Note: Descriptions are shown in the official language in which they were submitted.
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Vinyl Sulfoxides And A Process For Their Synthesis
The present invention is directed to novel vinyl
sulfoxides and to a new process for the synthesis of same, in
particular diarylvinyl sulfoxides. These compounds are
useful for the synthesis of benzo[b]thiophenes.
Benzo[b]thiophenes have been prepared by a number of
different synthetic routes. One of the most widely us~ed
methods is the oxidative cyclization oE o-mercaptocinni~mic
acids. This route is limited to the preparation of benzo[b]-
thiophene-2-carboxylates. 2-Phenylbenzo[b]thiophenes i~re
prepared by acid-catalyzed cyclization of 2-phenylthio~cetal-
dehyde dialkyl acetals. Unsubstituted benzo[b]thiophenes are
prepared by catalytic condensation of styrene and sulfur. 3-
Substituted benzo[b]thiophenes are prepared by acid-calalyzed
cyclization of arylthiomethyl ketones; however, this route is
limited to the preparation o~ 3-alkylbenzo[b]thiophenes. See
C~n~aigne, "Thiophenes and their Benzo Derivatives: (iii)
Synthesis and Applications," in Comprehensive Heterocy~:lic~
rh~n;stry (Katritzky and Rees, eds.), Volume IV, Part }:II,
863-934 (1984). 3-Chloro-2-phenylbenzo[b]thiophene is
prepared by the reaction of cliphenylacetylene with sulfur
dichloride. Barton and Zika, ~. Org. Chem., 35, 1729-1733
(19-70). Benzo[b]thiophenes have also been prepared by
pyrolysis of styryl sulfoxides. However, low yields and
extremely high temperatures make this route unsuitable for
production-scale syntheses. See Ando, J. Chem. Soc., C'hem.
Comm., 704-705 (1975).
The preparation of 6-hydroxy-2-(4-hydroxyphenyl)benzo-
30 [b]thiophenes was described in U.S. Patent Nos. 4,133,~14 and
4,380,635. One process described in these patents is the
acid-catalyzed intramolecular cyclization/rearrangement of
a -(3-methoxyphenylthio)-4-methoxyacetophenone. The reaction
of t:his starting compound in neat polyphosphoric acid at
35 about 85~C to about 90~C gives an approximate 3:1 mixture of
two regioisomeric products: 6-methoxy-2-(4-methoxyphenyl)-
benzo[b]thiophene and 4-methoxy-2-(4-methoxyphenyl)benzo[b]-
~ = ~
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thiophene. These isomeric benzo[b]thiophenes co-precipitate
from the reaction mixture, producing a mixture containing
both compounds. To obtain a single regioisomer, the
regioisomers must be separated, such as by chromatography or
fractional crystallization. Therefore, there currently
exists a need for an efficient and regiospecific synthesis of
2-arylbenzo[b]thiophenes from readily available starting
materials. The compounds of the present invention are useful
for the efficient and regiospecific synthesis of 2-arylbenzo-
[b]thiophenes from readily available starting materials.
The present invention is directed to novel vinylsulfoxides and to a new process for their synthesis, in
particular diarylvinyl sulfoxides. Specifically, the present
invention is directed to a compound of the formula
~ S~ R3
Rl ~ ~ R2
wherein:
Rl is hydrogen, Cl-Cg alkoxy, arylalkoxy, halo, or amino;
R2 is hydrogen, Cl-Cg alkoxy, arylalkoxy, halo, or amino;
and
R3 is a thermally-labile or acid-labile C2-Clo alkyl,
Cg-Clo alkenyl, or aryl(Cl-Clo alkyl) group. Thus, the
present invention includes individually the B and Z isomers,
or mixtures thereof, of the formula II compounds. These
and Z regioisomers are represented by the ~ollowing
structures:
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~ ~ R2
Another aspect of the present invention is a process :Eor
preparing a compound oi the ~ormula
ll
~ S~R3
Rl--~ ~ R2
wherein:
Rl is hydrogen, Cl-C4 alkoxy, arylalkoxy, halo, or amino;
R2 is hydrogen, Cl-C4 alkoxy, arylalkoxy, halo, or amino;
and
R3 is a thermally-labile or acid-labile C2-Clo alkyl, C4-
Clo alkenyl, or aryl(Cl-C1o alkyl) group having a tertia:ry
carbon atom adjacent to the sulfur atom;
comprising the steps of:
(1) oxidizing a benzyl sulfide of the formula:
/ R3
~ S
wherein R2 and R3 are as defined above;
with an oxidizing agent ~o produce a benzyl sulfoxide oi the
formula:
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--4--
R3
ll 11
R2--
wherein R2 and R3 are as defined above;
(2) reacting said benzyl sulfoxide with a strong base to
form a benzylic anion;
(3) condensing said benzylic anion with a benzaldehyde
of the formula
o
~ 1I H
Rl~
wherein Rl is as defined above;
(4) reacting the condensation product from step 3 with
an acid chloride to produce an ester of the formula
OR4 ~ R2
Rl ~ o~ ~R
wherein:
Rl, R2, and R3 are as defined abovei and
R~ is CO(Cl-C6 alkyl), CO(aryl), CO(arylalkyl), SO2(Cl-C6
alkyl), SO2(aryl), SO2(arylalkyl), CO2(Cl-C6 alkyl),
CO2(aryl), CO2(arylalkyl), or CON(Cl-C6 alkyl)2; and
(5) treating said ester with a second strong base.
The ~ and Z regioisomers the ~ormula II compounds are
represented by the following structures:
-
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--5--
Rl O ~ R~
IIE IIZ
Another aspect of the present invention is a process ~or
the regioselective synthesis of the Z isomer of the ~ormula
II compounds. In particular, the present invention relates to
a process for preparing a compound o~ the formula
R~
_ I
\
o~5J~
R3 R2
IIZ
wherein:
R1 is hydrogen, Cl-Cg alkoxy, arylalkoxy, halo, or amino;
R2 is hydrogen, C1-C4 alkoxy, arylalkoxy, halo, or amino;
and
R3 is a thermally-labile or acid-labile C2-Clo alkyl, C4-
C1o alkenyl, or aryl(Cl-C1o alkyl) group having a terti,ry
car:bon atom adjacent to the sulfur atom;
comprising the steps o~:
(1) reacting a benzyl sulfide of the formula:
~--s~R3
R2 ~/
wherein R2 and R3 are as defined above;
with a strong base to form a benzylic anion;
,
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(2) condensing said benzylic anion with a benzaldehyde
of the formula
~f H
Rl
wherein R1 is as defined above;
(3) reacting the condensation product from step 2 with
an acid chloride to produce an ester of the formula
~R2
OR4
' ~/
Rl S~R3
wherein:
R1, R2, and R3 are as defined above; and
R4 is CO(C1-C6 alkyl), CO(aryl), CO(arylalkyl), SO2(C1-C6
alkyl), SO2(aryl), SO2(arylalkyl), CO2(Cl-C6 alkyl),
CO2(aryl), CO2(arylalkyl), or CON(C1-C6 alkyl)2;
(4) treating said ester with a second strong base to
produce a styryl sulfide of the formula
~R2
~<
ll ¦ S-R3
R1 ~ IIIZ
wherein R1, R2, and R3 are as defined above; and
(5) oxidizing said styryl sulfide with an oxidizing
agent.
