Note: Descriptions are shown in the official language in which they were submitted.
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Description:
ARYLOXY ESTER AND ACID COMPOUNDS
FIELD OF INVENTION
The present invention relates to aryloxy ester and acid compounds and to a
method
for their production.
REPORTED DEVELOPMENTS
Current methods for preparing aryloxy ester and acid compounds include a
multistep
synthesis in which an aryl or heteroaryl compound is deprotonated, halogenated
and
oxidized to form an aryl hydroxide or a heteroaryl hydroxide. The aryl
hydroxide or
heteroaryl hydroxide is then o-alkylated with an alkyl bromoester to form an
aryloxy
ester, which can be halogenated and hydrolyzed as desired.
Unfortunately, each of the several steps used in the aforementioned synthesis
result
in low yields. Additionally, many of the prior art reactions require the use
of
expensive reagents. Accordingly, there is a need for a more efficienfi and
less-costly
method of preparing aryloxy ester and acid compounds.
SUMMARY OF THE INVENTION
The present invention provides a family of aryloxy compounds, which exhibit
beneficial anticoagulant properties, and which can be utilized as
intermediates in the
synthesis of Factor Xa inhibitors to increase their potency and oral activity.
Additionally, a method for synthesizing compounds of the present invention is
provided.
According to the present invention, aryloxy compounds are provided having the
following structure of Formula 1:
Ar-O-(CH2)"-COOK {1)
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wherein Ar is an unsubstituted or substituted aryl group or an unsubstituted
or
substituted heteroaryl group; R is a hydrogen or an unsubstituted or
substituted
aliphatic group; and n=1 to about 6.
Another aspect of the present invention is the provision of a process for
preparing a
compound of Formula 1. In a preferred embodiment, the process comprises: (a)
reacting a trifluoroalkoxy aryl or trifluoroalkoxy heteroaryl compound to form
an
orthoester compound; and (b) converting the orthoester to a compound of
Formula 1.
DETAILED DESCRIPTION OF THE INVENTION
In Formula 1, Ar can be an unsubstituted or substituted aryl group or an
unsubstituted or substituted heteroaryl group. Preferably, Ar is an
unsubstituted or
substituted C3 to about C2o aryl group or an unsubstituted or substituted 3 to
about
member heteroaryl group. More preferably, Ar is an unsubstituted or
substituted
C6 to about C~5 aryl group or an unsubstituted or substituted 3 to about 6
member
heteroaryl group.
Examples of aryl groups are: phenyl, o-tolyl, m-tolyl, p-tolyl, o-xylyl, m-
xylyl, p-xylyl,
alpha-naphthyl or beta-naphthyl. In a particularly preferred class of
compounds, Ar
is C6 to about C~2 aryl group, especially phenyl.
Examples of heteroaryl groups are: pyrrole, furan, thiophene, pyridine or
derivatives
thereof. In a particularly preferred class of compounds, Ar is a 3 to about 6
member
heteroaryl group, especially thiophene.
Ar radicals may be substituted with essentially any conventional organic
moiety.
Examples of substitution groups include C1 to about C6 aliphatics such as
alkyls,
halogenated alkyls, alkoxys, and alkenyls, C6 to about C~~ aryls, halogens,
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particularly chlorine, C3 to about C$ cyclic aiiphatics, nitros, aminos
(primary and
secondary), amidos, cyanos and hydroxyls.
!n Formula 1, R can be hydrogen or an unsubstituted or substituted aliphatic
group,
which may be cyclic or acyclic. Examples of R groups are: methyl, ethyl, n-
propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-
heptyl, n-octyl,
2-ethylhexyl, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopentyl,
cyclohexyl,
methylcyclohexyl, dimethylcyclohexyl, cycloheptyl or cyclooctyl. Preferably, R
is an
unsubstituted or substituted C~ to about a C2o acyclic aliphatic group or an
unsubstituted or substituted C3 to about Czo cyclic aliphatic group. In a more
preferred embodiment, R is an unsubstituted or substituted C~ to about C~z
alkyl
group, or an unsubstituted or substituted C3 to about Coo cycloalkyl group. In
a
particularly preferred class of compounds R is a C2 to about C~ alkyB group,
such as
those mentioned above. Any of these alkyl or cycloalkyl groups may be
substituted
with essentially any conventional organic moiety, for example, methoxy,
ethoxy, n-
propoxy, isopropoxy, n-butoxy, methanesulphonyl, cyano, bromine, chlorine or
fluorine.
In the compounds of Formula 1, n is in the range of 1 to about 6, preferably 1
to
about 3, and more preferably n is 1.
'the compounds of Formula 1 may exist in isomeric form. All racemic and
isomeric
forms of the compounds of Formula 1, including pure enantiomeric, racemic and
geometric isomers and mixtures thereof, are within the scope of the invention.
