The first syntheses of 16β-chloro- and 16β-bromo-cyproterone acetate

Article abstract of DOI:10.1081/SCC-120018931

The first syntheses of 16β-chloro- and 16β-bromo-cyproterone acetate is described. The preparation of 16β-chlorocyproterone acetate was accomplished in eight steps (6.5% overall yield) from commercially available 16-dehydropregnenolone acetate. 16β-Bromocyproterone acetate was prepared from 16β-chlorocyproterone acetate with base-induced epoxide formation as the key step.

Full text of DOI:10.1081/SCC-120018931

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
The First Syntheses of 16β-Chloro- and 16β-Bromo-
cyproterone Acetate
Uthai Sakee , Ngampong Kongkathip & Boonsong Kongkathip
To cite this article: Uthai Sakee , Ngampong Kongkathip & Boonsong Kongkathip (2003)
The First Syntheses of 16β-Chloro- and 16β-Bromo-cyproterone Acetate, Synthetic
Communications, 33:10, 1695-1706, DOI: 10.1081/SCC-120018931
To link to this article: http://dx.doi.org/10.1081/SCC-120018931
Published online: 17 Aug 2006.
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 10, pp. 1695–1706, 2003
The First Syntheses of 16b-Chloro- and
1
6b-Bromo-cyproterone Acetate
Uthai Sakee, Ngampong Kongkathip,
and Boonsong Kongkathip*
Department of Chemistry, Faculty of Science,
Kasetsart University, Bangkok, Thailand
ABSTRACT
The first syntheses of 16b-chloro- and 16b-bromo-cyproterone
acetate is described. The preparation of 16b-chlorocyproterone
acetate was accomplished in eight steps (6.5% overall yield)
from commercially available 16-dehydropregnenolone acetate.
1
6b-Bromocyproterone acetate was prepared from 16b-chloro-
cyproterone acetate with base-induced epoxide formation as the
key step.
Key Words: 16b-Bromo-cyproterone acetate; 16b-Chloro-cyproter-
one acetate; 16-Dehydropregnenolone acetate; Synthesis.
*
Correspondence: Boonsong Kongkathip, Department of Chemistry, Faculty of
Science, Kasetsart University, Bangkok, 10900, Thailand; Fax: 662-579-3955;
E-mail: fscibsk@nontri.ku.ac.th.
1
695
DOI: 10.1081/SCC-120018931
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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696
Sakee, Kongkathip, and Kongkathip
Synthesis of ideal anti-androgenic molecule is still of interest because
it can offer useful treatment for androgen-mediated diseases, such as
prostate cancer, acne, seborrhea, androgenic alopecia, precocious puberty
and benign prostatic hyperplasia. So modification of steroid structures
represents a continuing effort on the part of the steroid chemist to alter
biological activity. The alterations in activity, although often predictable,
are in some case quite unexpected. A variety of steroids have been
synthesized showing higher androgenic activity than testosterone con-
comitant with several new compounds with anti-androgenic activity.
Examples of steroidal molecules with high anti-androgenic effects are
cyproterone acetate, which is an antagonist of androgen receptors, and
[
1]
finasteride, which selectively inhibits 5a-reductase isozyme type 2. The
6b-methylene group could increase progestational activity and enhanced
the anti-androgenic activity. The 16a- and 16b-methyl group have
1
[
2]
been described, but assay data is not available. In this connection, it
seemed of particular interest to examine derivatives of cyproterone acetate
substituted at the 16-position, in view of progestational potentiating effect
[
2–4]
reported for 16-methylene- and 16a-methyl-cyproterone acetate.
Accordingly, we prepared of 16b-chlorocyproterone acetate (11)
and 16b-bromocyproterone acetate (14). Theirantian do rg enic and
progestational activities will be published in due course.
Thesynthesisof16b-chlorocyproteroneacetate(11)usedcommercially
available 16-dehydropregnenolone acetate (1) as the starting material.
The preparation of 1,4,6-trienone epoxide (3), a key intermediate, was
obtained by epoxidation of 1 using 30% H O /NaOH in methanol to
2
2
give epoxide (2) in 89% yield followed by oxidative-dehydrogenation with
[
5,6]
2,4-dichloro-5,6-dicyanobenzoquinone (DDQ)
provide the compound 3 in 66% yield. Ketalization of the 20-keto group
in refluxing dioxane to
[
7]
of 3 with ethylene glycol, ethyl orthoformate and p-toluenesulfonic acid
provided 16a,17a-epoxy-1,4,6-pregnatriene-20-ethylene ketal-3-one (4) in
0% yield. A cyclopropyl group was introduced into the 1,2-position of
7
[
8]
(
4) using dimethyl sulfoxonium methylide followed by hydrolysis of
20-ketal with p-toluenesulfonic acid in dichloromethane to afford
1a,2a-cyclomethylene-16a,17a-epoxy-1,4,6-pregnatriene-3,20-dione (5) in
71% yield (Sch. 1).