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WO 96/410691 PCT/U~,G~51~3
Yet another aspect of the present invention is a process for
the synthesis of a compound of the formula
~ ~N/ ~HX
XII
wherein:
R8 is hydrogen, halo, amino, or hydroxyl;
Rg is hydrogen, halo, amino, or hydroxyl;
Rs and R6 are independently C1-C4 alkyl, or R5 and R6
together with the adjacent nitrogen atom form a heterocyc].ic
ring selected from the group consisting of pyrrolidino,
piperidino, hexamethyleneimino, and morpholino; and
HX is HCl or HBr;
comprising the steps of:
(a) cyclizing in the presence of an acid catalyst a compound
of lhe formula
~ S~R3
wherein:
Rl is hydrogen, Cl-C4 alkoxy, arylalkoxy, halo, or amino;
R2 is hydrogen, Cl-C4 alkoxy, arylalkoxy, halo, or amino;
and - . .
R3 is a thermally-labile or acid-labile C2-C10 alk
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C4-Clo alkenyl, or aryl(C1-Clo alkyl) group to prepare a
benzothiophene compound of the formula
R~ S~3~
I R2
wherein R1 and R2 are as defined above;
(b) acylating said ben~othiophene compound with an acylating
agent of the formula
R ~ O'~'~'N~ R5
wherein:
Rs, R6, and HX are as defined previously; and
R7 is chloro, bromo, or hydroxyl; in the presence of
BX'3, wherein X~ is chloro or bromo;
(c) when Rl and/or R2 is C1-C4 alkoxy or arylalkoxy,
dealkylating one or more phenolic groups of the acylation
product of step (b) by reacting with additional BX'3, wherein
X' is as defined above; and
(d) isolating the formula XII compound.
The term "C1-C6 alkyl" represents a straight or branched
alkyl chain having from one to six carbon atoms. Typical Cl-
C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl,
n-hexyl, 2-methylpentyl, and the like. The term "C1-C~ alkyl"
represents a straight or branched alkyl chain having from one
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to four carbon atoms, and includes metltlyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, i-butyl~ and t-butyl.
The term l'Cl-C4 alkoxy~ represents groups such as
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy,
and like groups. The term "halo" refers to fluoro, ch.loro,
bro:mo, or iodo groups.
The term "aryl" represents groups such as phenyl and
substituted phenyl. The term "substituted phenyl" rep:resents
a phenyl group substituted with one or more moieties c].losen
fro:m the group consisting of halo, hydroxy, nitro, Cl-('4
alkyl, Cl-C4 alkoxy, trichloromethyl, and trifluoromet~Lyl.
Examples of a substituted phenyl group include 4-chloro-
phe:nyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichloro-
phe:nyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, :3,4--
dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, 4~
hyd.roxyphenyl, 3-hydroxyphell~l, 2,4-dihydroxyphenyl, 3--nitro-
phe:nyl, 4-nitrophenyl, 2,4-dinitrophenyl, 4-methylphen~l, 4-
eth~ylphenyl, 4-methoxyphenyl, 4-propylphenyl, 4-n-buty:L-
phe:nyl, 4-t-butylphenyl, 3-~luoro-2-methylphenyl, 2,3-
difluorophenyl, 2,6-difluorophenyl, 2,6-dimethylphenyl,. 2
fluoro-5-methylphenyl, 2,4,6-trifluorophenyl, 2-trifluoro--
met~ylphenyl, 2-chloro-5-trifluoromethylphenyl, 3,5-bi~;-
(tr:ifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxypherryl,
3,5-dimethoxyphenyl, 4-hydroxy-3-methylphenyl, 3,5-dimethyl,
4-hydroxyphenyl, 2-methyl-4-nitrophenyl, 4-methoxy-2-nitro-
phe~yl, and the like.
The term ''arylalkylll represents a Cl-C4 alkyl group
bea:ring one or more aryl groups. Representatives of this
group include benzyl, o-nitrobenzyl, p-nitrobenzyl, p-
halobenzyl (such as p-chlorobenzyl, p-bromobenzyl, p-
iodobenzyl), l-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-
phe]lylbutyl, 2-methyl-2-phenylpropyl, (2,6-
dichlorophenyl)methyl, bis(2,6-dichlorophenyl)methyl, (4-
hyd:roxyphenyl)methyl, (2,4-dinitrophenyl)methyl,
diphenylmethyl, triphenylmethyl, (p-methoxyphenyl)-
diphenylmethyl, bis(p-methoxyphenyl)methyl, bis(2-
nitrophenyl)methyl, and the like.
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--10--
The term "arylalkoxy" represents a C1-C4 alkoxy group
bearing one or more aryl groups. Representatives o~ this
group include benzyloxy, o-nitrobenzyloxy, p-nitrobenzyloxy,
p-halobenzyloxy (such as p-chlorobenzyloxy, p-bromobenzyloxy,
p-iodobenzyloxy), 1-phenylethoxy, 2-phenylethoxy, 3-
phenylpropoxy, 4-phenylbutoxy, 2-methyl-2-phenylpropoxy,
(2,6-dichlorophenyl)methoxy, bis(2,6-dichlorophenyl)methoxy,
(4-hydroxyphenyl)methoxy, (2,4-dinitrophenyl)methoxy,
diphenylmethoxy, triphenylmethoxy, (p-methoxyphenyl)-
diphenylmethoxy, bis(p-methoxyphenyl)methoxy, bis(2-
nitrophenyl)methoxy, and the like.
The term "thermally-labile or acid-labile C2-C10 alkyl,
C4-C1o alkenyl, or aryl(C1-C1o alkyl) group~ represents a
group that is readily removed from the sulfoxide (SO) group
under heating or by treatment with the acid catalyst. The
thermally-labile or acid-labile C2-C1o alkyl groups are
straight or branched alkyl ch~; n~ having from two to ten
carbon atoms and having at least one beta-hydrogen atom.
