A safe and practical method for the preparation of 7α-Thioether and thioester derivatives of spironolactone

Article abstract of DOI:10.1016/j.steroids.2012.09.005

Spironolactone is a renal competitive aldosterone antagonist. One of its most important metabolite is the 7α-methylthio spironolactone: thus it is very important to have an efficient and safe access to this compound, for pharmacokinetic studies. In this context, we synthesized this metabolite by thioalkylation of 7α-Thio spironolactone using Hu?nig's base with a very good yield. We also used our procedure to prepare, with an easy work-up and high yields, 7α-Thioether and thioester derivatives of spironolactone, that could be useful for further Structure-Activity Relationships studies.

Full text of DOI:10.1016/j.steroids.2012.09.005

Steroids 78 (2013) 102–107
Contents lists available at SciVerse ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
A safe and practical method for the preparation of 7
and thioester derivatives of spironolactone
a-thioether
Géraldine Agusti a, Sandrine Bourgeois a, Nathalie Cartiser b, Hatem Fessi a, Marc Le Borgne b,
Thierry Lomberget b,
⇑
a Université de Lyon, F-69622 Lyon, France; Université Lyon 1, Villeurbanne; LAGEP, UMR 5007, CNRS, CPE, 43 bd du 11 novembre, 69100 Villeurbanne, France
b Université de Lyon, Université Lyon 1, Faculté de Pharmacie – ISPB, EA 4446 Biomolécules Cancer et Chimiorésistances, SFR Santé Lyon-Est CNRS UMS3453 – INSERM US7,
8 avenue Rockefeller, F-69373 Lyon Cedex 8, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2012
Received in revised form 28 August 2012
Accepted 7 September 2012
Available online 10 October 2012
Spironolactone is a renal competitive aldosterone antagonist. One of its most important metabolite is the
7
a
-methylthio spironolactone: thus it is very important to have an efficient and safe access to this com-
pound, for pharmacokinetic studies. In this context, we synthesized this metabolite by thioalkylation of
-thio spironolactone using Hünig’s base with a very good yield. We also used our procedure to prepare,
with an easy work-up and high yields, 7 -thioether and thioester derivatives of spironolactone, that
could be useful for further Structure–Activity Relationships studies.
Ó 2012 Elsevier Inc. All rights reserved.
7
a
a
Keywords:
Spironolactone
Canrenone
Metabolite
Thioalkylation
Synthesis
1. Introduction
group was modified with various thioalkyl and thioester side
chains to enhance the inhibitory potency of SL. So, the second
aim of the methodology we described herein was to bring an easy
access to such derivatives.
Spironolactone (SL, 1), a C19-steroidal compound, having a spi-
rannic c-lactone at the C-17 position is a well-known anti-aldoste-
rone [1,2]. SL has been widely used for over 40 years to treat fluid
retention, mild high blood pressure and a few rare hormonal prob-
lems [3–5]. In vivo studies have shown that the two major hepatic
2. Experimental
metabolites of SL are canrenone (CAN, 2) and 7a-methylthio SL
2.1. General remarks
(TM, 3) [6,7] (Fig. 1). Both metabolites contribute to the antiminer-
alocorticoid effects of SL; however, the higher affinity for renal
aldosterone receptors combined with the higher plasma concen-
trations of TM, indicate that this metabolite plays a major role
for these effects [8,9]. Consequently, there is a need for pharmaco-
kinetic studies on SL to have this metabolite in reasonable quanti-
Spironolactone was purchased from Amplachem, USA.
