Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
wo 93~16097 2 t 2 ~ Pcr/uss3/0l0~8
- Process of Preparing 3-Carbonylandrostadiene
1 7-Carboxarnides
The present invention relates to an improved
process for the conversion of substituted steroidal 3-
halogen 3,5 diene derivatives to substituted steroidal
3,5-diene-3-carboxylic acid derivati~es. Such compounds
are described in U.S. Patent No. 5,017,568, issued on
May 21, 1991 to Holt, et al. as being useful in
inhibiting steroid 5-a-reductase.
~- =~G
Processes for the preparation of substituted
steroidal 3,5-diene-3-carboxylic acid derivatives from
substituted steroidal 3-halogen 3,5 diene intermedial:es
have previously been described. In particular the use
of catalytic or alkyllithium mediated carboxylation of
steroidal 3-bromo-3,5 diene intermediates to yield
steroidal-3,5-diene-3-car~oxylic acid derivatives (in
15% yield when N-butyl lithium was used) is reported in
U.S. Patent No. 5,01~,568. The use of a basic medium,
when applicable, to selectively deprotonate acidic
hydrogen atoms of the brominated intermediate in the
above reaction prior to the addition of a dehalogenating
reagent has been shown to increase the yield of the
resulting steroidal 3,5 diene~3-car~oxylic acid
derivative in U.S. Application No. 07/817,179 filed on
January 6, 1992 (63-~ for the preparation of N-t-butyl-
androst-3,5-diene-17~-carboxamide-3-carboxylic acid from
N-t-butyl-androst-3,5-diene-3-bromQ-17~-carboxamide).
Disclosed therein as preferred bases utilized in
preparing said basic medium are ethylmagnesium bromide
and ethylmagnesium chloride.
In addition to a low overall yield, the principle
shortcoming of these disclosures is that N-butyl lithium
and ethylmagnesium bromide and ethylmagnesium chloride
are expensive reagents adding significant cost to an
industrial process. Further, N-butyl lithium is
flammable and the car~oxyiation reaction is performed at
WO93/16097 ~ ~ 9 3 PCT/US93/0106
dilute concentrations. Thus, there is a need in the art
for a safe, economical and reliable method to convert
substituted steroidal 3-halogen 3,5 diene derivatives to
substituted steroidal 3,5-diene-3-carboxylic acid
derivatives.
~ mmary of the Invention
This invention relates to an improved process for
converting steroidal 3-halogen 3,5 diene derivatives to
steroidal 3,5-diene-3-carboxylic acid derivatives.
This invention specifically relates to an improved
process for the preparation of N-t-butyl-androst-3,5-
diene-17~-carboxamide-3-carboxylic acid.
In a further aspect of the invention there are
provided novel intermediates useful in the presently
invented process.
petailed DescriDtion of the Inver~tion
As used above and throughoùt the remainder of the
specification and claims the carbons of the steroid
nucleus are numbered and the rings are lettered as
follows: ~
~12~ ~
C l3D ~16
~ ~14--~5
I A I B I
3~
~5
Pharmaceutically acceptable salts hydrates and
sol~ates of Formula (I) compounds are formed where
appropriate by methods well known to those of skill in
the art.
Unless otherwise specified the term "halogen" as
used herein and in the claims means chlorine, bromine or
1 odlne .
Preferably the term "halogen" as used herein means
bromine or iodine.
2129342
WO93/160g7 PCT/U~93/~1068
The present invention provides a process for the
production of a compound of Formula ( I )
o ~ ~ ~
HO~
in which
Rl is
(i) CoNR2R3, where R2 and R3 are each
independently selected from hydrogen, Cl_~alkyl,
C3_6cycloalkyl and phenyl; or R2 and R3 taken toget:her
wi~h the nitrogen to which they are attached represent a
5-6 membered saturated ring comprising up to one ot:her
heteroatom selected from oxygen and nitrogen; or
(ii) moieties which are chemically convertible to
moieties of (i), such as -C~N, -COOH or -COOCl_6alkyl;
or a pharmaceutically acceptable salt, hydrate or
solvate thereof,
which comprises cyanation of a compound of Formula (II)
H
X ~ ~II)
in which Rl is as defined above and
X is halogen; in the presence of a cyanating reagent and
an appropriate solvent, preferably dimethylformamide, to
form a compound of Formula (III)
-- 3 --
WO93~16097 Q 3 ~ .~ PCT/US93J0106X
N-C ~ (III)
in which Rl is as defined above and subsequently
saponifying the compound of Formula (III) to form a
compound of Formula (I) and thereafter cptionally
forming a pharmaceutically acceptable salt, hydrate or
solvate thereof.
