An efficient synthesis of 11β-(4-aminophenyl)spiro[estr-4-ene-17β,2'(5'H)-furan]-3,5'-dione

Article abstract of DOI:10.1016/S0040-4020(00)00602-5

An efficient synthesis has been developed affording 11β-(4-aminophenyl)spiro[estr-4-ene-17β,2'(5'H)-furan]-3,5'-dione (2), main metabolite of antiprogestin (Z)- 11β-[4-(dimethylamino)phenyl] - 17β-hydroxy- 17α-(3-hydroxyprop- 1-enyl)estr-4-en-3-one (1), i

Full text of DOI:10.1016/S0040-4020(00)00602-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6489±6492
An Ef®cient Synthesis of
11b-(4-Aminophenyl)spiro[estr-4-ene-17b,20(50H)-furan]-
3,50-dione
b
a
Jens Geisler,a, Arwed Cleve and Michael Harre
*
aProcess Research of Schering AG, D-13342 Berlin, Germany
bResearch Laboratories of Schering AG, D-13342 Berlin, Germany
Received 23 May 2000; accepted 4 July 2000
AbstractÐAn ef®cient synthesis has been developed affording 11b-(4-aminophenyl)spiro[estr-4-ene-17b,20(50H)-furan]-3,50-dione (2),
main metabolite of antiprogestin (Z)-11b-[4-(dimethylamino)phenyl]-17b-hydroxy-17a-(3-hydroxyprop-1-enyl)estr-4-en-3-one (1), in an
overall yield of 21%. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Establishing an aromatic amino group in an 11b-phenyl
steroid of the 19-nor-10-H-series proved dif®cult. Two
routes to introduce a phenyl residue at the 11b-position of
a steroid have been described, the copper salt catalyzed
SN20-addition of aryl Grignard reagents to a D9(11)-5a,10a-
epoxide,1 and the aryl cross-coupling with steroidal 9(11)-
enol tri¯ates.2 After introduction of the aryl moiety, the SN20
pathway includes a deprotection step, a Birch reduction of
the dienone 5, and an isomerization of the non-conjugated
double bond in enones of type 6 under proton catalysis
(Scheme 1).3 Yields of the latter two steps normally are in
the range of 50%. Therefore, the shorter cross-coupling
sequence to 11b-arylestr-4-en-3-ones seemed more attrac-
tive for the synthesis of the metabolite.
(Z)-11b-[4-(Dimethylamino)phenyl]-17b-hydroxy-17a-(3-
hydroxyprop-1-enyl)estr-4-en-3-one (1) is a 19-nor steroid
exhibiting progesterone antagonistic activity. The main
metabolite of this compound in monkeys has been identi®ed
to be 11b-(4-aminophenyl)spiro[estr-4-ene-17b,20(50H)-
furan]-3,50-dione (2), an oxidative degradation product of 1.
11-Arylsteroids are easily obtained from Suzuki cross-
coupling reactions of enol per¯uoroalkylsulfonates like
compound 8 with arylboronic acids (Scheme 2). Reduction
of styrene 9 to the corresponding 9a,11a-dihydrosteroid 10
is achieved in stereospeci®c manner by reaction with
lithium in liquid ammonia.
This Birch type reduction tolerates electron donating aryl
substituents such as alkoxy and dialkylamino. However, in
the presence of hydrogen bearing oxygen or nitrogen groups
reduction does not takes place, because deprotonated
hydroxy- or aminostyrenes are too electron rich to be
attacked by solvated electrons. Cleavage of common acyl
and silyl amino protecting groups by lithium in liquid
ammonia is faster than reduction of the 9(11)-double
bond. Protecting the amino group by alkyl substituents or
as a pyrrole would permit clean reduction of the styrene
system. In the presence of the respective oxygen functions
at a later stage of the synthesis, cleaving such protecting
groups is not expected to proceed in satisfactory yield.
As a larger amount of this substance was required for toxi-
cological studies and the known synthesis in our labora-
tories afforded 2 only in extremely low overall yields, we
set out to develop a new synthesis of compound 2.
Keywords: hormones; metabolites; nitration; steroids.
* Corresponding author. Tel.: 130-46815139; fax: 130-46895139;
e-mail: jens.geisler@schering.de
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00602-5