4-Methoxybenzyl bromide (5a) [13] and 4-t-butyldimethylsilyl-
oxybenzyl bromide (5b) [14] were prepared as described in the lit-
erature. All reagents and solvents were purchased from Acros
Organics or Sigma Aldrich and were used without further purifica-
tion. Reactions were monitored by thin layer chromatography (TLC,
UV254nm) aluminum sheets coated with Kieselgel 60F254. Product
purification by flash column chromatography was performed using
ties: this prompted us to develop an easy preparation of 7
a-
thiomethylspironolactone 3 and the first part of this work will de-
scribe our optimization process, implying the methylation of a 7
thiol precursor.
a-
Kieselgel 60 Å (40–63 lm). Melting points were determined on a
Furthermore, a recent review [10] reported an additional bio-
logical activity of SL as an inhibitor of type 2 17b-hydroxysteroid
differential scanning calorimeter apparatus, Q200Ò from TA Instru-
ments. Proton nuclear magnetic resonance (1H NMR) spectra were
recorded on Brüker ALS300 and DRX300 Fourier transform spec-
trometers, using an internal deuterium lock, operating at
300 MHz. Chemical shifts are reported in parts per million (ppm)
relative to internal standard (tetramethylsilane, TMS). Data are
presented as follows: chemical shift (d, ppm), multiplicity (s, sin-
glet; d, doublet; t, triplet; q, quadruplet; m, multiplet), coupling
dehydrogenase (17b-HSD). Investigations on spiro-
c-lactones
demonstrated the biological interest of C18-steroidal lactones
[11] and some SL analogues [12]. Particularly, the 7a-thioacetyl
⇑
Corresponding author. Tel.: +33 478 777 082.
E-mail address: thierry.lomberget@univ-lyon1.fr (T. Lomberget).
0039-128X/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.steroids.2012.09.005

G. Agusti et al. / Steroids 78 (2013) 102–107
103
O
O
O
O
17
O
17
O
17
7
7
O
S
O
7
O
S
6
O
CAN 2
SL 1
TM 3
Fig. 1. Chemical structures of SL 1 and its two metabolites, CAN 2 and TM 3.
constant (J, reported in Hz), integration, assignment. Carbon mag-
netic resonance (13C NMR) spectra were recorded on Brüker
DRX300 and DRX400 Fourier transform spectrometers, using an
internal deuterium lock, operating at 75 and 100 MHz, respec-
tively. FT-IR spectra were recorded on IR Prestige-21 from Shima-
dzu. Electrospray ionization (ESI) mass spectra were recorded on
an Agilent 1290 system coupled with 6120 single quadrupole Mass
Spectrometer. High-resolution mass spectra were recorded on a
Brüker MicroTOF Q Mass Spectrometer.
product was purified by flash chromatography (cyclohexane/EtOAc
7/3) to afford compound 7a (183 mg, 43%) as a white solid; the
spectral data were identical to those reported in the literature
[16]. 1H NMR (300 MHz, CDCl3): d 0.90 (t, J = 7.2, 3H, S-(CH2)3–
CH3), 0.97 (s, 3H, 18-CH3), 1.20 (s, 3H, 19-CH3), 3.02–3.05 (m, 1H,
7b-CH), 5.77 (s, 1H, 4-CH).
2.3.3. 3-Oxo-17
carbolactone (7b)
According to general procedure, scale: CH3CN (7 mL), DIPEA
(0.44 mL, 2.5 mmol), compound 4 (374 mg, 1 mmol), methyl
a-pregna-4-ene-7a-(methylacetylthia)-21,17-
2.2. Synthesis of 3-oxo-17a-pregna-4-ene-7a-(thia)-21,17-
a-
carbolactone (4)
bromoacetate (0.11 mL, 1.2 mmol); reaction time at 80 °C = 1 h.
The crude product was purified by flash chromatography (cyclo-
hexane/EtOAc 7/3) to afford compound 7b (390 mg, 87%) as a
white solid; mp 182–185 °C. IR mmax (cmꢀ1): 1768, 1730, 1650,
1616. 1H (CDCl3, 300 MHz): d 0.97(s, 3H, 18-CH3), 1.22 (s, 3H, 19-
CH3), 3.13–3.26 (m, 3H, CH2–CO and 7b-CH), 3.73 (s, 3H, O–CH3),
5.76 (s, 1H, 4-CH). 13C (CDCl3, 300 MHz): d 198.2 (C-3), 176.4 (C-
22), 170.3 (C-20), 166.0 (C-5), 158.7 (C-50), 126.7 (C-4), 95.4 (C-
17), 52.2 (C-30), 46.7 (C-9), 45.6 (C-13), 45.1 (C-14), 44.0 (C-7),
39.4 (C-8), 38.1 (C-10), 37.3 (C-6), 35.2 (C-1), 34.9 (C-16), 33.6
(C-10), 31.4 (C-2), 30.9 (C-20), 30.8 (C-21), 28.9 (C-2), 21.7 (C-11),
20.2 (C-15), 17.6 (C-19), 14.2 (C-18). HRMS (ESI+) m/z calcd for C25-
H34NaO2S (M+Na)+, 469.2006; found, 469.2019.