Preferably R1, as used in the above process, is;
(i) CoNR2R3, where R2 and R3 are each
independently selected from hydrogen, C1 ~alkyl,
C3_6cycloalkyl and phenyl; or
(ii) -C_N,-COOH or -COOC1_~alkyl.
Most, preferably Rl, as used in the above process,
is ~-CoNR2R3, where ~2 and R3 are each independently
selected from hydrogen, C1_8alkyl, C3_6cycloalkyl and
phenyl.
Compounds of Formula I comprise R1 or moieties
which can be chemically converted to those of-R1 by
known chemical reactions such as described in Derek
Barton and U.D. Ollis, S~D119~5i~9_9~9k~ 3L3t~y_
~ Puk:
Pergamon Press (1979) provided that Rl does not include
any such moieties that render inoperative the presently
invented process. ~eactions to convert said moieties to
Rl are performed on products of the synthe~ic pathways
disclosed or claimed herein or, where appropriate or
preferable on certain intermediates in these synthetic
pathways. For example, carboxylic acid substituents can
be converted to the carboxamide by conversion to the
acid halide followed by reacting the same with an amine.
Esters can be converted to the acid and treated as
above. Nitriles can be converted to carboxamides by
WO93/1~097 2 1 2 ~ PCT/US93/01~68
reaction with an alkylating agent, such as t-
butylacetate or t-butanol, under acidic catalysis.
In utilizing the presently invented process to
prepare compounds of Formula (I~, novel intermediates of
the following Formula (IV) are synthesized;
R
~ H
N--C ~ (IV)
in which:
~l is
~i) CoNR2R3, where R~ and R3 are each independently
selected from hydrogen, Cl_8alkyl, C3_6cycloalkyl and
phenyl; or R2 and R3 taken together with the nitrogen to
which they are attached represent a 5-6 membered
saturated ring comprising up to one other heteroatom
selected from oxygen and nitrogen; or
~ii) moieties which are chemically convertihle ~o
moieties of ~i), such as -C~ NJ ~COOH or -COOCl_6alkyl;
Preferably Rl, as used in the above compound of
formula (iv), is,
~i) CoNR2R3, where R2 and R3 are each
independently seleet~d from hydxogen, C~_~alkyl,
C3_6cycloalkyl and phenyl; or
(ii3 -C-N,-COVH or -COOCl_6alkyl.
Most preferably Rl, as used in the abo~e compound
of formula (IV), is; ~-CoNR2R3, where R2 and R3 are each
independen~ly selected from hydrogen, Cl~8alkyl,
C3_6cycloalkyl and phenyl.
The presently invented proc.ess discloses several
advantages over the cited references. Specifically,
reagents and conditions used to convert 3-halogen
steroidal-3,5-dienes to steroidal-3,5-diene 3~carboxylic
acids are safe, inexpensive, can be reacted in high
concentrations and result in high yields of the desired
3 ~
WO93/16097 - PCT/US93/0106X
compound thereby rendering said processes appropriate
for industrial scale utilization.
As used herein and in the claims, unless otherwise
specified, Cl_nalkyl means a straight or branched
hydrocarbon chain having Cl_n carbons.
By the term "cyanating reagent" as used herein and
in the claims is meant reagents which are capable of
reacting, under certain conditions, with a halogenated
moiety to form a cyanated moiety. Preferably said
cyanated moiety is prepared by reacting the
corresponding halogenated moiety with a cyanating
reagent in an appropriate solvent, such as N,N-dimethyl-
N,N-propylene urea ~DMPU), N,N-dimethylformamide tD1~F)
or N-methyl-2-pyrrolidinone (NMP), preferably DMF, at
- lS increased temperatures.
By the term "saponifying" as used herein and in the
claims is meant a compound or reagent or a series of
reagents which are capable of reacting with a nitrile to
form a carboxylic acid substituted moiety under
appropriate conditions. Preferably said carboxylic acid
substituted moiety is prepared by reacting the
corresponding cyanated moiety with a hydroxide base,
preferably aqueous sodium hydroxide, in an appropriate
solvent, such as; ethylene glycol, isopropyl alcohol or
ethanol, preferably ethanol, at increased temperatures
with subsequent acidification.
