4-(2,3-Dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-bis(methoxycarbonyl) , 4-(2,4-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-bis(methoxycarbonyl) , and 4-(2,3,5-trichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-bis(methoxycarbon yl):

Article abstract of DOI:10.1023/A:1011904401069

Hydrogen bonding interactions displayed by three crystalline chloro-substituted 4-phenyl-1,4-dihydropyridine molecules 4-(2,3-Dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-bis(methoxycarbonyl) , 4-(2,4-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridi

Full text of DOI:10.1023/A:1011904401069

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c
Journal of Chemical Crystallography, Vol. 30, No. 10, October 2000 ( 2001)
4-(2,3-Dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-bis(methoxycarbonyl), 4-(2,4-dichlorophenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-bis(methoxycarbonyl), and
4-(2,3,5-trichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-bis(methoxycarbonyl): conformational observations
in the crystalline state
Gregori A. Caignan(1) and Elizabeth M. Holt(1)*
Received December 18, 2000
Hydrogen bonding interactions displayed by three crystalline chloro-substituted 4-phenyl-
1,4-dihydropyridine molecules 4-(2,3-Dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-bis(methoxycarbonyl), 4-(2,4-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-bis
(methoxycarbonyl) and 4-(2,3,5-trichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-bis
(methoxycarbonyl), suggests that, in contrast to previous observation, sp orientation of the 3
or 5 substituted carbonyl group accomodates hydrogen bonding to the carbonyl oxygen atom
when polar orthosubstituents exist on the phenyl ring.
KEY WORDS: Hydrogen bonding; 1,4-dihydropyridine; calcium beta blockers; single crystal structures.
Introduction
1,4-Dihydropyridine derivatives (DHPs, Fig. 1)
narity achieved by making ring A aromatic is detri-
mental to activity.4,5 The B ring substituted at the four
position should be found in a pseudo axial orientation
---- ---- ----
comprise a class of calcium antagonists which are
widely marketed for use as vasodilators and in the
treatment of angina and cardiac arrhythmia. DHPs
inhibit the flow of extracellular Ca2+ ions through
the voltage sensitive L-type calcium channels found
in skeletal and cardiac smooth muscle.1 Early work
using rabbit skeletal muscle trans-tubule membrane
established the amino acid sequence of a 29 residue
moiety located in the alpha1 subunit of such channels
which appears to contain the receptor site.2
and close to orthogonality with the C2 C3 C5 C6
basal plane of the DHP boat. Ortho and meta sub-
stituents on the B ring should point away from the
A ring (prow position) and not back over the A ring.
Electron withdrawing substituents on the B ring con-
tribute to potency in relation to their position: or-
tho substituents improving potency more than meta
ones; while para substitution has little effect. The car-
bonyl double bonds of the ester moieties at C3 and
C5 of ring A are usually found to be coplanar with
Structure activity relationship studies3 have es-
tablished certain conformational requirements for
potency. An active DHP molecule (Fig. 1) should have
its A ring in a flattened boat conformation (total pla-
the conjugated C C bonds of the A ring. This is to
==
be expected because electron delocalization through
the conjugated system increases the stability of the
molecule. The conformation of the carbonyl groups
of the ester moieties may be ap or sp relative to the
near double bond of the DHP ring (Fig. 1).
(1) Department of Chemistry, Oklahoma State University,
Stillwater, Oklahoma 74078, USA.
*To whom correspondence should be addressed.
Evaluation of the potential potency of a DHP
molecule may be achieved by using molecular
677
C
1074-1542/01/1000-0677$18.00/0 2001 Plenum Publishing Corporation