Representative thermally-labile or acid-labile C2-C1o alkyl
groups include ethyl, n-propyl, i-propyl, 1,1-dimethyl-
propyl, n-butyl, sec-butyl, t-butyl, 1,1-dimethylbutyl, 2-
methylbutyl, 3-methylbutyl, 1-methylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,4-dimethylbutyl, 3,3-dimethylbutyl, n-
pentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-
methylpentyl, n-hexyl, and the like. The thermally-labile or
acid-labile C4-C10 alkenyl groups are straight or branched
alkenyl chains having from ~our to ten carbon atoms, at least
one site of unsaturation, and either a beta-hydrogen or
delta-hydrogen atom. Representative thermally-labile or
acid-labile C4-C10 alkenyl groups include 2-butenyl, 3-
butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 2-methyl-3-
butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-2-
pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 2-methyl-
3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 2-
methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl,
2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and the like.
The term thermally-labile or acid-labile aryl(C1-C1O alkyl)
-
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represents thermally-labile or acid-labile C2-Clo alkyl groups
additionally containing one or more aryl groups and aryl-
substituted methyl groups. Representative aryl(Cl-Clo alkyl)
groups include benzyl, diphenylmethyl, triphenylmethyl, p--
methoxybenzyl, 2-phenylethyl, 2-phenyl-propyl, 3-phenyL-
propyl, and the like. The term "thermally-labile or acid--
lab:ile C2-C10 alkyl, C4-Clo alkenyl, or aryl(Cl-Clo alkyl)
group having a tertiary carbon atom adjacent to the su].fur
atom" includes, but is not limited to, such groups as t-
butyl, l,l-dimethylpropyl, l,l-dimethylbutyl, l-ethyl-l-
methylpropyl, l,l-dimethylpentyl, l-ethyl-l-methylbuty]., 1,1-
dielhylpropyl, l,l-dimethylhexyl, triphenylmethyl, and the
like.
The term "acid chloride" includes acyl chlorides, suc:h
as acetyl chloride and benzoyl chloride; sulfonyl chlorides,
such as methanesulfonyl chloride, benzenesulfonyl chloride,
l-butanesulfonyl chloride, ethanesulfonyl chloride,
isopropylsulfonyl chloride, and p-toluenesulfonyl chloride;
alkoxycarbonyl chlorides, such as methoxycarbonyl chloride
and benzyloxycarbonyl chloride; and dialkylaminocarbonyl
chlorides, such as N,N-dimethylaminocarbonyl chloride.
Prei.erably the acid chloride is a sulfonyl chloride. More
preierably, the acid chloride is methanesulfonyl chloride.
The compounds of the present invention can be prepared
by a number of routes. One method for preparing the formula
II compounds is shown in Scheme 1.
Sch~e 1
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-12-
Rl ~ ~ HSR3 ~ ~
IX R2 Rl III R2
S-R3
Rl ~R2
Generally, a formula IX compound is converted to a
styryl sulfide by reaction with a mercaptan of the formula
HSR3 in the presence of a Lewis acid. The formula III
compound is then oxidized to a styryl sulfoxide, a compound
of formula II compound.
More specifically, a formula IX compound, wherein Rl and
R2 are as defined above, is treated with a Lewis acid, such
as titanium(IV) chloride. This reaction is carried out in an
anhydrous organic solvent, such as dry tetrahydrofuran, at a
temperature of about 0~C to about 35~C. After about fifteen
minutes to about one hour, the reaction mixture is treated
with an amine base and a mercaptan of the formula HSR3, where
R3 is as defined above. Preferably, the mercaptan and amine
base are added as a solution in the reaction solvent. A
representative amine base is triethylamine. After the
addition of the mercaptan and amine base, the reaction is
generally heated to a temperature of about 35~C to about
65~C, preferably at about 50~C. The products of this
reaction can be purified using techniques well known in the
chemical arts, such as by crystallization or chromatography.
The formula III compound, where Rl, R2, and R3 are as
defined above, is then oxidized to produce the formula II
compounds. Suitable oxidizing agents for this reaction are
peracids, such as peracetic acid and m-chloroperoxybenzoic
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acid, and hydrogen peroxide. This oxidation reaction is
typically run in an organic solvent, such as toluene,
methylene chloride, chloroform, or carbon tetrachloride.
When a peracid is used as the oxidant, the reaction is
generally carried out at a temperature of about -30~C t:o
about 15~C, preferably at about -20~C. The products of the
reaction are easily purified by recrystallization. When R3
is t-butyl, the crystalline product of this reaction sequence
is the ~ regioisomer of formula II.
10When R3 has a tertiary carbon adjacent to the suliur
atom, the Z regioisomer of the formula II compounds can be
prepared selectively by a route as shown in Scheme 2.
Sch~me 2
o
R2 ~ R35H ~ ~ R3
IIZ
Generally, a benzyl alcohol, a formula V compound, is
reacted with a mercaptan of the formula R3SH to produce a
benzyl sulfide, a fonmula VI compound. This benzyl su:Lfide
is reacted with a strong base, forming a benzylic anion,
which is condensed with a benzaldehyde. This condensat:ion
pro~1uct is reacted with an acid chloride and the result:ing
intermediate ester treated with a second strong base to
produce a styryl sulfide, a formula IIIZ compound. This
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. -14-
styryl sulfide is then oxidized with an oxidizing agent to
produce the formula IIZ compound.
The first step in the synthesis of the Z styryl
sulfoxide compounds is the conversion o~ a benzyl alcohol to
a benzyl sulfide, formula VI compound. The reac~ion of the
formula V compound, where R2 is as defined above, with a
mercaptan of the formula ~3SH, wherein R3 is a therm~lly-
labile or acid-labile C2-C10 alkyl, Cg-Clo alkenyl, or
aryl(Cl-Clo alkyl) group having a tertiary carbon atom
adjacent to the sulfur atom, in the presence of a Lewis acid
produces the benzyl sul~ide, a ~ormula VI compound. Suitable
Lewis acids for this transformation are zinc bromide, zinc
chloride, zinc iodide, ferric chloride, titanium(IV)
chloride, aluminum trichloride, and aluminum tribromide,
preferably zinc iodide. The reaction is generally carried
out in an organic solvent, such as l,2-dichloroethane or
methylene chloride. When the reaction is carried out at room
temperature, the reaction is complete after about 18 hours.