By the term "increased temperatures" ~s used herein
and in the claims is meant above 25C, preferably at
reflux temperatures.
Prefera~ly cyanating reagents for use in the
presently invented process utilize cyanide complexes
such as described in Richard C. Larock, CQm~hrehen~;ve
Or~an;c Transformations: ~
E~3L~U~i21~- Pub: VCH Publishers, Inc. (l989) P. 861.
An example of a cyanide complex as used herein is the ~n
5i~ co-mixture of KCN, NiBr2(PPh3)2, 2n, PPh3. Other
examples include: Co(CN) 4; K4Ni2(CH)6, KCN; KCN, cat
WO 93/160g7 2 1 2 9 3 4 2 PCT/VS93/01068
Pd(PPh3)4; Co(CN)5; CuCN and NaCu(CN)2. As used herein
the term "NaCu~CN)2" refers to the reagent formed by co-
mixing CuCN and NaCN ln ~l~.
Preferred among the above cyanating complexes are
CuCN and NaCu(CN)2.
Particularly preferred among the above cyanating
complexes is NaCu~CN)2.
Preferably said NaCu(CN)2 complex is prepared by
adding l molar equivalent of sodium cyanide to cuprous
cyanide ~n ~i~.
By the term "solvent" or "appropriate solvent" as
used herein and in the claims is meant a solvent such as
methylene chloride, ethylene chloride, chloroform,
ethylene glycol, carbon tetrachloride, tetrahydrofuran
(THF), ethyl ether, toluene, ethyl acetate,
dimethylsulfoxide, N,N'-dimethyl-N,N'-propylene urea, N-
methyl-2-pyrrolidinone, methanol, isopropylalcohol,
dimethylformamide, water, pyridine, quinoline or
ethanol.
Preferably, therefore, the process of the present
invention is particularly useful for preparing a
compound of structure (IIIA)
N +
~ H H
NQ~J (IIIA)
and converting the same into the following compound of
structure (IA)
Q3~3~ PCT/US93/0106~
, O
~ I t
~ ~l IH H
O ~ >
~~ (IA)
Without further elaboration, it is believed that
one skilled in the art can, using the preceding
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
way .
Dimethylformamide, and cuprous cyanide are
available from Aldrich Chemical Co. (Milwaukee, WI)
androst-4-en-3-one-17~-carboxylic acid is available from
Berlichem, Inc. (Wayne, NJ).
~rbQX
(i~ N-t-butyl-androst-3,5-diene-3-bromo-17
carboxami~e
A flask under nitrogen atmosphere was charged-with
lQ0 mL of methylene chloride and 6.12 mL ~2.5 molar
equivalents) of dimethylformamide. The solution was
cooled to Q-5C, and was treated with 6.9 mL ~2.5 molar
equivalents) of vxalyl chloride while maintaining the
temperature between 0-10C~ A white precipitate formed.
After stirring for one hour, 50~1 grams (19.6 molar
equivalents) of 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
WO93J16097 2 1 2 9 3 ~ ~ PCT/US93/01~8
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 stirred 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.
About lO0 mL of water were added and the biphase mixture
was filtered through a pad of Celite. The organic phase
was separated and reduced to about half its volum2 by
vacuum distillation. The solution was restored to its
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
product. The suspension was cooled, and the product, N-
t-butyl-androst-3,5-diene-3-bromo-17~-carboxamide, was
isolated by filtration and dried. Yield 89%, mp 181-
- 183C.
~ yl-and~s~ ~5-di~ne-3-~yan~-17~-
A stirred mixture of N-t-butyl androst~-3,5-diene-3-
bromo-17~-carhoxamide ~50 grams, l molar equivalent~,
cuprous cyanide (11.0 grams, 1.1 molar equivalents3, and
dimethylform~mide (200 mL) was hea~ed to reflux for 3.5
hours. The reaction was cooled to 90-100C and quenched
with stirring into a solution of 100 mL of conc. aqueous
ammonia and 200 mL of water. The reaction flask was
rinsed out with 25 mL of dimethylformamide, which was
also added to the quench solution. The resulting
~5 suspension was extracted twice with 200 mL portions of
methylene chloride, and the organic extracts were
filtered through a pad of celite. The organic phase was
W093/l6097 ~,934~ PCT/US93/01~68
washed with three 200 mL portions of 50/50 v/v conc.
aqueous ammonia/water, followed by two 200 mL portions
of water. The organic phase was concentrated under
vacuum to 150 mL and 250 mL of ethanol were added. The
solution was again concentrated under vacuum to 150 mL,
and 250 mL of ethanol were added. The solution was
concentrated under vacuum to 300 mL, and 30 mL of water
were added to induce crystallization. The resulting
suspension was chilled for 2 hours at 0-5C. The solid
product was collected by filtration and was dried at
65C under vacuum to afford 37.0 grams of N-t-butyl-
androst-3,5-diene-3-cyano-17~-carboxamide as yellow
crystals in 85~ yield. mp 195-197C.
(iii)
3-car~oxyl;c ac;d.
A mixture of N-t-butyl-androst-3,5-diene-3-cyano-
17B-carboxamide (20.0 grams, 1 molar equivalent), 50%
aqueous sodium hydroxide (80 mL, 30 molar equivalents),
~0 and ethanol (200 mL) was heated to reflux for 18 hours.
The reaction suspension was cooled to 50C and was added
to a stirred mixture of 6N hydrochloxic acid.~300 mL)
and methylene chloride (200 mL). The final pH of the
aquevus phase was 1.5-2Ø The organic phase was
separated and the aqueous phase was reextracted wlth 250
mL of methylene chloride. The combined organic phases
were stirred with 2 grams of decolorizing charcoal for
one hour and were filtered through a pad of celite. The
organic phase was concentrated under vacuum to 120 mL
and ~00 mL of ethyl acetate were added. The suspension
was again concentrated under vacuum to 120 mL and 200 mL
of ethyl acetate were added. The resulting suspension
was concentrated under vacuum to a final volume of 120
mL and was heated at reflux for 2 hours. The suspension
was chilled at 0-5C for two hours and filtered. The
solid product was dried under vacuum at 65C to afford
14.8 grams, 71% yield, of N-t-butyl-androst-3,5-diene-
-- 10 --
W O 93/16097 21 2 9 ~ 4 ~-J PC~r/US93/01068
17~-carboxamide-3-carboxylic acid. Recrystalization of
the mother liquors afforded an additional 3.14 grams
(15% yield) of product. 86% total yield for reaction.
mp 250-251C.
Exam~le 2
tyl-a~drQ~t-3~-diene-3-cyano-17~-carhoYamide
A 5 L 3-neck flask (Morton) equipped with a
mechanical stirrer, thermometer, and reflux condenser
was charged with 250 grams of N-t-butyl-androst-3,5-
diene-3-bromo-17~-carboxamide (prepared as in Example 1
(i)), 55 grams of cuprous cyanide, 29 grams of sodium
cyanide, and 1 liter of dimethylformamide. The reaction
mixture was heated to reflux (152-153C) for at least 12
hours. The reaction mixture was slowly cooled to ;25-
30C with a cold water ba~h, and was quenched with oneliter of 50% aqueous ammonium hydroxide ~50/50 v~v conc.
ammonia/water) with rapid stirring. After stirring 15-
20 minutes, one liter of methylene chloride was charged,
and the two phase system was allowed to separate. The
phases were separated and the aqueous phase was
reextracted with 2 x 500 mL of methylene chloride. The
combined methylene chloride extracts were passed through
a celite filter pad to remove insoluble copper salts.
The celite pad was washed with 150 mL of methylene
chloride. The combined methylene chloride phases were
washed with 3 x 500 mL ammonium hydroxide to remove last
traces of copper salts. The organic phase was
concentrated by atmospheric distillation, removing
approximately 1.5 liters of methylene chloride. A 600
mL portion of ethanol was charged to the reactor and the
concentration/displacement of methylene chloride was
continued by distilling a second 500 mL portion of
solvent. A second 600 mL portion of ethanol was charged
to the reactor and the atmospheric distillation was
continued until the vapor temperature reached 82-84C.
A 60 mL portion of water was charged to the reactor and
the resulting suspension was chilled at 0-5C for at
WO93/16097 ~9~ PCT/US93~1068
least two hours. The solid was collected, washed with
75 mL 50% aqueous alcohol and dried at 60-65C under
vacuum to yield 191.3 grams of the title compound. 88%
yieid; mp=l90-192C.
While the preferred embodiments of the invention
are illustrated by the above, i~ is understood that the
invention is not limited to the precise instructions
herein disclosed and that the right to all modifications
coming within the scope of the following claims is
reserved.
- 12 -
