Synthesis and crystal structure of a novel substituted 1,4-dihydropyridine

Article abstract of DOI:10.1080/15421400701693534

The title compound, C15H16N2O3, was synthesized, characterized spectroscopically, and finally confirmed by X-ray diffraction studies. The compound crystallizes in the monoclinic space group P21/n with cell parameters a=10.314(9) , b=17.976(15) , c=12.762(11), =113.331(3), Z=4, and V=2173(3) 3. The dihydropyridine ring in the structure is in a flattened-boat conformation. The 2-nitrophenyl ring is orthogonal to the 1,4-dihydropyridine ring. The structure exhibits an intermolecular hydrogen bond of the type C-HO.

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Synthesis and Crystal Structure
of a novel substituted 1,4-
dihydropyridine
S. Naveen a , Sridhar M. Anandalwar a , J.
Shashidhara Prasad a , Rajesh Kakadiya b , Jitender
Bariwal b , Vijay Virsodia b , Denish Karia b & Anamik
Shah b
a Department of Studies in Physics, University of
Mysore, Mysore, India
b Department of Chemistry, Saurashtra University,
Rajkot, India
Published online: 22 Sep 2010.
To cite this article: S. Naveen , Sridhar M. Anandalwar , J. Shashidhara Prasad ,
Rajesh Kakadiya , Jitender Bariwal , Vijay Virsodia , Denish Karia & Anamik Shah
(2007): Synthesis and Crystal Structure of a novel substituted 1,4-dihydropyridine,
Molecular Crystals and Liquid Crystals, 474:1, 55-65
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Mol. Cryst. Liq. Cryst., Vol. 474, pp. 55–65, 2007
Copyright # Taylor & Francis Group, LLC
ISSN: 1542-1406 print=1563-5287 online
DOI: 10.1080/15421400701693534
Synthesis and Crystal Structure of a Novel n-Substituted
1,4-dihydropyridine
S. Naveen
Sridhar M. Anandalwar
J. Shashidhara Prasad
Department of Studies in Physics, University of Mysore, Mysore, India
Rajesh Kakadiya
Jitender Bariwal
Vijay Virsodia
Denish Karia
Anamik Shah
Department of Chemistry, Saurashtra University, Rajkot, India
The title compound, C15H16N2O3, was synthesized, characterized spectroscopi-
cally, and finally confirmed by X-ray diffraction studies. The compound crystal-
ꢀ
lizes in the monoclinic space group P21=n with cell parameters a ¼ 10.314(9) A,
ꢀ
ꢀ
ꢀ
b ¼ 17.976(15) A, c ¼ 12.762(11) A, b ¼ 113.331(3)ꢀ, Z ¼ 4, and V ¼ 2173(3) A3.
The dihydropyridine ring in the structure is in a flattened-boat conformation.
The 2-nitrophenyl ring is orthogonal to the 1,4-dihydropyridine ring. The struc-
ture exhibits an intermolecular hydrogen bond of the type CꢁH ꢂ ꢂ ꢂ O.
Keywords: 1,4-dihydropyridine; flattened boat; hydrogen bond
INTRODUCTION
The Ca2þ channel antagonists are a heterogeneous group of agents
possessing a common property, the ability to block current through
potential-dependent Ca2þ channels [1]. Structurally, a diverse group
of organic compounds are known to be calcium channel antagonists.
The most potent class of antagonists comprises derivatives of
1,4-dihydropyridines, of which the most widely known agent is
Address correspondence to Dr. M. A. Sridhar, Department of Studies in Physics,
Manasagangotri, University of Mysore, Mysore 570 006, India. E-mail: mas@physics.
uni-mysore.ac.in
55

