Synthesis of two steroids derivatives and its relationship with some physicochemical parameters

Article abstract of DOI:10.1155/2012/481769

Two danazol derivatives were synthesized and characterized by spectral analyses. In order to characterize the structural and physicochemical requirements of danazol derivatives, several parameters such HOMO-LUMO gap, ΔH_f, RMS_g, dipol

Full text of DOI:10.1155/2012/481769

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
http://www.e-journals.net
2012, 9(1), 27-34
Synthesis of Two Steroids Derivatives and its
Relationship with some Physicochemical Parameters
LAURO FIGUEROA-VALVERDE§*, FRANCISCO DÍAZ-CEDILLO
and ELODIA GARCIA-CERVERA§
§Lab. Farmacoquímica, Facultad de Ciencias Químico-Biológicas,
Universidad Autónoma de Campeche, Av. Agustín Melgar,
Col Buenavista C.P.24039 Campeche Cam., México.
Esc. Nal. de Ciencias Biológicas del Instituto Politécnico Nacional. Prol. Carpio y Plan de
Ayala s/n Col. Santo Tomas, México, D.F. C.P. 11340.
lauro_1999@yahoo.com
Received 27 February 2011; Accepted 27 April 2011
Abstract: Two danazol derivatives were synthesized and characterized by
spectral analyses. In order to characterize the structural and physicochemical
requirements of danazol derivatives, several parameters such HOMO-LUMO
gap, ∆Hf, RMSg, dipole moment (µ) and bond length were evaluated. The
results showed that HOMO and µ was high in the compound 5 in comparison
with the compound 3. In conclusion all these data indicate that increase in the
length of chain induce greater moment dipole and increase HOMO gap in the
compound 5 with respect to 3.
Keywords: Danazol derivatives, Steroids, Physicochemical parameters, Synthesis
Introduction
Quantitative structure-activity relationship (QSAR) studies are very important in medicinal
chemistry1-3. There are reports of QSAR studies on several steroid types4-6, for example the
structure-activity analysis from a series of steroids binding to globulin was made using the
electro topological state index for each atom in the molecule7. Other studies reported by
Bravi8 and Tong9 showed a comparative 3D QSAR study in a series of steroids using the
comparative molecular field (CoMFA) method. Additionally, there is a report of a
comparative QSAR study using CoMFA, HQSAR (hologram quantitative structure-activity
relationship) methods for the steroid-receptor interaction10. Other studies have developed a

