Synthesis of a succinate-dihydrotestosterone-dihydropyrimidine conjugate

Article abstract of DOI:10.1007/s00706-009-0223-6

In this work a new steroid-dihydropyrimidine derivative was synthesized. The route involved preparation of a dihydrotestosterone-dihydropyrimidine derivative using dihydrotestosterone, benzaldehyde, and thiourea in the presence of hydrochloric acid, followed by esterification of the dihydrotestosterone- dihydropyrimidine derivative with succinic acid to form a succinate- dihydrotestosterone-dihydropyrimidine conjugate.

Full text of DOI:10.1007/s00706-009-0223-6

Monatsh Chem (2010) 141:75–78
DOI 10.1007/s00706-009-0223-6
ORIGINAL PAPER
Synthesis of a succinate–dihydrotestosterone–dihydropyrimidine
conjugate
•
Lauro Figueroa-Valverde Francisco Dıaz-Cedillo
•
´
Abelardo Camacho-Luis
Received: 7 September 2009 / Accepted: 19 November 2009 / Published online: 8 December 2009
Ó Springer-Verlag 2009
Abstract In this work a new steroid–dihydropyrimidine
derivative was synthesized. The route involved preparation
multi-component reactions for synthesis of dihydropyrim-
idines, for example the work reported by Hantzsch [5],
which described preparation of 1,4-dihydropyridine using a
three-component coupling reaction (acetoacetic ester,
benzaldehyde, and ammonia or ammonium salts) in ethanol
under reflux. Biginelli [6] has reported the synthesis of
dihydropyrimidine derivatives using ethyl acetoacetate,
benzaldehyde, and urea. In addition, dihydropyrimidin-
2(1H)-one was recently synthesized by use of the three-
component system urea/thiourea, ethyl acetoacetate, and
acetyl acetone in the presence of phosphorus pentoxide [7].
Additionally, in other work Surya and coworkers [8]
achieved the synthesis of 3,4-dihydropyrimidin-2(1H)-ones
under solvent-free conditions using ruthenium(III) chloride
as catalyst. In addition, Kappe and coworkers [9] have
reported highly versatile solid-phase synthesis of biofunc-
tional 4-aryl-3,4-dihydropyrimidines using resin-bound
isothiourea building blocks and multidirectional resin
cleavage.
of
a dihydrotestosterone–dihydropyrimidine derivative
using dihydrotestosterone, benzaldehyde, and thiourea
in the presence of hydrochloric acid, followed by ester-
ification of the dihydrotestosterone–dihydropyrimidine
derivative with succinic acid to form a succinate–dihy-
drotestosterone–dihydropyrimidine conjugate.
Keywords Steroid–dihydropyrimidine derivative ꢀ
Benzaldehyde ꢀ Thiourea
Introduction
In recent decades several dihydropyrimidine derivatives
have been synthesized with a wide spectrum of biological
actions [1], as antibacterials [2, 3], antivirals [4], and
antitumor agents. In this sense, there are several reports of
Another study reported by Shirini and coworkers [10]
showed that Fe(HSO4)3 can be an efficient catalyst for
preparation of 3,4-dihydropyrimidin-2(1H)-ones using the
three-component system b-keto ester, benzaldehyde, and
thiourea. Additionally, Salehia and coworkers [11] have
reported the synthesis of dihydropyrimidinones using
aldehyde derivatives, dicarbonyl compounds, and urea or
thiourea in the presence of diammonium hydrogen
phosphate.
L. Figueroa-Valverde (&)
´
Facultad de Ciencias Quımico-Biologicas,
Lab. de Farmaco-quımica, Universidad Autonoma de Campeche,
´
´
´
´
Av. Agustın Melgar s/n entre calle Juan de la Barrera y C-20,
Col Buenavista, C.P. 24039, Campeche, Campeche, Mexico
e-mail: lauro_1999@yahoo.com
´
´
F. Dıaz-Cedillo (&)
Escuela de Ciencias Biologicas del IPN, Plan de San Luıs y Dıaz
´
Miron s/n Col. Santo Tomas, C.P. 11340, Mexico D.F., Mexico
´
´
These experimental results show several procedures are
available for synthesis of dihydropyrimidine derivatives by
use of the Biginelli reaction; expensive reagents and spe-
cial conditions are required, however. In this work,
therefore, our initial design included a facile synthesis of a
steroid–dihydropyrimidine derivative that contains, in the
cyclopentane ring of the succinate–dihydrotestosterone–
´
e-mail: stybium@yahoo.com
´
´
A. Camacho-Luis (&)
Facultad de Medicina de la Universidad Juarez del Estado de
´
Durango, Av. Fanny Anitua s/n Esq. Av. Universidad, Durango,
´
Durango, Mexico
e-mail: loky001@hotmail.com
123

