An efficient synthesis of 5α-androst-1-ene-3,17-dione

Article abstract of DOI:10.1016/j.steroids.2006.09.008

5α-Androst-1-ene-3,17-dione (5) as a prodrug of 1-testosterone (4) was prepared in four steps from 17β-Acetoxy-5α-androstan-3-one (stanolone acetate) (1) in high yield. Thus, stanolone acetate (1) was brominated in the presence of hydrogen chloride in acetic acid to give 17β-acetoxy-2-bromo-5α-androstan-3-one (2), which underwent dehydrobromination using lithium carbonate as base with lithium bromide as an additive to give 17β-acetoxy-5α-androst-1-en-3-one (3) in almost quantitative yield with 97% of purity. Compound (3) was hydrolyzed with sodium hydroxide to give 17β-hydroxy-5α-androst-1-en-3-one (4,1-testosterone), which was oxidized with chromium trioxide to afford 5α-androst-1-ene-3,17-dione (5). The overall yield of 5 was 78.2% with purity of 99%. In this method, the formation of 4-ene was diminished when 1-ene was introduced, and its mechanism was also discussed.

Full text of DOI:10.1016/j.steroids.2006.09.008

steroids 7 1 ( 2 0 0 6 ) 1088–1090
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An efficient synthesis of 5␣-androst-1-ene-3,17-dione
∗
Huyue Zhang, Zhuibai Qiu
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
5␣-Androst-1-ene-3,17-dione (5) as a prodrug of 1-testosterone (4) was prepared in four
steps from 17␤-Acetoxy-5␣-androstan-3-one (stanolone acetate) (1) in high yield. Thus,
stanolone acetate (1) was brominated in the presence of hydrogen chloride in acetic acid to
give 17␤-acetoxy-2-bromo-5␣-androstan-3-one (2), which underwent dehydrobromination
using lithium carbonate as base with lithium bromide as an additive to give 17␤-acetoxy-
Received 23 May 2006
Received in revised form
14 August 2006
Accepted 22 September 2006
5␣-androst-1-en-3-one (3) in almost quantitative yield with 97% of purity. Compound (3)
was hydrolyzed with sodium hydroxide to give 17␤-hydroxy-5␣-androst-1-en-3-one (4,1-
testosterone), which was oxidized with chromium trioxide to afford 5␣-androst-1-ene-3,17-
dione (5). The overall yield of 5 was 78.2% with purity of 99%. In this method, the formation of
4-ene was diminished when 1-ene was introduced, and its mechanism was also discussed.
© 2006 Elsevier Inc. All rights reserved.
Keywords:
5
␣-Androst-1-ene-3,17-dione
Bromination
Dehydrobromination
Synthesis
1
.
Introduction
2.
Experimental
5␣-Androst-1-ene-3,17-dione (5), as
a
prodrug of 1-
Mass spectrometry was carried out using a FINNIGAN
testosterone, can be converted to 17␤-hydrxy-5␣-androst-1-
en-3-one (4,1-testosterone) in the body, which is an effective
androgen [1]. The key step for synthesis of 5 is the for-
mation of 1-ene. A few reports about the introduction of
MAT95XL spectrometer. High-pressure liquid chromatography
was performed with column C18 on a HP1100-FINNIGAN LCQ
(MeOH-H2O grads system). H NMR spectra was recorded on a
BRUKER DPX 300 MHz spectrometer or a Mercury Plus 400 MHz
spectrometer with TMS as an internal reference. Optical rota-
tions were measured on a Horiba SEPA-200. All melting points
were determined in open capillary tubes and are not corrected.
Analytical thin layer chromatography was performed on Qing-
dao silica gel GF-254 precoated plates.
1
1
-ene have been described, either through bromination and
dehydrobromination from 5␣-androstane-3,17-dione [2] or
stanolone acetate (1) [3], or via 1,2-dehydrogenating of 5␣-
androstane-3,17-dione by selenium compounds [4]. However,
4
-ene formation was observed in previous bromination and
dehydrobromination route, and the selenium routes also
produced a mixture of 1-en-3-one, 1-chloro-2-en-3-one and
2.1.
17ˇ-acetoxy-2-bromo-5˛-androstan-3-one (2)
4
-en-3-one besides selenium compounds are toxic agents
themselves. Here, we reported a modified method using
bromination and dehydrobromination to prepare the com-
pound (5), in which the formation of 4-ene was diminished
To a mixture of 1 (57 g, 171.4 mmol) and hydrogen chlo-
ride (0.285 g) in acetic acid (399 ml), a solution of bromine
(27.4 g, 171.5 mmol) in acetic acid (27.4 ml) was added drop-
◦
(Scheme 1).
wisely at 20–25 C. The mixture was stirred for 1 h, and
∗
Corresponding author. Tel.: +86 21 54237595; fax: +86 21 54237758.
E-mail address: zbqiu@shmu.edu.cn (Z. Qiu).
0039-128X/$ – see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2006.09.008