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J. Geisler et al. / Tetrahedron 56 (2000) 6489±6492
Scheme 1. The SN20 aryl introduction pathway.
Therefore, introducing the nitrogen substituent after having
established the 11b-aryl situation appeared to be the more
promising synthetic strategy.
salts5,6 or peroxides7,8 and the reaction with chloroformates9
are described. All attempts applying these methods to
compound 1a only resulted in the formation of the corre-
sponding monomethylamino derivative. In no case a double
demethylation took place. Reacting compound 1 under
various oxidizing conditions (silver carbonate/Celitew,
Ru-salts/t-BuOOH, Mn(OAc)3/AcOH, FeCl3/H2O2) ended
in the formation of lactone 1a, but the desired compound
2 was not observed.
Results and Discussion
Before entering into a completely new synthesis, our ®rst
plan was to start with the available drug substance 1. After
oxidizing the alcohol in the side chain to the corresponding
lactone 1a and demethylating the dimethylamino group
it was expected to obtain the desired compound 2
(Scheme 3).
These results prompted us to establish a new synthetic route
to aminolactone 2. Our approach was based on 11b-phenyl-
estr-4-ene-3,17-dione 7 (RˆH, XˆO). This compound was
obtained from 11a-hydroxy-NAD in six chemical steps
according to the protocol of Ottow et al.2 (Scheme 2).
Reaction of compound 7 (RˆH, XˆO) with the potassium
salt of propargyl alcohol in tetrahydrofuran resulted in the
formation of compound 11 in a very clean reaction, and after
chromatography the propargyl compound was obtained in
99% yield (Scheme 4). Catalytic hydrogenation of acetylene
Oxidation of compound 1 in toluene with silver carbonate/
Celitew at re¯ux for 1 h4 gave the desired lactone 1a in 98%
yield without further puri®cation. The demethylation of an
aromatic dimethylamino group to a monomethylamino
group is a well-known procedure in literature. Oxidative
demethylation using oxidizing agents like palladium
Scheme 2. The Suzuki cross-coupling aryl introduction pathway.

J. Geisler et al. / Tetrahedron 56 (2000) 6489±6492
6491
Scheme 3.
Scheme 4. (i) Propargyl alcohol, KOtBu, THF, 99%; (ii) H2, Pd/CaCO3, pyridine, THF, 98%; (iii) Ag2CO3/Celitew, toluene, 69%; (iv) nitronium tetra¯uoro-
borate, sulpholane, CH2Cl2, 72%; (v) Fe, acetic acid, ethyl acetate, 43%.
11 with Pd/CaCO3 in tetrahydrofuran/pyridine resulted in a
98% yield of Z-ole®n 12 after chromatography. Compound
12 was oxidized to unsaturated lactone 13 by silver carbon-
ate on Celitew in 69% yield. The nitration of compound 13
by nitronium tetra¯uoroborate in sulpholane and methylene
chloride proceeded smoothly without formation of regio-
isomers. After chromatography, the desired compound
was obtained in 72% yield. Finally, the reduction of nitro
compound 14 with iron powder in acetic acid gave target
compound 2. After puri®cation of the raw material we
obtained the metabolite in 43% yield.
Experimental
Flash column chromatography was performed on Merck
silica gel (grade 60, 230±400 mesh); TLC was performed
on Merck HPTLC plates 60 F254. The melting points
are uncorrected. IR spectra were measured on a Bruker
FT-IFS 25 spectrometer. Mass spectra were recorded on
a
Micromass AutoSpec EQ mass spectrometer. 1H
NMR spectra (300 MHz) were recorded using TMS or
the solvent as internal standard on a Bruker AC 300
spectrometer.