Attempts to open the epoxide of 5 using 5 equiv. of N,N-dimethyl
[9]
acetamide hydrochloride in chloroform at room-temperature caused
cyclopropane ring opening with the formation of a 1-chloromethylene
product (7) in 55% yield. However, reducing the amount of
N,N-dimethylacetamide hydrochloride to 3.0 equiv. gave the desired
compound (6) and the 1-chloromethylene product (7) in 40 and 34%
yields, respectively. Acetylation of 6 using acetic acid, trifluoroacetic

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1
6b-Chloro- and 16b-Bromo-cyproterone Acetate
1697
Scheme 1.
[10]
anhydride and p-toluenesulfonic acid gave the acetate compound (9) in
8
9% yield. Acetate (9) was also obtained by acetylation of 7 to give
ꢀ
intermediate 8 followed by treatment with pyridine at 100 C for15 min
to afford 9 in 62% yield (Sch. 2).
Epoxidation of 9 using MCPBA provided 10 in 68% yield. When
epoxide (10) was treated with N,N-dimethylacetamide hydrochloride in
ꢀ
DMSO at 55 C for30 h, 16 b-chlorocyproterone acetate (11) was
obtained in 60% yield (Sch. 3).
The synthesis of 16b-bromocyproterone acetate (14) from 16b-
chlorocyproterone acetate (11) was accomplished by treatment of 11
with basic Al O in benzene to produce 6a,17a-epoxy-1a,2a-cyclo-
2
3
methylene-6-chloro-4,6-pregnadiene-3,20-dione (12) in 75% yield
followed by epoxide ring opening using a mixture of bromine and
PPh3 in THF to provide 1a,2a-cyclomethylene-6-chloro-16b-bromo-
1
7a-hydroxy-4,6-pregnadiene-3,20-dione (13) in 70% yield. 16b-
Bromocyproterone acetate (14) was obtained afteracetylation of 13 in
5% yield (Sch. 4).
8
EXPERIMENTAL
Melting points were determined on MEI-TEMP capillary melting
point apparatus and are uncorrected. Tetrahydrofuran (THF) was
dried over sodium benzophenone ketyl anion radical and distilled
undera d ry N atm immediately prior to use. All other chemicals were
2
obtained from Aldrich Chemical Co. and were used without further
purification. Purification of reaction products was carried out by flash

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698
Sakee, Kongkathip, and Kongkathip
Scheme 2.
Scheme 3.
Scheme 4.
column chromatography using a glass column, dry packed with silica gel
[
11] 1
13
H and C-
(230–400 mesh) according to the method of Still et al.
NMR spectra were recorded with a Gemini 2000 (300 MHz) spectrometer
and Brucker WH 400 (400 MHz) and signals are in ꢀ (ppm) relative to

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1
6b-Chloro- and 16b-Bromo-cyproterone Acetate
1699
TMS at 0.0. Mass spectra were measured on VG7070F mass spectrom-
eter at 6 kV. Elemental analyses were performed by Atlantic Microlab Inc.
3
pregnadiene-20-one (1) (10 g, 28.09 mmol) was dissolved in methanol
b-Hydroxy-16a,17a-epoxy 5-pregnene-20-one (2): 3b-Acetoxy-5,16-
ꢀ
(
hydroxide (20 mL) and then immediately with 30% hydrogen
1L). This solution was treated after chilling to 15 C with 4 N sodium-
peroxide (40 mL). The mixture was then stored in the refrigerator at
ꢀ
5
C for24 h. At this time, examination of sample indicated the absence
of an a,b-unsaturated ketone as evidenced by absorption in the ultravio-
let. The methanol solution was poured into water (1L) and the resulting
white solid separated. The solid, which was washed well with water and
ꢀ
dried weighed (8.23 g, 89%); m.p. 175–177 C. The crude product 2 as a
white solid was used without further purification.
