Novel 17-Azolyl Steroids
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 909
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215-217 °C; H NMR δ 1.08 (3H, s, 18-Me), 1.18 (3H, s, 19-
140 mg, 0.3415 mmol). Purification of the crude product by
FCC [petroleum ether/EtOAc (3:1)] gave the title compound
16 (45 mg, 34.5%): 1H NMR δ 1.08 (3H, s, 18-Me), 1.20 (3H,
s, 19-Me), 2.04 (3H, s, 3â-OAc), 4.62 (1H, m, 3R-H), 5.42 (1H,
d, J ) 4.6 Hz, 6-H), 6.00 (1H, s, 16-H), 8.93 (1H, s, 5′-H). This
compound was not particularly stable at room temperature
(TLC evidence) and was therefore used for the subsequent
reaction without further characterization.
Me), 2.04 (3H, s, 3â-OAc), 4.63 (1H, m, 3R-H), 5.43 (1H, d, J
) 4.2 Hz, 6-H), 7.85 (2H, s, 4′- and 5′-H), 9.94 (1H, s, 16-CHO).
Anal. (C24H31O3N3) C, H, N.
3â-Acetoxy-17-(2H-tetr a zol-2-yl)-16-for m yla n d r osta -5,-
16-d ien e (10) a n d 3â-Acetoxy-17-(1H-tetr a zol-1-yl)-16-
for m yla n d r osta -5,16-d ien e (11). The method followed that
described for compounds 8 and 9, but using 2 (0.5 g, 1.329
mmol), 1H-tetrazole (187 mg, 1.59 mmol), and Li2CO3 (287 mg,
3.94 mmol) gave a crude product (520 mg). Flash column
chromatography on elution with petroleum ether/EtOAc (5:1)
gave first 3â-acetoxy-17-(2H-tetrazol-2-yl)-16-formylandrosta-
3â-H yd r oxy-17-(1H -im id a zol-1-yl)a n d r ost a -5,16-d i-
en e (17). Details of the synthesis of this compound have been
published previously.18
3â-Hyd r oxy-17-(2H-1,2,3-tr ia zol-2-yl)a n d r osta -5,16-d i-
en e (18). The method followed that described for compound
6 but using 3â-acetoxy-17-(2H-1,2,3-triazol-2-yl)androsta-5,-
16-diene (13; 110 mg, 0.289 mmol). Purification of the crude
product by FCC [petroleum ether/EtOAc (3:1)] gave the title
compound 18 (95 mg, 97.1%) which was crystallized from
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5,16-diene (10; 92 mg, 28.2%): mp 170-172 °C dec; H NMR
δ 1.1 (3H, s, 18-Me), 1.29 (3H, s, 19-Me), 2.04 (3H, s, 3â-OAc),
4.62 (1H, m, 3R-H), 5.42 (1H, d, J ) 4.2 Hz, 6-H), 8.68 (1H, s,
5′-H), 10.46 (1H, s, 16-CHO). Anal. (C23H30O3N4) C, H, N.
Further elution with petroleum ether/EtOAc/Et3N (7:3:0.3)
afforded 3â-acetoxy-17-(1H-tetrazol-1-yl)-16-formylandrosta-
5,16-diene (11; 146 mg, 44.6%): mp 196-198 °C dec; 1H NMR
δ 1.09 (3H, s, 18-Me), 1.20 (3H, s, 19-Me), 2.04 (3H, s, 3â-OAc),
4.62 (1H, m, 3R-H), 5.43 (1H, d, J ) 4.8 Hz, 6-H), 8.93 (1H, s,
5′-H), 9.92 (1H, s, 16-CHO). Anal. (C23H30O3N4) C, H, N.
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hexane/EtOAc: mp 176-177 °C; H NMR δ 1.09 (3H, s, 18-
Me), 1.15 (3H, s, 19-Me), 3.54 (1H, m, 3R-H), 5.39 (1H, d, J )
5.1 Hz, 6-H), 6.17 (1H, s, 16-H), 7.68 (2H, s, 4′- and 5′-H). Anal.
(C21H29ON3) C, H, N.