The benzyl sulfide is reacted with a strong base to form
a benzylic anion. Suitable strong bases for this reaction
include metal alkoxides, such as sodium methoxide, sodium
ethoxide, lithium ethoxide, lithium t-butoxide, and potassium
t-butoxide; sodium hydride; and alkyllithiums, such as n-
butyllithium, t-butyllithium, sec-butyllithium, and
methyllithium. The preferred strong base for this reaction
is n-butyllithium. The preferred solvent for this reaction
is dry tetrahydrofuran. When n-butyllithium is used as the
strong base, the reaction is carried out at a temperature of
about -35~C to about -15~C.
The benzylic anion is condensed with a benzaldehyde to
prepare an intermediate condensation product. The
benzaldehyde has the general formula Rl(C6H4)CHO, wherein R
is hydrogen, Cl-C4 alkoxy, arylalkoxy, halo, or amino.
Preferably, the benzylic anion is prepared and the
condensation product is formed in situ by adding the
benzaldehyde to the cold solution of the benzylic anion.
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The condensation product is treated with an acid
chloride to produce an intermediate ester. Representat:iv~
acid chlorides include acyl chlorides, such as acetyl
chloride and benzoyl chloride; sulfonyl chlorides, such as
met]~Lanesulfonyl chloride, benzenesulfonyl chloride, 1-
butanesulfonyl chloride, ethanesulfonyl chloride,
isopropylsulfonyl chloride, and p-toluenesulfonyl chloride;
alkoxycarbonyl chlorides, such as methoxycarbonyl chloride
and benzyloxycarbonyl chloride; and dialkylarrLinocarbon~1
chlorides, such as N,N-dimethylaminocarbonyl chloride;
pre~erably a sulfonyl chloride. Preferably, methanesulfo~Lyl
chloride is added to the reaction mixture shortly after
forrnation of the condensation product.
This intermediate ester is reacted with a second strong
base to produce a styryl sul~ide, a formula IIIZ compound
where Rl, R2, and R3 are as defined above. Suitable strong
bases for this reaction include metal alkoxides, such as
sodium methoxide, sodium ethoxide, lithium ethoxide, lithium
t-butoxide, and potassium t-butoxide; sodium hydride;
alk~llithiums, such as n-butyllithium, t-butyllithium, sec-
butyllithium, and methyllithium; and metal amides, such as
sodium amide, magnesium diisopropylamide, and lithium
diisopropylamide. The preferred strong base for this
reaction is potassium t-butoxide. Generally, this reaction
is carried out at about 15~C to about room temperature,
preferably at room temperature.
The styryl sulfide is oxidized to prepare the
corresponding styryl sulfoxide. Suitable oxidizing agents
for this reaction are peracids, such as peracetic acid and m-
chloroperoxybenzoic acid; organic peroxides, such as t-butyl
peroxide; and hydrogen peroxide. Preferably the oxidizing
agent is peracetic acid. This oxidation is typically carried
out in an organic solvent, such as toluene, benzene, xylene,
methanol, ethanol, methylacetate, ethylacetate, methylene
chloride, 1,2-dichloroethane, or chloroform; preferably
methylene chloride. This oxidation can be carried out at a
temperature of about -40~C to about 0~C.
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Alternatively, when R3 has a tertiary carbon adjacent to
the sulfur atom, the benzyl sulfide intermediate (formula VI
compound) can be used to produce a mixture of E and Z isomers
of the styryl sulfoxides, the formula II compounds. This
synthesis is outlined in Scheme 3.
SchQme 3
~AH
R2 ~ S~ R3 R2 ~ ~ R3 R
VI ~ X
~S-R3
II ~ R2
The benzyl sulfide, prepared as described above, is
oxidized to produce the corresponding benzyl sulfoxide. This
benzyl sulfoxide is reacted with a strong base, and the
resulting anion condensed with a benzaldehyde. The
condensation product is reacted with an acid chloride and the
resulting intermediate ester reacted with a second strong
base to produce the styryl sulfoxide.
The benzyl sulfide, the formula VI compound, wherein R2
is as defined above and R3 is a thermally-labile or acid-
labile C2-C1o alkyl, C4-C1o alkenyl, or aryl(C1-C10 alkyl)
group having a tertiary carbon atom adjacent to the sulfur
atom, is oxidized to produce the corresponding benzyl
sulfoxide, formula X compound. Suitable oxidizing agents for
this reaction are peracids, such as peracetic acid and m-
chloroperoxybenzoic acid; organic peroxides, such as t-butyl
peroxide; and hydrogen peroxide. Preferably the oxidizing
agent is peracetic acid. This oxidation is typically carried
_
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-17-
out. in an organic solvent, such as toluene, benzene, xylene,
~ met.hanol, ethanol, methylacetate, ethylacetate, methylene
chl.oride, 1,2-dichloroethane, or chloroform; preferably at a
te~lperature of about -30~C to about 5~C.
The benzyl sul~oxide, ~ormula X compound wherein R2 and
R3 are as defined above, is reacted wi~h a strong base to
produce a benzylic anion. Suitable strong bases for this
rea.ction include metal alkoxides, such as sodium methoxide,
sod.ium ethoxide, lithium ethoxide, lithium t-butoxide, and
potassium t-butoxide; sodium hydride; alkyllithiums, such as.
n-butyllithium, t-butyllithium, sec-butyllithium, and
methyllithium; and metal amides, such as sodium amide,
magnesium diisopropylamide, and lithium diisopropylamide.
The preferred base for this transformation is n-butyllithium.
This deprotonation reaction is carried out in a dry organic
solvent, such as tetrahydrofuran or 1,2-dimethoxyethane, at a
tem.perature of about -25~C.
The benzylic anion is condensed, without isolatio:n, with
a benzaldehyde compound of the formula p-R1(C6H4)CHO, ~Iherein
R1 is as defined above. Preferably, about one e~uivalent of
the benzaldehyde is added to the cold solution prepared as
described in the preceding paragraph. The resulting
diastereomeric mixture of condensation products may be
isolated, or preferably used in the next step without
isolation.