76
L. Figueroa-Valverde et al.
dihydropyrimidine conjugate nucleus, a spacer arm with
both ester and acid functional groups. The route involves
preparation of dihydrotestosterone–dihydropyrimidine
derivative 4 using, first, the three-component system
5a-androstan-17b-ol-3-one, benzaldehyde, and thiourea
in the presence of hydrochloric acid as catalyst, followed
by esterification of the steroid–dihydropyrimidine deriva-
tive with succinic acid and 1,3-dicyclohexylcarbodiimide
to form succinate–dihydrotestosterone–dihydropyrimidine
conjugate 5.
conventional methods have found only limited use for this
purpose. During recent years, carbodiimides and, espe-
cially, dicyclohexylcarbodiimide (DCC) have attracted
increasing attention as condensing agents in ester synthesis
[19, 20]. Nevertheless, it is important to mention that when
dicyclohexylcarbodiimide is used as condensing agent in
esters synthesis, yields of the esters are often unsatisfactory
because of formation of the N-acylurea derivative as
by-product. Some reports reveal that addition of a catalytic
amount of a strong acid to the esterification reaction in
the presence of dicyclohexylcarbodiimide considerably
increases the yield of esters and reduces the formation of
the N-acylurea compound [21]. For this reason, esterifica-
tion of the hydroxyl group of dihydrotestosterone–
dihydropyrimidine derivative 4 with succinic acid in the
presence of dicyclohexylcarbodiimide and p-toluenesul-
fonic acid (Scheme 1) was used to increase the yield of
the succinate–dihydrotestosterone–dihydropyrimidine con-
jugate 5.
Results and discussion
It is important to mention that many procedures for for-
mation of dihydropyrimidine derivatives are available in
the literature. The most widely practiced methods employ
boric acid [12], silica sulfuric acid [13], poly-(4-vinylpyr-
idine-co-divinylbenzene)-Cu(II) complex [14], H2SO4
[15], silica triflate [16], and phosphorus pentoxide [7].
Nevertheless, despite their wide scope, these procedures
suffer from several drawbacks; some reagents are of lim-
ited stability, and preparation can be dangerous.
1
The H NMR spectrum of 5 shows signals at 0.76 and
0.83 ppm for methyl groups present in the heterocyclic ring
and at 4.81 ppm for CH in the pyrimidine ring. In addition,
at low field there are several signals (7.24–7.43 ppm)
corresponding to protons in the aromatic ring. Finally, the
spectrum contains a signal with a chemical shift of
8.60 ppm for NH (pyrimidine ring) and CO2H.
The 13C NMR spectrum of 5 contains peaks at chemical
shifts of 11.98 and 12.13 ppm for the carbons of the methyl
groups present in the heterocyclic ring. The chemical shifts
of methylene joined to the pyrimidine ring are at 108.02
(C–C=C) and 125.58 ppm (C=C–N). At low field there are
several signals (125.60, 127.39, 127.42, 128.35, 139.32,
and 142.02 ppm) corresponding to the carbons of the aro-
matic ring. Two chemical shifts at 172.81 (CO2H) and
180.62 ppm (N–C=S, pyrimidine ring) are also found.
In the mass spectrum the molecular ion is at m/z = 534.31
([M ? H]?), which confirms the structure of 5.
Therefore, in this work we report a straightforward
route for synthesis of a new steroid–dihydropyrimidine
derivative. The first step involves preparation of dihydro-
testosterone–dihydropyrimidine derivative 4 using the
three-component system 5a-androstan-17b-ol-3-one, benz-
aldehyde, and thiourea in presence of hydrochloric acid
as catalyst (Scheme 1). The 1H NMR spectrum of the
dihydrotestosterone–dihydropyrimidine derivative shows
signals at 0.74 and 0.78 ppm for methyl groups present in the
heterocyclic ring and at 4.83 ppm for CH involved in the
pyrimidine ring; at low field there are several chemical shifts
(7.21–7.29 and 7.46 ppm) corresponding to protons in the
aromatic ring. Finally, the spectrum contains a signal at a
chemical shift of 7.38 ppm for the NH (pyrimidine ring)
and OH.
The 13C NMR spectrum contains peaks at chemical
shifts of 11.94 and 12.11 ppm for the carbons of the methyl
groups present in the heterocyclic ring. The chemical shifts
of methylene joined to the pyrimidine ring are at 109.01
(C–C=C) and 125.57 ppm (C=C–N). Downfield there are
several signals (125.60, 127.38, 127.46, 128.33, and
139.31 ppm) corresponding to the carbons of the aromatic
ring.
In conclusion, in this work we report an efficient and
simple method for synthesis of the new steroid–dihydro-
pyrimidine derivative 4, using a multi-component system in
the presence of hydrochloric acid as catalyst. It is important
to mention that this method is highly versatile and the
yield is good. In addition, esterification of the dihydro-
testos_terone–dihydropyrimidine derivative using succinic
acid in the presence of 1,3-dicyclohexylcarbodiimide and
p-toluenesulfonic acid is a good system for increasing the
yield of 5.
In the mass spectrum the molecular ion is at m/z = 436.16
([M ? H]?), which confirms the structure of 4.
The second step involves esterification of the hydroxyl
group of the dihydrotestosterone–dihydropyrimidine
derivative by reaction of 4 with succinic acid. It is
important to mention that diverse reagents are available for
producing ester derivatives [17, 18]; nevertheless, most
Experimental
Dihydrotestosterone (5a-androstan-17b-ol-3-one) and the
other compounds evaluated in this study were purchased
123

