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Boletín de la Sociedad Chilena de Química

versión impresa ISSN 0366-1644

Bol. Soc. Chil. Quím. v.45 n.2 Concepción jun. 2000

http://dx.doi.org/10.4067/S0366-16442000000200002 

CRYSTAL STRUCTURE OF METHYL-2,7,7-TRIMETHYL-4-PHENYL-5-OXO-1,4,5,6,7,8-HEXAHYDROQUINOLINE-3-CARBOXYLATE.

JULIO DUQUE1*, RAMON POMES1, MARGARITA SUAREZ2, ESTAEL OCHOA2, GRACIELA PUNTE3 AND GUSTAVO ECHEVARRIA3

1X-ray Laboratory, National Center for Scientific Research, P.O. Box 6990, Havana, Cuba.
2Laboratory of Organic Synthesis, Faculty of Chemistry, Havana University, Cuba.
3Diffraction Laboratory (LANADI), University of La Plata, La Plata Argentina.
(Received: November 17, 1999 - Accepted: December 16, 1999)

In memoriam of Doctor Guido S. Canessa C.

ABSTRACT

The crystal and molecular structure of the Methyl-2,7,7-trimethyl-4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3 carboxylate, C20 H23 NO3, has been determined by X-ray diffraction. Crystals are monoclinic, space group P21/n; a = 9.646(2), b = 16.586(2), c = 11.111(1) Å, b = 102.35(1)°, Z = 4. The conformation of the 1,4-dihydropyridine ring (1,4-DHP) is described in trms of the torsion angles about the intraring bonds. The molecules are linked by intermolecular bond between the N atoms and the pirymidine O3 atom of a neighboring molecule [N1....O3: 2.865(4) Å].

KEY WORDS: crystal structure, 1,4 dihydropyridine, molecular conformation and calcium channel antagonist.

RESUMEN

La estructura cristalina y molecular del Metil-2,7,7-trimetil-4-fenil-5-oxo-1,4,5,6,7,8-hexahidroquinolina-3-carboxilato, C20 H23 NO3 , fue determianda utilizando difracción de rayos-X en monocristales. Los cristales pertenecen al sistema monoclínico, con grupo espacial de simetría P21/n; a = 9.646(2), b = 16.586(2), c = 11.111(1 Å, b = 102.35(1)°, Z = 4. La conformación del anillo de 1,4-dihidropiridina (1,4-DHP) se define por los ángulos de torsión de dicho anillo. Las moléculas en el cristal están unidas por puentes de hidrógenos intermoleculares entre el átomo de N y el átomo de O3 de la pirimidina de la molécula vecina [N1....O3: 2,865(4) Å].

PALABRAS CLAVES: estructura cristalina, 1,4 dihidropiridina, conformación molecular y antagonista de los canales de calcio.

INTRODUCTION

The calcium channel antagonists are a group of structurally diverse drugs which inhibit the influx of Ca2+ through plasma membrane channels, thus dilating vascular smooth muscle and alleviating the force of cardiac muscle contraction1). The chiral 4-aryl-1,4-dihydropyridines offer an exciting field for the investigation of calcium channels, particularly since the discovery that enantiomers could have exactly the opposite action profile, one of them being a calcium antagonist and the other an agonist2,3). The study of these compounds should facilitate information about structural requirements for improved biological activity but also implies a chemical challenge since resolution of enantiomers or development of stereoselective syntheses to obtain novel dihydropyridines with improved therapeutical applications4). Many derivatives of 4-aryl-1,4-dihydropyridine structures exhibit high affinity for calcium channel receptors and may act as agonist or antagonists, depending on the nature of the derivative.

In this work we have determined crystal structure of methyl-2,7,7,7-trimethyl-4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate.

