HALOGENATION USING HALO-VILSMEIER REAGENT

HALOGENATION A L'AIDE DU REACTIF DE HALO-VILSMEIER

English Abstract

2127272 9314106 PCTABS00024
The invention provides an improved process for the preparation of
a halogenated steroidal diene. The process involves the
simultaneous transformation of the steroidal 3-one to 3-halo and
17-carboxylic acid to 17-carboxamide in a single reaction without the
isolation of an intermediate. The process takes place by reacting
the steroidal starting material with a halogen-Vilsmeier reagent.

Claims

WO 93/14106 PCT/US93/00079
What is claimed is:
1. A process for the preparation of a compound of
formula (I)
<IMG> (I)
in which:
R1 is NR3R4, where R3 and R4 are each independently
selected from hydrogen, C1-8 alkyl, C3-6 cycloalkyl,
phenyl; or R3 and R4 taken together with the nitrogen to
which they are attached represent a 5-6 membered
saturated ring containing up to one other heteroatom
selected from oxygen and nitrogen; and
R2 is an acid or ester;
or a pharmaceutically acceptable salt, hydrate or
solvate thereof, which comprises
(a) reacting, at a reduced temperature, a compound
of formula (II)
<IMG> (II)
in the presence of a halogen-Vilsmeier reagent and a
solvent then quenching with excess H-R1, where R1 is as
defined above, to form a compound of formula (III)

WO 93/14106 PCT/US93/00079
16
<IMG> (III)
in which
halogen is bromine or iodine; and
R1 is as defined above and
(b) subsequently, in an appropriate solvent and at
a reduced temperature, adding an alkyllithium reagent
followed by a coupling reagent to form a compound of
formula (I),
provided that when R3 and/or R4 is H the compound of
formula (III) is subjected to a basic medium suitable
for the selective deprotonation of the amide, prior to
addition of alkyllithium reagent, and thereafter
optionally forming a pharmaceutically acceptable salt,
hydrate or solvate.
2. A process according to claim 1 in which the
halogen-vilsmeier reagent is prepared by reacting,
preferably at reduced temperatures, a chloride source
such as oxalyl chloride or thionyl chloride, with a
disubstituted formamide reagent, such as a dialkyl
substitued formamide reagent preferably
dimethylformamide, in an appropriate solvent, preferably
methylene chloride, to form a chloro-Vilsmeier reagent,
said chloro-Vilsmeier reagent being reacted in situ,
preferably at reduced temperatures, with a bromide
source or an iodide source, preferably hydrogen bromide
gas.
3. A process according to claim 2 in which the
halogen-Vilsmeier reagent is a bromo-Vilsmeier reagent.

WO 93/14106 PCT/US93/00079
17
4. A process according to claim 2 in which the
halogen-Vilsmeier reagent is an iodo-Vilsmeier reagent.
5. A process according to claim 3 in which the
bromo-Vilsmeier reagent is (bromomethylene) dimethyl
ammonium bromide.
6. A process according to claim 2 in which R2 is:
-SO3H, -P(O)(OH)2, -PH(O)OH or -(CH2)1-3-COOH.
7. A process according to claim 2 in which R2 is
-COOH.
8. A process according to claim 2 in which the
base used to prepare said basic medium is selected from
a group consisting essentially of: hydrides, alkyl
lithium, grignard reagents and metal alkoxides.
9. A process according to claim 8 in which the
base is ethylmagnesium bromide or ethylmagnesium
chloride.
10. A process according to claim 9 in which the
base is ethylmagnesium chloride.
11. A process according to claim 2 in which the
alkyllithium reagent is sec-butyllithium.
12. A process according to claim Z in which R1 is
-N(H)C(CH3)3.
13. A process according to claim 2 in which the
compound prepared is