28
V. Lauro Figueroa et al.
MTD model (minimal the topologic difference) to evaluate the steroid-receptor
interactions11,12. In addition, there are QSAR studies which suggest a correlation between
logP and lipophilicity degree for some steroids13 for example, the reports of Li et al.14 which
showed that logP have a correlation with the passive diffusion from some steroids.
Additionally, several studies15,16 have determined the relationship of some steroid
derivatives with the physicochemical descriptors such as logPπ, Rm, Vm and the frontier
molecular orbitals (HOMO-LUMO gap)17,18. All these works show several protocols for QSAR
study of steroids that involved; geometry optimization, conformational analysis and electronic
energy. In this work our initial design included the synthesis of two danazol derivatives and its
relationship with HOMO-LUMO gap, ∆Hf, RMSg, dipole moment and bond length.
Experimental
General methods
Danazol succinate (1) was prepared according to a previously reported method by several
investigators19. The other compounds evaluated in this study were purchased from Sigma-Aldrich
Co., Ltd. The melting points for the different compounds were determined on an Electrothermal
(900 model). Infrared spectra (IR) were recorded using KBr pellets on a Perkin Elmer Lambda 40
1
spectrometer. H and 13C NMR spectra were recorded on a Varian VXR-300/5 FT NMR
spectrometer at 300 and 75.4 MHz in CDCl3 using TMS as internal standard. EIMS spectra were
obtained with a Finnigan Trace GCPolaris Q. spectrometer. Elementary analysis data were
acquired from a Perkin Elmer Ser. II CHNS/0 2400 elemental analyzer.
N-(-Amino-ethyl)succinamic acid 1-ethynyl-10a,12a-dimethyl-2,3,3a,3b,4,5,5a,6,6a,9a,10
10a,10b,11,12,12a-hexadecahydro-1H-7-oxa-8-aza-dicyclopenta[a,h]phenanthren-1-yl
ester (3).
Method A
A solution of 1(100 mg, 0.23 mmol), ethylenediamine (28 µL, 0.46 mmol) and 26 mg boric
acid (0.42 mmol) in toluene (10 mL) was heated under reflux for 8 h. The reaction was
allowed to cool to room temperature and the toluene was evaporated under vacuum. The
reaction mixture was dissolved in ethyl acetate (10 mL) and water (20 mL); the organic
layer was separated and the aqueous layer was re-extracted with ethyl acetate (10 mL). The
combined organic layers were washed with water (15 mL) and then dried over sodium
carbonate (anhydrous). The organic phase was evaporated to dryness under reduced pressure
(Scheme 1). The residue was purified by crystallization from methanol:water (3:1) yielding 45
% of product , m.p. 190 oC; IR υmax 3380, 2138, 1730 cm-1; 1H NMR (300 MHz, CDCl3) δH:
0.96 (s, 3H,), 0.98 (m, 1H), 1.01 (s, 3H), 1.04-1.42 (m, 2H), 1.56-1.90 (m, 10H ), 2.10-2.26
(m, 2H), 2.34-2.42 (m, 2H), 2.49 (t, 2H, J = 6.5 Hz), 2.69 (t, 2H, J = 6.5 Hz), 2.90 (s, 1H),
2.96 (t, 2H), 3.30 (t, 2H), 4.78 (broad), 6.53 (s, 1H), 7.98 (s, 1H) ppm. 13C NMR (74.5 MHz,
DMSO-d6) δC: 14.91 (C-22), 19.66 (C-21), 21.05 (C-19), 23.88 (C-13), 30.43, (C-29), 30.60
(C-17), 31.30 (C-28), 31.70 (C-20), 32.90 (C-18), 33.71 (C-5), 33.84 (C-12), 37.65 (C-8),
38.70 (C-6), 39.44 (C-33), 4050 (C-34), 46.43 (C-10), 52.90 (C-9), 53.12 (C-7), 75.43 (C-27),
84.43 (C-11), 84.64 (C-26), 110.50 (C-15), 121.63 (C-4), 141.60 (C-16), 149.60 (C-3), 156.07
(C-14), 168.20 (C-24), 171.90 (C-30) ppm. MS (70 ev): m/z 479.20 [M+]; Anal. Calcd. For
C28H37N3O4: C, 70.12; H, 7.78; N, 8.76; 0, 13.34. Found: C, 70.10; H, 7.72.
Method B
A solution of 1(100 mg, 0.23 mmol), ethylenediamine (28 µL, 0.46mmol) and 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (60 mg , 0.31 mmol) in acetonitrile-water