EXPERIMENTAL

A mixture of dimedone (10 mmol), methyl-b-aminocrotonate (10 mmol), 2-chlorobenzaldehyde (10 mmol) in ethanol, was refluxed for 1 hour and then poured into ice water. The solid taht precipitated was collected by filtration. Yield 58%, mp. 248-250°C. IR:/Gmax 1648, 1700; 3280 1H-RMN/G 0.93,, 1.05 (s, 6H, CH3 (7a,b); 2.15(m, 2H, CH2)); 2.24(m, 2H, CH2(6)); 2.25(s, 3H, CH3(2a)); 3.59(s, 3H, OCH3); 5.39(s, 1H, H4); 6.71(s, 1H, NH), 7.10-7,37 (m, 4H, phenyl) 13C-RMN/g. 19.1(C2a); 27.2, 29.4 (C7a,b); 32.5(C7); 35.6(C4); 40.9(C8); 50.7 (C6); 105.1(C3); 111.3(C4a); 126.4-144(Ca5); 144.4(C2); 168(COO); 195.6(CO). Anal. Calcd for C20H22NO3Cl; C, 66.76; N, 3.89; H, 6.11, Found: C, 66.85; N, 3.95; H, 6.17. X-ray quality crystals were grown by slow evaporation from ethanol.

A crystal of dimensions 0.3 x 0.3 x 0.2 mm was selected and mounted on the diffractometers (Enraf-Nonius CAD-4), and data collection preceded at 293 K using Mo Ka radiation (l = 0.71069 Å). Unit cell constants were derivative by least-squares from 25 carefully centered reflections in the range 10 < q < 16°. 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 structure was solved by using direct methods SHELXL97 program10). Most of the non-hydrogen atoms were locate in the E-map, and the remainders were found in a subsequent difference electron density map. They were refined on F2 by full matrix least-squares, originally with isotropic and later anisotropic temperature factors. All H-atoms were calculated at he idealized positions based on the molecular geometry. They were assigned isotropic temperature factors set at 1.2 time temperature factors of respective factors to which they were bonded. Refinement was continued until all shift/error ratios were 0.1. Least-squares refinement was performed minimizing the wR value. In the final difference Fourier map, the deepest hole was -0.226 e Å-3, and the highest peak was 0.287 e Å-3. All program used are part of the SHELXL97. Details on crytal data, data collections and structure solutions and refinement can be found in Table I

 

TABLE I. Summary of crystal data and conditions for crytallographic data collection structure solution
and refinement.

Crystal Data

 

C20H24NO3

MoKa, radiation: l = 0.71069 Å

M.W. = 325.41

Cell parameters from 25 reflections

Crystal system: Monoclinic

Absorption coefficient (µ): 0.0833 mm-1

Space group: P21/n

Temperature: 293(2) K

Cell parameters:

Crystal color: yellow
a = 9.646(2) Å Crystal form: laminar
b = 16.586(2) Å Crystal dimensions: 0.3x0.3x0.2
c = 11.111(1) Å Crystal source: Recrystallization from ethanol
b = 102.35(1)°  
Unit cell content (Z): 4  
V = 1736.5(4) Å3  
Calculated density (Dx): 1,2447 Mg m-3  
   

Data collection

 

Enraf-Nonius CAD 4 diffratometer

Rint = 0.0378

w-2q scan

qmax = 25.0°

Absorption correction: none

h = -10 to 10

2794 measured reflections

k = -1 to 18

2452 independent reflections

l = 0 to 11

1381 observed reflections

 
   

Refinement

 

Refinement on F2

R(F) = 0.0534

wR(F2) = 0.1730

S = 1.04

w = 1/s2(Fo2) + (0.0567P)2 + 2.0437P]

(D/s)max = 0.01

Where: P = (Fo2 + 2Fo2)/3

Drrmax = 0.287 e Å-3
 

Drrmin = -0.226 e Å-3

RESULTS AND DISCUSSION

We have determined crystal structure of methyl-2,7,7-trimethyl-4-phenyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate. The structure of title compound is similar to that of related analogs, the 4-aryl substituent occupies a pseudoaxial position, almost orthogonal to the plane of the dihydropyridine ring (87.6°). This pseudoaxial position of the 4-aryl ring, which is reported to be essential for phamacological activity6). The ester group adopts an "equatorial" arrangement because of sp2 hybridization of the dihydropyridine C3 atom. The ester group shows a preference for the cis-cis arrangement with respect to the double bond of the dihydropyridine ring, the cis arrangement of at least one of the ester group seems to be enough for a satisfactory calcium antagonist effect and hydrogen bonding to receptor7).