steroids 7 1 ( 2 0 0 6 ) 1088–1090
1089
Scheme 1 – Synthesis of 5␣-androst-1-ene-3,17-dione (5) from stanolone acetate (1).
◦
2
◦
−1
poured into water. The solid was collected by filtration,
127–129 C. Lit mp 125–130 C. IR(KCl): 1729.53, 1684.69 cm
washed with water and dried to give 2 (62 g 88%). mp
(ꢀCacetate,C3 O).
58–160 C; 1H NMR (300 MHz, CDCl3) ı = 0.81 (s, 3H, C18–CH3),
◦
1
1
.10 (s, 3H, C19–CH3), 2.04 (s, 3H, 17–acetate–CH3), 4.56–4.62
(
dd, 1H, J1 = 7.80 Hz, J2 = 9.09, C17˛–H), 4.72–4.79 (dd, 1H,
2
.3.
17ˇ-hydroxy-5˛-androst-1-en-3-one (4)
−
1
J1 = 6.34 Hz, J2 = 13.34 Hz, C2–H). IR(KCl): 1732.09, 1720.13 cm
(
ꢀC ,C
O).
3
acetate
To a solution of sodium hydroxide (6.61 g, 165.3 mmol) in
methanol (744 ml), 3 (49.6 g, 150.1 mmol) was added. The mix-
ture was stirred at room temperature for 2 h, neutralized with
acetic acid, concentrated under reduced pressure and poured
into ice water. Resultant crystals were filtered, washed with
2
.2.
17ˇ-acetoxy-5˛-androst-1-en-3-one (3)
mixture of lithium bromide (31 g, 357 mmol) and
To
a
◦
lithium carbonate (31 g, 419.5 mmol) in N,N-dimethyl forma-
minde (1240 ml), 2 (62 g, 150.7 mmol) was added. The mix-
ture was refluxed for 30 min, and poured into the solution
of 10% hydrochloric acid (1500 ml). Resulting solid was fil-
tered, washed with water till neutral, dried to give 3 (49.6 g,
water, dried to give 4 (43.2 g, 99.8%). mp 150–151 C; MS m/z
+
25
◦
1
288 (M ); [˛]D = +54.5 (c 1.0, MeOH); H NMR (300 MHz, CDCl3)
ı = 0.78 (s, 3H, C18–CH3), 1.03 (s, 3H, C19–CH3), 3.66 (t, 1H,
C17˛–H, J = 8 Hz), 5.85 (d, 1H, C2–H, J = 10 Hz), 7.15 (d, 1H, C1–H,
J = 10 Hz). Lit5 mp 156–157 C; 1H NMR (CDCl3) ı = 0.79 (s, 3H,
C18–CH3), 1.02 (s, 3H, C19–CH3), 3.64 (t, 1H, C17˛–H, J = 8 Hz),
5.85 (d, 1H, C2–H, J = 10 Hz), 7.12 (d, 1H, C1–H, J = 10 Hz). IR(KCl):
◦
◦
+
9
(
9.6%). mp 123–126 C; MS m/z 330 (M ); UV (EtOH) ꢁmax
ε) = 229 nm (10,200). Purity 97% (HPLC). The crystals was
recrystallizated with methanol to obtained the crystals: mp
−
1
−1
3425.21 cm (␯O–H), 1668.35 cm (␯C3 O).
Scheme 2 – The mechanism of dehydrobromination.