56
S. Naveen et al.
nifedipine. 1,4-Dihydropyridine (1,4-DHP) moiety is very interesting
because of its recognition as a calcium channel antagonist, chemother-
apeutic agent for multidrug resistance (MDR) reversal [2] in tumor
cells, potent immunomodulator [3], and antitubercular agent [4]. A
further study of N-alkylated DHP at the labile hydrogen of the DHP
skeleton proved that it is important for MDR reversal in tumor cells,
and this has created new interest in N-phenyl substituted 1,4-dihydro-
pyridines [5]. In structure–activity relationships, the effects of substi-
tution on the 1,4-dihydropyridine rings have been meticulously
studied [6]. These have indicated specific conformational details that
correlate with high binding efficiency [7].
The crystallographic studies of both 1,4-dihydropyridine antagonist
and agonist show several common conformational features . The DHP
antagonist blocks transmembrane Ca2þ influx, thereby causing relax-
ation of smooth and cardiac muscle [8,9], whereas the DHP agonist
produces the opposite pharmacological effect [10,11]. As a part of our
ongoing research on such potent molecules, the title compound was
synthesized, and the structure of the title compound was established
on the basis of Fourier transform infrared (FTIR) absorption spec-
troscopy, NMR, elemental analysis, and X-ray crystallography.
EXPERIMENTAL
The melting point was determined in an open capillary melting-point
apparatus. The FTIR absorption spectrum was recorded on a Shimadzu
FTIR-8400 spectrometer (KBr Pellet sample technique, 1000–
4000 cmꢀ1 frequency ranges. 1H NMR spectrum was recorded on a
Bruker AC 300-MHz FT–NMR spectrometer in Dimethylsulfoxide
DMSO-d6 solution (2.5%). Mass spectra were obtained using a Jeol
SX 102=DA6000 spectrometer (for FAB). Elemental analyses were
done on a CHN EA 1108 elemental analyser. Analytical thin-layer
chromatography (TLC) was performed on 0.25-mm silica-gel plates
(Merck 60 F254). The procedure for synthesis is shown in Fig. 1.
Synthesis and Method of Crystallization
The n-substituted-1,4-dihydropyridine was synthesized by refluxing
methyl acetoacetate (0.01 mol), 2-anisidine (0.01 mol), and 2-nitro ben-
zaldehyde (0.01 mol) in acetic acid (30 ml) for 10 h. The completion of
the reaction was monitored by TLC. The reaction mixture was allowed
to cool for 12 h at room temperature. The solid obtained was filtered,
washed with cold methanol, dried in a hot-air oven, and recrystallized
from dimethylformamide. Yield ¼ 65%, mp 220ꢁC.

Synthesis and Crystal Structure
57
FIGURE 1 Reaction scheme.
ꢀ1
IR: 1703 cmꢀ1 (C O str.), 1265 cm (CꢀOꢀC, str.), 3010 cmꢀ1 (aro-
=
matic CꢀH str.), 1652 cmꢀ1 (aromatic C C str.), 2910 cmꢀ1 (CH3 sym-
=
metric str.), 2845 cmꢀ1 (CH3 asymmetric str). 1H NMR: 2.21d ppm (3H, s),
2.32d ppm (3H, s), 3.48d ppm (6H, s), 3.58d ppm (3H, s), 5.45d ppm
(1H, s), 6.92d ppm (1H, d), 7.04d ppm (1H, t), 7.12d ppm (1H, t),
7.17d ppm (1H, d), 7.56d ppm (1H, d), 7.72d ppm (1H, t), 7.78d ppm
(1H, t), 7.88d ppm (1H, d). Mass: 453 (Mþ1), 390, 374, 330, 300, 148,
92, 77. C,H,N analysis: Calculated %: C (63.71), H (5.35), N (6.19)
Found %: C (63.74), H (5.34), N (6.17).
The compound (2 g) was taken in mixture of 10 ml of dimethylforma-
mide and 5 ml of ethanol. Charcoal (2 g) was added, and the solution
was heated for 4 min. The solution was filtered while hot through
Whatmann no. 42 filter paper in a corkable 50-ml conical flask. The
flask was corked and kept for several days. Light yellow crystals were
grown by the thin-film evaporation technique.
Crystal Structure Determination
A single crystal of the title compound with dimensions 0.3 ꢂ 0.27 ꢂ
0.25 mm was chosen for an X-ray diffraction study. The data were