The 1,4-dihydropyridine ring adopts a "boat" conformation. The ring puckering DS(N) = 0.0010(2). The deviations from the least-squares plane through C3, C2, C4a, C8a are: C3 = 0.007(4), C2 = 0.008(4), C4a = -0.006(4), C8a = 0.007(4), C4 = -0.287(4), N = -0.115(4)8). The distorsion from planarity of the atoms comprising the dihydropyridine ring can be clearly seen from the torsion angles calculated about the ring bonds (Table III). The magnitude of these angles would be zero degrees if the ring atoms were coplanar. The greatest displacement from zero occurs about the bonds from N and C4, indicating that the greatest degree of ring puckering occurs at these positions, the distortion being greatest at the C4 position. The magnitude and sing of these torsion angles indicate that both C4 and N are displaced from the ring in the same direction, opposite to that of the phenyl ring, which imparts a boat type conformation to the dihydropyridine ring.

 

TABLE III. Bonds distances (Å), select torsion angles (°) and intermolecular hydrogen bonding.

C1'-C2' 1.381(6) C5'-C6' 1.381(7)
C1'-C6' 1.388(6) C4-C4A 1.516(5)
C1'-C4 1.515(6) C4-C3 1.524(5)
C2'-C3' 1.367(7) C3-C2 1.351(5)
C3'-C4' 1.343(8) C3-C3A 1.458(6)
C4'-C5' 1.378(8) C2-N1 1.377(5)
C5'-C6' 1.381(7) N1-C8A 1.362(5)
N1-C8A 1.362(5) C7-C6 1.530(5)
C8A-C4A 1.355(5) C6-C5 1.501(6)
C8A-C8 1.491(5) C5-O3 1.238(4)
C8-C7 1.529(6) C5-C4A 1.437(5)
C7-C7A 1.518(6) O1-C3A 1.352(5)
C7-C7B 1.520(6) O1-C9 1.427(5)
C7-C6 1.530(5) O2-C3A 1.202(5)
  O2-C3A 1.202(5)  
       
C4A-C4-C3-C2 -23.39(5) C3-C2-N-C8A 10.88(6)
C8-C8A-C4A-C4 175.85(4) C3-C4-C4A-C8A 21.93(5)
C2-N-C8A-C4A -12.39(6) C4-C3-C2-N 8.63(6)
N-C8A-C4A-C4 -5.79(5)    
       
D-H D....A H....A D-H....A
N1-H1A: 0.900(3) N1....O3: 2.865(4) H1A....O3: 2.030(3) N1-H1A....03: 153.73(2)

The ester group is considered cis because the carbonyl group eclipses the adjacent double bond (C2-C3) of the dihydropyridine ring9). The carbonyl group of the C3 methyl ester is synperiplanar to the C3-C2 ring double bond, with torsion angles of -2.2° for C2-C3-C3a-O2. The values for these parameters also agree with those reported for other 1,4-dihydropyridine calcium channel antagonist. The molecules are linked by an intermolecular hydrogen bond between the N atom and the pyrimidine ring O3 atom of neighboring molecules [N1....O3: 2.865(4) Å; (x-.5; -y+.5; z-.5)].

Final fractional coordinates for the non-hydrogen atoms and equivalent isotropic temperature factor can be found in Table II. Table III summarizes the bond distances, bond angles involving non-hydrogen atoms and intermolecular hydrogen bonding with e.s.d.'s Thermal ellipsoids plot (SHELTXTL-Plus; Sheldrick, 1991), hydrogen atoms are represented as spheres of arbitrary radii shown in Figure 1. The arrangement of the molecules in the unit cell is presented in Figure 2. (The intermolecular hydrogen bonds are denoted by dashed lines).