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General Preparation of an ester or acid of Formula 1
According to the method of the present invention, ester and acid compounds of
Formula 1 may be produced in two steps from a starting material comprising a
1,1,1-
trifluoroalkoxy aryl or a 1,1,1-trifluoroalkoxy heteroaryl described in more
detail
below. In the first step, the trifluoromethyl moiety (-CF3) of the starting
material is
converted to an orthoester moiety, that is, a carbon having three o-aliphatic
substituents, to form an orthoester intermediate compound. In the second step,
the
orthoester intermediate is converted to a compound of Formula 1.
Generally, the first step is performed by introducing aliphatic oxy reagents
in
sufficient amount to fully displace the fluoride substituents of the starting
material. In
this manner, orthoester intermediates having the same or different ("mixed") o-
aliphatic substituents can be formed by using sources of aliphatic oxy ions,
such as,
for example, metal aliphatic oxides or deprotonated aliphatic alcohols,
deriving from
one or more aliphatics.
In the second step of the method of the present invention, the intermediate
orthoester compound formed in the first step is converted to a compound of
Formula
I, preferably using conventional acid hydrolysis techniques.
Starting Material of the Present Invention
As mentioned above, the preparation of the aforementioned ester or acid
compounds of Formula 1 involves the use of a trifluon starting material
comprising a
1,1,1-trifluoroalkoxy aryl or 1,1,1-trifluoroalkoxy heteroaryl having the
following
general Formula 2
Ar-O-(CH2)"-CF3 (2)
wherein n is the same as described above for Formula 1, that is 1 to about 6.
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Such starting materials are known in the literature and are capable of being
prepared by art-recognized procedures. See, for example, Keegstra, et al.,
Tetrahedron, Vo1.14, No.17, 3633-3652 (1992); or Suzuki, et al., Synthesis,
No. 5,
499-500 (May 1985). The disclosures of these publications are incorporated
herein
by reference.
Preparation of the Orthoester intermediates
The orthoester intermediates may be prepared by the use of any aliphatic oxy
compound which can replace selectively the fluorine substituents of the
trifluon
starting material with a desired aliphatic oxide group. Suitable aliphatic oxy
compounds include metal aliphatic oxides such as, for example, sodium
ethoxide,
sodium n-butoxide, sodium tent-butoxide, potassium ethoxide, potassium n-
butoxide,
potassium tart-butoxide. Of these, sodium ethoxide, sodium n-butoxide and
sodium
tent-butoxide are preferred.
To form the orthoester intermediate, at least three moles of aliphatic oxide
need to
be provided for each mole of trifluon starting material. An excess of
aliphatic oxide
may be provided to ensure a more complete reaction.
In a preferred embodiment, the first step is performed by mixing the selected
Formula 2 trifluon starting material and metal aliphatic oxide with an
anhydrous
alcohol solvent and heating the reaction mixture to form the orthoester
intermediate.
Typically, the reaction occurs at temperatures between about 100 °C
and about
200 °C, preferably between about 130 °C and 175 °C.
Reaction times may range
from~a few minutes to several days.
Those of ordinary skill in the art will recognize that both the alcohol and
metal
aliphatic oxide used in the aforementioned reaction are possible sources of
aliphatic
oxide ions which can displace the fluoride substituents of the trifluon
starting material
to form orthoesters. When dissolved in solution, the aliphatic oxide ions
formed
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from the metal aliphatic oxide may directly displace fluoride substituents of
the
starting material or may deprotonate the alcohol to form more, possibly
different,
aliphatic oxide ions. Therefore, both the metal aliphatic oxide and the
alcohol used
in the present invention should be chosen such that the aliphatic oxide ions
formed
therefrom represent desired aliphatic oxy groups of the orthoester.
Accordingly, to form an orthoester having three of the same aliphatic oxy
substituents via the process of the present invention, it is preferred to use
a metal
aliphatic oxide and alcohol derived from the same aliphatic oxide ion. In this
manner, the aliphatic oxide ions formed from either the metal aliphatic oxide
or the
alcohol correspond to the desired aliphatic oxy substituents of the orthoester
product. For example, to form a triethoxy orthoester, a trifluoroalkoxy
starting
material compound is reacted with a metal ethoxide and ethanol. Thus,
displacement of the fluoride groups by alkoxide ions deriving from either the
metal
ethoxide or ethanol lead to formation of the desired product and formation of
mixed
orthoesters is minimized.
