C(1A)-N(2A)-C(5A) / 119.5(1)
C(1A)-N(2A)-C(6A) / 122.2(1) / C(5A)-N(2A)-C(6A) / 118.3(1)
C(9A)-O(4A)-C(10A) / 116.3(1) / N(1A)-C(1A)-N(2A) / 118.3(1)
N(1A)-C(1A)-C(2A) / 120.7(1) / N(2A)-C(1A)-C(2A) / 121.0(1)
C(3A)-C(2A)-C(1A) / 119.8(1) / C(2A)-C(3A)-C(4A) / 118.2(1)
C(2A)-C(3A)-C(12A) / 121.1(1) / C(4A)-C(3A)-C(12A) / 120.8(1)
C(5A)-C(4A)-C(3A) / 121.0(1) / C(4A)-C(5A)-N(2A) / 120.6(1)
O(2A)-C(6A)-C(7A) / 129.1(1) / O(2A)-C(6A)-N(2A) / 115.0(1)
C(7A)-C(6A)-N(2A) / 115.9(1) / C(6A)-C(7A)-C(8A) / 121.2(1)
C(6A)-C(7A)-C(9A) / 116.7(1) / C(8A)-C(7A)-C(9A) / 122.0(1)
O(1A)-C(8A)-N(1A) / 115.8(1) / O(1A)-C(8A)-C(7A) / 128.2(1)
N(1A)-C(8A)-C(7A) / 116.0(1) / O(3A)-C(9A)-O(4A) / 122.0(1)
O(3A)-C(9A)-C(7A) / 125.7(1) / O(4A)-C(9A)-C(7A) / 112.3(1)
O(4A)-C(10A)-C(11A) / 112.4(1) / C(1B)-N(1B)-C(8B) / 125.9(1)
C(1B)-N(2B)-C(5B) / 119.9(1) / C(1B)-N(2B)-C(6B) / 121.9(1)
C(5B)-N(2B)-C(6B) / 118.2(1) / C(9B)-O(4B)-C(10B) / 114.2(1)
N(1B)-C(1B)-N(2B) / 118.5(1) / N(1B)-C(1B)-C(2B) / 120.8(1)
N(2B)-C(1B)-C(2B) / 120.7(1) / C(3B)-C(2B)-C(1B) / 119.7(1)
C(2B)-C(3B)-C(4B) / 118.5(1) / C(2B)-C(3B)-C(12B) / 121.4(1)
C(4B)-C(3B)-C(12B) / 120.2(1) / C(5B)-C(4B)-C(3B) / 120.7(1)
C(4B)-C(5B)-N(2B) / 120.5(1) / O(2B)-C(6B)-C(7B) / 128.3(1)
O(2B)-C(6B)-N(2B) / 115.3(1) / C(7B)-C(6B)-N(2B) / 116.4(1)
C(6B)-C(7B)-C(8B) / 121.2(1) / C(6B)-C(7B)-C(9B) / 115.9(1)
C(8B)-C(7B)-C(9B) / 123.0(1) / O(1B)-C(8B)-N(1B) / 115.5(1)
O(1B)-C(8B)-C(7B) / 128.8(1) / N(1B)-C(8B)-C(7B) / 115.6(1)
O(3B)-C(9B)-O(4B) / 121.4(1) / O(3B)-C(9B)-C(7B) / 125.3(1)
O(4B)-C(9B)-C(7B) / 113.3(1) / O(4B)-C(10B)-C(11B) / 107.7(1)
Ethyl group in the ester moiety is ар-conformation with respect to communication С(7)-С(9) [the С(10)-О(4)-С(9)-С(7) torsion angle is -174.7(1)º in А and -177.6(1)º in В]. Bond С(10)-С(11) in molecule А substantially orthogonal to the С(9)-О(4), and in molecule В is in antiperiplanary conformation relatively close to the same communication [the С(9)-О(4)-С(10)-С(11) torsion angle is -83.8(2)º in molecule А and -166.1(1)º in molecule В]. Such orientation ethyl group gives rise to interaction attractant Н(10а)…О(3) 2.39 Å in А and 2.38 Å in В.
In the crystal, molecules А and В, alternately flat form infinite chains by intermolecular hydrogen bonds hydrogen bonds N(1a)-H(1Na)…O(2b)' H…O 1.87 Å, N-H…O 171º and C(2a)-H(2a)…O(3b)' H…O 2.28 Å, C-H…O 159º between one pair of molecules А and В and intermolecular hydrogen bonds N(1b)-H(1Nb)…O(2a)' (1 + x, y, z - 1) H…O 1.92 Å, N-H…O 174º and C(2b)-H(2b)…O(3a)' (1 + x, y, z - 1) H…O 2.37 Å, C-H…O 163º between the next pair В and А. Degree of overlap and distance (3.3 Å) between neighboring chains suggest the existence between them sufficiently strong stacking interactions, leading to the appearance of crystal stacks. Water molecules are localized in the cavities between adjacent stacks, connect them through intermolecular hydrogen bonds O(1w)-H(1wa)…O(1a)' (1 - x, 1 – y, 2 - z) H…O 2.23 Å, O-H…O 148º; O(1w)-H(1wa)…O(4a)' (1 - x, 1 - y, 2 - z) H…O 2.31 Å, O-H…O 138º; O(1w)-H(1wb)…O(1b)' (x - 1, y, z + 1) H…O 1.96 Å, O-H…O 160º; O(2w)-H(2wb)…O(1a)' H…O 2.13 Å, O-H…O 164º; O(3w)-H(3wb)…O(1w)' (1 - x, 1 - y, 1 - z) H…O 2.00 Å, O-H…O 171º; O(3w)-H(3wa)…O(2w)' H…O 1.96 Å, O-H…O 170º.