WO 93/14106 PCT/US93/00079
18
<IMG> (IA)
or a pharmaceutically acceptable salt, hydrate or
solvate thereof.
14. A process for the preparation of a steroidal
carboxamide substituent which comprises halogenation of
the corresponding carboxylic acid with a halogen-
Vilsmeier reagent followed by quenching with excess H-R1
in which R1 is NR3R4, where R3 and R4 are each
independently selected from hydrogen, C1-8 alkyl, C3-6
cycloalkyl, phenyl; or R3 and R4 taken together with the
nitrogen to which they are attached represent a 5-6
membered saturated ring containing up to one other
heteroatom selected from oxygen and nitrogen.
15. A process according to claim 14 in which the
halogen-vilsmeier reagent is prepared by reacting,
preferably at reduced temperatures, a chloride source
such as oxalyl chloride or thionyl chloride, with a
disubstituted formamide reagent, such as a dialkyl
substitued formamide reagent preferably
dimethylformamide, in an appropriate solvent, preferably
methylene chloride, to form a chloro-Vilsmeier reagent,
said chloro-Vilsmeier reagent being reacted in situ,
preferably at reduced temperatures, with a bromide
source or an iodide source, preferably hydrogen bromide
gas.
16. A process according to claim 15 in which the
halogen is a bromine.

WO 93/14106 PCT/US93/00079
19
17. A process according to claim 16 in which the
bromo-Vilsmeier reagent is prepared and utilized in
situ.
18. A process of claim 17 in which the bromo-
Vilsmeier reagent is (bromomethylene) dimethyl ammonium
bromide.
18. A process for the preparation of a steroidal
halo-1,3-dienes which comprises halogenation of the
corresponding .alpha.,.beta.-unsaturated ketone with a halogen-
Vilsmeier reagent.
19. A process according to claim 18 in which the
halogen-vilsmeier reagent is prepared by reacting,
preferably at reduced temperatures, a chloride source
such as oxalyl chloride or thionyl chloride, with a
disubstituted formamide reagent, such as a dialkyl
substitued formamide reagent preferably
dimethylformamide, in an appropriate solvent, preferably
methylene chloride, to form a chloro-Vilsmeier reagent,
said chloro-Vilsmeier reagent being reacted in situ,
preferably at reduced temperatures, with a bromide
source or an iodide source, preferably hydrogen bromide
gas.
20. A process according to claim 19 in which the
compound prepared is a steroidal bromo-1,3-diene.
21. A process according to claim 19 in which the
compound prepared is a steroidal 3-bromo-3,5-diene.
22. A process of claim 21 in which the halogen-
Vilsmeier reagent is (bromomethylene) dimethyl ammonium
bromide.

WO 93/14106 PCT/US93/00079
23. A process for the halogenation of multiple
functional groups on a single molecule which comprises
halogenation of a molecule with multiple functional
groups with a halogen-Vilsmeier reagent.
24. A process according to claim 23 in which the
halogen-vilsmeier reagent is prepared by reacting,
preferably at reduced temperatures, a chloride source
such as oxalyl chloride or thionyl chloride, with a
disubstituted formamide reagent, such as a dialkyl
substitued formamide reagent preferably
dimethylformamide, in an appropriate solvent, preferably
methylene chloride, to form a chloro-Vilsmeier reagent,
said chloro-Vilsmeier reagent being reacted in situ,
preferably at reduced temperatures, with a bromide
source or an iodide source, preferably hydrogen bromide
gas.