16a,17a-Epoxy-1,4,6-pregnatriene-3,20-dione (3): A solution of 2
(
(
555 mg, 2.23 mmol) in dry dioxane (45 mL) was added with DDQ
2.5 g) and refluxed under N for 24 h. After removing the precipitate
2
by filtration, the filtrate was concentrated and the residue was dissolved
in CH Cl (30 mL), then washed with satd. aq. NaHCO (20 mL), H O
2
2
3
2
(10 mL), brine (10 mL), dried (MgSO ) and evaporated to give crude
4
residue. This residue was purified by flash column chromatography on
silica gel (1:1 EtOAc/hexane) to give the compound 3 as a colorless solid
ꢀ
ꢁ1
(
474 mg, 66%); m.p. 175–176 C; IR (KBr): 1697, 1649, 1600, 892 cm
;
1
H NMR (CDCl , 300 MHz) ꢀ 7.0 (d, 1H, -CH¼CH-C¼O, J ¼ 3.0 Hz),
3
6
-
3
.2 (m, 2H, -CH¼CH-C¼CH-C¼O, -CH¼CH-C¼O), 5.98 (s, 1H,
CH¼CH-C¼CH-C¼O), 5.9 (d, 1H, CH¼CH-C¼CH-C¼O, J ¼ 2.4 Hz),
.7 (s, 1H, -CH-O-(epoxide)), 2.3 (m, 1H), 1.0–2.2 (m, 8H), 2.0 (s, 3H,
þ
CH C¼O), 1.2 (s, 3H, CH ), 1.1 (s, 3H, CH ); MS m/z (%) 324 (M , 5),
3
3
3
263 (100), 248 (30), 170 (30), 128 (30); HRMS m/z 324.1723 (calcd. for
C H O , 324.1725); Anal. calcd. forC H O : C, 77.75; H, 7.46.
2
1
24
3
21 24
3
Found: C, 77.58; H, 7.50.
6a,17a-Epoxy-1,4,6-pregnatriene-20-ethylene ketal-3-one (4): A solu-
1
tion of 16a,17a-epoxy-1,4,6-pregnatriene-3,20-dione (3) (1.5 g, 4.62 mmol)
in CH Cl (7.5 mL) was added with ethylene glycol (0.8 mL), ethyl ortho-
2
2
formate (1.1 mL) and p-toluenesulfonic acid (150 mg). The reaction mix-
ture was stirred at room temperature for 3 h. Neutralization performed
with trimethylamine (0.15 mL). The mixture was washed with water and
dried over sodium sulfate anhydrous and evaporated to give a residue.
This residue was chromatrographed on silica gel (1:1 EtOAc/hexane) to
ꢀ
give 4 as a colorless solid (1.2 g, 72%); m.p. 144–146 C; IR (KBr): 1701,
ꢁ
658, 1603, 1043, 878 cm ; H NMR (CDCl , 400 MHz) ꢀ 7.05 (d, 1H,
3
1 1
1
C-CH¼CH-C¼O, J ¼ 3.0 Hz), 6.23 (dd, 1H, C-CH¼CH-C¼O,
J ¼ 3.0, 0.9 Hz), 6.25 (dd, 1H, CH¼CH-C¼CH-C¼O, J ¼ 2.4, 0.56 Hz),

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Sakee, Kongkathip, and Kongkathip
6
.02 (s, 1H, CH¼CH-C¼CH-C¼O), 5.97 (d, 1H, -CH¼CH-C¼CH-
C¼O, J ¼ 2.4 Hz), 3.9–4.05 (m, 4H, -O-CH -CH -O-), 3.45 (s, 1H,
2
2
1
6
21
CH-O (epoxide), 1.22 (s, 3H, CH ), 1.43 (s, 3H, CH C-O), 1.12
3
3
þ
(
(
s, 3H, CH ); MS m/z (%) 368 (M , 2), 87 (100); HRMS m/z 368.1978
3
calcd. forC 23H O , 368.1988).
28
4
1
a,2a-Cyclomethylene-16a,17a-epoxy-4,6-prenadiene-3,20-dione (5):
A solution of trimethyl sulfoxonium iodide (5.53 g, 24.2 mmol) in
DMSO (37 mL) was added to NaH (659 mg of a 50% mineral oil suspen-
sion). The reaction mixture was stirred at room temperature. After 1 h a
solution of 16a,17a-epoxy-1,4,6-pregnatriene-20-ethylene ketal-3-one (4)
(1.87 g, 5.07 mmol) in DMSO (24 mL) was added and then the reaction
mixture was stirred at room temperature for 3 h. The reaction mixture
was added to H O (100 mL), the precipitate was collected by filtration.