Mixed orthoesters, if desired, are formed according to the present invention
by using
metal aliphatic oxides and alcohols deriving from different aliphatic oxy
groups.
iNhen using metal aliphatic oxides and alcohols deriving from different
aliphatic oxy
groups, different mixed orthoesters and non-mixed ortho-esters are possible
products. However, one of ordinary skill in the art can determine readily and
optimize the reaction conditions for preparing mixed orthoester compounds of
the
present invention without undue experimentation. Furthermore, the compounds
obtained from the aforementioned reaction may be purified by conventional
methods
known to those skilled in the art.
In light of this disclosure, one of ordinary skill in the art can determine
readily and
optimize the reaction conditions for preparing the orthoester intermediate
compounds of the present invention without undue experimentation. Furthermore,
the compounds obtained from the aforementioned reaction may be purified by
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conventional methods known to those skilled in the art. For example, aqueous
washing, drying, concentrating under reduced pressure, distillation, and the
like are
methods which may be used.
Preparation of Compounds of Formula 1 from the Orthoester Intermediate
The compounds of Formula 1 may be prepared from the orthoester intermediates
using conventional acid-catalyzed hydrolysis methods. For example, the
orthoester
intermediate may be dissolved in solvent and treated with acid to form an
ester or
acid compound of Formula 1.
Whether an ester or acid compound is formed from the hydrolysis step is
believed to
be determined by the choice of anhydrous or aqueous solvent. In general, the
use
of an anhydrous solvent for hydrolysis will produce a greater isolation of
ester
products. However, when an aqueous solvent or organic/aqueous solvent mixture
is
used, the major product isolated is an acid of Formula 1.
Examples of suitable anhydrous alcohols for use in the present invention
include
methanol, ethanol, n-propanol, isopropanol, n-butanol, or t-butanol,
preferably
ethanol or n-butanol.
Suitable aqueous solvents include mixtures of water and alcohols, such as
methanol
or ethanol. 11llixtures of THF/alcohol/water may also be used, such as a 5:5:2
THF/alcohol/water.
Hydrolysis of esters is a well-known procedure accomplished with an alkali
hydroxide, such as sodium, potassium or lithium hydroxide in an aqueous
alcohol
(such as ethanol or methanol) medium.
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One of ordinary skill in the art can determine readily and optimize reaction
conditions
for preparing an ester or acid compound of Formula 1 from an orthoester
intermediate without undue experimentation. Generally, reaction temperatures
range from about 0 °C to about 50 °C, and reaction times range
from a few minutes
to several hours.
Preparation of Halogenated Compounds of Formula 1
A halogenated aryloxy ester of Formula 1 may be prepared from a non-
halogenated
aryloxy ester by employing an additional halogenation step. Thereafter, the
preparation of a halogenated aryloxy acid compound by using an optional
hydrolysis
step is described. Additionally, the use of halogenated starting materials to
prepare
halogenated compounds of Formula 1 is described.
In one embodiment of the present invention, ester compounds of the Formula I
having an Ar- group comprising a halogenated aryl or haiogenated heteroaryl
may
be made by the method of the present invention further comprising the step of
halogenating the ester compound of Formula I. This halogenation step is
preferably
done under conditions sufficient to achieve halogenation of the Ar- group
without
reaction or decomposition of the rest of the molecule.
One embodiment of the halogenation step comprises reacting an ester of the
present invention with a halogenating agent, either in the presence or absence
of an
acid catalyst. hialogenating agents suitable for use in the present invention
preferably comprise reagents, which can halogenate selectively aryl or
heteroaryl
moieties in good yield under mild conditions. Examples of preferred
halogenating
agents are n-chlorosuccinimide and n-bromosuccinimide.
Substitution of aryls and heteroaryls with halogens is known in the art and
can be
accomplished through conventional methods. Thus, one of ordinary skill in the
art
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can determine readily and optimize reaction conditions for preparing a
halogenated
ester compound of Formula 1 without undue experimentation.
Because acids of Formula 1 tend to react readily with halogenating agents,
direct
halogenation of acid compounds of the present invention is a relatively
inefficient
method for recovering desired halogenated acid compounds. However, in another
embodiment of the present invention, halogenated acid compounds of Formula 1
can be made by subjecting corresponding halogenated ester compounds of Formula
1 to a further hydrolysis step.
Hydrolysis of halogenated esters can be achieved using conventional methods.
Those of ordinary skill in the art can determine readily and optimize reaction
conditions for the hydrolysis of halogenated esters to make halogenated acid
compounds of Formula 1. Generally, reaction temperature range from about 0
°C to
about 50 °C and reaction times range from a few minutes to several
hours.
Chlorinated or fluorinated compounds of Formula 1 can also be made directly
via the
present method by using starting materials having aryl or heteroaryl chlorine
or
fluorine substituents in place prior to orthoester formation. In this manner,
chlorinated and fluorinated compounds can be produced without the need for an
additional chlorination or fluorination step after conversion of the
orthoester to
compounds of Formula 1.
