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Boletín de la Sociedad Chilena de Química

versão impressa ISSN 0366-1644

Bol. Soc. Chil. Quím. v.46 n.2 Concepción jun. 2001

http://dx.doi.org/10.4067/S0366-16442001000200002 

CRYSTAL STRUCTURE OF 3-CARBOXYMETHYL-4-(4-
CHLOROPHENYL)-2,7,7-TRIMETHYL-5-OXO-1,4,5,6,7,8-
HEXAHYDROQUINOLEINE.

JULIO DUQUE 1*, RAMON POMES 1, MARGARITA SUAREZ 2, ESTAEL
OCHOA 2, YAMILA VERDECIA2, GRACIELA PUNTE 3 AND GUSTAVO
ECHEVARRIA 3

1 X-ray Laboratory, National Center for Scientific Research, P.O.Box 6990, Havana, Cuba.
2 Laboratory of Organic Synthesis, Faculty of Chemistry, Havana University, Cuba.
3 Diffraction Laboratory. (LANADI). University of La Plata, La Plata Argentina.
(Received: Febrero 25, 2000 - Accepted: July 24, 2000)

ABSTRACT

3- carboxymethyl- 4- (4-chlorophenyl) -2, 7, 7- trimethyl- 5-oxo -1,4,5,6,7,8-hexahydroquinoleine C20 H22 O3 N Cl cristallyzed from ethanol solution as transparent white crystal, the crystal belong to an monoclinic system with space group P21/n, with a= 9.331(2), b= 18.340(4) and c= 11.493(2) Å,b= 109.74(2)°, Z=4.

The 4-aryl substituent occupies a pseudoaxial possition, almost orthogonal to the plane of the dihydropyridine ring. The ester group show a preference for the trans arrangement with respect to the double bond of the dihydropyridine ring. The 1,4-dihydropyridine ring adopts a "boat" conformation. There are two hydrogen bonds, intramolecular hydrogen bond between C2A methyl group O1 [C2A....O1]: 2.724(8) Å and intermolecular hydrogen bond [N....O3]: 2.861(1) Å.

KEYWORDS: x-ray diffraction, Molecular conformation, Pharmacological effect.

RESUMEN

El compuesto, 3- carboximetil- 4- (4-clorofenil) -2, 7, 7- trimetil- 5-oxo -1,4,5,6,7,8-hexahidroquinoleina C20 H22 O3 N Cl, se recristalizó a partir de una solución de etanol, obteniéndose cristales transparentes de color blanco, cristaliza en el sistema monoclínico con grupo espacial P21/n, a= 9.331(2), b= 18.340(4) y c= 11.493(2) Å, b= 109.74(2)°, Z=4.

El sustituyente 4-aril ocupa una posición pseudoaxial ortogonal al plano del anillo de dihydropyridina. El grupo éster muestra preferencia por el ordenamiento trans con respecto al doble enlace del anillo de dihydropyridina. El anillo 1,4-dihydropyridina adopta conformación tipo "bote". Existen dos puentes de hidrógenos, uno intramolecular entre el C2A del grupo metil y el O1 [C2A.O1]: 2.724(8) Å y uno intermolecular [N.O3]: 2.861(1) Å.

PALABRAS CLAVES: Difracción de rayos x, conformación molecular, efecto farmacológico.

INTRODUCTION

Since the discovery of the pharmacological effects of the 1,4-dihydropyridine (1,4 DHP) as calcium channel blockers (1), a great deal of work has been directed towards the synthesis of novel 1,4-DHP acting as calcium antagonist (1). Substitution on the 1,4 DHP ring has been widely studied (2) due to dramatic effects that some substituents have on their biological activities. For these reasons is interesting to know which conformation produces the optimum result in 1,4 DHP of Nifedipine type and, consequently the relationship between conformation and pharmacological effect (3). Most of the syntheses are based on the Hantzsch condensation of b-aminocrotonates and the appropriate aldehydes. Others dicarbonyl compounds have been used to obtain fused 1,4 DHP systems (4).

We have determined the crystal structure of the 3-carboxymethyl-4-(4-chlorophenyl) -2,7,7-trimethyl- 5-oxo -1,4,5,6,7,8-hexahydroquinoleine

EXPERIMENTAL

A mixture of dimedone (10 mmol), methyl-b-aminocrotonate, (10 mmol), 4-chlorobenzaldehyde (10 mmol) in ethanol, was refluxed for 1 hour and then poured into ice water. The solid that precipited was collected by filtration. Yield 65 %, m.p. 252-254o. IR: \gmax 1650, 1700; 3300 1H RMN \g 095 (s, 6H, CH3), 2.15 (m, 2H, CH2); 2.42(m, 2H, CH2); 2.26 (s, 3H, CH3); 3.59 (s, 3H, OCH3); 5.39 (s, 1H, H-4), 7.10-7.3 (q, 4H, phenyl); 9.18 (s, 1H, NH) 13H RMN \g 18.4 (C2a); 26.4, 29.2 (C7ab); 32.2 (C7); 35.5 (C4); 50.2 (C8); 50.7 (C6); 102.8 (C3); 109.7 (C4a); 127.8, 129.2, 130.4, 145.8, 146.9 (CAr); 149.7 (C2); 167.2 (COO); 194.4 (CO). Anal. Calcd for C20H22NO3CL: C, 66.76; N, 3.89; H, 6.11. Found: C 66.80; N, 3.98; H, 6.20.