The condensation product is optionally treated with a
base, such as n-butyllithium, and reacted with an acid
chloride. Representative acid chlorides include acyl
chlorides, such as acetyl chloride and benzoyl chloride;
sulfonyl chlorides, such as methanesulfonyl chloride,
benzenesulfonyl chloride, 1-butanesulfonyl chloride,
ethanesulfonyl chloride, isopropylsulfonyl chloride, and p-
toluenesulfonyl chloride; alkoxycarbonyl chlorides, such as
methoxycarbonyl chloride and benzyloxycarbonyl chloride; and
dialkylaminocarbonyl chlorides, such as N, N-
dimethylaminocarbonyl chloride; preferably a sulfonyl
chloride. The acid chloride is added to the cold reacl_ion
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mixture, then the resulting mixture is allowed to warm to
room temperature. Preferably, methanesulfonyl chloride is
added to the reaction mixture shortly after formation of the
condensation product, which eliminates the need to add
additional base.
The resulting intermediate ester is reacted with a
second strong base to produce the E and Z styryl sulfoxides,
formula II compounds where Rl, R2, and R3 are as defined
above. Representative second strong bases for this
elimination reaction include metal alkoxides, such as sodium
methoxide, sodium ethoxide, lithium ethoxide, lithium t-
butoxide, and potassium t-butoxide; sodium hydride;
alkyllithiums, such as n-butyllithium, t-butyllithium, sec-
butyllithium, and methyllithium; and metal amides, such as
sodium amide, magnesium diisopropylamide, and lithium
diisopropylamide. The preferred base for this transformation
is potassium t-butoxide. Preferably, a 20~ excess, such as
1.2 equivalents, of the second base are added. Generally,
this reaction is carried out at a temperature of about 15~C
to about room temperature, preferably at room temperature.
The intermediate styryl sulfoxides are useful for the
synthesis of 2-arylbenzo[b]thiophenes as shown in Scheme 4.
.Srh~ . 4
R~ Rz ~ R2
Generally, the intermediate styryl sulfoxide compounds
are heated and treated with acid catalysts to produce the
formula I compounds. Suitable acid catalysts for this
reaction include Lewis acids or Br0nsted acids.
Representative Lewis acids include zinc chloride, zinc
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-19 -
iodide, aluminum chloride, and alumin~lm bromide.
Representative sr~ns~ed acids include inorganic acids, such
as sulfuric and phosphoric acidsi carboxylic acids, s~lch as
acetic and trifluoroacetic acids; sulfonic acids, such as
met:hanesulfonic, benzenesulfonic, 1-naphthalenesulfonic, 1-
but:anesulfonic, ethanesulfonic, 4-ethylbenzenesulfonic:, 1-
he~anesulfonic, 1,5-naphthalenedisulfonic, 1-octanesulfonic,
ca~nphorsulfonic, trifluoromethanesulfonic, and p-toluene-
su]fonic acids; and polymeric arylsulfonic acids, such as
Nafion~, Amberlyst~, or Amberlite~. The more preferred acid
cat:alysts are sulfonic acids, such as methanesulfonic acid,
benezene-sulfonic acid, camphorsulfonic, and p-
to]uenesulfonic acid. The most preferred acid catalyst is p-
to].uenesulfonic acid. Typically, a solution of the acid
cat:alyst in organic solvent, such as toluene, benzene,
xy]ene, or a high-boiling halogenated hydrocarbon solv-ents,
such as 1,1,2-trichloro-ethane, is heated to about 80~ to
about 140~C, and treated with a solution of the styryl
su].foxide in the same solvent. An excess amount of the acid
cat:alyst is used, preferably two ecruivalents o~ the acid.
For best results, the final concentration of the starting
compound is about 0.01 M to about 0.2 M, preferably 0.05 M.
Furthermore, best yields are obtained when the styryl
sulfoxide is slowly added to the heated acid solution over a
period of about 20 minutes to about three hours. For best
results, residual water is removed from the reaction solution
by the use of a Dean-Stark trap or Soxhlet extractor, and the
reaction is purged with purified nitrogen.
The formula I compounds are useful as intermediates in
the synthesis of a series of 3-aroyl-2-arylbenzo[b]-
thiophenes. U.S. Patent Nos. 4,133,814 and 4,418,068, which
are incorporated herein by reference, described these 3-
aroyl-2-arylbenzo[b]thiophenes, as well as methods for their
preparation from the formula I compounds. An improved
synthesis of a group of these 3-aroyl-2-arylbenzo[b]-
thiophenes from the formula I compounds, wherein R1 and R2 are
hyclrogen, C1-C4 alkoxy, or arylalkoxy, is outlined in
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Scheme 5.
Scheme 5
~l ~ ~ R~ ~6 ~ ~ ~R5
R9 ~ ~ ~ -HCl\
XII R8
The benzothiophene Formula I compound, wherein R1 and R2
are hydrogen, C1-C4 alkoxy, or arylalkoxy, is acylated with
the formula XI compound, wherein R7 is chloro or hydroxy, in
the presence of boron trichloride or boron tribromide; boron
trichloride is preferred. The reaction can be carried out in
a variety of organic solvents, such as chloroform, methylene
chloride, 1,2-dichloroethane, 1,2,3-dichloropropane, 1,1,2,2-
tetra-chloroethane, 1,2-dichlorobenzene, chlorobenzene, and
fluorobenzene. The preferred solvent for this synthesis is
1,2-dichloroethane. The reaction is carried out at a
temperature of about -10~C to about 25~C, preferably at 0~C.
The reaction is best carried out at a concentration of the
benzothiophene formula I compound of about 0.2 M to about
1.0 M. The acylation reaction is generally complete after
about two hours to about eight hours.
When Rl and/or R2 is a C1-C~ alkoxy or arylalkoxy group,
the acylated benzothiophene, is converted to a formula XI
compound wherein R8 and/or Rg are hydroxy, without isola~ion
of the product from the acylation reaction. This conversion
-
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is performed by adding additional boron trihalide or boron
tribromide and heating the reaction mixture. PreferabLy, two
to :Eive molar equivalents of boron trihalide are added to the
reaction mixture, most preferably three molar equivalents.
This reaction is carried out at a temperature of about 25~C
to about 40~C, preferably at 35~C. The reaction is gen~erally
complete after about 4 to 48 hours.
The acylation reaction or acylation/dealkylation
reaction is quenched with an alcohol or a mixture of
alcohols. Suitable alcohols for use in quenching the
reaction include methanol, ethanol, and isopropanol.
Prei-erably, the acylation/dealkylation reaction mixture is
added to a 95:5 mixture of ethanol and methanol (3A ethanol).
The 3A ethanol can be at room temperature or heated to
re~]ux, preferably at reflux. When the quench is performed
in t:his manner, the Formula XII compound conveniently
crystallizes from the resulting alcoholic mixture.
Generally, 1.25 mL to 3.75 mL of alcohol per millimole of the
benzothiophene starting material are used.