Synthesis of Two Steroids Derivatives
29
(10 mL, 4:1). After stirring at room temperature for 18 h, the solution was concentrated and
the product was extracted with ethyl acetate and water (2:1) to give the compound 3 (68%
yield). Similar 1H NMR and 13C NMR data were obtained compared with method A product.
OH
O
H2N
O
O
C
H
3
NH2
CH
+
2
CH
3
1
Method B
Method A
N
O
NH
O
C
H
3
O
NH2
O
CH
C
H
3
3
N
O
Scheme 1. Reaction of danazol succinate (1) with ethylenediamine (2) to form steroid
derivative (3); Catalysts- Method A: Boric acid, Method B- 1-ethyl-3-(3-dimethyl
aminopropyl)carbodiimidehydrochloride.
N-[2-(4-Hydroxy-benzoilamino)ethyl]-succinamic acid 1-ethynyl-10a-12a-dimethyl-
2,3,3a,3b,4,5,5a,6,6a,9a,10,10a,10b,11,12,12a-hexadecahydro-1H-7-oxa-8-aza-
dicyclo- penta[a,h]phenanthren-1-yl ester (5)
A solution of 3 (100 mg, 0.21mmol), 4-hydroxybenzoic acid (40 mg, 0.29 mmol) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.31 mmol) in
acetonitrile-water (10 mL, 4:1). After stirring at room temperature for 18 h, the solution was
concentrated and the product was extracted with ethyl acetate and water (2:1) to give the
1
compound 5 (Scheme 2) with 68% yield. IR υmax, cm-1: 2138, 1730, 1650; H NMR (300
HMz, DMSO-d6) δH: 0.98 (s, 3H), 0.99 (m, 1H), 1.01 (s, 3H), 1.05-1.44 (m, 2H), 1.53-1.92
(m, 10H), 2.10-2.26 (m, 2H), 2.34-2.42 (m, 2H), 2.49 (t, 2H, J = 6.5 Hz), 2.69 (t, 2H, J = 6.5
Hz), 2.90 (s, 1H), 342 (t, 2H, J = 6.5 Hz), 350 (t, 2H, J = 6.5 Hz), 6.44 (broad, 3H), 6.53 (s,
1H), 6.95 (d, 2H), 7.59 (d, 2H), 7.98 (s, 1H) ppm. 13C NMR (74.5 MHz, DMSO-d6) δC:
14.91 (C-22), 19.66 (C-21), 21.05 (C-19), 23.88 (C-13), 30.43, (C-29), 30.69 (C-17), 31.35
(C-28), 31.70 (C-20), 32.90(C-18), 33.71 (C-5), 33.84 (C-12), 37.65 (C-8), 38.71 (C-34),
39.44 (C-33), 4050 (C-6), 46.43 (C-10), 52.90 (C-9), 53.12 (C-7), 75.43 (C-27), 84.43 (C-
11), 84.64 (C-26), 110.50 (C-15), 115.10 (C-40, C-42), 121.63 (C-4), 127.56 (C-38),
128.92 (C-39, C-43), 141.60 (C-16), 149.60 (C-3), 156.07 (C-14), 160.42 (C-41), 162.35
(C-36), 168.20 (C-24), 171.90 (C-30) ppm. MS (70 ev): m/z 599.29 [M+]; Anal. Calcd. For
C35H41N3O6: C, 70.10; H, 6.89; N, 7.01; 0, 16.01. Found: C, 70.08; H, 6.86.

30
V. Lauro Figueroa et al.
NH
HO
O
NH2
O
O
O
CH
3
CH
+
CH
3
OH
EDC
4
N
O
3
NH
O
O
C
H
3
O
NH
O
C
H
CH3
N
OH
5
O
Scheme 2. Synthesis of danazol derivative (5); reaction between the compound 3 with 4-
Hydroxybenzoic acid (4) using as catalyst1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide
hydrochloride (EDC) to form 5.
Results and Discussion
Chemistry analyses
In this study we report a straight forward route for the synthesis of two danazol derivatives.
The first step was achieved by reacting 1 with ethylendiamine hydrochloride (2) to form 3
(Scheme 1) since the nature of functional groups contained in the chemical structure of this
compound involves both amine and amide groups in the arm bound to steroid nucleus of 3.
It is important to mention that many procedures for the formation of amide groups are
known in the literature20-22, the most widely practiced method employs carboxylic acid
chlorides as the electrophiles which react with the amino group in the presence of an acid
scavenger23. Despite its wide scope, the former protocol suffers from several drawbacks;
most notable are the limited stability of many acid chlorides and the need for hazardous
reagents for their preparation (thionyl chloride)24. In this study, two different methods for
amide formation were employed; in the first one the technique reported by Pingwah25 for
boric acid catalyzed amidation of carboxylic acids and amines (method A) was used; in the
second one we used a derivative of carbodiimide (method B) as catalyzer26 to form the
compound 3. It was found that the use of carbodiimide results in higher yields compared to
the amide bond formed with method A. 1H NMR spectra of 3 showed chemical shifts at 0.96
and 1.01 ppm for methyls present in the steroid nucleus. In addition, other signals at 0.98,
1.04-2.42 ppm for hydrogens involved in the steroid nucleus were found. Other signals at
2.49-3.30 ppm for methylenes involved in the arm bound to danazol fragment were display.
Finally, two signals at 2.88 ppm for proton involved in the alkyne group and at 4.70 ppm for
hydrogens corresponding to amino groups were found. The 13C NMR spectra display
chemical shifts at 14.91 and 19.66 ppm for the carbons of methyls presents in the steroid
nucleus of 3. Another chemical shifts at 21.05-23.88, 30.60; 31.70-38.70, 47.43-53.12 and
110.50-156.07 ppm for carbons of methylenes involved in the steroid nucleus were
exhibited. Additionally, several signals at 30.43, 31.30, 39.44 and 40.50 ppm for carbons