58
S. Naveen et al.
collected on a DIPLabo Image Plate system equipped with a normal-
focus, 3-kW, sealed X-ray source (graphite monochromated MoKa).
The crystal-to-detector distance is fixed at 120 mm with a detector
area of 441 ꢂ 240 mm2. Thirty-six frames of data were collected at
room temperature by the oscillation method. Each exposure of the
image plate was set to a period of 400 s. Successive frames were
scanned in steps of 5ꢁ per minute with an oscillation range of 5ꢁ. Image
processing and data reduction were done using Denzo [12]. The reflec-
tions were merged with Scalepack [13]. All of the frames could be
indexed using a primitive monoclinic lattice. The structure was solved
by direct methods using SHELXS-97 [14]. All of the nonhydrogen
atoms were revealed in the first Fourier map itself. Least-squares
refinement using SHELXL-97 [15] with isotropic temperature factors
for all the nonhydrogen atoms converged the residual R1 to 0.1866.
Subsequent refinements were carried out with anisotropic thermal
parameters for nonhydrogen atoms. After eight cycles of refinement,
the residuals converged to 0.0887. The hydrogen atoms were fixed
at chemically acceptable positions and were allowed to ride on their
parent atoms. The details of crystal data and refinement are given
in Table l.y Table 2 gives the atomic coordinates and equivalent ther-
mal parameters of the nonhydrogen atoms. Tables 3 and 4 give the list
of bond lengths and bond angles, respectively, which are in good agre-
ement with the standard values. Figure 2 is the ORTEP [16] diagram
of the molecule with thermal ellipsoids drawn at 30% probability.
A study of torsion angles, asymmetric parameters, and least
squares plane calculations revealed that the 1,4-dihydropyridine ring
in the structure is in a flattened-boat conformation with the atoms N1
˚
˚
and C4 lying at 0.076(3) A and 0.117(3) A from the least squares plane
defined by the atoms C2=C3=C5=C6. The torsion angle values C3–C4–
C5–C6 ¼ ꢀ20.24ꢁ and C2–C3–C4–C5 ¼ 16.12ꢁ is higher in the 1,4-
dihydropyridine ring, indicating that there is greater puckering at
C4 than at N1. The degrees of ring distortions at N1 and C4 are
directly reflected on the magnitude of torsion angles emanating from
these two atoms. The 2-nitrophenyl ring is positioned pseudo-axially,
as indicated by the average magnitude of the C6–C5–C4–C25 torsion
angle value of 101.3ꢁ with respect to the C4 position of the dihydropyr-
idine ring. Another conformation of the planarity of the 1,4-dihydro-
pyridine ring is the sum of magnitudes of the six intraring torsion
yCCDC 621009 contains the supplementary crystallographic data for this article.
These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: þ44(0)1223-336033; E-mail: deposit@ccdc.cam.ac.uk.

Synthesis and Crystal Structure
59
TABLE 1 Crystal Data and Structure Refinement
Parameter
Value
Empirical formula
Formula weight
Temperature
C24H24N2O7
452.45
293(2) K
˚
Wavelength
0.71073 A
Crystal system
Space group
Cell dimensions
Monoclinic
P21=n
˚
a ¼ 10.314(9) A
˚
˚
b ¼ 17.976(15) A
c ¼ 12.762(11) A
b ¼ 113.331(3)ꢁ
3
˚
Volume
2173(3) A
Z
4
Density (calculated)
Absorption coefficient
F000
1.383 Mg=m3
0.103 mmꢀ1
952
Crystal size
Theta range for data collection
Index ranges
0.3 ꢂ 0.27 ꢂ 0.25 mm
2.07ꢁ to 25.03ꢁ
ꢀ12 ꢃ h ꢃ 12
ꢀ21 ꢃ k ꢃ 21
ꢀ15 ꢃ l ꢃ 15
Reflections collected
7330
Independent reflections
Absorption correction
Refinement method
Data=restraints=parameters
Goodness of fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
3826 [R(int) ¼ 0.0277]
None
Full-matrix least-squares on F2
3826=0=304
1.080
R1 ¼ 0.0887, wR2 ¼ 0.2419
R1 ¼ 0.1199, wR2 ¼ 0.2915
0.038(7)
Extinction coefficient
Largest diff. peak and hole
ꢀ3
˚
0.626 and ꢀ0.404 e.A
angles, RP, around the ring. For the compound under study, RP is
63.55ꢁ. This value is a bit low when compared to the corresponding
value of 72ꢁ reported for nifedipine drug molecule [17]. Such a mild
flattening might have significant implications for the pharmacological
potency of the title compound as a calcium channel antagonist,
because Fossheim [18] has suggested that the most active compounds
in the nifedipine and nisoldipine series possess the shallowest boat
conformations. The dihedral angle between the nitrophenyl ring and
the dihydropyridine ring is 87.01(16)ꢁ, implying that the nitrophenyl
ring is nearly orthogonal to the dihydropyridine ring. The dihedral
angle between the dihydropyridine ring and the methoxyphenyl ring
is 84.64(16)ꢁ. These values are comparable with the corresponding