Description

,3~'W093/141~6 ~ 7 .;~ 7 2 PCT/US93~00079
"HALOGENATION USING HALO-VILSMEIER REAGENT".
ilThe present invention relates to an improved
process for the preparation of substituted steroidaI
dienes. Such compounds are described ~ US Paten- Nc.
5,017,568, issued on May 21, 1991 ~o Holt et al., as
being useful in inhibiting steroid 5~a-reductase.
Back~ro~n~ Sh~_Inv~on.
Processes for the preparation of substituted
steroidal diene derivatives, have previously been
described. In particular the use of oxalyl bromide .o
convert steroidal ~,~-unsaturated-3 ke~ones to 3-bromo-
3,5-diene intermediates ~in 40% yield) followed by
catalytic or alkyllithium mediated carboxylation (in 1~%
yield when N-butyl lithium was used) to yield steroidal-
3,5-diene-3-carboxylic acid derivatives is reported in
US Patent No. 5,017,568.
;
In addition to a low o~erall yield, another
shortcoming of this disclosure is that oxalyl bromide is
a toxic, expensive liquid which is dif-icult to store
and is no~ readily available in the buIk amounts neeàed
for an industrial process.
The use of oxalyl chloride to haloqenate steroida`
~ unsaturated ketones to chloro-steroidal dienes
proceeds wi~h only marginal results. Furthermore, the
~, relatively low reactivity of~the res-lLtan. chloro~
substituent poses non-trivial synthetic oonsidera~ions
in subsequent transformations.~ Thus~, there is a need in
the ar; for a safe, economical and reLiable method t_
halogena~e steroidal ~,~-unsaturated ketones to haIc-
1,3-dienes. Preferably, said methoa w l bromlnate ~-
35 ~ iodinate steroidal a,~-unsaturated~ketones to thei-
corresponding halo-1,3-dienes. ~

WO93/1~106 PCT/US93/~079
J ~ ~ ~ r~ 2
..
This invention relates to a process for the
halogenation of a compound with multiple functional
groups on the same molecule.
This invention relates to an improved process for
converting steroidal a,~-unsaturated ketones to their
corresponding halo-1,3 diene derivatives.
This invention relates to an improved process for
the formation of acid-halide from a steroidal carboxylic
- acid substituent ~ollowed by nucleiophilic displacement
of said halide.
This invention specifically relates to an improved
process for the Ln si~ conversion of steroidal
carboxylic acids to steroidal carboxamides.
This invention specifically relates to a process
for the simultaneous bromination and amidation of 3-one-
4-ene-17-carboxylic acid steroidal compounds.
This invention specifically relates to an improved
process for the preparation of N-t-butyl-androst-3,5-
diene-17~-carboxamide-3-carboxylic acid.
~ G _
By the term "simultaneous" as used herein is meant
that the triansformation of the steroidal 3-one to 3-halo~
and 17-carboxylic acid to 17-carboxamide is performed in
a single reaction without the isolation of an ,
intermediate.
As used above and throughout the remainder of the
specification and claims the carbons of the steroid
'
:

WO93/14106 2:l, 7 i~J~ PC~/US93/00~79
! ; 3
nucleus are numbered and the rings are lettered as
follows:
~ 12~--17
11 C 1 3 D
/1~/9~ /14--15
I A 1 E3 1
3~/\~?
4 6
~ By the term "reduced temperature" as used herein is
meant below ~5C, preferably between -15 and 15C, most
preferably between 0 and 10C.
By the term "coupling reagent" as used herein is
10 , meant a compound and/or conditions which are capable of
reacting with a metalated moiety to form an acid, ester,
C1_6alkylcarbanyl or C1_20alkyl moiety. Preferably said
metalated moiety is a lithium metalated moiety prepared
by reacting the corresponding halogenated moiety with an
. 15 ~alkyllithium reagent. Compounds useful as coupling
; reagents include chloro formates, alkyl bromides and
acid chlorides. Preferably said coupling reagent will
uti}ize carbon dioxide as the~reacting compound.
` ~ : : : : : ` : :
,~
~` 20 ~ By the term "ac1d" as used hereln is meant any
group which is c~apable of acting as a proton donor
including but not limited to; -COOH, -PtO)(OH)2,
~ ) ~ PH(O)OH, -SO3H and;-~tCH2)1-3-CH- ~
; 25~ By the~te,rm 'lester" as used herein ls meant a group
cons1sting of an acid, as defined above, in which the
donata~le proton or~protons~are replaced~by alkyl
subst~ituents. ~
~;;30 ~ ~ 3y~Ch-~term "solvent"~or ;"appronrlate solvent" as
used herein` is meant an organic solvent such as
methylene~chlorlde, ethylene~ chloride, chloroform,
:: ~
.
.