Synthesis of Two Steroids Derivatives
31
corresponding to methylenes involved in the arm bound to danazol nucleus were found.
Finally, other signals at 75.43 and 84.62 for carbons involved in the alkyne group; at 168.20
ppm for ester group; at 171.90 ppm for amide group and at 221.00 for ketone group were
exhibited. The presence of 3 was further confirmed from mass spectrum which showed a
molecular ion at m/z 479.20.
On the other hand, the second stage was achieved by reacting 3 with benzoic acid (4) in
presence of 1-ethyl-3(3-dimethylamino-propyl)-carbodiimide to form 5 (Scheme 2). The
results indicate that 1H NMR spectrum of 5 showed signals at 0.98 and 1.01 ppm for methyls
present in the steroid nucleus. Additionally, other signals at 0.99, 1.05-2.42 ppm for
hydrogens involved in the steroid nucleus were found. Other signals at 2.49-3.50 ppm for
methylenes involved in the spacer arm between danazol fragment and phenyl group were
display. Finally, several signals at 6.44 ppm for both amine and hydroxyl groups; at 6.95-
7.59 for phenyl group were found. The 13C NMR spectra display chemical shifts at 14.91
and 19.66 ppm for the carbons of methyls presents in the steroid nucleus of 5. Other
chemical shifts at 21.05-23.88, 30.69, 31.70-37-65, 40.50-53.12, 84.43, 110.50, 121.63,
141.60-156.07 ppm for carbons of methylenes involved steroid nucleus were exhibited.
Additionally, several signals at 30.43-39.44 ppm for carbons corresponding to spacer arm
between steroid nucleus and phenyl group were found. Finally, other signals at 115.10-
160.42 ppm for phenyl group; at 162.35 and 171.90 ppm for amide groups and at 168.20
ppm for ketone group were exhibited. The presence of 5 was further confirmed from mass
spectrum which showed a molecular ion at m/z 599.29.
Electronic parameters
Molecular orbital and their properties, like energy and their frontier electron density are used
for predicting the most reactive position in π-electron systems and several types of reactions
in conjugated system. This theory indicate that the highest occupied molecular orbital
(HOMO) and lowest unoccupied molecular orbital (LUMO) values and their energy gap
reflect the chemical activity of the molecule. There are reports which show that the energy
gap between HOMO and LUMO have correlation with biological activity27. To evaluate
these physiochemical parameters, some methods have been developed within the
mathematical framework of the molecular orbital theory to evaluate the electronic properties
of several compounds. For example, there are studies which showed the evaluation of the
frontier molecular orbitals (HOMO-LUMO gap) of some steroids using the MINDO and
ZINDO models28,29
.
Analyzing these data in this study, HOMO-LUMO gap of compound 5 were evaluated
using a theoretical method (ZINDO/S, hyperchem 6.0). The results showed two energy
levels for HOMO (-598.6163 eV) and for LUMO (-0.8229007 eV) in the compound 5
(Table 1). These frontier orbital molecular values were compared with the data obtained for
the compound 3, in order to evaluate if changes in the structure 5 chemical affect the energy
levels. The results showed that the HOMO-LUMO gap values were different for 5 in
comparison with 3. This phenomenon could be conditioned by π orbital which is localized in
the amide group involved in the spacer arm between steroid nucleus and phenyl group of 5
in comparison with 3. In addition, also the compound 5 showed other differences with
respect to 3, in this case the π orbitals are localized in the phenyl group involved in the
chemical structure of 5. All these data suggest that functional groups could induce changes
in the organic superconductivity of 5 as it happens in other steroid derivatives, which show
that molecular orbitals (C-2p) are aligned along of the molecular axes30, this phenomenon,
could bring like consequence variations in the electronic transmittance.