Sodium methoxide was first prepared by adding sodium (1.3 g,
56 mmol) to cold methanol (0 °C) (96 mL). SL 1, (10.0 g, 24 mmol)
was then added to this solution and the resulting mixture was stir-
red at room temperature for 40 min. Then, the reaction mixture
was neutralized (pH 7) with acetic acid and water (200 mL) was
added. The beige solid (13.6 g) was recovered by filtration and
recrystallized with methanol (130 mL) to afford compound 4
(6.0 g, 69%) as a yellow powder. The physical and spectral data
were identical to those reported in the literature [15]. 1H NMR
(300 MHz, CDCl3): d 0.99 (s, 3H, 18-CH3), 1.20 (s, 3H, 19-CH3),
3.33–3.27 (m, 1H, 7b-CH), 5.79 (s, 1H, 4-CH).
2.3. General procedure for the synthesis of compounds 3 and 7a–h
2.3.4. 3-Oxo-17a-pregna-4-ene-7a-(allylthia)-21,17-carbolactone
(7c)
To
a solution of diisopropylethylamine (DIPEA) (0.44 mL,
According to general procedure, scale: CH3CN (7 mL), DIPEA
(0.44 mL, 2.5 mmol), compound 4 (374 mg, 1 mmol), allyl bromide
(0.10 mL, 1.2 mmol); reaction time at 80 °C = 2 h. The crude prod-
uct was purified by flash chromatography (cyclohexane/EtOAc 7/
3) to afford compound 7c (318 mg, 77%) as a white solid; the spec-
tral data were identical to those reported in the literature [16]. 1H
NMR (300 MHz, CDCl3): d 0.97 (s, 3H, 18-CH3), 1.21 (s, 3H, 19-CH3),
2.98–3.02 (m, 1H, 7b-CH), 3.06–3.11 (m, 2H, CH2@CH–CH2), 5.05–
5.11 (m, 2H, CH2@CH–CH2), 5.67–5.80 (m, 2H, 4-CH and CH2@CH–
CH2).
2.5 mmol) in acetonitrile (7 mL) was added compound 4 (374 mg,
1 mmol) followed by the corresponding halide (1.2 mmol). At the
end of the reaction, the volatiles were removed under reduced
pressure and the crude product was then purified by column
chromatography.
2.3.1. 3-Oxo-17a-pregna-4-ene-7a-(methylthia)-21,17-carbolactone
(TM 3)
According to general procedure, scale: CH3CN (7 mL), DIPEA
(0.44 mL, 2.5 mmol), compound 4 (374 mg, 1 mmol), methyliodide
(0.074 mL, 1.2 mmol); reaction time at rt = 30 min. The crude prod-
uct was purified by flash chromatography (cyclohexane/EtOAc 7/3)
to afford compound TM 3 (300 mg, 77%) as a white solid; the spec-
tral data were identical to those reported in the literature [15]. 1H
NMR (300 MHz, CDCl3): d 0.98 (s, 3H, 18-CH3), 1.21 (s, 3H, 19-CH3),
2.04 (s, 3H, S-CH3), 2.95–2.98 (m, 1H, 7b-CH), 5.78 (s, 1H, 4-CH).