Synthesis of a succinate–dihydrotestosterone–dihydropyrimidine conjugate
77
Scheme 1
OH
OH
H C
O
3
S
HCl
Ethanol
+
+
H N
NH
2
2
HN
O
S
N
H
1
2
3
4
Succinic acid
DCC / p-toluenesulfonic acid
Acetonitrile / water
O
O
OH
O
HN
S
N
H
5
CDCl3): d = 11.94 (CH3), 12.11 (CH3), 20.55, 23.56,
27.87, 27.89, 30.33, 34.93, 35.36, 35.38, 36.41, 42.66,
50.58, 50.77, 53.39, 53.43, 58.25, 61.32, 82.84 (C–OH),
109.01 (C–C=C), 125.57 (C=C–N), 125.60, 127.38,
127.46, 128.33, 139.31 (Ar), 179.30 (pyrimidine ring)
ppm; EI-MS: m/z = 436.16 ([M ? H]?).
from Sigma–Aldrich. Melting points were determined on
an Electrothermal model 900. Ultraviolet spectroscopy
(UV) was carried out in dry methanol on a Perkin–Elmer
model 552 spectrophotometer and infrared spectra (IR)
were recorded using KBr pellets on a Perkin–Elmer
1
Lambda 40 spectrometer. H and 13C NMR spectra were
recorded on a Varian VXR-300/5 FT NMR spectrometer at
300 and 75.4 MHz, respectively, in CDCl3, using TMS as
internal standard. EI-MS spectra were obtained with a
Finnigan Trace GCPolaris Q spectrometer. Elemental
analysis data were obtained by use of a Perkin–Elmer Ser.
II CHNS/0 2400 elemental analyzer.
Succinic acid mono(10,20,30,60-tetrahydro-60-phenyl-20-
thioxoandrost-2-eno[3,2-d]pyrimidin-17-yl)ester
(5, C31H40N2O4S)
Dihydrotestosterone derivative 4 (100 mg, 0.23 mmol)
was added to
a solution of 85 mg succinic acid
(0.72 mmol) and 100 mg 1,3-dicyclohexylcarbodiimide
(0.48 mmol) in 15 cm3 acetonitrile–water (3:1) and 69 mg
p-toluenesulfonic acid monohydrate (0.36 mmol) was
added and the mixture was stirred at room temperature
for 72 h. The solvent was then removed under vacuum
and the crude product was purified by crystallization from
methanol–hexane–water (3:2:1) yielding 78% of product
5. M.p.: 121 °C; UV (MeOH): kmax (log e) = 218 (0.19),
30,60-Dihydro-17-hydroxy-60-phenylandrost-2-eno[3,2-d]
pyrimidine-20(10H)-thione (4, C27H36N2OS)
A solution of 118 mg dihydrotestosterone (0.41 mmol),
123.70 mg thiourea (1.62 mmol), and 0.65 cm3 benzalde-
hyde (1.62 mmol) in 10 cm3 ethanol was stirred for 10 min
at room temperature. Then 1 cm3 hydrochloric acid was
added and the mixture was stirred for 48 h at room