The following examples further illustrate the present
invention. The examples are not intended to be limiting to
the scope of the invention in any respect, and should not be
so construed. All experiments were run under positive
pressure of dry nitrogen. All solvents and reagents were
usecl as obtained. The percentages are generally calculated
on a. weight (w/w) basisi except for high performance liquid
chromatography (HPLC) solvents which are calculated on a
volume (v/v) basis. Proton nuclear magnetic resonance
(lH MMR) spectra and 13C nuclear magnetic resonance spectra
(13C NMR) were obtained on a Bruker AC-300 FTNMR spectrome~:er
at 300.135 MHz or a GE QE-300 spectrometer at 300.15 MHz.
Silica-gel flash chromatography was performed as described by
Still et al. using Silica Gel 60 (230-400 mesh, E. Merck).
Still et al., J. Org. Chem., 43, 2923 (1978). Elemental
analyses for carbon, hydrogen, and nitrogen were determined
on a Control Equipmen~ Corporation 440 Elemental Analyzer.
Elemental analyses for sulfur were determined on a Brinkman
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Colorimetric Elemental Analyzer. MeLting points were
determined in open glass capillaries on a Mel-Temp II melting
point apparatus or a Mettler FP62 Automatic instrument, and
are uncorrected. Field desorption mass spectra ~FDMS) were
obtained using a Varian Instruments VG 70-SE or VG ZAB-3F
mass spectrometer. High resolution free atom bombardment
mass spectra (FABMS) were obtained using a Varian Instruments
VG ZAB-2SE mass spectrometer.
The in situ yields of 6-methoxy-2-(4-
methoxyphenyl)benzo[b]thiophene were determined by high
performance liquid chromatography (HPLC~ in comparison to an
authentic sample of this compound prepared by published
synthetic routes. See U. S. Patent No. 4,133,814. ~enerally,
samples of the reaction mixture was diluted with acetonitrile
and the diluted sample assayed by HPLC using a Zorbax RX-C8
column (4.6 mm x 25 cm) with W detection (280 nm). The
following linear-gradient solvent system was used for this
analysis:
Gradient Solvent System
Time (min) A (%) B (%)
0 50 50
2 50 50
37 50 50
A: 0.01 M agueous sodium phosphate (pH 2.0)
B. acetonitrile
The amount (percentages) of 6-hydroxy-2-(4-
hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-
benzo[b]thiophene hydrochloride in the crystalline material
(potency) was determined by the following method. A sampleof the crystalline solid (5 mg) was weighed into a 100-mL
volumetric ~lask, and dissolved in a 70/30 (v/v) mixture of
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75 mM potassium phosphate buffer (pH 2.0) and acetonit:rile.
An ali~uot of this solution (10 ~ L) was assayed by hiqh
per~ormance liquid chromatography, using a Zorbax Rx-C8
~ column (25 cm x 4.6 mm ID, 5 ~particle) and W detection
(280 nm). The following gradient solvent system was u<,ed:
Gr~;~t Solve~t System (Potency)
Time (min) A (%) B (%)
0 70 30
12 70 30
14 25 75
16 70 30
A: 75 mM KH2P04 buffer (pH 2.0)
B: acetonitrile
The percentage of 6-hydroxy-2-t4-hydroxyphenyl)-3--[4--(2-
piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride in
the sample was calculated using the peak area, slope (m), and
intercept (b) of the calibration curve with the following
equation:
% potency = peak area - b sample volume (mL)
m sample weight (mg)
The amount (percentage) of solvent, such as 1,2-
dichloroethane, present in the crystalline material was
determined by gas chromatography. A sample of the
crystalline solid (50 mg) was weighed into a 10-mL volumetrlc
flask, and dissolved in a solution of 2-butanol (0.025 mg/mL)
in climeth~-lsulfoxide. A sample of this solution was ana:Lyzed
on a gas chromatograph using a DB Wax column (30 m x 0.5:3 mrn
ID, 1 ~ particle), with a column flow of 10 mL/min and flame
ionization detection. The column temperature was heated from
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35~C to 230~C over a 12 minute period. The amount of solvent
was determined by comparison to the internal standard (2-
butanol).
Exam~le 1
~-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide
A. Preparation of E-t-Butyl 4,4'-Dimethoxystilbenyl
Sulfide
A solution of desoxyanisoin (12.82 g) in tetrahydrofuran
(100 mL) was treated with titanium (IV) chloride (10.43 g).
During the dropwise addition of titanium (IV) chloride, the
reaction mixture was cooled to maintain the temperature below
35~C. Upon complete addition, the resulting mixture was
stirred at 30~C. After an additional 30 minutes, this
mixture was treated with a solution of 2-methyl-2-propane-
thiol (6.76 mL) and triethylamine (16.70 mL) in tetrahydro-
furan (15 mL). The resulting mixture was stirred at 50~C.
After two hours, the mixture was added to ten percent sodium
carbonate (500 mL). The resulting mixture was extracted with
methylene chloride. The combined methylene chloride extracts
were dried over magnesium sulfate, filtered, and concentrated
in vacuo to give 17.2 g of an oil, which crystallized upon
cooling to room temperature. This crystalline material was
recrystallized from hot ethanol to give 12.3 g of the title
compound. Melting point 71-73~C.
Analysis calculated for C2oH24O2S: C, 73.13; H, 7.36; S,
9.76. Found: C, 73.37; H, 7.51; S, 9.87.
B. Preparation of E-t-Butyl 4,4'-Dimethoxystilbenyl
Sulfoxide
The crystalline compound prepared as described in
Example lA was dissolved in toluene (150 mL), and the
resulting solution cooled to about -20~C. The cold solution
was treated with peracetic acid (32% w/w in dilute acetic
acid, 1.24 g) over ten minutes. The resulting mixture was
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extracted with saturated sodium sulfite and brine. The
- organic phase was concentrated in vacuo. The residue was
recrystallized from ethyl acetate/heptane to give 14 1:L g of
the title compound. Melting point 104~C (dec).
Analysis calculated ~or C20H24O3S: C, 69.74; H, 7.02; S,
9.31. Found: C, 69.47; H, 7.04; S, 9.54.
~xample 2
Z-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide
A. Preparation of t-Butyl 4-Methoxybenzyl Sulfide
A mixture o~ 4-methoxybenzyl alcohol (10.13 g) and zinc
iod:ide (11.7 g) in 1,2-dichloroethane ~120 mL) was treated
Wit]l 2-methyl-2-propanethiol (9.92 mL) in one portion. The
resulting mixture was stirrecl at room temperature. Aft:er
about 18 hours, the reaction was diluted with water (1()0 mL)
and methylene chloride (100 mL). The organic phase was
removed, dried over magneSiUnl sulfate, ~iltered, and
concentrated in vacuo to give 14.4 g of an oil.
lH NMR (CDC13): ~7.28 (d, 2H), 6.~5 (d, 2H), 3.77
(s, 3H), 3.73 (s, 2H), 1.36 (s, 9H).