2.3.5. 3-Oxo-17a-pregna-4-ene-7a-(propargylthia)-21,17-
carbolactone (7d)
According to general procedure, scale: CH3CN (7 mL), DIPEA
(0.44 mL, 2.5 mmol), compound 4 (374 mg, 1 mmol), propargyl
bromide (0.10 mL, 1.2 mmol); reaction time at 80 °C = 1 h. The
crude product was purified by flash chromatography (cyclohex-
ane/EtOAc 7/3) to afford compound 7d (360 mg, 79%) as a white
solid; mp 172 °C (dec). IR mmax (cmꢀ1): 3223, 1762, 1649, 1618,
1170. 1H NMR (300 MHz, CDCl3): d 0.99 (s, 3H, 18-CH3), 1.22 (s,
3H, 19-CH3), 3.20 (dd, J = 17.1–2.5, 1H, CH2–C„CH), 3.27 (dd,
J = 17.1–2.5, 1H, CH2–C„CH) 3.34–3.37 (m, 1H, 7b-CH), 5.77 (d,
J = 1.2, 1H, 4-CH). 13C (CDCl3, 300 MHz): d 198.4 (C-3), 176.5 (C-
2.3.2. 3-Oxo-17a-pregna-4-ene-7a-(butylthia)-21,17-carbolactone
(7a)
According to general procedure, scale: CH3CN (7 mL), DIPEA
(0.44 mL, 2.5 mmol), compound 4 (374 mg, 1 mmol), butyl bro-
mide (0.34 mL, 1.2 mmol); reaction time at 80 °C = 24 h. The crude

104
G. Agusti et al. / Steroids 78 (2013) 102–107
22), 166.3 (C-5), 126.8 (C-4), 95.5 (C-17), 79.4 (C-20), 71.2 (C-30),
47.3 (C-9), 45.2 (C-13), 45.1 (C14), 45.0 (C-7), 39.5 (C-8), 38.2 (C-
10), 37.5 (C-6), 35.3 (C-1), 35.0 (C-16), 33.7 (C-10), 31.0 (C-20),
31.0 (C-21), 29.0 (C-2 et C-12), 21.8 (C-11), 20.3 (C-15), 17.7 (C-
J = 15.0, 2H, CH2Ph), 5.75 (s, 1H, 4-CH), 6.76 (d, J = 9, 2H, Ph), 7.12
(d, J = 8.4, 2H, Ph).
2.3.9. 3-Oxo-17a-pregna-4-ene-7a-(benzoylthia)-21,17-carbolactone
(7h)
19), 14.3 (C-18). HRMS (ESI+) m/z calcd for
C25H32NaO3S
(M+Na)+, 435.1955; found, 435.1964.
According to general procedure, scale: CH3CN (7 mL), DIPEA
(0.44 mL, 2.5 mmol), compound 4 (374 mg, 1 mmol), benzoyl chlo-
ride (0.14 mL, 1.2 mmol); reaction time at 80 °C = 1 h. The crude
product was purified by flash chromatography (cyclohexane/EtOAc
7/3) to afford compound 7h (290 mg, 75%) as a yellow solid; the
spectral data were identical to those reported in the literature
[12]. 1H NMR (300 MHz, CDCl3): d 1.01 (s, 3H, 18-CH3), 1.27 (s,
3H, 19-CH3), 4.23–4.26 (m, 1H, 7b-CH), 5.71 (s, 1H, 4-CH), 7.45
(t, J = 7.8, 2H, Ph), 7.59 (t, J = 7.5, 1H, Ph), 7.96 (d, J = 7.2, 2H, Ph).
2.3.6. 3-Oxo-17a-pregna-4-ene-7a-(benzylthia)-21,17-carbolactone
(7e)
According to general procedure, scale: CH3CN (7 mL), DIPEA
(0.44 mL, 2.5 mmol), compound 4 (374 mg, 1 mmol), benzyl bro-
mide (0.14 mL, 1.2 mmol); reaction time at 80 °C = 2 h. The crude
product was purified by flash chromatography (cyclohexane/EtOAc
7/3) to afford compound 7e (326 mg, 77%) as a white solid; the
spectral data were identical to those reported in the literature
[12]. 1H NMR (300 MHz, CDCl3): d 0.85 (s, 3H, 18-CH3), 1.11 (s,
3H, 19-CH3), 2.79–2.82 (m, 1H, 7b-CH), 3.51 (q, J = 13.5, 2H, CH2-
Ph), 5.67 (d, J = 1.5, 1H, 4-CH), 7.14–7.20 (m, 5H, Ph).
3. Results and discussion
The first part of this work was to find an efficient synthesis of
metabolite TM 3. In the 70’s Karim and Brown [15] proposed the
preparation of this compound using a conjugated addition of gas-
eous methyl mercaptan on CAN 2.
CAN 2 was first prepared in a good yield from SL 1, after re-
moval under basic conditions (excess of MeONa) of the thioacetyl
group, according to a retro-Michael elimination (Scheme 1) [12].
In a second step, a conjugated 1,6-addition of gaseous methylmer-
2.3.7. 3-Oxo-17
carbolactone (7f)
a-pregna-4-ene-7a-(p-methoxybenzylthia)-21,17-
According to general procedure, scale: CH3CN (7 ml), DIPEA
(0.44 mL, 2.5 mmol), compound 4 (374 mg, 1 mmol), 4-Methoxy-
benzyl bromide (5a) (241 mg, 1.2 mmol); reaction time at
80 °C = 4 h. The crude product was purified by flash chromatogra-
phy (cyclohexane/EtOAc 7/3) to afford compound 7f (350 mg,
71%) as a white solid; mp 228–233 °C. IR mmax (cmꢀ1):1762, 1734,
1665, 1608, 1170. 1H NMR (300 MHz, CDCl3): d 0.93 (s, 3H, 18-
CH3), 1.18 (s, 3H, 19-CH3), 2.85–2.87 (m, 1H, 7b-CH), 3.61 (q,
J = 12, 2H, CH2-Ph), 3.78 (s, 3H, O–CH3), 5.74 (s, 1H, 4-CH), 6.82
(d, J = 9, 2H, C6H5), 7.18 (d, J = 9, 9H, C6H5). 13C (CDCl3, 400 MHz):
d 198.5 (C-3), 176.6 (C-22), 166.9 (C-5), 158.6 (C-50), 129.8 (C-30),
129.7 (C-20), 126.7 (C-4), 113.7 (C-40), 95.6 (C-17), 55.1 (C-60),
47.1 (C-9), 45.1 (C-13), 44.9 (C-14), 44.5 (C-7), 39.6 (C-8), 38.2
(C-10), 38.0 (C-6), 35.3 (C-1), 35.1 (C-16), 34.3 (C-10), 33.8 (C-2),
31.1 (C-12), 31.1 (C-20), 29.1 (C-21), 21.7 (C-11), 20.3 (C-15),
17.7 (C-19), 14.3 (C-18). C30H38NaO4S (M+Na)+, 517.2385; found,
517.2383.
captan under pressure, led to the desired 7a-thiomethyl derivative
(TM 3) after 20 h of reaction time. Beside the major drawback of
this method, i.e. the use of a toxic gas in drastic reaction conditions
(and the olfactive nuisance as well), there was a lack of versatility
for this approach, which also requires a long reaction time for the
functionalization second step.
In order to improve this synthesis, we decided to design a new
two steps pathway, based on an alkylation reaction of a 7a-thiol
derivative 4 (Scheme 2), thus avoiding the use of gaseous MeSH.
First, the acetyl group of SL 1 was cleaved using sodium meth-
oxide in methanol to yield 7a thiol derivative 4 (Scheme 2) [17].
In the second key step, methyl iodide was used as the electro-
phile for the alkylation of the thiol function of 4 and, to determine
the optimal conditions, both the nature of base and solvent were
investigated (Table 1).
2.3.8. 3-Oxo-17a-pregna-4-ene-7a-[(4-t-butyldimethylsilyloxy)-
benzylthia)]-21,17-carbolactone (7g)
According to general procedure, scale: CH3CN (3.5 ml), DIPEA
(0.22 mL, 1.75 mmol), compound 4 (187 mg, 0.5 mmol), 4-t-butyl-
dimethylsilyloxybenzyl bromide (5b) (180.6 mg, 0.6 mmol); reac-
tion time at 60 °C = 2 h. The crude product was purified by flash
chromatography (cyclohexane/EtOAc 7/3) to afford compound 7g
(210 mg, 71%) as a white solid; the spectral data were identical
to those reported in the literature [12]. 1H NMR (300 MHz, CDCl3):
d 0.17 (s, 6H, 2 Si–(CH3)), 0.92 (s, 3H, 18-CH3), 0.97 (s, 9H, Si–C–
(CH3)3), 1.118 (s, 3H, 19-CH3), 2.83–2.85 (m, 1H, 7b-CH), 3.59 (q,
Initially, the reaction was carried out using a slight excess of so-
dium methoxide in methanol [18] but, unfortunately, the expected
product TM 3 was not observed as CAN 2 was detected as the sole
product (Table 1, entry 1), isolated with a 14% yield. The use of so-
dium hydride as the base improved the reaction as compound TM
3 was detected in the crude product (Table 1, entry 2): CAN 2 was
still obtained as the major product. The formation of this undesired
compound seemed to occur when the concentration of the thiolate
anion was high, compared to the quantity of the MeI electrophile:
O
O
O
O
O
O
i
ii
O
S
O
S
O
O
3
2
1
Scheme 1. Reagents and conditions: (i) MeONa 5.8 equiv, THF, rt, 18 h; (ii) piperidine, gaseous MeSH, MeOH, rt, 20 h.

G. Agusti et al. / Steroids 78 (2013) 102–107
105
O
O
O
O
O
O
i
ii
O
S
O
S
H
O
S
O
1
3
4
and/or
O
O
O
2
Scheme 2. Reagents and conditions: (i) MeONa 2.8 equiv, MeOH, rt, 40 min, 69%; (ii) MeI 1.2 equiv, base, solvent.
Table 1
Optimization of reaction conditions for preparation of TM 3.
Entrya
Base
Equivalent
Solvent
Time (h)
Ratio 2/3/4b
Yield of TM 3 (%)
1
2
3
4
5
6
MeONa
NaH
1.2
1.2
1.2
2.5
2.5
2.5
MeOH
THF
THF
THF
THF
1
2
2
2
2
0.5
100/0/0
71/29/0c
2/98/0
1/33/66
1/99/0
0
nd
67
nd
71
77
NaHd
NEt3
DIPEA
DIPEA
CH3CN
1/99/0
nd, not determined.
a
All reactions were performed at room temperature and MeI was added at the end, except for entry 3.
Determined by 1H NMR analysis of the crude product, except for entry 2.
Determined by LC/MS analysis of the crude product.
b
c
d
In situ quench: the electrophile MeI was added before the base.
the high concentration of this basic species might probably be at
the origin of the elimination process leading to CAN 2.
Compound 7a was synthesized using bromobutane which was
much less reactive than iodomethane, thus leading to the expected
product in a low yield, though after a very long reaction time (Ta-
ble 2, entry 1).
To confirm this hypothesis, we then decided to carry out an
in situ trapping of the anion with the electrophile and this was real-
ized by doing a ‘‘reverse addition’’ of the electrophile. These condi-
tions have drastically limited CAN 2 formation and compound TM
3 was obtained with a 67% yield (Table 1, entry 3).
Yield substantially increased when methyl bromoacetate was
used for the preparation of compound 7b, which was obtained
with an excellent 87% isolated yield (Table 2, entry 2).
It is also important to point out that our protocol is very
simple and convenient, first for the synthesis, but also for the
work-up: after evaporation of acetonitrile, the crude product
was directly purified by flash chromatography. This new two-
step method for the preparation of diverse derivatives of SL
has been guided by the principle of ‘‘benign by design’’ [19].
The process avoids both the use of gaseous and malodorous re-
agents and the use of additional solvents for a supplementary
extraction step.