60
S. Naveen et al.
TABLE 2 Atomic Coordinates and Equivalent Thermal Parameters of the
Nonhydrogen Atoms
Atom
x
y
z
Ueq
N1
C2
C3
C4
C5
C6
C7
C8
ꢀ0.0421(3)
0.0080(3)
0.1113(3)
0.1820(3)
0.0945(3)
ꢀ0.0023(3)
ꢀ0.0742(4)
ꢀ0.0646(3)
ꢀ0.1338(3)
ꢀ0.0741(4)
ꢀ0.1581(4)
ꢀ0.3012(5)
ꢀ0.3620(4)
ꢀ0.2772(3)
0.0688(2)
0.1359(5)
0.1697(4)
0.1482(4)
0.2557(3)
0.3289(5)
0.1199(3)
0.0671(3)
0.2109(3)
0.2327(5)
0.3307(3)
0.3458(4)
0.4742(4)
0.5933(4)
0.5835(4)
0.4548(3)
0.4575(3)
0.5279(3)
0.3944(3)
0.0768(2)
0.1057(2)
0.0700(2)
0.0002(2)
ꢀ0.0340(2)
0.0063(2)
ꢀ0.0185(2)
0.1751(2)
0.1227(2)
0.1642(2)
0.2087(2)
0.2127(2)
0.1702(2)
0.1265(2)
0.1564(2)
0.1990(2)
0.1001(2)
0.1603(2)
0.0529(2)
0.0791(2)
ꢀ0.1120(2)
ꢀ0.1483(2)
ꢀ0.1440(2)
ꢀ0.2229(2)
0.0190(2)
0.0800(2)
0.1008(2)
0.0599(3)
ꢀ0.0020(3)
ꢀ0.0214(2)
ꢀ0.0878(2)
ꢀ0.1415(2)
ꢀ0.0877(2)
0.2109(2)
0.1322(2)
0.1128(2)
0.1778(2)
0.2380(2)
0.2602(3)
0.3357(3)
0.0722(3)
0.2461(3)
0.3456(3)
0.3813(4)
0.3158(4)
0.2176(3)
0.1834(3)
0.4035(2)
0.5052(3)
0.0334(3)
ꢀ0.0118(3)
0.0147(2)
ꢀ0.0526(4)
0.2719(3)
0.3247(3)
0.2351(2)
0.2552(5)
0.2664(2)
0.3371(3)
0.4208(3)
0.4385(3)
0.3738(3)
0.2877(3)
0.2207(3)
0.2742(3)
0.1177(2)
0.0625(7)
0.0608(8)
0.0571(7)
0.0568(7)
0.0567(7)
0.0611(8)
0.0793(1)
0.0750(9)
0.0664(8)
0.0722(9)
0.0823(1)
0.0880(2)
0.086(2)
0.0733(9)
0.0874(8)
0.1001(2)
0.0652(8)
0.1290(2)
0.0837(8)
0.093(2)
0.0656(8)
0.1060(2)
0.0791(8)
0.1030(2)
0.0596(8)
0.0698(9)
0.0860(2)
0.0930(2)
0.0870(2)
0.0701(9)
0.0822(9)
0.1220(2)
0.0928(9)
C9
C10
C11
C12
C13
C14
O15
C16
C17
O18
O19
C20
C21
O22
O23
C24
C25
C26
C27
C28
C29
C30
N31
O32
O33
values of 83.94ꢁ and 84.94ꢁ reported earlier [19]. The torsion angle
values of ꢀ134.9(3)ꢁ and ꢀ73.9(4)ꢁ for C3–C4–C25–C30 and C5–C4–
C25–C26, respectively, determine the conformation of the junction
between the nitrophenyl and the dihydropyridine ring. The other
structural aspect is the conformation of the carbethoxy groups on
the dihydropyridine ring. Each carbethoxy group is oriented in a cis
=
conformation with respect to the adjacent C C bond as indicated by
the torsion angle values of 9.08(59)ꢁ and ꢀ3.19(55)ꢁ, respectively, for