2
The residue was dissolved with dichloromethane (20 mL) and added p-
TsOHꢂH O and then the reaction mixture was stirred at room tempera-
2
ture for 2 h. Cold 20% aq. K CO was added carefully until the mixture
2
3
was basic. The mixture was extracted with CH Cl (3 ꢃ 20 mL) and
2
2
washed with H O (50 mL), brine (50 mL), dried (MgSO ) and evaporated
2
4
to afford a thick residue. This residue was purified by flash column chro-
matography on silica gel (6:5 EtOAc/hexane) to provide 5 as a colorless
ꢀ
solid (1.21 g, 71%); m.p. 236–238 C; IR (KBr) 1701, 1657, 1621,
1
ꢁ
1
906 cm
;
H NMR (CDCl , 400 MHz): ꢀ 5.99 (d, 1H, CH¼CH-
3
C¼CH-C¼O, J ¼ 3.0 Hz), 5.83 (d, 1H, -CH¼CH-C¼CH-C¼O,
1
6
J ¼ 3.0 Hz), 5.44 (s, 1H, CH¼CH-C¼CH-C¼O), 3.8 (s, 1H, CH-O
2
1
(
O), 0.72 (m, 1H, CH (cyclopropane)); MS m/z (%) 338 (M , 8), 295 (80),
epoxide), 1.15 (s, 3H, CH ), 1.07 (s, 3H, CH ), 1.98 (s, 3H, CH C-
3 3 3
þ
2
278 (100), 263 (27); HRMS m/z 338.1876 (calcd. forC H O ,
22 26 3
3
24.1882).
Conversion of 1a,2a-cyclomethylene-16a,17a-epoxy-4,6-pregnadiene-
,20-dione (5) to 1a,2a-cyclomethylene-16b-chloro-17a-hydroxy-4,6-preg-
3
nadiene-3,20-dione (6): A solution of 5 (493 mg, 1.46 mmol) in chloroform
31 mL) was added with N,N-dimethyl acetamide hydrochloride (180 mg,
equiv.). The reaction mixture was stirred at room temperature for 24 h
(
3
and then was poured into satd. aq. NaHCO (20 mL). The organic phase
3
was separated and the aqueous phase was extracted with CH Cl2
2
(
(
3 ꢃ 15 mL). The combined organic phase was washed with H O
2
30 mL), brine (30 mL), dried (MgSO ) and concentrated under reduced
4
pressure to give crude product. The crude product was purified by flash
column chromatography on silica gel (2:3 EtOAc/hexane) to give 1a-
chloromethyl-16b-chloro-17a-hydroxy-4,6-pregnadiene-3,20-dione (7) as
a colorless solid (204 mg, 34%) and 1a,2a-cyclomethylene-16b-chloro-
17a-hydroxy-4,6-pregnadiene-3,20-dione (6) as a white solid (217 mg, 40%).

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1
6b-Chloro- and 16b-Bromo-cyproterone Acetate
1701
ꢀ
ꢁ1
1
6
: M.p. 217–219 C; IR (KBr): 3421, 1716, 1649 cm
;
H NMR
(
5
CDCl , 400 MHz) ꢀ 6.0 (d, 1H, CH¼CH-C¼CH-C¼O, J ¼ 3.0 Hz),
3
.87 (d, 1H, -CH¼CH-C¼CH-C¼O, J ¼ 3.0 Hz), 5.45 (s, 1H, CH¼CH-
1
6
C¼CH-C¼O), 3.3 (s, 1H, OH), 4.1 (t, 1 H, CH-Cl), 1.25 (s, 3H, CH ),
3
2
1
1.15 (s, 3H, CH ), 2.36 (s, 3H, CH C-O), 0.72 (m, 1H, CH (cyclopro-
pane)); MS m/z (%) 374 (Mþ, 91), 338 (53), 332 (36), 320 (30), 312 (62),
3 3 2
294 (60), 43 (100); HRMS m/z 374.1651 (calcd. forC
H ClO ,
27
2
2
3
3
74.1749).