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678
Caignan and Holt
Fig. 1. View of the 1,4-dihydropyridine framework showing num-
bering, ring identification, and defining ap and sp orientation of
carbonyl groups.
(a)
modeling to observe the strength of the interaction of
docking of the drug into a receptor site. Early work us-
ing Sybyl6 involved observation of the most favorable
binding energies when a static DHP molecule was fit,
B ring first, into a static receptor site. Comparison of
these “best” binding strengths paralleled in vivo activ-
ity. ThereforeSybylwaswidelyappliedtoevaluatepo-
tential potency of DHP derivatives prior to synthesis.
Second-generation software7,8 permits rotation
about specified bonds of both drug and receptor
site groups and thus a more realistic approach to
the docked state of the molecule. However, these
programs often do not agree on the way in which the
drug is bound to the supposed receptor site nor on
the specific location of the DHP receptor site. Thus
one seeks other avenues to knowledge of modes of
DHP interaction with polar environments as a basis
for evaluation of the molecular modeling results and
as a basis for understanding how to maximize binding
efficiency by DHP design.
(b)
The DHP environment in the crystalline solid,
where near neighbors are other identical molecules
and perhaps some solvent molecules, is surely differ-
ent from that of the environment of the receptor site.
However, the process of crystallization, of maximiz-
Fig. 2. (a, b) Projection views of the two molecules per asymmetric
unit of 4-(2,3-Dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-bis(methoxycarbonyl) (ellipsoids are shown at the 50% proba-
bility level).
----
ing hydrogen bonding, dipole dipole, and van der
Waals-type interactions within the assembling solid
must mimic the behavior of maximizing these same
interactions when a molecule approaches its dock-
ing site. Both are processes of molecular recognition,
i.e., the DHP molecules response to potential inter-
actions as it crystallizes must be similar to its behav-
ior while docking. Thus it is worthwhile to examine
patterns of molecular interaction in the crystal as a
guide to what to expect in the docked molecule. Of
interest are patterns of rotation of carbonyl groups
and/or the B ring in response to hydrogen bond-
ing opportunities. Particularly useful to this end are
examinations of series of DHP structures contain-
ing similar B-ring substituents because they offer

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Chlorophenyl-substituted dihydropyridines
679
Experimental synthesis
4-(2,3-Dichlorophenyl)-2,6-dimethyl-1,4-
dihydopyridine-3,5-bis (methoxy carbonyl) (I)
2,3-Dichlorobenzaldehyde (5 g, 2.86 10 2 mol),
2
methyl acetoacetate (6.635 g, 5.72 10 mol), and
2
2.002 g (5.72
10 mol) of concentrated ammo-
nium hydroxide were mixed in 40 ml of methanol and
refluxed for 12 hr. The methanol was then removed by
rotary evaporation leaving a yellow solid which was
dissolved in acetonitrile. The solution was dried over
MgSO4. Yellow crystals formed upon slow evapora-
tion of the acetonitrile solution.
4-(2,4-Dichlorophenyl-2,6-dimethyl-1,4-
dihydropyridine-3,5-bis (methoxycarbonyl) (II)
Fig. 3. Projection view of 4-(2,4-dichlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-bis(methoxycarbonyl)(ellipsoidsareshownat
the 50% probability level).
2,4-Dichlorobenzaldehyde (5 g, 2.86 10 2 mol),
methyl acetoacetate (6.635 g, 5.72 10 mol), and
2
2.002 g (5.72 10 2 mol) of concentrated ammonium
hydroxide were mixed in 40 ml of methanol and re-
fluxed for 12 hr. The methanol was then removed
under reduced pressure and the yellow solid which
remained was dissolved in acetonitrile and the solu-
tion dried over MgSO4. Yellow crystals formed on
standing.
multiple observations of the molecule adapting to its
environment. We have prepared three DHP deriva-
tives with chloro substituted B rings to further this
investigation.
4-(2,3,5-Trichlorophenyl)-2,6-dimethyl-1,4-
dihydropyridine-3,5-bis (methoxycarbonyl) (III)
2
2,3,5-Trichlorobenzaldehyde (3 g, 1.44
10
10
2
mol), methyl acetoacetate (3.341 g, 2.88
2
mol), and 1.008 g (2.88
10 mol) of concen-
trated ammonium hydroxide were mixed in 40 ml
of methanol and heated under reflux for 12 hr. The
methanol was then removed by rotary evaporation
and the residual yellow solid dissolved in acetoni-
trile and the solution dried over MgSO4. Yellow crys-
tals formed upon slow evaporation of the acetonitrile
solution.
X-ray crystallography
Single crystals of (I), (II), and (III) were mounted
on a Siemens P4 automated single-crystal diffrac-
tometer. Data were collected (Table 1) and cor-
rected for Lorentz, polarization, and background
effects.9 The intensities of 3 standard reflections were
Fig. 4. Projection view of 4-(2,3,5-trichlorophenyl)-2,6-dimethyl-
1,4-dihydropyridine-3,5-bis(methoxycarbonyl) (ellipsoids are
shown at the 50% probability level).