3â-Hyd r oxy-17-(1H-1,2,3-tr ia zol-1-yl)a n d r osta -5,16-d i-
en e (19). The method followed that described for compound
6 but using 3â-acetoxy-17-(1H-1,2,3-triazol-1-yl)androsta-5,-
16-diene (14; 1.5 g, 3.94 mmol). The product was recrystallized
fron EtOAc/MeOH to give the title compound 19 (1.20 g,
3â-Acet oxy-17-(1H -im id a zol-1-yl)a n d r ost a -5,16-d ien e
(12). A solution of 3â-acetoxy-17-(1H-imidazol-1-yl)-16-formyl-
androsta-5,16-diene (7; 4.0 g, 9.8 mmol) in dry benzonitrile
(40 mL) was refluxed in the presence of 10% palladium on
activated charcoal (2 g, i.e., 50% weight of the 16-formyl azole)
for 3.5 h. After cooling to room temperature, the catalyst was
removed by filtration through a Celite pad. The filtrate was
evaporated, and the residue was purified by FCC [petroleum
ether/EtOAc/Et3N (6:4:0.3)] to give the title compound 12 (2.72
g, 73.2%): mp 138-140 °C; 1H NMR δ 1.0 (3H, s, 18-Me), 1.07
(3H, s, 19-Me), 2.04 (3H, s, 3â-OAc), 4.60 (1H, m, 3R-H), 5.41
(1H, s, 6-H), 5.68 (1H, s, 16-H), 7.02 (1H, s, 4′-H), 7.08 (1H, s,
5′-H), 7.60 (1H, s, 2′-H); HRMS calcd 408.2413 (C25H32O3N2),
found 408.2426. Anal. (C25H32O3N2) C, H, N.
3â-Acet oxy-17-(2H -1,2,3-t r ia zol-2-yl)a n d r ost a -5,16-d i-
en e (13). A mixture of 3â-acetoxy-17-(2H-1,2,3-triazol-2-yl)-
16-formylandrosta-5,16-diene (8; 140 mg, 0.342 mmol) in dry
toluene (6 mL) and tris(triphenylphosphine)rhodium(I) chlo-
ride (Wilkinson’s catalyst; 332 mg, 0.351 mmol) was refluxed
under N2 for 5 h. After the mixture cooled to room tempera-
ture, EtOH (12 mL) was added, and on further cooling at
approximately 0 °C, the yellow precipitate of bis(triphenylphos-
phine)carbonylchlororhodium (I) formed. Following filtration,
the filtrate was concentrated to give the crude product. This
was purified by FCC [petroleum ether/EtOAc (15:1)] to give
the title compound 13 (120 mg, 92%): mp 154-155 °C; 1H
NMR δ 1.09 (3H, s, 18-Me), 1.14 (3H, s, 19-Me), 2.04 (3H, s,
3â-OAc), 4.60 (1H, m, 3R-H), 5.42 (1H, d, J ) 4.2 Hz, 6-H),
6.17 (1H, br s, 16-H), 7.68 (2H, s, 4′- and 5′-H). Anal.
(C23H31O2N3) C, H, N.
3â-Acet oxy-17-(1H -1,2,3-t r ia zol-1-yl)a n d r ost a -5,16-d i-
en e (14). The method followed that described for compound
5 but using 3â-acetoxy-17-(1H-1,2,3-triazol-1-yl)-16-formylan-
drosta-5,16-diene (9; 2.0 g, 4.89 mmol). Purification of the
crude product by FCC [petroleum ether/EtOAc/Et3N (7.7:2:0.3)]
gave the title compound 14 (1.67 g, 89.9%): mp 158-160 °C;
1H NMR δ 1.09 (3H, s, 18-Me), 1.14 (3H, s, 19-Me), 2.04 (3H,
s, 3â-OAc), 4.60 (1H, m, 3R-H), 5.40 (1H, d, J ) 4.2 Hz, 6-H),
5.98 (1H, br s, 16-H), 7.73 (2H, s, 4′- and 5′-H). Anal.
(C23H31O2N3) C, H, N.
3â-Acetoxy-17-(2H-tetr azol-2-yl)an dr osta-5,16-dien e (15).
The method followed that described for compound 13 but using
3â-acetoxy-17-(2H-tetrazol-2-yl)-16-formylandrosta-5,16-di-
ene (10; 124 mg, 0.302 mmol). Purification of the crude
product by FCC [petroleum ether/EtOAc (10:1)] gave the title
compound 15 (61 mg, 52.8%): mp 155-156 °C; 1H NMR δ 1.10
(3H, s, 18-Me), 1.17 (3H, s, 19-Me), 2.04 (3H, s, 3â-OAc), 4.62
(1H, m, 3R-H), 5.42 (1H, d, J ) 4.85 Hz, 6-H), 6.46 (1H, s,
16-H), 8.52 (1H, s, 5′-H). Anal. (C22H30O2N4) C, H, N.
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90%): mp 220-224 °C; H NMR δ 1.08 (3H, s, 18-Me), 1.14
(3H, s, 19-Me), 3.54 (1H, m, 3R-H), 5.39 (1H, d, J ) 4.8 Hz,
6-H), 5.97 (1H, s, 16-H), 7.72 (2H, s, 4′- and 5′-H). Anal.