: M.p.180–182 C; IR (KBr): 3422, 1717, 1656, 1625, 755 cm
ꢀ
ꢁ1
7
;
1
H NMR (CDCl , 400 MHz) ꢀ 6.0–6.2 (dd, 2 H, -CH=CH-C¼CH-
3
C¼O), 5.7 (s, 1H, -CH¼CH-C¼CH-C¼O), 4.1 (m, 1H, ClCH-C-),
3.2–3.75 (dd, 2H, ClCH -CH-), 3.35 (s, 1H, OH), 2.7–3.0 (m, 2H), 1.0-
2
2
.4 (m,10H), 2.45 (s, 3H, CH C¼O), 1.3 (s, 3H, CH ), 1.25 (s, 3H, CH );
3
3
3
þ
MS m/z (%) 410 (M , 15), 374 (19), 368 (14), 349 (20), 312 (12), 274 (19),
59 (100); HRMS m/z 410.1407 (calcd. forC 22H Cl O , 410.1415).
28 2 3
Acetylation of 1a,2a-cyclomethylene-16b-chloro-17a-hydroxy-4,6-
pregnadiene-3,20-dione (6): Undera N atmosphere, acetic acid
0.69 mL, 11.73 mmol) was added to a well stirred mixture of TFAA
1.6 mL, 27.2 mmol) in CH Cl (4.5 mL) and the mixture was stirred
2
(
(
2
2
at room temperature for 30 min. p-TsOHꢂH O (93 mg, 0.54 mmol) was
2
ꢀ
then added and the mixture was cooled to 0 C. The 1a,2a-cyclomethy-
lene-16b-chloro-17a-hydroxy-4,6-pregnadiene-3,20-dione (6) (217 mg,
0
.58 mmol) was dissolved in CH Cl (5 mL), cooled in an ice bath and
ꢀ
2 2
added to the stirred mixed anhydride and stirring at 0 C for20 min. Cold
0% aq. K CO was added carefully until the mixture was basic. The
mixture was diluted with H O until the CH Cl phase became the lower
2
2
3
2
2
2
phase. The mixture was extracted with CH Cl (3 ꢃ 20 mL) and washed
2
2
with H O (50 mL), brine (50 mL), dried (MgSO ) and evaporated to
4
2
afford a thick syrup. The syrup was purified by flash column chromato-
graphy on silica gel (1:10 EtOAc/CH Cl ) to give 1a,2a-cyclomethylene-
2
2
1
6b-chloro-17a-acetoxy-4,6-pregnadiene-3,20-dione (9) as a colorless
ꢀ
solid (215 mg, 89%); m.p. 163–165 C; IR (KBr): 1737, 1650, 1613,
þ
ꢁ1
1
238, 1025 cm ; MS m/z (%) 416 (M , 2), 376 (11), 338 (11), 332 (12),
12 (4), 296 (23), 276 (22), 238 (21), 58 (100); HRMS m/z 416.1740 (calcd.
3
forC 24H ClO , 416.1754).
29
4
Acetylation of 1a-chloromethyl-16b-chloro-17a-hydroxy-4,6-pregna-
diene-3,20-dione (8): Undera N 2 atmosphere, acetic acid (0.59 mL,
9
2
.97 mmol) was added to a well stirred mixture of TFAA (1.4 mL,
3.8 mmol) in CH Cl (10 mL) and the mixture was stirred at room
2
2
temperature for 30 min. p-TsOHꢂH O (80 mg, 0.46 mmol) was then
2
ꢀ
added and the mixture was cooled to 0 C. The 1a-chloromethyl-16b-
chloro-17a-hydroxy-4,6-pregnadiene-3,20-dione (7) (204 mg, 0.496 mmol)

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Sakee, Kongkathip, and Kongkathip
was dissolved in CH Cl (5 mL), cooled in an ice bath and added to the
2
2
ꢀ
stirred mixed anhydride and stirring at 0 C for20 min. Cold 20% aq.