The structure was solved by direct method using the Shelxl-97 program, (5) and the position of all the non-hydrogen atoms in the molecule were successfully assigned.

The structure was refined by full-matrix least-squares methods, the positions of all hydrogen atoms were assigned geometrically, all non-hydrogen atoms were refined together with the positional and anisotropic thermal parameters, the final R value was 0.0672 for 1914 non-zero reflections, throughout the refinements, a unit weight was given to the intensity of each reflection.

A crystal of dimensions 0.2 x 0.2 x 0.1 mm was selected and mounted on the diffractometers Enraf-Nonius CAD-4 (6), and data collection preceded at 293 K using Mo Ka radiation (l= 0.71069 Å). Unit cell constants were derivated by least-squares from 25 reflections. The q/2q scan mode was used to record the integrate intensities. Peaks were subjected to profile analysis, and any portions of the scan not included in the peaks were used to improve background estimates.

The deepest hole was ­0.357 e Å-3, and the highest peak was 0.322 e Å-3. All program used are part of the SHELXL97. Details of crystal data, data collections and structure solutions and refinement can be found in Table I.

RESULTS AND DISCUSSION

The 4-aryl substituent occupies a pseudoaxial position, almost orthogonal to the plane of the dihydropyridine ring (85.1o). This pseudoaxial position of the 4-aryl, is also accompanied by the rotation of the aryl ring with respect to the bisectrize of the intraanular angle C3-C4-C4A. The dihydropyridine ring adopts a boat conformation, with asymmetric parameters DS(N)= 0.000(4) and DS(C4A-C8A)= 0.036(3) (7). The ester in the 3 position of the dihydropyridine ring assumes the antiperiplanar conformation (ester carbonyl with respect to the dihydropyridine double bond).

The sum of the absolute values of the six interior torsions angles of this compound [C2-C3-C4-C4A: 23.61; C4-C3-C2-N: -6.52; C3-C4-C4A-C8A: -23.73; C2-N-C8A-C4A: 13.23; C8A-N-C2-C3: -13.33; C4-C4A-C8A-N: 6.77] is 87.19o. This parameter has been shown to correlated with pharmacologic potency as a calcium channel antagonist (The smaller this sum, the greater the biological activity), for references, the analogous sum in Nifedipine is 72.1o (8). The value of the C2-N-C8a valence angle is 122.3o determined by X-ray, showing an sp2 hydridization for the nitrogen atom.

The N hydrogen atom is involved in an intermolecular hydrogen bond. The aceptor atom in this case is a carbonyl oxygen of the cyclohexanone of a neighboring molecules, [N....O3: 2.861(1) Å, .5+x;.5-y; .5+z)], and there is an intramolecular hydrogen bond between C2A methyl group and O1 atom, [C2A....O1: 2.724(8) Å]. Pairs of molecules related by centres of symmetry are connected forming dimers.

It is important to note that the geometrical parameters calculated for this conformation are in good agreement with those found by X-ray analysis for conformational feature on this class of compound.

The final atomic coordinates and isotropic thermal parameters for the non-hydrogen atoms are give in Table II. The bond lengths (Å), selected torsion angles (o) and intermolecular and intramolecular hydrogen bonding with e.s.d.'s are listed in Table III. Thermal ellipsoids plot (9), hydrogen atoms are represented as spheres of arbitrary radii shown in Fig. 1. The arrangement of the molecules in the unit cell is presented in Fig .2 (The intermolecular and intramolecular hydrogen bonds are denoted by dashed lines).

Fig.1 Molecular structure of C20 H22 O3 N Cl, showing 50% probability displacement.

Fig 2. Packing of the molecules in the unit cell (hydrogen bond as denoted by dashed lines)

SUPLEMENTARY MATERIALS

List of obesrved and calculated structure factors are available, on request, from X-ray Laboratory, National Center for Scientific Research (CNIC), P.O. Box 6990, Havana, Cuba.(e mail : xray@infomed.sld.cu).

ACKNOWLEDGEMENT

The authors thank the Third World Academy of Science for financial support through the TWAS South-South research program and gratefully acknowledgements to Proyectos Alma Mater (Havana University) for financial support.

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