32
V. Lauro Figueroa et al.
Table 1. Parameters Physicochemical (HOMO and LUMO), ∆Hf, RMSg (RM gradient) and
Dipolar Moment (µ) of compounds 3 and 5.
Compound
µ
HOMO,
LUMO,
∆HfRMSg,
kcal/Å mol) Debyes
eV
eV
kcal/mol
-528.4316 -1.532452 -182113.2 912.1
-598.6163 -0.8629007 -242058.1 1178
4.101
4.460
3
5
Table 2. Bond length of atoms involved in the chemical structure of compound 3
Atom
O-C (Isoxazole ring)
O-N (Isoxazole ring) 0.23121 C19-C20
Length
0.40694
Atom
C7-C19
Length
0.23121 C30-N
0.23401 N-C33
Atom
Length
0.23001
0.23001
N-C3
C3-C4
C4-C5
C4-C14
C14-C15
C15-C16
C6-C16
C6-C7
0.23402 C20-C10
0.23402 C9-C10
0. 23402 C10-C11
0. 23121 C9-C13
0.23001 C13-C12
0.23402 C11-C12
0.23121 C11-C26
0.23402 C26-C27
0.23401 C33-C34 0.22600
0.23121 C34-N
0.23001
0.23401
0.40231
0.23121
0.23001
0.23121
0.23121
C6-C21
C7-C8
C16-C17
C17-C18
C18-C8
C8-C9
0.23121 C11-O(ring D) 0.23121
0.23001 O-C24
0.23001 C24 =O
0.23402 C24-C28
0.23121 C28-C29
0.23402 C29-C30
C30=O
0.23121
0.23402
0.23402
0.23121
0.23001
0.23001
Table 3. Bond length of atoms involved in the chemical structure of compound 5
Atom
O-C (Isoxazole ring)
O-N (Isoxazole ring)
N-C3
C3-C4
C4-C5
C4-C14
C14-C15 (C=C)
C15-C16
C6-C16
C6-C7
C6-C21
C7-C8
C16-C17
C17-C18
C18-C8
C8-C9
Length
Atom
Length
Atom
N-C33
C33-C34 0.23001
Length
0.23001
0.40694
0.23121
0.23402
0.23402
0. 23402 C10-C11
0. 23121 C9-C13
0.23001
0.23402
0.23121
0.23402
0.23121
0.23001
0.23001
0.23402
0.23121
0.23402
C7-C19
C19-C20
C20-C10
C9-C10
0.23121
0.23401
0.23401
0.23121
0.23401
0.40231
0.23121
0.23001
0.23121
0.23121
C34-N
N-C36
C36=O
C36-C38 0.23402
C38-C39 0.23121
C39-C40 0.23001
C40-C41 0. 23001
C41-C42 0. 23001
C42-C43 0.23001
C38-C43 0.23001
0.22600
0.23001
0.23121
C13-C12
C11-C12
C11-C26
C26-C27
C11-O (ring D) 0.23121
O-C24
C24 =O
C24-C28
C28-C29
C29-C30
C30=O
0.23121
0.23402
0.23402
0.23121
0.23001
0.23001
C41-O
0.23121

Synthesis of Two Steroids Derivatives
33
On the other hand, it is important to mention that there are studies31 which indicate that
the size of the energy gap between the highest occupied and lowest unoccupied molecular
orbitals (HOMO−LUMO gap) is directly related to the extent of bond-length alternation of
some compounds. Therefore, in this study was interesting to evaluate the bond length of
each atom involved in the chemical structure of 5 and compare it with the obtained values
for the compound 3. The results indicate (c.f. Table 2 and 3) that both phenyl and amide
groups involved in the structure chemical of 5 caninduce diminish the levels of energy from
HOMO−LUMO gap of this compound in comparison with obtained values 3. It is important
to mention that also length of chain has been relationship with the changes in the dipole
moment (µ) of 5 as it happens in other compounds32; therefore, in this study µof 5 was
evaluated and compared with the values of 3. The results showed that µwas high in 5 in
comparison with 3 (c.f. Table 1); this data indicate that increase in the length of chain induce
greater moment dipole.
Conclusion
In conclusion all these data indicate a relationship of physicochemical parameters HOMO-
LUMO gap with length of chain and µ of the compound 5.
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Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
Volume 2014
Volume 2014
Volume 2014