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680
Caignan and Holt
Table 1. Crystal Data for Compounds I, II, and III
Compound
I
II
III
CCDC Deposit no.
Formula
CCDC-1003/5956
C17 H17 Cl2 N O4
370.22
Triclinic
P1bar
9.809(4)
12.714(7)
16.071(9)
112.36(3)
91.40(3)
101.72(3)
1803.4(16)
4
CCDC-1003/5957
C17 H17 Cl2 N O4
370.22
Monoclinic
P21/c
10.951(10)
11.358(11)
14.77(3)
CCDC-1003/5958
C17 H16 Cl3 N O4
404.66
Monoclinic
P21
8.654(4)
10.206(5)
Molecular weight
Crystal system
Space group
˚
a, A
˚
b, A
˚
c, A
10.463(5)
,
,
,
97.58(8)
90.45(4)
3
˚
V, A
1821(5)
4
1.351
924.1(8)
2
1.454
Z
D
3
cal, Mg m
1.364
Temperature, K
F(000)
301
768
301
768
301
416
Crystal size, mm
Lattice determination
, mm
0.05 0.1 0.1
0.1 0.1 0.1
0.05 0.1 0.3
44 reflections 4.908 < < 14.288 48 reflections 4.994 < < 12.674 32 reflections 7.716 < < 12.718
0.380
1
0.376
0.517
Data collection range
Range of indices
3.5 < 2 < 48.82
h, 11 to 1; k, 14 to
3.5 < 2 < 45.44
h, 1 to 11; k, 1 to 11;
3.5 < 2 < 53.74
h, 10 to 1; k, 12 to 1;
14; l, 18 to 18
l, 16 to 16
l, 13 to 13
Scan type
2
2
2
Scan range ( 2 )
Scan speed, /min
Reflections measured
Unique reflections
1.20
1.20
1.20
Variable 10 to 30
7053
5906
Variable 10 to 30
2973
2324
Variable 10 to 30
3677
2185
R
8.19
3.82
4.43
int
Weighting scheme
calc w = 1/[ 2(Fo2) +
calc w = 1/[ 2(Fo2)+
calc w = 1/[ 2(Fo2)+
(0.1127P)2 + 0.2222P]
(0.2000P)2 + 0.0000P]
(0.0372P)2 + 0.0000P]
where P = (Fo2 + 2Fc2)/3
where P = (Fo2 + 2Fc2)/3
where P = (Fo2 + 2Fc2)/3
R(I > 2 (I))
Goodness of fit
Number of parameters
6.17
1.026
434
5.83
1.001
220
5.98
1.00
231
Maximum peak in final
1F map, eA
0.39
0.23
0.27
3
˚
Minimum peak in final
1F map, eA
0.29
0.28
0.27
3
˚
monitored after every 97 reflections. Crystal decom-
position was found to be insignificant. Atomic posi-
tions were determined using SHELXS10 and refined
using full-matrix least squares (SHELXL11). Hydro-
gen positions were calculated and included in the final
cycles of refinement in constrained positions and with
fixed isotropic thermal parameters. Absorption cor-
rections were not made due to the small value of the
absorption coefficients (Table 1). Tables 2, 4, and 6
present positional parameters for (I), (II), and (III),
respectively, which are the basis for the bond angles
and distances of Tables 3, 5, and 7.
Discussion
There have been four observations of DHP
derivatives with a single chloro substituent in the 2
or ortho position of the B ring reported in the liter-
ature, and three of them crystallize with the chloro
substituent in the prow position and with sp, sp
conformation of the carbonyl groups.12 154-(2,3-
Dichlorophenyl)-2, 6-dimethyl-1, 4-dihydropyridine
-3,5-bis(methoxycarbonyl)(I), 4-(2,4-dichlorophenyl)
-2,6-dimethyl-1, 4-dihydropyridine-3, 5-bis(methoxy-
carbonyl)(II), and 4-(2,3,5-trichlorophenyl)-2,6-