~ WO93/14106 PCT/US93/00~79
. .,. ~
2 ~ J ~ 2 4
carbon tetrachloride, tetrahydrofuran (THF), ethyl ether
carbon, toluene or ethyl acetate.
;$
.~ By the term "halogen-Vilsmeier reagent" as used
herein is meant a halogenated disubstituted formamide
reagent of the structure:
\
N C
0 wherein R5 and R6 are independently selected from an
alkyl, aryl or arylalkyl group; and X is Br or I; and y
is a counter ion, which is prepared by
a) reacting, preferably at reduced tempe~atures,
a chloride source such as oxalyl chloride or thionyl
lS chloride, with a disubstituted formamide reagent, such
as a dialkyl substitued formamide reagent preferably
dimethylformamide, in an appropriate solvent, preferably
methylene chloride, to form a chloro-Vilsmeier reagent,
said chloro-Vilsmeier reagent being reacted ln ~l~,
preferably at reduced temperatures, with a bromide
source or an iodine source, preferably hydrogen bromide
gas
or
: ~ b) reacting, preferably at reduced temperatures,
a bromide source or an iodide source, preferably oxalyl
bromide, with a disubstituted formamide reagent, such as
a idialkyllsubstitiuted formamide reagent preferably
dimethylformamide in an appropriate solvent, prefera~ly
methylene chloride.
This invention, therefore, relates to the 1~
prepartation:and use:of a bro~mo-Vilsmeier reagent or an
iodo-Vilsmeier reagent, said reagents being prepared
safely and econoo1ca11y from known and readily available
-
.

WO~3/14106 '~1~' 7 '~ J 3 PCT/US~3/00079
~- 5 ~
reagents preferably the corresponding chloro-Vilsmeier
reagent. As such, this invention will have utility in
all reactions wherein bromo-Vilsmeier reagents or iodo-
Vilsmeier reagents are utilized.
Preferred alkyllithium reagents for use herein
include n-butyllithium, 5~-butyllithium and ~L~-
butyllithium.
Unless otherwise specified the term "halogen" and
its derivatives as used herein means bromine or iodine.
Pharmaceutically acceptable salts, hydrates and
solvates of Formula (I) compounds are formed where
appropriate by methods well known to those of skill in
the art.
The present invention provides a process for the
production of a compound of formuIa ~I)
O
Il ~ R
2 (I~
in which:
! ~, Rl' iS NR3R4, where R3 and R4 are each independently
selected from hydrogen, Cl_8aIkyl, C3_6cycloalkyl,
¦ phenyl; or R3 and R4 taken together with the nitrogen to
I~ which they are attached represent a 5-6 membered
¦ saturated ring containing up to one other heteroatom
selected ~rom oxyyen and nitrogeni and
R2 is an acid, ester, Cl_6alkylcarbonyl or Cl_20
i alkyl;
¦ ~ or a pharmaceutically acceptable salt, hydrate or
: ,

W~g3/1~106 PCT/U~93/00079
2 ~ 7 ;~ 7 2 6
solvate thereof, which comprises reacting, at a reduced
temperature, a compound of formula (II)
¦¦ ~OH
(II)
S
in the presence of a halogen-Vilsmeier reagent and a
solvent then quenching with excess H-Rl, where Rl is as
described above, to form a compound of formula (III)
¦¦,,R
~bgen (III)
i.n which Rl is as defined above and subsequently, in an
appropriat~ solvent and at a reduced temperature, adding
an alkyllithium reagent followed by a coupling reag~n~
to form a compound of formula ~I), provided that when R3
and/or R4 is H the compound of formula (III) is
subjected to a basic medium suLtable for the selective
deprotination of the amide prior to ~he addition of the
: : alkyllithium reagent, and ther~after optionally forming
a pharmaceutically accep~able salt, hydrate or soIvate
thereof .
~ Preferably~said halogen-vilsmeier reagent is
;~ prepared by reacting, preferably at reduced
; ~emperatures, a chloride source such as oxalyl chloride
25 or thionyl chloride, with a disubstituted formamiàe