K CO was added carefully until the mixture was basic. The mixture was
diluted with H O until the CH Cl phase became the lowerphase. The
2
3
2
2
2
mixture was extracted with CH Cl (3 ꢃ 20 mL) and washed with H O
2
2
2
(
syrup. The syrup was purified by flash column chromatography on silica
50 mL), brine (50 mL), dried (MgSO ) and evaporated to give a thick
4
gel (1:20 EtOAc/CH Cl ) to provide the 1a-chloromethyl-16b-chloro-
2
2
1
7a-acetoxy-4,6-pregnadiene-3,20-dione (8) as a white solid (203 mg,
ꢀ
ꢁ1
9
0%); m.p. 204–206 C; IR (KBr): 1738, 1651, 1614, 1238 cm
;
1
H NMR (CDCl , 400 MHz) ꢀ 6.2 (d, 1H, -CH¼CH-C¼CH-C¼O,
3
J ¼ 3.0 Hz), 6.06 (d, 1H, -CH¼CH-C¼CH-C¼O, J ¼ 3.0 Hz), 5.75 (s,
1
6
1
1
H, -CH¼CH-C¼CH-C¼O), 4.3 (t, 1H, CH-Cl), 3.7 (t, 1H, CH-
CH Cl), 3.3 (dd, 2H, ClCH -CH-), 3.3 (dd, 1H, CH-CH Cl, J ¼ 3.4,
2 2 2
2
1
2
3
.3 Hz), 2.98 (d, 1H, CH CH-CH Cl, J ¼ 5.3 Hz), 2.83 (m, 1H,
2
2
1
CH CH-CH Cl), 2.22 (s, 3H, CH COO-), 2.18 (s, 3H, CH C¼O),
2 2 3 3
þ
1
.3 (s, 6H, CH ); MS m/z (%) 452 (M , 5), 416 (7), 349 (55), 332 (35),
3
2
77 (7), 43 (100); HRMS m/z 452.1508 (calcd. forC H Cl O ,
2
4
30
2
4
452.1521); Anal. calcd. forC 24H Cl O : C, 63.58; H, 6.67. Found:
C, 63.57; H, 6.74.
30 2 4
Conversion of 1a-chloromethyl-16b-chloro-17a-acetoxy-4,6-pregna-
diene-3,20-dione (8) to 1a,2a-cyclomethylene-16b-chloro-17a-acetoxy-4,6-
pregnadiene-3,20-dione (9): A solution of 8 (205 mg, 0.45 mmol) in
ꢀ
pyridine (5 mL) was heated at 100 C for30 min. Afteraddition to H 2O
(
10 mL), the precipitate was extracted with CH Cl (5 ꢃ 5 mL) and the
2
2
combined extract was washed with water (20 mL), brine (20 mL), dried
MgSO ) and evaporated under reduced pressure. The residue was pur-
ified by flash column chromatography on silica gel (1:20 EtOAc/CH Cl )
(
4
2
2
to provide 9 (117 mg, 62%).
Epoxidation of 1a,2a-cyclomethylene-16b-chloro-17a-acetoxy-4,6-
pregnadiene-3,20-dione (9): MCPBA (460 mg, 68%) was added to a solu-
tion of 9 (518 mg, 1.24 mmol) in CH Cl (10 mL). The reaction mixture
2
2
was stirred at room temperature for 12 h and then was poured into satd.
aq. NaHCO (15 mL). The organic phase was separated and the aqueous
3
phase was extracted with CH Cl (3 ꢃ 15 mL). The combined organic
2
2
phase was washed with H O (50 mL), brine (50 mL), dried (MgSO )
4
2
and concentrated under reduced pressure to give crude product. The
crude product was purified by chromatography on silica gel (3:2
EtOAc/hexane) to provide 6a,7a-epoxy-1a,2a-cyclomethylene-16b-
chloro-17a-acetoxy-4-pregnene-3,20-dione (10) as a white solid (345 mg,
ꢀ
ꢁ1
1
6
(
4%); m.p. 185–187 C; IR (KBr): 1737, 1654, 1241 cm
; H NMR
1
6
CDCl , 400 MHz) ꢀ 5.95 (s, 1H, C¼CHC¼O), 4.3 (t, 1H, CHCl,
3

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1
6b-Chloro- and 16b-Bromo-cyproterone Acetate
1703
6
7
J ¼ 7.0 Hz), 3.45 (s, 1H, CH-O (epoxide)), 3.25 (s, 1H, CH-O (epoxide))
0
.80–2.20 (m, 11H), 0.86–0.94 (m, 2H), 2.17 (s, 3H, CH COO-), 2.15 (s,
3
3
H, CH C¼O), 1.25 (s, 3H, CH ), 1.15 (s, 3H, CH ), 0.85 (m, 2H, CH
3
3
3
2
þ
(cyclopropane)); MS m/z (%) 432 (M , 1), 389 (2), 354 (29), 312 (100);
HRMS m/z 432.1726 (calcd. forC 24H ClO , 432.1704).