1
090
steroids 7 1 ( 2 0 0 6 ) 1088–1090
Previous dehydrobromination studies suggested that basic
Table 1 – The conditions and results of
dehydrobromination
conditions such as sodium carbonate, 2-methyl pyridine, 2,4,6-
trimethyl pyridine, etc., could facilitated the E1-elimination
pathway to give a mixture of 1-ene and 4-ene regioisomers
6,7].
Based on our previous experience in the elimination of
the related 2,4-dibromo compounds [8], we hypothesized that
increasing the basicity of the reaction system via addition
of soluble bromide salts as additives could facilitated the E2
pathway and thus diminished the by-products. Thus, we com-
pared the effect of lithium carbonate and calcium carbonate
with and without the corresponding additive lithium bro-
mide and sodium bromide. The results are summarized in
Table 1.
−a
Entry
Basea
Br
Ratio of
-ene (%)
Ratio of
b
4-eneb (%)
1
[
1
2
3
4
5
Li2CO3
LiBr
–
LiBr
NaBr
–
97
91
94
61
53
1
7
4
37
45
Li2CO3
CaCO3 + 4%H2O
CaCO3
CaCO3
The reaction substrate was the compound (3) using the same batch.
a
The quantities of carbonate and bromide were 2.78 and 2.38 mol
to 1 mol of 3.
The ratio was measured by HPLC.
b
It is interesting to note that the best condition seemed to be
of lithium carbonate as base ab lithium bromide as an additive
2
.4.
5˛-androst-1-ene-3,17-dione (5)
(
entry 1 in Table 1). The yield was almost quantitative and the
To a solution of 4 (43.2 g, 149.8 mmol) in acetic acid (432 ml),
a solution of chromium trioxide (17 g, 170.0 mmol) in water
conversion of 1-ene compound reached to 97%, comparing to
sodium carbonate as base with no additive (entry 5 in Table 1)
in which substantial amount of 4-ene regioisomer (45%) was
obtained.
In summary, 5␣-androst-1-ene-3,17-dione (5) was prepared
by bromination, dehydrobromination, hydrolysis and oxida-
tion from stanolone acetate (1) in high yield. This route might
be suitable for industrial scale synthesis.
(
17 ml) was added slowly with stirring. The reaction mixture
◦
was stirred at 25–30 C for 1 h, poured into a solution of sodium
sulfite in ice water (2000 ml). Resultant crystals were filtered,
washed with water, dried to obtain 5 (42.7 g) (crude). Then, the
crude was recrystallized from ethyl acetate to form 5 (38.4 g,
◦
+
25
D
◦
8
8.9%). mp 139.5–140.5 C; MS m/z 286 (M ); [˛] = +140 (c 1.0,
1
MeOH); H NMR (300 MHz, CDCl3) ı = 0.91 (s, 3H, C18–CH3), 1.04
(
s, 3H, C19–CH3), 5.87 (d, 1H, C2–H, J = 10 Hz), 7.13 (d, 1H, C1–H,
r e f e r e n c e s
J = 10 Hz). Lit mp 139–140 C; 1H NMR (CDCl3) ı = 0.91 (s, 3H),
4
◦
1
1
.05 (s, 3H), 5.86 (d, 1H, J = 10 Hz), 7.12 (d, 1H, J = 10 Hz). IR(KCl):
739.52 and 1671.92 cm 1 (ꢀC17,C O).
−
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