13C NMR (CDC13): ~ 130, 114, 56, 35, 32.
Analysis calculated for C12H1gOS: C, 68.52; H, 8.6:3.
Found: C, 68.8; H, 8.67.
B. Preparation of Z-t-Butyl 4,4'Dimethoxystilbenyl Sulfide
A solution of the compound prepared as described in
Example 2A (2.51 g) in tetrahydrofuran (50 mL) was cooled to
about -20~C. This cold solution was treated with a solution
of Il-butyllithium in hexane (1.6 M, 7.47 mL) over ten
minutes. The resulting solution was allowed to warm to about
0~C over 35 minutes. This cold solution was treated wi~h p-
anisaldehyde (1.46 mL). After an additional 15 minutes, the
reaction solution was treated with methanesulfonyl chloride
(O.S~5 mL). The resulting reaction was allowed to warm to
room temperature. After an additional 45 minutes, the
-
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reaction mixture was treated with a solution of potassium ~-
butoxide in tetrahydrofuran (1.0 M, 12.0 mL). After an
additional 45 minutes, the reaction was quenched by the
addition of lN hydrochloric acid (12.0 mL). The organic
phase was separated, dried over magnesium sulfate, filtered,
and concentrated to an oil (4.4 g).
lH NMR (CDCl3): ~7.95 (d, H), 7.05 (s, H), 6.9 (d, H),
6.8 (dd, 2H), 3.75 (s, 3H), 0.95 (s, 9H).
13C NMR (CDCl3): ~ 153, 139, 137, 114, 56, 32.
C. Preparation of Z-t-Butyl 4,4'-Dimethoxystilbenyl
Sulfoxide
The compound from Example 2B was converted to the title
compound using the procedure substantially as described in
Example lB.
1H NMR (CDCl3): ~7.61 (d, H), 7.56 (d, H), 7.1 (s, H),
6.9 (dd, 2H), 3.83 (s, 3H), 1.05 (s, 9H).
13C NMR (CDC13): ~ 142, 132.5, 131, 118, 117, 56, 24.
Analysis calculated for C20H24O3S: C, 69.74; H, 7.02.
Found: C, 69.98; H, 6.94.
Example 3
E and Z-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide
A. Preparation of t-Butyl 4-Methoxybenzyl Sulfide
A mixture of 4-methoxybenzyl alcohol (10.13 g) and zinc
iodide (11.7 g) in 1,2-dichloroethane (120 mL) was treated
with 2-methyl-2-propanethiol (9.92 mL) in one portion. The
resulting mixture was stirred at room temperature. After
about 18 hours, the reaction was diluted with water (100 mL)
and methylene chloride (100 mL). The organic phase was
removed, dried over magnesium sulfate, filtered, and
concentrated in vacuo to give 14.4 g of an oil.
1H MMR (CDC13): ~ 7.28 (d, 2H), 6.85 (d, 2H), 3.77
(s, 3H), 3.73 (s, 2H), 1.36 (s, 9H).
13C MMR (CDCl3): ~130, 114, 56, 35, 32.
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Analysis calculated for C12HlgOS: C, 68.52; H, 8.63.
Found: C, 68.8; H, 8.67.
B. Preparation of t-Butyl 4-Methoxybenzyl Sulfoxide
A solution of the compound prepared as described in
Exa]nple 3A (14.4 g) in 1,2-dichloroethane (50 mL) was coo]ed
to about 5~C and the cold solution treated with peracetic
acid (32% w/w in dilute acetic acid, 14.2 mL) over 30
mimltes. Upon complete addition of the peracetic acid, the
reaction was treated with brine and soclium bicarbonate. The
organic phase was removed, dried over magnesium sul~ate,
~iltered, and concentrated to a yellow precipitate. This
res:idue was treated with hexane (100 mL) and the resulting
mixture stirred at room temperature. After about 18 hourc,
the mixture was filtered and the solids washed with hexane
(10() mL). The solid material was dried in vacuo to gi~e
14 .()7 g of the title compound. Melting point 124-126~C.
lH NMR (CDCl3): ~ 7.26 (d, 2H), 6.89 (d, 2H), 3.79
20 (d, H), 3.78 (s, 3H), 3.58 (d, H), 1.3 (S, 9H) .
13c NMR (CDC13): ~ 132, 114, 56, 53, 23.
Analysis calculated for C12H18O2S: C, 63 . 68; H, 8 . 02 .
Found: C, 63.72; H, 7.93.
C. Preparation of E and Z-t-Butyl 4, 4 ' -Dimethoxystilbenyl
Sulfoxide
A solution of the compound prepared as described in
Example 3B (10.0 g) in tetrahydrofuran (140 mL) was cooled to
30 abou!t -30~ to -25~C (dry ice/acetone bath). This cold
solution was treated with n-butyllithium in cyclohexane
(1.6 M, 27.65 mL) over 25 minutes. After stirring ~or 35
minutes, the reaction mixture was treated with p-anisaldehyde
(5 .4 mL) . The dry ice/acetone bath was removed and the
35 reaction allowed to warm to about 20~C. This mixture was
treated with methanesulfonyl chloride (3 . 5 mL). The
temperature o~ the reaction rose ~rom about 20~ to about 35~C
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upon addition of the methanesulfonyl chloride. The mixture
was cooled to about 25~C, then treated with potassium t-
butoxide in tetrahydrofuran (1 M, 50.9 mL). After stirring
for an additional 35 minutes, the reaction was treated with
lN hydrochloric acid (51.0 mL). The phases were separated;
and the organic layer dried over magnesium sulfate, filtered,
and concentrated to an oil ( 16.67 g). This material was used
in the next step without further purification. The carbon
and proton NMR spectra were similar to that obtained for the
compound prepared as described in Examples 1 and 2.
Example 4
Z-t-Butyl 4,4'-Dimethoxystilbenyl Sulfoxide
A solution of the compound prepared as described in
Example 3B (3.0 g) in tetrahydrofuran (40 mL) was cooled to
about -15~C. This cold solution was treated with n-
butyllithium in cyclohexane (1. 6 M, 8.3 mL) over 15 minutes.