29
5
16b-Chlorocyproterone acetate (11): A solution of 10 (330 mg,
0
.76 mmol) in DMSO (4 mL) was added with dry N,N-dimethylacetamide
ꢀ
hydrochloride (750 mg) and then the mixture was stirred at 55 C under
N for30 h. Afteraddition to H O (10 mL), the precipitate was extracted
2
2
with CH Cl (5 ꢃ 10 mL) and the combined extract was washed with
2
2
water (40 mL), brine (40 mL), dried (MgSO ) and evaporated under
4
reduced pressure. The residue was purified by flash column chromatog-
raphy on silica gel (1:1 EtOAc/hexane) to afford 11 as a colorless solid
ꢀ
ꢁ1
(
152 mg, 60%); m.p. 190–192 C; IR (KBr): 1737, 1651, 1240 cm
;
1
H NMR (CDCl , 300 MHz) ꢀ 6.18 (s, 1H, C¼CHC¼O), 6.15 (s, 1H,
3
16
-
CH¼CCl-C¼CH-C¼O), 4.25 (m, 1H, CHCl), 2.18 (s, 3H, CH COO-),
3
2
2
1
4
.12 (s, 3H, CH C¼O), 1.28 (s, 3H, CH ),1.2 (s, 3H, CH ), 0.86–0.94 (m,
3
3
3
1
H), 0.83 (m, 2H, CH (cyclopropane)); C NMR (CDCl , 75 MHz) ꢀ
3
2
3
2.6, 15.1, 20.4, 21.3, 23.1, 25.4, 26.3, 28.8, 33.6, 37.6, 37.8, 33.9, 46.5,
8.0, 49.1, 61.2, 95.0, 120.9, 130.8, 135.9, 152.1, 170.0, 198.2, 199.8; MS
þ
m/z (%) 451 (M , 10), 414 (10), 390 (20), 372 (5), 347 (40), 330 (60), 311
(
100), 277 (25), 246 (10), 219 (15), 193 (13), 175 (10), 149 (35), 128 (25),
155 (27), 91 (30); HRMS m/z 450.1366 (calcd. forC H Cl O ,
24 28 2 4
4
50.1365).
Conversion of 16b-chlorocyproterone acetate (11) to 1a,2a-cyclo-
methylene-16a,17a-epoxy-6-chloro-4,6-pregnadiene-3,20-dione (12):
A
solution of 11 (25 mg, 0.0554 mmol) in benzene (10 mL) was
added with basic aluminium oxide (grade I) (500 mg) and stirred
at room temperature for 24 h. The mixture was filtered and eluted
with CH Cl (20 mL). The filtrate was evaporated under reduced
2
2
pressure to give the residue. This residue was purified by flash
column chromatography on silica gel (20:1 EtOAc/CH Cl ) to give 12
2
2
ꢀ
as a white solid (15.5 mg, 75%); m.p. 189–190 C; IR (KBr): 1703, 1663,
ꢁ
1 1
9
08 cm ; H NMR (CDCl , 400 MHz) ꢀ 6.18 (s, 1H, CH¼CCl-C¼CH-
3
1
6
C¼O), 6.15 (s, 1H, CH¼CCl-C¼CH-C¼O), 3.8 (s, 1H, CH-O (epox-
ide)), 2.08 (s, 3H, CH C¼O), 1.25 (s, 3H, CH ), 1.07 (s, 3H, CH ), 0.85
3
3
3
1
3
(
m, 1H, CH (cyclopropane)); C NMR (CDCl , 100 MHz): 205.0,
2 3
1
3
98.8, 152.9, 136.9, 130.9, 121.1, 70.9, 60.7, 49.1, 43.5, 42.9, 39.5,
6.6, 31.7, 27.4, 26.7, 26.5, 25.9, 23.4, 21.3, 15.6, 13.0; Anal. calcd.
forC 22H ClO : C, 70.86; H, 6.76. Found: C, 70.86; H, 6.67.