Synthesis and Crystal Structure
61
˚
TABLE 3 Bond Lengths (A)
Atoms
Length
N1–C2
N1–C6
N1–C9
C2–C3
C2–C8
C3–C17
C3–C4
C4–C5
C4–C25
C5–C6
1.399(4)
1.403(4)
1.453(4)
1.349(4)
1.500(4)
1.472(4)
1.521(4)
1.526(4)
1.540(4)
1.350(4)
1.460(4)
1.498(4)
1.376(4)
1.389(5)
1.369(4)
1.383(5)
1.381(6)
1.388(6)
1.370(5)
1.428(4)
1.205(4)
1.316(4)
1.429(4)
1.211(4)
1.335(4)
1.444(4)
1.390(4)
1.400(4)
1.384(5)
1.372(6)
1.365(6)
1.391(5)
1.475(5)
1.214(4)
1.237(4)
C5–C21
C6–C7
C9–C14
C9–C10
C10–O15
C10–C11
C11–C12
C12–C13
C13–C14
O15–C16
C17–O18
C17–O19
O19–C20
C21–O22
C21–O23
O23–C24
C25–C26
C25–C30
C26–C27
C27–C28
C28–C29
C29–C30
C30–N31
N31–O33
N31–O32
C2–C3–C19–O18 and C6–C5–C21–O22. The molecule exhibits trans=
trans conformation. The torsion angle values observed in the latter
are ꢀ171.7(3)ꢁ and 175.2(3)ꢁ, respectively, for C2–C3–C17–O19 and
C6–C5–C21–O23. Similar conformation was observed in the molecule
reported earlier [19]. The methoxy group lies in the plane of the phenyl
ring as indicated by the torsion angle value of ꢀ2.3(5)ꢁ for C11–C10–
O15–C16. The nitro group is twisted out of the plane of the phenyl ring
as indicated by the torsion angle values of 41.56(49)ꢁ and 43.13(52)ꢁ,

62
S. Naveen et al.
TABLE 4 Bond Angles (ꢁ)
Atoms
Angle
C2–N1–C6
C2–N1–C9
C6–N1–C9
C3–C2–N1
C3–C2–C8
N1–C2–C8
C2–C3–C17
C2–C3–C4
C17–C3–C4
C3–C4–C5
C3–C4–C25
C5–C4–C25
C6–C5–C21
C6–C5–C4
C21–C5–C4
C5–C6–N1
122.1(2)
118.8(2)
119.0(3)
119.9(3)
124.9(3)
115.1(3)
121.3(3)
122.4(3)
116.1(3)
110.7(2)
110.1(2)
109.6(2)
120.8(3)
121.7(3)
117.5(3)
119.9(3)
124.9(3)
115.2(3)
119.3(3)
122.0(3)
118.6(3)
124.2(3)
115.6(3)
120.2(3)
119.4(4)
120.6(3)
119.1(4)
121.2(3)
117.8(3)
120.2(3)
127.7(3)
112.1(3)
116.8(3)
119.8(3)
128.0(3)
112.2(3)
116.2(3)
115.0(3)
118.2(3)
126.7(3)
122.8(3)
120.1(4)
119.4(4)
120.0(4)
122.5(3)
C5–C6–C7
N1–C6–C7
C14–C9–C10
C14–C9–N1
C10–C9–N1
O15–C10–C11
O15–C10–C9
C11–C10–C9
C12–C11–C10
C11–C12–C13
C14–C13–C12
C13–C14–C9
C10–O15–C16
O18–C17–O19
O18–C17–C3
O19–C17–C3
C17–O19–C20
O22–C21–O23
O22–C21–C5
O23–C21–C5
C21–O23–C24
C26–C25–C30
C26–C25–C4
C30–C25–C4
C27–C26–C25
C28–C27–C26
C29–C28–C27
C28–C29–C30
C29–C30–C25
(Continued)

Synthesis and Crystal Structure
TABLE 4 Continued
63
Atoms
Angle
C29–C30–N31
C25–C30–N31
O33–N31–O32
O33–N31–C30
O32–N31–C30
115.4(3)
122.1(3)
123.1(4)
120.1(3)
116.9(3)
respectively, for O32–N31–C30–C29 and O33–N31–C30–C35. The
structure exhibits an intermolecular hydrogen bond of the type
CꢀH ꢄ ꢄ ꢄ O. The intermolecular hydrogen bond C12–H12 ꢄ ꢄ ꢄ O18 has a
ꢁ
˚
length of 3.352(6) A and an angle of 143 with symmetry code
ꢀ1=2 þ x, 1=2 þ y, 1=2 þ z. The presence of hydrogen bonding in the
crystal structure shows its major role in the calcium channel antagon-
ist effect [20]. The packing of the molecules (Fig. 3) when viewed down
the a axis indicates that the molecules are stacked and are linked by
the intermolecular hydrogen bond to form a linear polymeric chain.
FIGURE 2 ORTEP diagram of the molecule with thermal ellipsoids drawn at
30% probability.