.~ WO93/14106 ~ '! J' ?J 7 2 PCT/US93/~079
.~
:;;
. . .~
~ 7
.
~, .,
reagent, such as a dialkyl substitued formamide reagent
preferably dimethylformamide, in an appropriate solvent,
preferably methylene chloride, to form a chloro-
Vilsmeier reagent, said chloro-Vilsmeier reagent being
reacted ln 3l~, preferably at reduced temperatures,
; with a bromide source or an iodide source, preferably
hydrogen bromide ~as.
.
As used herein, unless otherwise specified, Cl n
alkyl means a straight or branched hydrocarbon chain
having Cl_n carbons.
~!
As used herein, unless otherwise specified, alkyl
means a straight or branched hydrocarbon chain.
As used herein, unless otherwise specified, aryl
means an aromatic carbocyclic or heterocyclic ring which
is un~ubstituted or substituted with non-reactive
substituents.
Preferably the halogen-Vilsmeier reagents used in
the dihalogenation of formula (II) compounds.are
prepared and uti1ized 1~
Preferably said halogen-Vilsmeier. reagent is a
bromo~Vilsmeier reagent.
Preferably said bromo-Vilsmeier reagent is
(bromomethylene) dimethyl ammonium bromide.
Preferred organic acids used to describe R2 in
formula (I~ include; -COOH, -P(O)(OH)2, -PH~O)(OH),
-SO3E~ and -(CH2)l_3COOH. Particularly preferred among .
the above acids is -COOH.
Preferred bases utilized in preparing the basic
medium used to selectively deprotonate the amide of

WO93~14106 PCT/US93/~079
~ 3~ r~ 9
~ormula (III) compounds include metal hydrides,
al~yllithium reagents, Grignard reagents and metal
alkoxides. Preferred among the above disclosed bases
axe ethylmagnesium bromide, butyllithium and
ethylmagnesium chloride. Particularly preferred among
the above disclosed bases is ethylmagensium chloride.
Preferably the selective deprotonation of said amide is
conducted at a temperature above 25C, most preferably
between 30 and 50C.
Pxeferably the alkyl lithium reagent used to
initiate the halogen-metal exchange on formula (III)
compounds is sec-butyllithium.
A preferred aspect of the invention is the
preparation of steroidal halo-1,3-diene systems from
steroidal a~-unsaturated ketones utilizing a halogen-
Vilsmeier reagent prepared ana utilized la si~.
A pref~rred aspect of the invention is the halogen-
Vilsmeier induced formation of an acid halide moiety
from a steroidal carboxylic acid moiety, said acid-
halide substituent being subject to displacement by a
nucleophilic reagent. Preferred nucleophilic reagen~s
as used herein include H-R1 where ~1 is as define~
above. ~specially preferred among the above
nuc}eophilic reagents is tert-butylamine.
Preferably, therefore, the process of the presenjt
invention is particularly useful for preparing a
compound of structure (IIIA)
,
,. ,

W093/14106 ;f ~ rl ~ s7 2 PCT/US93/00079
g
)C(C~3h
~r (IIIA)
and conver~ing the same into the following compound of
structure ~IA)
C N(H)C(~3)
O ~
11~
H ~ ~IA)
or a pharmaceutically acceptable salt, hydxate or
solvate thereof.
Without further elaboration, it is believed that
I one skilled in the art can, using the precediny
I description, utilize the present invention` to its
¦ fullest extent. The following Examples are, therefore,
to be construed as merely illustrative and not a
limitation of the scope of the present invention in any
I way.
Dimethylformamide, oxalyl chloride, oxalyl hromide, ~.
tert-butylamine, 2.OM ethylmagnesium chloride in THF,
~ 1.2M sec-butyllithium in cyclohexane, and (~)-4-
¦ cholesten-3-one are available from Aldrich Chemical Co.
i (Milwaukee, WI). Hy~ro~en bromide gas and car~on dioxide
gas are aYailable from Matheson (E. Rutherford, NJ~.
., .
i!
:!