After stirring for ten minutes, the reaction mixture was
warmed to O~C, and treated with p-anisaldehyde (1. 61 mL).
The ice bath was removed and the reaction allowed to warm to
about room temperature. This mixture was treated with acetyl
chloride (0. 95 mL). After about one hour, the reaction
mixture was treated with potassium t-butoxide in
tetrahydrofuran (1 M, 16.0 mL). After stirring for an
additional 1.5 hours, the reaction was treated with lN
hydrochloric acid (17.0 mL). The phases were separated, and
the organic layer dried over magnesium sulfate, filtered, and
concentrated to an oil (5.26 g). This material was used
without further purification. The carbon and proton NMR
spectra were similar to that obtained for the compound
prepared as described in Example 2.
Exam~le 5
3 5 6 -Methoxy-2-(4-methoxyphenyl)benzo~b]thiophene
A solution of p-toluenesulfonic acid monohydrate
-
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(2.:25 g) in toluene (60 mL) was heated to reflux, and water
4 was removed by allowing it to collect in a Dean-Stark t:rap.
Using a nitrogen gas purge vented through the top of the
condenser, a solution of the compound prepared as described
in ]3xample 1 (2.04 g) in toluene (33 mL) was added to t:he
ref:Luxing acid solution over 1.5 hours. The resulting
mixture was cooled to about 5~C under the nitrogen purge,
then treated with water (8 mL). The resulting slurry was
stirred for three hours. The slurry was filtered, and the
crystalline product washed with water (8 mL) and aceton.e
(8 n~). The crystalline product was dried in vacuo at 40~C
for about 18 hours to give 1.30 g of the title compound as a
light tan solid. This compound was identical to the ccmpound
prepared by a published route. Melting Point 196-199~C.
~y:~m~?l e 6
6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene
A solution of p-toluenesulfonic acid monohydrate
(2.49 g) in toluene (108 mL) was heated to reflux, and water
was removed by allowing it to collect in a Dean-Stark trap.
A solution of the compound prepared as described in Example 1
(9.00 g) in toluene (32 mL) was added to the refluxing acid
solution over six hours. Upon complete addition, absolute
ethanol (35 mL) was added to the reaction solution, and the
resulting mixture was allowed to cool to room temperature.
After about 18 hours, a precipitate was isolated by
filtration. This precipitate was washed with toluene/
absolute ethanol (4:1, 29 mL), and dried in vacuo at 40''C for
about 18 hours to give 4.86 g of a solid. This compound was
identical to the compound prepared by a published route.
Melting point 199-200~C.
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Exam~le 7
6-Hydroxy-2-(4-hydroxyphenyl) -3- [4-(2-piperidinoethoxy)-
benzoyl]benzo[b]thiophene Hydrochloride
1,2-Dichloroethane Solvate
5A. Preparation of Ethyl 4-(2-Piperidinoethoxy)benzoate
A mixture of ethyl 4-hydroxybenzoate (8.31 g), 1-(2-
chloroethyl)piperidine monohydrochloride (10.13 g), potassium
carbonate (16.59 g), and methyl ethyl ketone (60 mL) was
heated to 80~C. After one hour, the mixture was cooled to
about 55~C and treated with additional 1-(2-chloroethyl)-
piperidine monohydrochloride (0.92 g). The resulting mixture
was heated to 80~C. The reaction was monitored by thin layer
chromatography (TLC), using silica-gel plates and ethyl
acetate/acetonitrile/triethylamine (10:6:1, v/v). Additional
portions of l-(2-chloroethyl)piperidine hydrochloride are
added until the starting 4-hydroxybenzoate ester is consumed.
Upon complete reaction, the reaction mixture was treated with
water (60 mL) and allowed to cool to room temperature. The
aqueous layer was discarded and the organic layer
concentrated in vacuo at 40~C and 40 mm Hg. The resulting
oil was used in the next step without further purification.
B. Preparation o~ 4-(2-Piperidinoethoxy)benzoic
25Acid Hydrochloride
A solution of the compound prepared as described in
Example 7A (about 13.87 g) in methanol (30 mL) was treated
with 5 N sodium hydroxide (15 mL), and heated to 40~C. After
4 1/2 hours, water (40 mL) was added. The resulting mixture
was cooled to 5-10~C, and concentrated hydrochloric acid (18
mL) was added slowly. The title compound crystallized during
acidification. This crystalline product was collected by
~iltration, and dried in vacuo at 40-50~C to give 83~ yield
of the title compound. Melting point 270-271~C.
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C. Preparation of 4-(2-Piperidinoethoxy)benzoyl
- Chloride Hydrochloride
A solution of the compound prepared as described in
Example 7B (30.01 g) and dimethylformamide (2 mL) in
met]-Lylene chloride (500 mL) was treated with oxalyl ch~loride
(10.5 mL) over a 30-35 minute period. After stirring i-or
about 18 hours, the reaction was assayed for completion by
HPLC analysis. Additional o~:alyl chloride may be addecl to
the reaction i~ the starting carboxylic acid is present .
UPOI1 completion, the reaction solution was evaporated t:o
dryness in vacuo. The residue was dissolved in methylene
chloride (200 mL), and the resulting solution evaporated to
dryness. This dissolution/evaporation procedure was repeated
to ~ive the title compound as a solid. The title compound
may be stored as a solid or as a 0 2 M solution in methylene
chloride (500 mL).
D. Preparation of 6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-
piperidinoethoxy)benzoyl]benzotb]thiophene Hydrochloride
1,2-Dichloroethane Solvate
A mixture of the compound prepared as described in
ExaIllple 5 or 6 (2.92 g), the compound prepared as described
in Example 7C (3.45 g), and 1,2-dichloroethane (52 mL) was
coo]ed to about 0~C. Boron trichloride gas was condensed
into a cold graduated cylinder (2.8 mL), and added to the
colcl mixture described above. After eight hours at 0~C, the
reac:tion mixture was treated with additional boron
tric:hloride (2.8 mL). The resulting solution was heated to
35~C. After 16 hours, the reaction was complete.
Methanol (30 mL) was treated with the reaction mixture
from above over a 20-minute period, causing the methanol to
reflux. The resulting slurry was stirred at 25~C. After one
hour, the crystalline product was filtered, washed with cold
methanol (8 mL), and dried at 40~C in vacuo to give 5.1~ g of
the title compound. Melting point 225~C.
Potency: 86.8g~
1,2-Dichloroethane: 6.5% (gas chromatography)