64
S. Naveen et al.
FIGURE 3 Packing diagram of the molecules when viewed down the a axis.
The dotted lines represents the intermolecular hydrogen bond.
ACKNOWLEDGMENTS
The authors express their thanks to the Department of Chemistry,
Saurashtra University, Rajkot, for the laboratory facility under the
Fund for Improvement of Science and Technology Infrastructure in
Higher Educational Institutions (FIST), Department of Science and
Technology (DST), University Grants Commission (UGC), Special
Assistance Programme (SAP) programs, and DST, government of
India, for financial assistance under Project SP=I2=FOO=93.
REFERENCES
[1] Janis, R. A. & Triggle, D. J. (1985). J. Med. Chem., 26, 775.
[2] Shah, A., Gaveriya, H., Motohashi, N., Kawase, M., Saito, S., Sakagami, H., Satoh, Y.,
Solymosi, A., Walfard, K., & Molnar, J. (2000). Anticanc. Res., 20, 373.
[3] Shah, A., Gaveriya, H., Motohashi, N., Kawase, M., Farkas, S., Gyorgyi, G., &
Molnar, J. (2002). Ins. J. Antimicro. Agents, 20, 227.
[4] Shah, A., Vora, V., Desai, B., & Gaveriya, H. (2001). Hetero. Commun., 7, 481.
[5] Ohsumi, K., Ohishi, K., Morinaga, Y., Nakagawa, R., Suga, Y., Sekiyama, T.,
Akiyama, Y., Tsuji, T., & Tsuruo, T. (1995). Chem. Pharm. Bull., 43(5), 818.
[6] Metcalf, S. K. & Holt, E. M. (2000). Acta. Cryst., C56, 1228.

Synthesis and Crystal Structure
65
[7] Coburn, R. A., Wierzba, M., Suto, M. J., Solo, A. J., Triggle A. M., & Triggle, D. J.
(1988). J. Med. Chem., 31, 2103.
[8] Fleckstein, A. (1977). Annu. Rev. Pharmacol. Toxicol., 17, 149.
[9] Reuter, H. (1983). Nature, 301, 569.
[10] Schramm, M., Thomas, G., Towart, T., Franckowiak, G. (1983). Nature, 303, 535.
[11] Trog, A. G. (1983). Presentation at the 67th Annual Meeting of the Federation of
American Societies for Experimental Biology, Chicago.
[12] Otwinowski, Z. & Minor, W. (1997). In: Methods in Enzymology, Carter, C. W., Jr. &
Sweet, R. M. (Eds.), Processing of x-ray diffraction data collected oscillation model.
Academic Press: New York, vol. 276, 307–326.
[13] Mackay, S., Gillmore, C. J., Edwards, C., Stewart, N., & Shankland, K. (1999).
maXus Computer Program for the Solution and Refinement of Crystal Structures,
Bruker Nonius: Delft, The Netherlands.
[14] Sheldrick, G. M. (1997). SHELXS-97: Program for Crystal Structure Solution,
¨
¨
University of Gottingen: Gottingen, Germany.
[15] Sheldrick, G. M. (1997). SHELXL-97: Program for Crystal Structure Solution,
¨
¨
University of Gottingen: Gottingen, Germany.
[16] Johnson, C. K. (1976). ORTEPII: Report ORNL-5138, Oak Ridge National Labora-
tory: Tenn.
[17] Miyamae, A., Koda, S., & Morimoto, Y. (1986). Chem. Pharm. Bull., 34, 3071.
[18] Fossheim, R., Joslyn, A., Solo, A. J., Luchowski, E., Rutledge, A., & Triggle, D. J.
(1988). J. Med. Chem., 31, 300.
[19] Mahendra, M.,Doreswamy,B. H., Parecha,A. R.,Patel,J. A., Shah,A.,Sridhar,M. A.,
& Shashidhara Prasad, J. (2004). Anal. Sci., 20, x19.
[20] Coburn, R. A., Wierzba, M., Suto, M. J., Solo, A. J., Triggle, A. M., & Triggle, D. J.
(1988). J. Med. Chem., 31, 2103.