WO93/14106 PCr/US93/00079
,~}1 ~7~72
Androst-4-en-3-one-17~-carboxylic acid is available from
Berlichem, Inc. ~Wayne, NJ). 3~Bromo-androsta 3,5-diene-
17~ carboxylic acid was prepared as described in U.S.
Patent 5,017,5~8 (~xample 25B~ii)).
~ ' .
~ .
d ~
(i) 3-Bromo-N-(l,1-dimethylethyl)-androsta-3,5-diene-
17~-carboxamide
A flask under nitrogen atmosphere was charged with
100 mL of methylene chloride and 6.12 mL (2.5 molar
equivalents) of dimethylformamide. The solution was
cooled to 0-5C, and was treated with 6.9 mL (2.5 molar
equivalents) of oxalyl chloride while maintaining the
temperature between 0-10C. A white precipitate formed.
After stirring for one hour, 50.1 grams (19.6 molar
equivalents) af hydrogen bromide gas were bubbled
through the solution while maintaining the temperature
between 0~10C. The suspension became a clear colorless
solution. The solution was degassed by reducing the
solution volume by about one-half by vacuum distillation
and restoring to its original volume with methylene
chloride. This concentration/refill procedure was
repeated. Androst-4-en-3-one-17~-carboxyLic acid, 10.0
grams (1 molar equivalent), was added to the resulting
white suspension and the mixture was warmed to room
temperature and s~tirred for 2 hours. The reaction
mixture was quenched into a vessel containing 100 mL of
methylene chloride and 23.1 grams (10 molar equivalents)
of tert-butylamine while maintaining the temperature~
between 0-10C. The mixture was stirred for 30 minutes.
Abou~ 100 mL of water were added and the biphase mixture
was filtered through a pad of Celite. The organic phase
was separa~ed and reduced to about half its volume by
vacuum distillation. The solution was restored to its
,:

wo g3/l4l06 ~ 2 ~ PCT/U~93/00079
11
original volume with acetone. This concentration/fill
procedure was repeated twice more. The resulting acetone
solution (about 300 mL) was warmed to about 50C and was
treated with about 100 mL of water to precipitate the
5 product. The suspension was cooled, and the product, 3- ;
bromo-N (1,1-dimethylethyl)-androsta-3,5-diene-17~-
carboxamide, was isolated by filtration and dried. Yield
89%, mp 181-183C.
(ii) 17~-[[~1ll-dimethylethyl)amino]carbonyl]androsta-
3,5-diene-3-earboxylic acid
A solution of tO.O g (1 molar equivalent) of 3- ``
~ bromo-N-(1,1-dimethylethyl)-androsta-3,5-diene~17~-
carboxamide in 250 mL of dry THF was warmed to 30C
under a nitrogen atmosphere. The solution was treated
with 29 mL of 2.OM ethylmagnesium chloride (2.5 molar
equivalents) in THF, and the temperature was allowed to
rise to about 40-50C. After stirring for 20 minutes,
the reaction was cooled to 0-5C and treated with 82.5
mL of 1.2M sec-butyllithium in cyclohexane (2.5 molar
equivalents). After stirring for S minutes, excess dry
carbon dioxide was bubbled through the solution. The
gassing was continued as the solution was allowed to
warm to room temperature. The resulting suspension was ~;
~hen washed with 100 mL of 3.3M aq. hydrochloric acid
and the aqueous phase was removed. The organic phase was
washed twice with about 150 mL of water. About 85 mL of
water was added to the organic phase, and the organic
phase was then removed by distillation under reduced
` 30 pressure. The resulting aqueous suspension of product
was extracted into 100 mL of methyl e~hyl ketone. The
aqueous phase was separated and the organic phase was ~-
washed with 100 mL of water. The organic phase was ~-
treated with 0.6 g of decolorizing carbon and was
filtered through celite. E~aporation of the filtrate
followed by trituration in ethyl acetate to afford 6.4 g