25
3
1
a,2a-Cyclomethylene-6-chloro-16b-bromo-17a-hydroxy-4,6-preg-
nadiene-3,20-dione (13): A solution of bromine (0.1 mL) in dry THF

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1
704
Sakee, Kongkathip, and Kongkathip
(
(
(
5 mL) 1 mL was added to the solution of PPh (125 mg) in dry THF
3
2 mL). This mixture was stirred for 30 min and the solution of 12
50 mg, 0.13 mmol) in dry THF (2 mL) was added. The reaction was
stirred at room temperature for 30 min and then the solvent was
removed under reduced pressure and the residue was dissolved
with CH Cl (10 mL). The solution was washed with water(5 mL)
2
2
and dried over anhydrous sodium sulphate. The solution was stored
at room temperature for 2 days and then was evaporated under
reduced pressure to give the residue. This residue was purified by
flash column chromatography on silica gel (20:1 EtOAc/CH Cl )
2
2
ꢀ
to provide 13 as a white solid (42 mg, 70%); m.p. 180–182 C; IR
ꢁ
KBr): 3443, 1717, 1636, 1606 cm ; H NMR (CDCl , 400 MHz) ꢀ
3
1
1
(
6
.20 (s, 1 H, -CH¼CCl-C¼CH-C¼O), 6.17 (s, 1H, -CH¼CCl-
1
6
C¼CH-C¼O), 4.15 (m, 1H, CH-Br), 3.3 (br, 1H, OH), 2.45 (s,
2
1
3
CH2 (cyclopropane));
H, CH C¼O), 1.4 (s, 3H, CH ), 1.27 (s, 3H, CH ), 0.85 (m, 1H,
3 6
3
3
3
1
3
C NMR (CDCl þ DMSO-d , 100 MHz):
2
3
05.3, 198.7, 153.1, 137.5, 130.4, 120.7, 89.0, 51.6, 48.3, 48.9, 39.3,
8.1, 38.0, 31.5, 28.3, 26.6, 25.8, 23.4, 20.6, 15.6, 13.0; Anal.
calcd. forC
H, 5.70.
H BrClO : C, 58.23; H, 5.77. Found: C, 58.24;
26 3
2
2
Acetylation of 1a,2a-cyclomethylene-6-chloro-16b-bromo-17a-hydroxy-
,6-pregnadiene-3,20-dione (13): Undera N atmosphere, acetic acid
0.3 mL) was added to a well stirred mixture of TFAA (0.73 mL) in
4
2
(
CH Cl (2 mL) and the mixture was stirred at room temperature for
2
2
3
0 min. p-TsOHꢂH O (43 mg) was then added and the mixture was
2
ꢀ
cooled to 0 C. A solution of 13 (30 mg, 0.07 mmol) in CH Cl (1 mL)
2
2
was cooled in an ice bath and added to the stir r ed mixed anhydr ide and
ꢀ
stirring at 0 C for20 min. Cold 20% aq. K CO was added carefully until
2
3
the mixture was basic. The mixture was diluted with H O until the
2
CH Cl phase became the lowerphase. The mixtu er was ext ar cted with
2
2
CH Cl (3 ꢃ 5 mL) and washed with H O (10 mL), brine (10 mL), dried
2
2
2
(MgSO ), evaporated and purified by flash column chromatography on
silica gel (1:20 EtOAc/CH Cl ) to give 14 as a white solid (23.7 mg,
4
2
2
ꢀ
ꢁ1
7
1%); m.p. 165–166 C; IR (KBr): 1738, 1651, 1365, 1239, 1029 cm ;
1
HNMR (CDCl , 400MHz) ꢀ 6.20 (s, 1H, CH¼CCl-C¼CH-C¼O),
3
16
6
.16 (s, 1H, CH¼CCl-C¼CH-C¼O), 4.25 (t, 1H, CHBr), 2.8 (m, 1H),
.5 (t, 1H), 2.19 (s, 3H, CH COO-), 2.17 (s, 3H, CH C¼O), 1.33 (s, 3H,
2
CH ), 1.25 (s, 3H, CH ), 0.87 (m, 1H, CH (cyclopropane)); CNMR
3
3
13
3
3
2
(CDCl , 100 MHz): 200.0, 198.6, 170.6, 152.5, 136.3, 131.2, 121.4, 94.8,
3
49.8, 49.1, 48.4, 47.7, 39.3, 38.8, 38.1, 34.2, 28.8, 26.7, 25.9, 23.5, 21.7,
20.9, 16.0, 13.0; Anal. calcd. forC 24H BrClO : C, 58.14; H, 5.69. Found:
C, 58.14; H, 5.68.
26
4

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1
6b-Chloro- and 16b-Bromo-cyproterone Acetate
1705
ACKNOWLEDGMENTS
We thank the Thailand Research Fund (TRF) under the Royal
Golden Jubilee Ph.D. Program for Ph.D scholarship of the US. We
thank Prof. John W. Daly and Dr. T. Spande for providing a laboratory
and resources at the National Institutes of Health (NIH) and for proof of
the manuscript.
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MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
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2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1
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Received in the UK May 14, 2002