Note: Descriptions are shown in the official language in which they were submitted.
W093/14107 PCTIUS~3/~078
,, i ~ ., ; i
"PRO~ESS FOR PREPARING 3-ACYLESTRATRIENES AND ACYLBEN~ENES"
1 0 ~
The present invention relates to an improved process
for the preparation of substituted s~eroidal benzo
esters and substi~uted steroidal benzo acids. Such
compounds are described in U.S. Patent Nos. 4,954,446;
4,937,237; 4,970,205 and 4,882,3l9 as being useful for
or preparing compounds which are useful for inhibiting
steroid S-a-reductase.
Processes for the preparation of substituted
steroidal benzo esters and substitut:ed steroidal benzo
acids have previously been described. In particul2- the
use of ~rifluoxomethane sulfonic anhydride to convert
steroidal A--ring phenols to steroidal tri.luoromethyl
sulfonate intexmediates (in ~95% yield) followed by
metal-catalyzed carbonylation to the benzoic ester (in
73% yield) with subsequent hydrolysis to the
corresponding benzoic acid ~in 90% yield1 is reported ir.
U.S. Patent No. 4,954,446
Further, said steroidal trifluoromethyl sulfonate
intermediate has been reacted in metal-catalyzed
coupling reactions in the presence o~ various couplinq
reagents (followed by an optional, if applicable
hydrolysis reaction1 to form the corresponding steroidal
WO93/14107 PCT/US93/~078
h , 7 2 7 i -- 2
benzo esters and the corresponding steroidal benzo acids
in U.S. Patent Nos. 4,937,237 and 4,882,319.
In addition to a low overall yield, the principle
shortcoming of these disclosures is that
trifluoromethane sulfonic anhydride is an expensive
reagent adding significant cost to an industrial
process. Thus, there is a need in the art for a safe,
economical and reliable method to convert steroidal
phenols to steroidal benzo esters and steroidal benzo
acids.
SUMMAR~ OF THE INVENTIO~
This invention relates to an improved process ior
converting phenols to benzo es~ers and benzo acids.
This invention relates to an improved process for
converting steroidal phenols to steroidal benzo esters
and steroidal benzo acids.
This invention specifically relates to an improved
process for the preparation of 17B-(N-t-
butylcarboxamide)-estr-l,3,5(l0)-triene-3-carboxylic
acid and hydrates thereof.
In a further aspect of the invention there are
provided novel intermediates useful in the presently
invented process.
DE~aILED D~CRIPTION OF THE IN~E~TION
The present invention provides a process for the
production of a benzo acid or a benzo ester which
comprises reacting a phenol with fluorosulfonic
anhydride and a base, preferably a tertiaryamine base
such as triethylamine, pyridine or tributylamine in an
appropriate solvent to form a benzo fluorosulfonate
compound and subsequently reacting said benzo
WO93/14107 '~ ~ i7 2 7 :~ PCT/US93/00078
fluorosulfonate compound in a metal-catalyzed coupling
reaction in the presence of an appropriate coupling
reagent followed by an optional, if applicable
hydrolysis reaction.
The present invention specifically provides a
process for the production of a compound of Formula (I)
R ~ tI)
Rl is
(i) H and NR3R4, where R3 and R4 are each independently
selected form hydrogen, Cl_galkyl, C3_6cycloalkyl,
phenyl; or R3 and R4 taken together with the nitrogen to
which they are attached represent a 5-6 membered
lS saturated ring comprising up to one other heteroatom
selected from oxygen and nitrogen; or moieties which are
chemically conterible to moieties of (i) and
R2 is an acid or ester;
or a pharmaceutically acceptable salt, hydrate of
solvate thereof, which comprises reac:ting a compound of
the Formula (II)
R1
~\/
HO (II)
in which Rl and the broken lines are as described above
with fluorosulfonic anhydride and a base in a solvent to
form a compound of Formula III
W~93/14107 P~T/US~3/~07~
21 7 `! ~ 4 _
f~
F ~ O ~III)
in which Rl and the broken lines are as described above
and subsequently reacting said compound of Formula (III)
in a metal-catalyzed coupling reaction in the presence
of an appropriate coupling reagent, followed by an
optional, if applicable, hydrolysis reaction to fo:rm a
compound of Formula (I), and thereafter optionally
forming a pharmaceutically acceptable salt, hydrate or
solvate thereof.
Preferably the reaction to convert Formula II
compounds to formula III is preformed at a temperature
from -78C to 20C, particularly preferred temperature
range is from -lO to 10C.
Preferably the reaction to convert Formula III
compounds to Formula I compounds is preferred at a
temperature of 25C to 100C a particular preferred
temperature range is from 50 to gOC.
As used above and ~hroughout the remainder of the
speciication and claims the carbons of the steroid
nucleus are numbered ar.d the rings are let~ered as
follows:
l 7
1 ~ C 1 3 D
/1 ~9\ /14--15
I A ¦ 8 1
3 \ " ^~ /7
4 6
WO93/14107 2 .~? ~ PCT/US93/~078
- 5
Compounds of Formula I comprise Rl or moieties which
can be chemically conver~ed to those of Rl by known
chemical reactions such as described in J. Fried and J.
Edwardsj ~ , Pub:
Van Nostrand Reinhold Company (1972) provided that Rl
does not include any such moieties that render
inoperative the presently invented process. Reactions
to convert said moieties to ~l are performed on products
of the synthetic 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
car~oxamide by conversion to the acid halide followed by
reacting the same with an amine. Carboxylate
substituents can be converted to the acid and treated as
above. Nitriles can be converted to the carboxamide by
reaction with an alkylating agent, such as t-
butylacetate or t-butanol under acidic catalysis.
As used herein, unless otherwise specified,
Cl_nalkyl means a straight or branched hydrocarbon chain
having l to n carbons.
In utilizing the presently invented process to
prepare the preferred sterQidal benzo acids and
preferred steroidal benzoesters, of Formula (I),-novel
in~ermediates of the following Formula (IV) are
synthesized;
R1
F (IV)
in which:
Rl is
WO93J14107 PCT/US93/~078
7 ~ 6
~ .. . , ,~ , .,
(i) H and CoNR3R4, where R3 and R4 are each
independently selected from hydrogen, C1_galkyl,
C3_6cycloalkyl, phenyl; or R3 and R4 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 moieties which are chemically convertible to moieties
of ~i).
By the term "metal-catalyzed coupling reaction"
as used herein is meant that the prepared
fluorosulfonated compound is reacted in a suitable
organic solvent, preferably a dimethylsulfoxide-C1_l60H
solution (when an ester is desired) or toluene,
dimethylformamide or THF (when an acid is desired) with
a base, preferably a tertiaryamine base such as
triethylamine, pyridine or tributylamine, a phosphine
su~h as bis(diphenylphosphino)alkane, preferably l,3
bis(diphenylphosphino)propane or tri-o-tolylphosphine,
or a Cl_6alKOH, and a metal catalyst, preferably a
palladium catalyst such as palladium (II) acetate,
palladium (II) chloride and bis(triphenylphosphine)
palladium II acetate, and a coupling reagent.
By the term l'coupling reagent" as used herein is
meant a compound which is capable of reacting wit~ an
axyl radical to form an acid or an ester. Preferred
coupling reagents, which when added to the metal-
catalyzed coupling reaction, as described herein, yield
preferred acid and ester sroups, as disclosed herein,
are carbon monoxide (to yield -COOH~,
ethyltributylstannyl acetate (to yield -CH~COOH),
dimethyl phosphite (to yield -P(O)(OH)2) and
hypophosphorous acid crys~als (to yield -PH(O)OH).
By the term "phenol" as used herein is meant a
hydroxylated six membered aromatic ring, unsubstituted
W093/14107 ~ PCT/US93/~078
or substituted with non reactive substituents, said
aromatic ring may also be part of a polycyclic molecule
such as a naphthyl or steroidal moleucle, said molecule
being unsubstituted or substituted with non reactive
substituents.
By the term "acid" as used herein is meant any group
which is capable of acting as a proton donor including
but not limited to; -COOH, -P(O)(OH)2, -PH(O)OH, -S03H
and -(CH~ 3-COOH.
iO By the term "ester" as used herein is meant a g:roup
consisting of an acid, as defined above, in which the
donatable proton or protons are replaced by alkyl
substituents.
By the term "steroidal benzo" as used herein is
meant a steroid with an aromatic A ring.
8y the term "solvent" as used herein is meant an
organic solvent such as methylene chloride, ethylene
chloride, chloroform, carbon tetrachloride,
tetrahydrofuran (THF), ethyl ether, toluene,~ethyl
acetate, dimethylsulfoxide, methanol or
dimethylfoxamide.
Preferably the base utilized to prepare compounds of
Formula II is triethylamine. Preferably the solvent
utilized to prepare compounds of Formula II is methylene
chloride. Preferably the catalyst utilized in said
metal catalyzed coupling reaction is palladium (II)
acetate. Preferred acids used to describe R2 in Formula
(I) include; -COOH, -P(O)(OH)2, -PH(O)OH, -S03H, and -
(CH2)l_COOH. Particularly preferred among the above
acids is -COOH.
The present invention is usuful for the conversion
of phenols to benzo esters and benzo acids.
WO 93/14107 PCI`/US93/00078
r~ ^) j.t
,_/ . ! i .-- 8
A preferred aspect of the invention is the
conversion of steroidal phenols to steroidal ~enzo
esters and steroidal benzo acids.
Pharmaceutically acceptable salts of Formula (I)
compounds are formed, where appropriate, by methods well
known to those of skill in the art.
Preferably, therefore the process of the present
invention is particularly useful for preparing a
compound of Structure IIIA.
~ N-H
~/
FO~O
~ (IIIA)
and converting the same in one or two steps into the
following compound of structure (IA)
o t
~ N-H
HO-C (IA)
or a pharmaceutically acceptable salt, hydrate of
solvate thereof.
WO93/14107 ~ r~ ! PCI/US93/00078
_ g _
The following examples illustrate preparation of
~enzo esters and benzo acids from phenols utilizing
fluorosulfonic anhydride. The examples are not intended
to lim1t the scope of the invention as defined above or
as claimed below.
I. SYN~HF.TTC EXAMPLES
Dimethylformamide, oxalyl chloride, tert-
butylamine, triethylamine, dimethylsulfoxide, 1,3-
bis(diphenylphosphino)propane, palladium acetate, tri-n-
butylamine, formic acid, bis(triphenylphosphine)-
palladium acetate, zinc chloride, tri-o-tolylphosphine,
sodium fluoride, phenol, 1,3-dimethylphenol, estrone,
trimethylsilylcyanide, zinc iodide, phosphorus
oxychloride, 10% palladium on carbon, tert-butylacetate,
and 3-hydroxypyridine are available from Aldrich
Chemical Co. (Milwaukee, WI).
Carbcn monoxide is available from Matheson Gas
Products (E. Rutherford, NJ).
17~-Cyanoestra-1,3,5(10)-triene-3-yl
methanesulphonate was prepared as described by Barton,
et. al. J J. Chem. Soc. (CJ, 1968, 2283. Fluorosufonic
anhydride was prepared as described by S. Kongpricha,
et. al., Inorg. Syn. 1968, XI, 151. Ethyltributylstannyl
acetate was prepared as described by A. Zapata, et. al.,
Syn. Comm. 1984, 1~1, 27.
~mple 1
~5=~ L~c~LhI~ e. ~ tL~
~t 3-Hydroxyestra-1~3,~(10~-trien~ 17-~arboxylic
s~i~L_~L~L iL~s~5_
WO93/14107 PCT/US93/~078
`' 71 -lo-
A mixture of 17~-cyanoestra-1,3,5(10)-triene-3-yl
methanesulphonate_(10.0 grams, 1 molar equivalent),
sodium hydroxide (34 grams, 30.5 molar equivalents), and
ethylene glycol (200 mL) was heated to 150C for 5
hours. The hot reaction solution was cooled to 110C and
diluted with water (200 mL). The pH of the solution was
adjusted to 2.0 with concentrated hydrochloric acid, and
the resulting slurry was chilled to 0C and stirred for
l hour. The product was isolated by filtration, washed
thoroughly with water (600 mL), and dried under vacuum
at 100C to afford a mixture of 3-hydroxyestra-
1,3,5(10~-triene-17-carboxylic acid, 17~p isomers (8.5
grams, 77/23:17~ isomers) in 99% yield. mp 250-270C.
B. 3-Hydroxye$~ra-1,3 ~ -tLiene-l7~-N-t-
A vigorously stirred solution of DMF (348 mL, 4.1
molar equivalents) and methylene chloride (4800 mL) was
slowly charged with oxalyl chloride (384 mL, 4.0 molar
equivalents) while maintaining the reaction temperature
between 5-15C. A white flocculant suspension formed
while the reaction mixture was stirred for 30 minutes.
The reaction was charged with 3-hydroxyestra-1,3,5(10)-
triene-17-carboxylic acid, 17~ isomers (329 g, 1 molar
?5 equivalent, 77/23:17~ isomers) and was stirred for two
hours. The reaction solution was slowly quenched into a
vigorously stirred mixture of tert-butylamine (1200 mL,
10.4 molar equivalents) and methylene chloride (1600 mL)
while maintaining the reaction temperature between 5-15
C. The reaction mixture was stirred for 45 mi~utes~ The
reaction was charged with water (3.0 L) and stirred for
one hour. The product was suction filtered and the
filter cake was washed with water (14.0 L). The product
was dried in a vacuum oven (65C, house vacuum~ to
constant weight to afford 3-hydroxyestra-1,3,5(10)-
triene-17~-N-t-butylcarboxamide (233 grams) as a white
solid in 60% yield. mp 304-305C.
WO 93/141~)7 ~ ~ "; r~ ;7 r~ PCI`/US93/00078
C. 3-Fluorosulfonylestra~ tlO~-triene-17~-N-t-
butylcarboxamlde
A well-stirred solution of 3-hydroxyestra-
1,3,5(10)-triene-17~-N-t butylcarboxamide (231 grams, 1
molar equivalent), methylene chloride (2300 mL), and
triethylamine (132 grams, 2 molar equivalents) was
cooled to 0-10C. The resulting slurry was treated with
fluorosulfonic anhydride (154 grams, 1.3 molar
equivalents) while maintaining the reaction ~emperature
below 10C. The reaction was stirred for 30 min and
water (1.0 L) was added with vigorous stirring. The
organic phase was separated and distilled at atmospheric
pressure to a final volume of about 986 ml. Water (1283
mL) was added, and the distillation was continued until
the methylene chloride was completely removed, as
indicated by a drop in the head temperature below 35C.
Dimethylsulfoxide (4.26 L) was added to the residue and
the mixture was warmed to 100C. The stirred mixture was
cooled to room temperature over a 4 hour period, during
which the product crystallized. The reaction mixture was
stirred at 15-20C for 1.0 hour and was isolated by
filtration.The solid product was washed with water (1.0
L) and air dry thoroughly. This material was crushed and '
reslurried in 4 L of water for 30 minutes. The product-
was isolated by filtration and dried at 80C under
vacuum to afford 3-fluorosulfonylestra-1,3,5(10)-triene-
17~-N-t-butylcarboxamide (237.3 grams) in 83% yield. mp
138-141C.
~ c~boxamideL~I~=
A vessel was charged with dimethylsulfoxide (1350
mL), methanol (75 mL, 5.4 molar equivalents), 3-
fluorosulphonylestra-1,3,5(10)-triene-17~-N-t-
butylcarboxamide (lS0 g, 1 molar equivalent),
triethylamine (76.3 q, 2.2 molar equivalents), and 1,3-
WO93/14107 PCTIUS93/~07X
- 12 -
bis(diphenylphosphino)propane (1.41 g, 0.01 molar
equivalent). The mixture was stirred until a solution
was obtained. Palladium acetate (0.768 g, 0.01 molar
equivalent) was added and the flask was filled and
evacuated with carbon monoxide three times. The vessel
was pressurized with 7 psi carbon monoxide and the
reaction was stirred rapidly~ The reaction solution was
heated to 75C. The carbon monoxide uptake was finished
in about 1.5 hours. The reaction was cooled to 15C and
stirred for 2 hours.The solid product was isolated by
suction filtration, and the mother liquors were used to
rinse out the inside of the reactor. The solid product
was thoroughly washed with water (1.5 L) and dried lander
vacuum at 95C to afford pure methyl 17~-~N-tert-
butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylate
(116.4 g) in 85% yield. mp 155-157C.
~ l?~-N-t=~yl~2xks~amide-~ra-l~3~5(lQ)-triene
3-carboxyl~c_acid ~anhydrnu~ and hydr~d~.
A mixture of methanol (80 mL), water (80 mL),
methyl 17~-(N-tert-butylcarboxamide)-estra-1,3,5(10)-
triene-3-carboxylate (15.9 g, 1 molar equivalent), and
sodium hydroxide (~.80 g, 3 molar equivalents) was
heated to reflux for 8-12 hours. The hot reaction
solution was filtered through celite and the filter pad
was washed with 60C water (80 mL). The filtrate was
diluted with water (80 mL). The methanol was removed by
distillation to a head temperature of 100C. The mixture
was cooled to 60C and was quenched with vigorous
stirring into 1.5 N hydrochloric acid (160 mL). The
resulting white suspension was stirred for 15 minutes.
The slurry was cooled to 0-5C and stirred for 1 hour.
The product was isolated by filtration, washed with
deionized water, and dried under vacuum at 100C to
afford crude 17~-N-t-butylcarboxamide-estra-1,3,5(10)-
triene-3-carboxylic acid (15.1 grams) in 99% yield. mp
235-238C.
WO93/14107 ~ PCT/US93/~07X
Anhydrous 17~-N-t-butylcarboxamide~estra-1,3,5(10)-
triene-3-carboxylic acid was prepared by azeotropic
removal of water from the crude material by distilling
from acetonitrile, concentration, and cooling. The solid
was isolated by filtration and dried. Yield 71%.
Alternatively a hydrated form of 17~-N-t-
butylcarboxamide-estra-1,3,5(10)-triene-3-carboxylic
acid was prepared by recrystallization from aqueous
isopropanol. Yield 70-80%.
17~-(N-tert-Butylcarboxamide)-estra-1,3,5(10)-
triene-3-carboxylic acid is a compound which is
currently undergoing clinical investiga~ion for the
treatment of benign prostatic hypertrophy. The
isolation of anhydrous and hydrated forms of said
compound is necessary in order to establish an optimal
and reproducible bioavailability profile for said
compound.
2~ E~m~1~ 2
A vessel was charged with 5 volumes of
dimethylformamider 3-fluorosulphonylestra-1,3,5(10)-
triene-17~-N-t-butylcarboxamide (1 molar equivalent,
prepared as described in Example lC), tri-n-butylamine
(4.5 molar eq~ivalentsj, formic acid (2 molar
equivalents) and bis(triphenylphosphine)palladium
acetate (0.02 molar equivalents). The flask was
evacuated and filled with carbon monoxide three times.
The vessel was pressurized with 7 psi carbon monoxide
and the reaction was stirred rapidly. The reaction
solution was heated to 75C until the uptake of carbon
monoxide was complete. The reaction was cooled to xoom
temperature. Ethyl acetate and water were added, and the
organic layer was separated. The organic phase was
WO93/14107 PCT/US93/~078
,_ .. ` I .~; i -- 14 --
washed with water and dried over magnesium sulfate. The
organic phase was concentrated under vacuum to yield a
crude 17~(N-tert-butylcarboxamide)-estra-1,3,5~10)-
triene-3-carboxylic acid. Anhydrous and hydrated 17~(N-
tert-butylcarboxamide)-estra-1,3,5(10)-triene-3-
carboxylic acid were prepared as described in ~xample
lE. Yield 70-80%.
Example 3
F~hyl-17-heta-tN-tert-butylcarboxamide~-e~tra-1.3~5(10)-
,triene-3-acetic acid
Zinc Chloride (1.91 g, 1.4 molar equivalents) was
weighed into a 200 mL flask fitted with a stir bar and
serum cap. The mixture was heated to 150C under vacuum
~1.0 mm) ~or 1 hour. The flask was cooled to 25C and
the vacuum was broken with argon. 3-
Fluorosulphonylestra-1,3,5(10)-triene-17~-N-t-
butylcarboxamide (4.38 g, 1 molar equivalent, prepared
as described in Example lC), ethyltributylstannyl
acetate (5.28 g, 1.4 molar equivalents), and
dimethylformamide ( 20.0 mL) were added to the flask~
The ~lask was evacuated and flushed with argon three
times. Tri-o-tolylphosphine (0.091 ~, 0.03 molar
equivalent) and palladium acetate (0.045 g, 0.02 molar
equivalent) were added and the reaction vessel was
evacuated and flushed with argon three times. The
mixture was heated for 1.0 hour at 80C. Toluene (100
mL) and water (100 mL) were added and the mixture was
stirred for 5 minutes. The mixture was filtered ~hrough
celite and poured 1nto a separatory funnel. The aqueous
layer was separated and discarded. The organic phase was
washed again with water (lO0 mL). The organic phase was
washed with saturated sodium fluoride (2 x 50 mL) and
filtered through celite after each wash. The organic
phase was washed with water (2 x 50 mL), dried over
~ ? a ~ ~ rI ~. ;, s ! ~l
WO93/14107 ;~ ` PCT/US93/~078
- 15 -
sodium sulfate, filtered and concentrated under vacuum.
The product was isolated as a thick oil.
ExampL~ 4
~ethyl Benzoate
~
A solution of phenol (1 molar equivalent) and
triethylamine (2.5 molar equivalents) in methylene
chloride was cooled to -5~C and treated with
fluorosulfonic anhydride (1.3 molar equivalents) while
maintaining the temperature between -5 and 0C. After
stirring for one hour the reaction was quenched with
water (100 mL). The organic phase was separated, washed
with water ~100 mL~, and dried over magnesium sulfate.
The solution was concentrated under vacuum to afford
phenylfluorosulphonate as a crude eolorless oil.
B Methy~ benzoate
Phenyl fluorosulfonate (1.0 g, 1 molar equivalent)
was dissolved in dimethylsulfoxide (10 mL) under a
gentle stream of carbon monoxide with stirri~g at 23C.
Methanol (5.0 mL, 2.2 molar equivalents) and
triethylamine (1.15 g, 2 molar equivalents) were added
2S all at once. Palladium acetate (0.064 ~, 0.05 molar
equ iva l ent ) and 1, 3-bis(diphenylphosphino)propane (0.116
g, 0.05 molar equivalent) were mixed and added all at
once to the rapidly stirred mix~ure. The reaetion
temperature was raised to 70C over a fifteen minute
3G period. The color of the reaction solution went from
light yellow to red/black. After 1.0 hour the reaction
was cooled to 23C. The reaction mixture was poured
into water (SC mL) and the mixture was extracted with
methylene chloride (S0 mL). The methylene chloride
layer was extracted with water (5Q mL) three times and
was dried over magnesium sulfate and filtered. The
solvent was removed under vacuum. The crude product was
WO93/14107 PCT/US93/~078
2 ~ ~ r! 2 5~ /~ 16
purified by bulb to bulb distillation to yield methyl
benzoate (0.62 gram) as a colorless oil.
Exa~l~ 5
Benzoi~_a~ld
A vessel was chaxged with 5 volumes of
dimethylformamide, phenylfluorosulphonate (1 molar
equivalent, prepared as described in Example 4~), tri-n-
butylamine (4.5 molar equivalents), formic acid ~ molarequivalents) and bis(triphenylphosphine)-palladium
acetate (0.02 molar equivalents). The flask was
evacuated and filled with carbon monoxide three times.
The vessel was pressurized with 7 psi carbon monoxicle
and the reaction was stirred rapidly. The reaction
solution was heated to 75C until the uptake of carbon
monoxide was complete. The reaction was cooled to room
temperature. Ethyl acetate and water were added, and the
organic layer was separated. The organic phase was
washed with water and dried over magnesium sulfate. The
organic phase was concentrated under vacuum to yield a
crude benzoic acid which was purified by silica
chromatography (hexane/ethyl acetate).
Ea~m~ h
~ethyl ~,5-~imethyl~en7Qate
A solution of 1,3~dimethylphenol (1 molar
equivalent) and triethylamine (2.5 molar equivalen~s) in
methylene chloride was cooled to -SC and treated with
fluorosulfonic anhydride (1.3 molar equivalents) while
maintaining the temperature between -~ and 3C. After
stirring for one hour the reaction was quenched with
water (100 mL). The organic phase was separated, washed
with water (100 mL), and dried over magnesium sulfate.
The solution was concentrated under vacuum to afford
WO93/14107 ~ PCT/US93/~07X
- 17 -
1,3-dime~hylphenyl fluorosulfonate as a crude colorless
oil.
B. Methyl~3_9=2i~9~ ~lL~
1,3-Dimethylphenylfluorosulfonate (1.16 g, molar
equivalent) was combined with dimethylsulfoxide (10
mL), triethylamine (1.15 g, 2 molar equivalents), and
methanol (5.0 mL, 2.2 molar equivalents). The mixture
was evàcuated and flushed with carbon monoxide three
times. The mixture was kept under a slight positive
pressure of carbon monoxide. Palladium acetate (0.()64
g, O.OS molar equivalent) and 1,3-
bis~diphenylphosphino)propane (0.116 g, 0.05 molar
equivalent) were added all at once. The mixture was
evacuated and flushed with carbon monoxide. The mixt:ure
was heated to 65C for two hours under a slight positive
carbon monoxide pressure. The mixture was poured into
water (50 mL) and was extracted with methylene chloride
(3 x S0 mL). The methylene chloride layers were
combined and extracted with water (2 x 100 mL). The
methylene chloride layer was dried over magnesium
sulfate and filtered. The solvent was removed under
vacuum to afford methyl-3,5-dimethylbenzoate, 0.7S0 g,
as a colorless oil.
~am~
car~oxylic acid. (a~hydrQ~ and ~y~ra~d)
~ ~ o~ iene~ll~Qn~
A solution of estrone (10.0 grams~ l molar
equivalent) and triethylamine (9.3 grams, 2.S molar
equivalents) in methylene chloride (200 mL) was cooled
to -5C and treated with fluorosulfonic anhydride (4.9
grams, 1.3 molar equivalents) while maintaining the
temperature between -5 and 0C. After stirring for one
hour the reaction was quenched with water (100 mL). The
WOg3/14107 PCT/US93/00078
~ 18 -
organic phase was separated, washed with water (100 mI.),
and dried over magnesium sulfate. The solution was
concentrated under vacuum to afford a crude solid which
was recrystalli~ed fxom methanol using decolorizing
carbon, to afford 3-fluorosulfonylestra-1,3,5(10)-
triene-17-one (9.6 grams) in 74% yield. mp 99-102C.
B. 17n-Cy~nn~11~-trimethyLsilylQ~yestra-1,3~10~-
trien~-yL fluQrQsulfon~t~
A mixture of 3 fluorosulfonyl-estra-1,3,5(10~-
triene-17-one t2.0 grams, 1 molar equivalent),
trimethylsilylcyanide (1.4 grams, 2.5 molar
equivalents), zinc iodide (0.1 gram, 0.05 molar
equivalent), and methylene chloride ~20 mL) was warmed
to 45C and stirred for 45 minutes. The reaction was
quenched with water (25 mL). The organic phase was
separated, washed with water ~25 mL), and dried over
magnesium sulfate. The organic phase was concentrated
under vacuum to afford a crude solid which was
recrystalli~ed from methanol to afford 17a-cyano-17~-
trimethylsilyloxyestra-1,3,5(10)-triene-3-yl
fluorosulfonate (1.9 grams) in 76% yield. mp~104-108C.
~ ss~ e
A mixture of 17~-cvano-17~-trimethylsilyloxyestra-
1,3,5(10~-triene-3-yl fluorosulfonate (2.0 qrams, 1
molar equivalent), phosphorus oxychloride (2.2 grams,
2.5 molar equivalents), and pyridine (8 mL) was heated
to reflux for 17 hours. The reaction was cooled to room
temperature and was quenched into a mixture of
concentrated hydrochloric acid (25 mL) and crushed ice
(20 mL). The aqueous phase was separated and extracted
ethyl acetate ~50 mL). The organic phases were combined,
washed with water (2 x 25 mL), and dried over magnesium
sulfate. The orqanic phase was concentrated under vacuum
to afford a crude oil which was triturGted and
WO93/14107 ~ 72 1 ~ PCT/US93/~0~8
-- 19 --
recrystallized from ethanol to afford 17-cyano-
1,3,5(10),16-tetraene-3-yl fluorosulfonate (1.0 grams)
in 50% yield. mp 110-112C.
D. 17~-Cyano-1,3.5(1Q)-~Iiene-3-yl fluor~sulfoD~e
A mixture of 17-cyano-1,3,5(10),16-tetraene-3-yl
fluorosulfonate (0.5 gram, 1 molar equivalent), 10%
palladium on carbon (35 mg), glacial acetic acid (2 mL),
and ethyl acetate (25 mL) was stirred at room
temperature over one atmosphere of hydrogen for 6 hours.
The catalyst was removed by filtration, and the filtrate
was concentrated under vacuum to afford an oil which was
triturated with ethanol and recrystallized from the same
solvent to afford 17~-cyano-1,3,5(10)-triene-3-yl
fluorosulfonate (0.45 gram) in 90% yield. mp 126-129C.
A well-stirred solution of 17~-cyano-1,3,5(10)-
triene-3-yl fluorosulfonate(5 grams, 1 molar
equivalent), and tert-butylacetate (40 mL~ was warmed to
60C~ Concentrated sulfuric acid (1.0 mL, 1.3 molar
equivalents) was added, and the solution was stirred at
40-55C for 6.5 hours. The solution was cooled to room
~emperature, and was quenched into water (30 mL). More
water (40 mL) w~s added, and the mixture was extracted
with methylene chloride (?00 mL). The mixture was
adjusted to pH 7 with 3N aqueous sodium hydroxide. The
organic phase was separated and concentrated under
vacuum to give a crude solid. This solid was
recryst~llized from DMSO (90 mL)/water (4S mL) and dried
to afford 3-fluorosulfonylestr~ 3r5(lo)-triene-l7~-N
t-butylcarboxamide (5.23 grams) in 85% yield. mp 148-
150C.
3-Fluorosulfonylestra-1,3,5(10)-triene-17~-N-t-
butylcarboxamide was treated as described in Examples lD
WO93/14107 PCT/US93/~078
7 `) l
~ 20
and lE to prepare 17~-tN-tert-butylcarboxamide)-estra-
l,3,5(10)-triene-3-carboxylic acid, anhydrous and
hydrated.
~mel~
Methyl nicotinate
Pyridine-3-fluorQ~ulf-)nate
A solution of 3-hydroxypyridine (1 molar
equivalent) and triethylamine (2.5 molar equivalents) in
methylene chloride was cooled to -5C and treated with
fluorosulfonic anhydride (1.3 molar equivalents) while
maintaining the temperature between -5 and 0C. After
stirring for one hour the reaction was quenched with
water (100 mL). The organic phase was separated, washed
with water (100 mL), and dried over magnesium sulfate.
The solution was concentrated under vacuum to afford
pyridine-3-fluorosulfonate as a crude colorless oil.
B. Methyl nicotinate
Pyridine-3-fluorosulfonate (1 molar equivalent) was
dissolved in dimethylsulfoxide ( 10 mL) under a gentle
s~ream of carbon monoxide with stirring at 23C.
Methanol (5.0 mL) and triethylamine (2 molar
equivalents) were added all at once~ Palladium acetate
(0.~5 molar equivalents) and 1,3-
bis(diphenylphosphirlo)propane (0.05 molar equivalents)
were mixed and ad~ed all at once to the rapidly stirred
mixture. The reaction temperature was raised to 70C
over a fifteen minute period. After 1.0 hour the
reaction was cooled to 23C. The reaction mixture was
poured into water (50 mL) and the mixture was extracted
with methylene chloride (50 mL). The methylene chloride
layer was extracted with water (50 mL) three times and
was dried over magnesium sulfate and filtered. The
solvent was removed under vacuum. The crude product was
WO 93/14107 ~ ' rlJ ,;~ PCI'/US93/0007X
;-
- 21 -
purified by silica gel chromatography to yield methyl
nicotinate as a crystals.