WO93/14106 PCT/US93/~079
21~7~7~ 2 12 ~ ``
of 17~-[[(1,1-dimethylethyl)amino]-carbonyl]androsta-
3,5~diene-3~carboxylic acid. Yield 63%, mp 248-249C.
A solution of 10 mL of methylene chloride
con~aining 5 mg of p-quinone, and 0.328 g ~1.8 molar
equivalents) of dimethylformamide was cooled to 0C and
trea~ed with 0.85 g (1.6 molar equivalents) of oxalyl
bromide. The reaction mixture was allowed to warm to
room temperature and was stirred for 30 minutes. The
solution was cooled to about 5C and 0.95 y (1 molar
equivalent) of 3-bromo-androsta-3,5-diene-17~-carboxylic
aci~ in 20 mL of methylene chloride was added to the
white suspension. The solution was allowed to warm to
room temperature and was stirred for 1.5 hours. The
reaction mix~ure was quenched with 2.2 mL '~8.4 molar
equi~alents) of t-butylamine and stirred for 5 minutes.
The mixture was poured into 100 mL of ethyl acetate and
the organic phase was washed with 50 mL of 10% aq sodium
hydroxide. The aqueous phase was'separated and extracted ' '
w1th 50 mL of ethyl acetate. The combined organic phases
were dried,over magnes1um sulfate and filtered. The
filtrate was concentrated under vacuum to afford a crude
solid which was triturated with 24 mL of 50/50 t-
butylmethyl ether/hexane. The solid product was isolated ;'
by filtration and dried under vacuum to afford 0.5 gram
of 3-bromo-N-(1,1-dimethylethyl)~androsta-3,5-diene-17~-
carboxamide. The ~iltrate was concentrated and
triturated as above to yield ano~her 0.25 g of product.
The total yield of product was 69~. mp 181-183~C.

WO~3/14106 ~ 7 .~ ~~ 2 PCT/~S93/0007~ .
:
13
~ ~ ,
A solution of 10 mL of methylene chloride
containing 0.24 mL (1.2 molar equivalents) of
dimethylformamide was cooled to 0C and treated with
0~62 gram (1.1 molar equivalents) of oxalyl bromide. The
resulting white suspension was stirred at -5C for 45
minutes, a~d 1.0 gram (1 molar equivalent~ of (+)-4- .
cholesten-3~one in 6 mL of methylene chloride was added
to the white suspension. The solution was allowed to
warm to room temperature and was stirred for 30 minutes. ;~
The reaction mixture was poured into a mixture of 100 mL
of ethyl acetate.and 40 mL of water. The organic phase .
was separated and extracted with 50 mL of ethyl acetate.
The combined organic phases were washed wi~h 10 mL of
brine, dried over magnesium s~lfate and filtered. The
filtrate was concentrated under va~uum to afford a crude
solid which was purified by silica gel chromatography
using hexane to afford 1.1 g of 3-bromocholesta-3,5- -
diene. Yield 93~. A sample was recrys~allized from . ~:
methancl-diethyl ether which had mp 64-67C.
~ ~:
A flask under nitrogen atmosphere was charged with
dimethylformamide 0.6 g (2.6 molar equivalents) in
me~hylene chloride t20 ml). The solution was cooled to !~
0-5C, and treated with oxalyl bromide 1.71 g (2.5 molar `~i`
: equivalents) while maintaining ~he temperature between
0-10C. A white precipitate formed. Androst-4-en-3-
one-17~-carboxylic acid 1 g (l~molar equivalent) was
added to the resulting white suspension and the mixture j:`
was warmed to near room temperature and stirred for 30
minutes. The reaction was treated with tert-butylamine . .
2.2 ml (8 molar equivalents) in methylene chloride ~2
:'
"'''

wo 93JI4106 2 ~ ~) rJ~;3~ PCT/US93~079
14
ml) while maintaining the temperature between 0-10C.
The reaction was stirred for 10 minutes then poured into
a mixture of ethyl acetate (150 ml) and 10% sodium
hydroxide ~50 ml). The organic phase was separated,
S washed with brine, dried over magnesium sulfate and
concentrated to afford a solid. The solid was
triturated i~ a solution of t-Butyl methyl ether (4
ml)/hexanes (4 ml), isolated by filtration and dried to
yield 3-Bromo-N-(1,1-diemthylethyl)-androsta-3,5-diene-
10 17~-carboxamide. yield 58%. MP 177-179C.
. .
"
~, ,. -,
;;
":,
~ :,
,;`
.,
:~ '.
:: ,: