Ethyl 6-ethoxy­carbonyl­methyl-4-(2-hydroxy­phen­yl)-2-oxo-1,2,3,4-tetra­hydro­pyrimidine-5-carboxyl­ate

Viktor Kettmann; Jan Světlík; Lucia Veizerová

doi:10.1107/S1600536808012683

. 2008 May 17;64(Pt 6):o1092. doi: 10.1107/S1600536808012683

Ethyl 6-ethoxycarbonylmethyl-4-(2-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate

Viktor Kettmann ^a,^*, Jan Světlík ^a, Lucia Veizerová ^a

PMCID: PMC2961528 PMID: 21202607

Abstract

The title compound, C₁₇H₂₀N₂O₆, belongs to the monastrol-type of anticancer agents and was selected for crystal structure determination in order to confirm its molecular structure and explore some aspects of its structure–activity relationships. The central tetrahydropyrimidine ring has a flat-envelope conformation. The 4-hydroxyphenyl group occupies a pseudo-axial position and is inclined at an angle of 87.7 (2)° to the mean plane of the heterocyclic ring. Of the two ethyl ester groups, one (in the 5-position) is in a coplanar and the other (in the 6-position) is in a perpendicular orientation with respect to the heterocyclic plane. There is a three-dimensional hydrogen-bonding network in which all hydrogen-bond donors and acceptors are involved.

Related literature

For related literature, see: Allen (2002 ▶); Azizian et al. (2007 ▶); Qing-Fang et al. (2007 ▶); Endow & Baker (2003 ▶); Kettmann & Svetlík (1997 ▶); Světlík et al. (1991 ▶); Wood & Bergnes (2004 ▶).

Experimental

Crystal data

C₁₇H₂₀N₂O₆
M _r = 348.35
Triclinic,
a = 8.783 (2) Å
b = 9.336 (3) Å
c = 11.415 (4) Å
α = 71.47 (4)°
β = 82.78 (5)°
γ = 75.05 (4)°
V = 856.5 (5) Å³
Z = 2
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 296 (2) K
0.30 × 0.25 × 0.20 mm

Data collection

Siemens P4 diffractometer
Absorption correction: none
5849 measured reflections
4950 independent reflections
3935 reflections with I > 2σ(I)
R _int = 0.040
3 standard reflections every 97 reflections intensity decay: none

Refinement

R[F ² > 2σ(F ²)] = 0.057
wR(F ²) = 0.174
S = 1.04
4950 reflections
229 parameters
H-atom parameters constrained
Δρ_max = 0.31 e Å⁻³
Δρ_min = −0.32 e Å⁻³

Data collection: XSCANS (Siemens, 1991 ▶); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2003 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808012683/wk2083sup1.cif

e-64-o1092-sup1.cif^{(20.1KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808012683/wk2083Isup2.hkl

e-64-o1092-Isup2.hkl^{(242.4KB, hkl)}

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

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O1ⁱ	0.86	1.97	2.788 (2)	159
O2—H2⋯O3ⁱⁱ	0.82	1.95	2.772 (2)	177
N3—H3⋯O5ⁱⁱⁱ	0.86	2.20	3.0014 (18)	155

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Acknowledgments

This work was supported by the Grant Agency of the Slovak Republic, project Nos. 1/4298/07 and 1/4299/07.

supplementary crystallographic information

Comment

Recently, while we have been continuing in our programme aimed at synthesis of monastrol (1) analogues as valuable antitumour drugs (Wood & Bergnes, 2004), a related tetrahydropyrimidine compound (2) has been described by another group (Azizian et al., 2007). As we had reported earlier (Světlík et al., 1991; Kettmann & Svetlík, 1997) that classical Biginelli condensation with salicylaldehyde gives oxygen-bridged pyrimidine (3) rather than the 'open' molecule (4), the formation of (2) was accordingly unexpected. Thus, to verify the correctness of the title structure (2), an X-ray analysis was undertaken. As the cytotoxic activity of these derivatives is related to inhibition of the kinesin Eg5 protein (Endow & Baker, 2003), another purpose of this work was to determine detailed molecular conformation which is indispensable for an analysis of structure-activity relationships.

The structure determination has confirmed (Fig. 1) that the compound studied here has indeed the structure (2) (Fig. 2). As retrieved from the Cambridge Structural Database (Version of 2007; Allen, 2002), the bond lengths and angles (Table 1) within the tetrahydropyrimidine ring are equal within experimental error to those previously reported for a number of structures incorporating this molecular fragment (see, e.g., Qing-Fang et al., 2007). Bonding characteristics in other parts of the molecule also agree with those generally expected.

As noted above, from the biological standpoint, the conformational properties of the molecule are of prime interest here. First, the conformation of the central heterocycle can best be described as a flat envelope with atom C4 (at the flap) deviating by 0.433 (2) Å from the mean plane of the remaining atoms. As to the ring substituents, the 4-hydroxyphenyl group occupies the pseudoaxial position and is in a perpendicular orientation with respect to the tetrahydropyrimidine ring [dihedral angle 87.7 (2)°]; the conformation of the substituent on the exocyclic C4—C7 bond is synperiplanar, i.e. the hydroxy group is on the same side as the H atom on C4 (Fig.1). The ester group on C5 lies approximately in the plane of the C5=C6 double bond, with the carbonyl function oriented cis relative to this double bond. By contrast, the ethoxycarbonyl moiety of the 6-substituent is oriented, due to rather free rotation about the two C16 methylenic bonds, perpendicularly with respect to the mean plane of the heterocycle.

The crystal packing is dominated by hydrogen bonding. As shown in Table 2 and Fig. 3, each molecule forms two pairs of hydrogen bonds (N1-H···O1 and O2-H···O3) across centres of symmetry, which results in formation of chains of hydrogen-bonded molecules. The chains are interconnected by another independent hydrogen bond, N3-H···O5.

Experimental

Synthesis of the title compound, (2), has been described (Azizian et al., 2007). In short, heating of salicylaldehyde (0.52 ml, 5 mmol) with diethyl acetone-1,3-dicarboxylate (0.91 ml, 5 mmol) and urea (0.36 g, 6 mmol) under p-toluenesulfonic acid (0.04 g, 0.2 mmol) catalysis without solvent at 353–363 K for 3 h gave the desired product (50% yield; m.p. 488–490 K). Crystalssuitable for the X-ray analysis were obtained by a slow crystallization from ethanol.