Suitable chlorinated and fluorinated starting materials include 1,1,1-
trifluoroalkoxy
chlorothiophenes, such as 2-chloro-5-(1,1,1-trifluoroethoxy)-thiophene. These
starting materials may also include conventional organic substituent moieties,
such
as aryl, alkyl, alkoxy, nitro, amido, cyclic aliphatic, or amino groups.
EXAMPLE
The following example is illustrative of the claimed process of the present
invention,
illustrating a five-step process for the production of the claimed compound 5-
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chlorothiophen-2yloxyacetic acid. The structure ofi the compound produced in
each
step conformed with mass spectrum analysis.
Step 1. The preparation of 2-(2,2,2-trifluoroethoxy)thiophene from 2,2,2-
trifluoroethanoi.
To hexane-washed sodium spheres (3.2 g, 140 mmoi) was slowly added 2,2,2-
trifluoroethanoi (35 mL, 500 mmol) under a nitrogen atmosphere. The mixture
was
warmed to 55 °C - 60 °C during the addition of the alcohol.
Following dissolution of
the sodium metal, the excess 2,2,2-trifluoroethanol was removed under reduced
pressure. To the resulting white solid was added copper(() iodide (13.7 g, 7
mmol)
and 2-iodothiophene (14.7 g, 70 mmol). The mixture was heated at 110 °C
for 24 h
and was evaporated at 25 °C. The residue was diluted with hexane and
filtered
through a pad of silica gel. The filtrate was evaporated to yield 7.0 g (55%)
of 2-
(2,2,2-trifluoroethoxy)thiophene as a colorless liquid. The material can also
be
purified by distillation (boiling point 67 °C, 30 mm E-Ig).
Step 2. The preparation of 2-(2,2,2-triethoxy)ethoxythiophene from 2-(2,2,2-
trifiuoroethoxy)thiophene.
2-(2,2,2-trifluoroethoxy)thiophene (20 g, 110 mmol) and sodium ethoxide (45 g,
660
mmol) were placed in a steel reaction vessel. Anhydrous ethanol (100 mL) was
added and the mixture was heated at 150 °C for 72 hours. The mixture
was cooled
and subsequently diluted with water (500 mL). The aqueous phase was extracted
with four portions of diethyl ether (200 mL). The organic phases were
combined,
washed three times with 2N aqueous~sodium hydroxide, dried with magnesium
sulfate, filtered and evaporated to provide 16.5 g (57%) of 2-(2,2,2-
triethoxy)ethoxythiophene as a pale-yellow oil.
Step 3. The preparation of ethyl thiophen-2-yloxyacetate from 2-(2,2,2-
triethoxy)ethoxythiophene.
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2-(2,2,2-triethoxy)ethoxythiophene (18.4 g, 71 mmol) was dissolved in ethanol
(180
mL). One Normal hydrochloric acid (10 mL) was added and the mixture stirred
for 5
minutes. The reaction was diluted with saturated aqueous sodium bicarbonate
and
diethyl ether. The organic phase was washed once with brine, dried with sodium
sulfate, filtered and evaporated to yield ethyl thiophen-2-yloxyacetate (100%)
as a
yei(ow oil.
Step 4. The preparation of ethyl 5-chlorothiophen-2-yloxyacetate from ethyl
thiophen-2-yloxyacetate.
Ethyl thiophen-2-yloxyacetate (1.13 g, S mmot) was placed in acetic acid (20
mL)
and N-chlorosuccinimide (0.85 g, 6 mmol) was added. The mixture was stirred
for 2
hours and was diluted with diethyl ether. The organic phase was washed three
times with 2N aqueous sodium hydroxide, dried with magnesium sulfate and
evaporated. Purification by silica gel chromatography, eluting with 2:1
hexane/ethyl
acetate, gave 1.1 g ethyl 5-chlorothiophen-2-yloxyacetate (83%) as a clear,
colorless
oil. The material can also be isolated by distillation (boiling point 114
°C, 2-3 mm
Hg).
Step 5. The preparation of 5-chlorothiophen-2yloxyacetic acid from ethyl 5-
chlorothiophen-2-yloxyacetate.
Ethyl 5-chlorothiophen-2-yloxyacetate (10.9 g, 49 mmol) was placed in 100 mL
of a
5:5:2 THF/methanol/water solvent mixture. Lithium hydroxide (4.1 g, 98 mmol)
was
added. The mixture was stirred at room temperature for 18 hours and acidified
with
2N aqueous hydrochloric acid to pH 2 to 3. The aqueous phase was extracted
three
times with diethyl ether. The organic phases were combined, washed with brine,
dried with magnesium sulfate and evaporated. The residue was recrystallized
from
hexane/diethyl ether to yield 7.75 g (83%) of 5-chlorothiophen-2-yloxyacetic
acid.