(C21H29ON3) C, H, N.
3â-H yd r oxy-17-(2H -t et r a zol-2-yl)a n d r ost a -5,16-d ien e
(20). The method followed that described for compound 6 but
using 3â-acetoxy-17-(2H-tetrazol-2-yl)androsta-5,16-diene (15;
51 mg, 0.134 mmol). Recrystallization of the product from
hexane/EtOAc gave the title compound 20 (42 mg, 88%): mp
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195-198 °C; H NMR δ 1.09 (3H, s, 18-Me), 1.17 (3H, s, 19-
Me), 3.55 (1H, m, 3R-H), 5.34 (1H, d, J ) 5.2 Hz, 6-H), 6.46
(1H, s, 16-H), 8.53 (1H, s, 5′-H). Anal. (C20H28ON4) C, H, N.
3â-H yd r oxy-17-(1H -t et r a zol-1-yl)a n d r ost a -5,16-d ien e
(21). The method followed that described for 6 but using 3â-
acetoxy-17-(1H-tetrazol-1-yl)androsta-5,16-diene (16; 36 mg,
0.094 mmol). Recrystallization of the product from hexane/
EtOAc gave the title compound 21 (28 mg, 87.4%): mp 200-
204 °C dec; 1H NMR δ 1.06 (3H, s, 18-Me), 1.11 (3H, s, 19-
Me), 3.54 (1H, m, 3R-H), 5.38 (1H, br s, 6-H), 6.13 (1H, s, 16-
H), 8.73 (1H, s, 5′-H). Anal. (C20H28ON4) C, H, N.
R ea ct ion of Com p ou n d
2 w it h 1H -P yr a zole a n d
K2CO3: 3â-Acet oxy-17-(3H -p yr a zol-3-yl)-16-for m yla n d -
r osta -5,16-d ien e (22), 3â-Acetoxy-17r-(1H-p yr a zol-1-yl)-
a n d r ost-5-en e (24), a n d 3â-Acetoxy-17-(1H-p yr a zol-1-yl)-
a n d r osta -5,16-d ien e (25). Reaction of compound 2 (0.5 g,
1.329 mmol), pyrazole (136 mg, 1.994 mmol), and K2CO3 (551
mg, 3.99 mmol) as described for compound 7 and following
FCC [petroleum ether/EtOAc (4:1)] gave first 3â-acetoxy-17-
(3H-pyrazol-3-yl)-16-formylandrosta-5,16-diene (22; 63 mg,
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12%): mp 165-168 °C; H NMR δ 0.99 (3H, s, 18-Me), 1.07
(3H, s, 19-Me), 2.04 (3H, s, 3â-OAc), 4.60 (1H, m, 3R-H), 5.42
(1H, d, J ) 4.8 Hz, 6-H), 6.38 (1H, s, 5′-H), 7.64 (1H, d, J )
1.5 Hz, 4′-H), 9.30 (1H, d, J ) 2.4 Hz, 16-CHO). Anal.
(C25H32O3N2) C, H, N. Further elution afforded a mixture (341
mg, approximately 2.5:1, determined by 1H NMR) of 3â-
acetoxy-17-(1H-pyrazol-1-yl)-16-formylandrosta-5,16-diene (23)
and 3â-acetoxy-17R-(1H-pyrazol-1-yl)androst-5-ene (24). This
mixture resisted separation by chromatography. The mixture
(330 mg) was then subjected to the decarbonylation reaction
as described for 13 to give a crude product (350 mg). Flash
column chromatography on elution with petroleum ether/
EtOAc (15:1) gave first 3â-acetoxy-17-(1H-pyrazol-1yl)and-
rosta-5,16-diene (25; 123 mg, 25% from 2): mp 159-161 °C;
1H NMR δ 1.08 (3H, s, 18-Me), 1.11 (3H, s, 19-Me), 2.04 (3H,
s, 3â-OAc), 4.62 (1H, m, 3R-H), 5.42 (1H, d, J ) 5.1 Hz, 6-H),
5.77 (1H, s, 16-H), 6.32 (1H, s, 4′-H), 7.60 (1H, s, 3′-H), 7.63
(1H, d, J ) 2.4 Hz, 5′-H). Anal. (C24H32O2N2) C, H, N.
Further elution with petroleum ether/EtOAc (5:1) afforded
3â-Acetoxy-17-(1H-tetr azol-1-yl)an dr osta-5,16-dien e (16).
The method followed that described for 13 but using 3â-
acetoxy-17-(1H-tetrazol-1-yl)-16-formylandrosta-5,16-diene (11;