The use of an organic base, such as triethylamine, to trap the
hydroiodic acid released after the alkylation was envisaged and
this modification reduced CAN 2 formation, but also reaction rate
(Table 1, entry 4), as starting material 4 was detected after a 2 h
reaction time. We then turned our attention to a more basic ter-
tiary amine, diisopropylethylamine (DIPEA), also known as Hünig’s
base, to promote the reaction: in this case, only trace amount of the
side-product CAN 2 was detected and the desired compound TM 3
was obtained with a good 71% isolated yield (Table 1, entry 5).
The use of acetonitrile instead of THF dramatically reduced the
reaction time, from 2 h to 30 min, and slightly improved the yield
(Table 1, entry 6), which constitutes an ultimate improvement for
this reaction.
The use of activated
a-unsaturated halides such as allyl and
propargyl bromide, provided compounds 7c and 7d with good
77% and 79% yields, respectively (Table 2, entries 3 and 4). These
derivatives 7c and 7d could be used as precursors for a subsequent
With these optimal conditions in hand, we then decided to
grafting of functional groups on the 7a side-chain, by employing
study the scope of this reaction by synthesizing several 7
thioalkyl SL derivatives (Scheme 3 and Table 2).
a
-
Heck or cross-metathesis reactions on the double unsaturation or
Sonogashira coupling reaction on the triple bond.

106
G. Agusti et al. / Steroids 78 (2013) 102–107
O
O
O
O
O
R
Br
or
Ph
Cl
DIPEA, CH3CN, T°C
O
S
O
S
H
R
4
7a-h
7a (R = n-Bu)
7b (R = CH2CO2Me
7c (R = CH2-CH=CH2)
7d (R = CH2-CCH)
7e (R = Bn)
7f (R = CH2-Ph-p-OMe)
7g (R = CH2-Ph-p-OTBDMS)
7h (R = COPh)
Scheme 3. The reaction was carried out with the conditions obtained for the synthesis of compound TM 3 but, as the alkyl bromides we used were less reactive than methyl
iodide, the temperature was increased to 60–80 °C in order to reduce the reaction time (Table 2).
Table 2
Thioalkylation of 4 in the presence of DIPEA (2.5 equiv) in CH3CN.
Entry
Compound
R
Reaction conditions (time, temp.)
Yield (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
n-Bu
24 h, 80 °C
1 h, 80 °C
2 h, 80 °C
1 h, 80 °C
2 h, 80 °C
4 h, 80 °C
2 h, 60 °C
1 h, 80 °C
43
87
77
79
77
71
71
75
CH2–CO2Me
CH2–CH@CH2
CH2–CꢁCH
Bn
CH2-Ph-p-OMe
CH2-Ph-p-OTBDMS
COPha
7g
7h
a
Benzoyl chloride was used.
According to our methodology, compounds 7e–g were synthe-
5b. The Institut des Sciences Pharmaceutiques et Biologiques (ISPB)
of Lyon is also gratefully acknowledged (special thanks to Pr Franç-
ois Locher) for the funding of an uHPLC/DAD/MS system, a power-
ful analytical tool, also useful for ‘‘connecting researchers’’.
sized in good yields (Table 2, entries 5–7) using the corresponding
benzyl bromides [20]. 7f and 7g are the precursors of the phenolic
derivative, a known inhibitor of type 2 17b-HSD [12], and this func-
tion could be used to attach linkers (e.g. polyethyleneglycol, fre-
quently reported in the literature [21] as biocompatible and
‘‘easily-tunable’’, for its length) on the steroid.
Appendix A. Supplementary data
Finally, our approach is also applicable to benzoyl chlorides, as
shown by the preparation of 7a-thiobenzoate derivative 7h (Ta-
ble 2, entry 8): this last example illustrates the fact that our meth-
odology is also applicable for the preparation of various thioester
derivatives of spironolactone.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.steroids.
2012.09.005.
In conclusion, a new method for the preparation of 7a-thio-
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Our approach can indeed be applied for the preparation of new ste-
roidal derivatives that could be useful for further functionalization
and so to study new Structure–Activity Relationships.
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