TABLE II. Fractional atomic coordinates and equivalent isotropic displacement parameters (Å2).

 

Ueq = (1/3) SiSjUij ai aj ai.aj


Atom

X/a Y/b Z/c Ueq

C1'

-0.0519(4) 0.2672(4) 0.1919(6) 0.0385

C2'

-0.0066(3) 0.2722(3) 0.3183(1) 0.0585
C3' -0.0836(7) 0.3132(7) 0.3886(5) 0.0814
C4' -0.2043(3) 0.3517(4) 0.3371(4) 0.0829
C5' -0.2527(3) 0.3485(2) 0.2113(1) 0.0770
C6' -0.1775(5) 0.3062(8) 0.1393(5) 0.0541
C4 0.0298(4) 0.2191(3) 0.1142(4) 0.0356
C3 -0.0463(4) 0.1401(4) 0.0725(6) 0.0365
C2 -0.1259(3) 0.1318(4) -0.0425(8) 0.0391
N -0.1241(4) 0,1911(0) -0.1289(9) 0.0410
C8A -0.0280(9) 0.2525(4) -0.1101(4) 0.0349
C8 -0.0176(5) 0.3000(6) -0.2219(5) 0.0428
C7 0.0452(3) 0.3841(6) -0.1921(5) 0.0401
C6 0.1805(5) 0.3742(8) -0.0921(7) 0.0467
C5 0.1611(0) 0.3272(4) 0.0185(6) 0.0375
C4A 0.0530(8) 0.2662(4) 0.0033(3) 0.0326
O1 0.0543(4) 0.0930(8) 0.2692(7) 0.0569
O2 -0.0980(6) 0.0116(1) 0.1493(3) 0.0696
O3 0.2415(1) 0.3400(9) 0.1195(6) 0.0541
C3A -0.0375(5) 0.0753(7) 0.1625(1) 0.0444
C9 0.0636(9) 0.0354(2) 0.3661(5) 0.0699
C2A -0.2222(6) 0.0626(7) -0.0910(1) 0.0518
C7A -0.0593(3) 0.4380(3) -0.1457(3) 0.0624
C7B 0.0811(4) 0,4210(3) -0.3068(0) 0.0622


FIG. 1. Molecular structure of C20H23NO3, showing 50% probability displacement


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

SUPPLEMENTARY MATERIALS

List of observed and calculated structure factors are available, on request, from X-ray Laboratory, National Center for Scientific Research (CNIC), P.O. Box 6990, Havana, Cuba.

ACKNOWLEDGEMENTS

The authors thank the Third World Academy of Science for financial support through the TWAS South-South research program.

*To whom corrspondence should be addressed

 

REFERENCES

1. R.A. Janis, P. Silver and D.J. Triggle. Adv. Drug Res., 16, 309-391 (1987).

2. G. Franckowiak, M. Bechem, M. Schramm and G. Thomas. Eur. J. Pharmacol., 114, 223-226 (1985).

3. M. Schramm, G. Thomas, R. Towart and G. Franckowiak. Nature, 303, 535-537 (1983).

4. X.Y. Wei, E.M. Luchowski, A. Rutledge and D.J. Triggle. J. Pharmacol. Exp. Ther., 239, 144-153 (1986).

5. G.M. Sheldrick. The SHELX-97 Manual, Univ. of Gottingem, Germany (1997).

6. D.A. Langs and D. Triggle. Acta Crystallogr. Sect. C: Crystal Structure Commun., C43, 707-711 (1987).

7. R. Fossheim. J. Med. Chem., 29, 305-307 (1986).

8. W.L. Duax, C.M. Weeks and D.C. Rohres. Topics in Stereochemistry Vol. 9, ed. Eliel, E.L. and Allinger, N. New York, John Wiley, 217-383 (1976).

9. C.K. Oliver and M.F. Walte.r. Tetrahedron, 53(8), 2803-2816 (1997).

10. G.M. Sheldrick. SHELXTL-Plus Release 4.1 Siemens Analytical X-Ray Instrument Inc., Madison, Wisconsin, USA (1991).