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J. Geisler et al. / Tetrahedron 56 (2000) 6489±6492
17b-Hydroxy-17a-(3-hydroxyprop-1-inyl)-11b-phenyl-
estr-4-en-3-one (11). To a suspension of potassium tert-
butoxide (34.4 g, 306 mmol) in dry THF (270 ml) at 08C,
11b-phenylestr-4-ene-3,17-dione 7 (15.25 g, 44 mmol) in
dry THF (200 ml) was slowly added and stirring was con-
tinued for 30 min. Propargyl alcohol (10.3 ml, 17.5 mmol)
was added and stirring was continued for 2 h. The reaction
mixture was diluted with water and extracted with ethyl
acetate. The organic layer was washed twice with water
and brine, dried over anhydrous MgSO4, and evaporated
under reduced pressure affording a crude product, which
was puri®ed by column chromatography (ethyl acetate±
hexane 7:3) to give 11 (17.64 g, 99.7%): mp 126±1308C;
HRMS (EI, m/z) found: 404,2347 (M1z); calcd for C27H32O3:
404,2351; 1H NMR (300 MHz, CDCl3) d 0.63 (3H, s,
18-CH3), 2.80±2.92 (1H, m, 10-CH), 3.40±3.44 (1H, m,
11-CH), 4.35 (2H, s, 22-CH2), 5.86 (1H, s, 4-CH), 7.15±
7.20 (1H, m, ar-CH), 7.26±7.28 (2H, m, ar-CH), 7.40±7.43
(2H, m, ar-CH).
was slowly added and stirring was continued for 30 min at
58C. Solvent was evaporated under reduced pressure and the
crude compound was puri®ed by column chromatography
(ethyl acetate±hexane 8:2) to give 14 (6.7 g, 72%):
mp.2208C; HRMS (EI, m/z) found: 447,2062 (M1z);
calcd for C27H29NO5: 404,2351; 1H NMR (300 MHz,
CDCl3) d 0.78 (3H, s, 18-CH3), 2.73±2.85 (1H, m, 10-
CH), 3.40±3.47 (1H, m, 11-CH), 5.90 (1H, s, 4-CH), 5.99
(1H, d, Jˆ5 Hz, 21-CH), 7.44 (1H, d, Jˆ5 Hz, 20-CH), 7.57
(2H,d, Jˆ8.5 Hz, ar-CH), 8.17 (2H, d, Jˆ8.5 Hz, ar-CH).
11b-(4-Aminophenyl)spiro[estr-4-ene-17b,20(50H)-furan]-
3,50-dione (2). To a suspension of iron powder (6.5 g,
116 mmol) in acetic acid (5%, 500 ml) at 608C, a solution
of 14 (10.28 g, 23 mmol) in ethyl acetate (260 ml) and
acetic acid (260 ml) was slowly added and stirring was
continued for 60 min at 808C. The reaction mixture was
cooled to room temperature, ®ltered through Celitew and
washed with ethyl acetate. Solvent was evaporated under
reduced pressure and the residue was dissolved in ethyl
acetate. The organic layer was washed with saturated
NaHCO3 solution and water, and dried over anhydrous
MgSO4. The solvent was evaporated under reduced
pressure. The crude product was puri®ed by column chro-
matography (ethyl acetate) to give 2 (4.1 g, 43%):
mp.2308C (decomp.); IR (KBr, cm21): 1760 (CvO),
1668 (CvO); HRMS (EI, m/z) found: 417,2302 (M1z);
calcd for C27H31NO3: 417,2304; 1H NMR (300 MHz,
CDCl3) d 0.86 (3H, s, 18-CH3), 2.77±2.90 (1H, m, 10-
CH), 3.18±3.26 (1H, m, 11-CH), 3.68 (2H, br s, NH2),
5.86 (1H, s, 4-CH), 5.95 (1H, d, Jˆ5 Hz, 21-CH), 6.61
(2H, d, Jˆ8.5 Hz, ar-CH), 7.11 (2H,d, Jˆ8.5 Hz, ar-CH),
7.48 (1H, d, Jˆ5 Hz, 20-CH).
(Z)-17b-Hydroxy-17a-(3-hydroxyprop-1-enyl)-11b-
phenylestr-4-en-3-one (12). To a solution of 11 (17.6 g,
44 mmol) in dry THF (94 ml) and pyridine (18 ml),
palladium on calcium carbonate (5%, 1.76 g) was added,
and the reaction mixture was stirred at room temperature
under hydrogen atmosphere. After 30 min, the mixture was
®ltered through Celitew and washed with THF. The solvent
was evaporated under reduced pressure. The crude product
was puri®ed by column chromatography (ethyl acetate±
hexane 8:2) to give 12 (17.45 g, 98%): mp 198±2008C;
HRMS (EI, m/z) found: 406,2495 (M1z); calcd for
1
C27H34O3: 406,2508; H NMR (300 MHz, CDCl3) d 0.70
(3H, s, 18-CH3), 2.80±2.92 (1H, m, 10-CH), 3.35±3.39 (1H,
m, 11-CH), 4.24±4.26 (2H, m, 22-CH2), 5.61±5.68 (1H, m,
21-CH), 5.72±5.76 (1H, m, 20-CH), 5.85 (1H, s, 4-CH),
7.15±7.20 (1H, m, ar-CH), 7.25±7.30 (2H, m, ar-CH),
7.40±7.43 (2H, m, ar-CH).
Acknowledgements
We gratefully thank the Spectroscopical Department of
Schering AG for the measurement of physical data, and
Susanne Buchwald for technical assistance.
11b-Phenylspiro[estr-4-ene-17b,20(50H)-furan]-3,50-
dione (13). To a solution of 12 (17.45 g, 43 mmol) in dry
toluene (425 ml), silver carbonate on Celitew (122.15 g,
21.4 mmol) was added. After re¯uxing the for 3 h, the reac-
tion mixture was cooled to room temperature. The mixture
was ®ltered through Celitew and washed with ethyl acetate.
The organic layer was washed twice with water and dried
over anhydrous MgSO4. The solvent was evaporated under
reduced pressure. The crude product was puri®ed by column
chromatography (ethyl acetate±hexane 7:3) to give 13
(11.88 g, 69%): mp.2208C; HRMS (EI, m/z) found:
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