temperature. The reaction mixture was evaporated to a
smaller volume, diluted with water, and extracted with
chloroform. The organic phase was evaporated to dryness
under reduced pressure, the residue was purified by
crystallization from methanol–water (3:1) yielding 80%
of product 4. M.p.: 107 °C; UV (MeOH): kmax (log
e) = 217 (0.18), 258 (0.09) nm; IR: vꢀ = 3,330, 1,620,
261 (0.20) nm; IR: vꢀ = 3,326, 1,615, 1,712 cm-1
;
1H NMR (300 MHz, CDCl3): d = 0.76 (s, 3H, CH3),
0.83 (s, 3H, CH3), 0.87 (m, 1H), 1.10 (m, 1H), 1.10–1.80
(m, 11H), 1.85–1.90 (m, 2H), 2.03–2.43 (m, 4H), 2.57 (m,
2H), 3.62 (m, 1H), 3.81 (m, 2H), 4.44 (m, 1H), 4.81 (s,
1H), 7.24–7.43 (m, 5H, ArH), 8.60 (1H, br s, NH
pyrimidine ring and CO2H) ppm; 13C NMR (74.5 MHz,
CDCl3): d = 11.98 (CH3-22), 12.13 (CH3-23), 20.55,
23.52, 27.85, 27.89, 29.73, 29.81, 30.31, 32.01, 34.96,
35.34, 35.36, 36.44, 42.69, 50.56, 50.71, 53.31, 53.45,
61.37, 82.83 (C–C–O, cyclopentane), 108.02 (C–C=C),
125.58 (N–C=C), 125.60, 127.39, 127.42, 128.35, 139.32,
142.02 (C–Ar), 172.81 CO2H), 173.05 (CO2), 180.62
1,470 cm-1 1H NMR (300 MHz, CDCl3): d = 0.74 (s,
;
3H, CH3), 0.78 (s, 3H, CH3), 0.87 (m, 1H, H-7), 0.96–1.09
(m, 2H), 1.11–1.79 (m, 11H), 1.85–1.90 (m, 2H), 2.06–
2.52 (m, 4H), 3.61 (m, 1H), 3.80 (m, 1H), 4.83 (s, 1H),
7.21–7.29 (m, 3H, ArH), 7.38 (m, NH pyrimidine ring and
OH), 7.46 (m, 2H, ArH) ppm; 13C NMR (74.5 MHz,
123

78
L. Figueroa-Valverde et al.
7. Deshmukh MB, Prashant V, Anbhule PV, Jadhav SD, Mali AR,
Jagtap SS, Deshmukh SA (2007) Indian J Chem 46B:1545
8. De SK, Gibbs RA (2005) Synthesis 1748
(N–C=S, pyrimidine ring) ppm; EI-MS: m/z = 534.31
([M ? H]?).
9. Kappe CO (2000) Bioorg Med Chem Lett 10:49
10. Shirinia F, Zolfigolb MA, Abria AR (2008) J Iran Chem Soc 5:96
11. Salehi P, Dabiri M, Khosropour AR, Roozbehniya P (2006) J Iran
Chem Soc 3:98
Acknowledgments We are grateful to Gloria Velazquez Zea for
discussions and to Professors Lenin Hau Heredia and Gladys Perez
Cruz for financial support.
12. Tu S, Fang F, Miao C, Jiang H, Feng Y, Shi D, Wang X (2003)
Tetrahedron Lett 44:6153
13. Salehi P, Dabiri M, Zolfigol MA, Fard MB (2003) Tetrahedron
Lett 44:2889
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