Mass and NMR spectra and least important and provide useful information on the structure of ester 1 but, unlike X-ray analysis does not allow its uniquely treated so as not to contradict the principle of any of the above tautomeric forms. In particular, the signal of the proton of the hydroxyl group in the proton spectrum strongly broadened, which impedes correlation experiments, and thus establish its exact location. In 13C NMR spectrum broadened signals atoms C(2) and C(9) located near the nitrogen atom of N(1), which is obviously due to the presence of rapid metabolism in the molecule fragment. On this basis, it can be assumed that hydrogen is not fixed at the 2-OH group, and ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate in solution exists as an equilibrium mixture of the two tautomeric forms: 1 « 1а. However, rigorous proof of the existence of such tautomerism this fact, of course, can not be considered.
Experimental
1H and 13C NMR spectra of ester 1 recorded on a Varian Mercury-400 (at 400 and 100 MHz, respectively) in a solution of DMSO-d6, TMS internal standard. Mass spectra were recorded of a Varian 1200L instrument in full scan mode in the range of 35-700 m/z, with EI ionization (70 eV) and direct sample introduction. Elemental analysis was performed by microprobe EuroVector EA-3000. Melting points were determined on a capillary melting point of the digital analyzer SMP10 Stuart. Commercial 2-amino-4-methylpyridine and triethylmethanetricarboxylate from Fluka were used in this work.
Ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1). To heated to 150 оС 6.31 mL (0.03 mol) triethylmethanetricarboxylate (3) with vigorous stirring, a solution of 1.08 g (0.01 mol) 2-amino-4-methylpyridine (2) in 4.21 mL (0.02 mol) triethylmethanetricarboxylate at such a rate that the temperature the reaction mixture is in the range 150-155 оС, and gradually catching ethanol was distilled through mimicking reflux condenser. After addition of 2-amino-4-methylpyridine, stirring was continued for 1 h at the same temperature. Then change to a downtrend dephlagmator fridge and excess triethylmethane-tricarboxylate distilled under reduced pressure. The residue is cooled and crystallized from water. Obtained 2.23 g (81 %) of colorless crystals of hydrate of ester 1. M. p. 231-233 оС. 1H NMR spectrum, δ, ppm (J, Hz): 12.26 (1Н, br. s, ОН); 8.78 (1Н, d, J = 7.1, Н-6); 7.22 (1Н, d. d, J = 7.0 and 1.5, Н-7); 7.11 (1Н, s, Н-9); 4.12 (2H, k, J = 7.1, ОСН2); 2.44 (3Н, s, СН3); 1.20 (3Н, t, J = 7.1, СН2СН3). 13C NMR spectrum, δ, ppm: 166.03 (СОО), 159.89 (С-2), 156.98 (С-4), 154.20 (C-9а), 146.97 (C-8), 126.59 (C-7), 118.78 (C-6), 114.03 (C-9), 89.73 (C-3), 59.95 (OCH2), 21.88 (CH3), 14.85 (OCH2CH3). Mass spectrum, m/z (Irel, %): 248 (35.4) [M]+, 203 (23.4) [M-OEt]+, 176 (59.1) [M-COOC2H4]+, 148 (41) [M-COOC2H4-CO]+, 135 (100). Found, %: C 52.47; H 5.56; N 10.11. C12H12N2O4 · 1.5H2O. Calculated, %: C 52.36; H 5.49; N 10.18.
X-ray Structural Analysis. The resulting crystals from water hydrate of ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1) monoclinic [2(C12H12N2O4) · 3(H2O)], at –173 °С a = 10.706(2), b = 29.139(5), c = 8.006(1) Å, β = 90.02(1)°, V = 2497.6(7) Å3, Mr = 550.52, Z = 4, space group P21/c, dcalc = 1.464 г/см3, m(MoKa) = 0.117 мм-1, F(000) = 1160. The unit cell parameters and intensities of 25818 reflections (7260 independent reflections, Rint = 0.056) were measured on an Xcalibur-3 diffractometer using MoKa radiation, a CCD detector, graphite monochromator, and 2qmax = 60°).
The structure was solved by the direct method using the SHELXTL program package [27]. The positions of the hydrogen atoms were found from the electron density difference map and refined using the rider model with Uiso =nUeq (n = 1.5 for methyl groups and n = 1.2 for the other hydrogen atoms). The hydrogen atoms involved in hydrogen bonding, except for hydrogen atoms of the molecule H2О(3w), were refined isotropically. The structure was refined relative to F2 by the method of least squares anisotropically for non-hydrogen atoms to wR2 = 0.086 for 7200 reflections (R1 = 0.042 for 3753 reflections with F > 4s (F), S = 0.778). The interatomic distances and angles are shown in Tables 1 and 2 respectively. The complete crystallographic data about structure of ethyl 2-hydroxy-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylate (1) were deposited at the Cambridge Crystallographic Data Center – deposit № CCDC 1009990.
Conclusions