WO 2006/096624 PCT/US2006/007887
PROCESS FOR THE PURIFICATION OF SUBSTITUTED
BENZOXAZOLE COMPOUNDS
This application claims benefit of priority to US provisional patent application
serial no. 60/659,212 filed on March 7, 2005, which is hereby incorporated in its
entirety.
FIELD OF THE INVENTION
The present invention relates to processes for the purification of substituted
benzoxazole compounds, and in particular 2-(3-fluoro-4-hydroxy-phenyl}-7-vinyl-
benzooxazol-5-o1. The processes Include recrystallizlng the compound from a
solution comprising acetone and acetonitrile; treating the crude purified product with
a clarifying agent in a solution comprising ethyl acetate, and precipitating or triturating
the compound from a mixed solvent system.
BACKGROUND OF THE INVENTION
The pleiotropic effects of estrogens in mammalian tissues have been well
documented, and it is now appreciated that estrogens affect many organ systems
[Mendelsohn and Karas, New England Journal of Medicine 340:1801-1811 (1999),
Epperson, et al., Psychosomatic Medicine 61:676-697 (1999), Crandall, Journal of
Womens Health & Gender Based Medicine 8:1155-1166 (1999), Monk and Brodaty,
Dementia & Geriatric Cognitive Disorders 11:1-10 (2000), Hum and Macrae, Journal
of Cerebral Blood Flow & Metabolism 20:631-652 (2000), Calvin, Maturitas 34:195-
210 (2000), Finking, et al., Zeitschrift fur Kardiologie 89:442-453 (2000), Brincat,
Maturitas 35:107-117 (2000), Al-Azzawi, Postgraduate Medical Journal 77:292-304
(2001)}. Estrogens can exert effects on tissues in several ways, and the most well
characterized mechanism of action is their interaction with estrogen receptors leading
to alterations in gene transcription. Estrogen receptors are ligand-activated
transcription factors and belong to the nuclear hormone receptor superfamily. Other
members of this family include the progesterone, androgen, glucocorticoid and
mineralocorticoid receptors. Upon binding ligand, these receptors dimerize and can
activate gene transcription either by directly binding to specific sequences on DNA
(known as response elements) or by interacting with other transcription factors (such
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WO 2006/096624 PCT/US2006/007887
as AP1), which in turn bind directly to specific DNA sequences [Moggs and
Orphanides, EMBO Reports 2:775-781 (2001), Hall, et al., Journal of Biological
Chemistry 276: 36869-36872 (2001), McDonnell, Principles Of Molecular Regulation.
p351-361 (2000)]. A class of "coregulatory" proteins can also interact with the ligand-
bound receptor and further modulate Its transcriptional activity [McKenna, et al.,
Endocrine Reviews 20:321-344 (1999)]. It has also been shown that estrogen
receptors can suppress NFkB-mediated transcription in both a ligand-dependent and
independent manner [Quaedackers, et al., Endocrinology 142:1156-1166 (2001),
Bhat, et al., Journal of Steroid Biochemistry & Molecular Biology 67:233-240 (1998),
Pelzer, et al., Biochemical & Biophysical Research Communications 286:1153-7
(2001)].
Estrogen receptors can also be activated by phosphorylation. This
phosphorylation is mediated by growth factors such as EGF and causes changes in
gene transcription in the absence of ligand [Moggs and Orphanides, EMBO Reports
2:775-781 (2001), Hall, et al., Journal of Biological Chemistry 276: 36869-36872
(2001)].
A less well-characterized means by which estrogens can affect cells is
through a so-called membrane receptor. The existence of such a receptor is
controversial, but it has been well documented that estrogens can elicit very-rapid
non-genomic responses from cells. The molecular entity responsible for transducing
these effects has not been definitively isolated, but there is evidence to suggest it is
at least related to the nuclear forms of the estrogen receptors [Levin, Journal of
Applied Physiology 91:1860-1867 (2001), Levin, Trends in Endocrinology &
Metabolism 10: 374-377 (1999)].
Two estrogen receptors have been discovered to date. The first estrogen
receptor was cloned about 15 years ago and is now referred to as ERa [Green, et al.,
Nature 320:134-9 (1986)]. The second form of the estrogen receptor was found
comparatively recently and is called ERb [Kuiper, et al., Proceedings of the National
Academy of Sciences of the United States of America 93: 5925-5930 (1996)]. Early
work on ERp focused on defining its affinity for a variety of ligands and indeed, some
differences with ERa were seen. The tissue distribution of ERp has been well
mapped in the rodent and it is not coincident with ERa. Tissues such as the mouse
and rat uterus express predominantly ERa, whereas the mouse and rat lung express
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predominantly ERb [Couse, et al., Endocrinology 138:4613-4621 (1997), Kuiper, et
al., Endocrinology 138: 863-870 (1997)]. Even within the same organ, the
distribution of ERa and ERb can be compartmentalized. For example, in the mouse
ovary, ERb is highly expressed in the granulosa cells and ERa is restricted to the
thecal and stromal cells [Sar and Welsch, Endocrinology 140: 963-971 (1999),
Fitzpatrick, et al., Endocrinology 140: 2581-2591 (1999)]. However, there are
examples where the receptors are coexpressed and there is evidence from in vitro
studies that ERa and ERb can form heterodimers [Cowley, et al., Journal of
Biological Chemistry 272:19858-19862 (1997)].
A large number of compounds have been described that either mimic or block
the activity of 17b-estradiol. Compounds having roughly the same biological effects
as 17b-estradiol, the most potent endogenous estrogen, are referred to as "estrogen
receptor agonists". Those which, when given in combination with 17p-estradiol,
block its effects are called "estrogen receptor antagonists". In reality there is a
continuum between estrogen receptor agonist and estrogen receptor antagonist
activity and indeed some compounds behave as estrogen receptor agonists in some
tissues and estrogen receptor antagonists in others. These compounds with mixed
activity are called selective estrogen receptor modulators (SERMS) and are
therapeutically useful agents (e.g. EVISTA) [McDonnell, Journal of the Society for
Gynecologic Investigation 7: S10-S15 (2000), Goldstein, et al., Human Reproduction
Update 6: 212-224 (2000)]. The precise reason why the same compound can have
cell-specific effects has not been elucidated, but the differences in receptor
conformation and/or in the milieu of coregulatory proteins have been suggested.
It has been known for some time that estrogen receptors adopt different
conformations when binding ligands. However, the consequence and subtlety of
these changes has been only recently revealed. The three dimensional structures of
ERa and ERb have been solved by co-crystallization with various ligands and clearly
show the repositioning of helix 12 in the presence of an estrogen receptor antagonist
which sterically hinders the protein sequences required for receptor-coregulatory
protein interaction [Pike, et al., Embo 18:4608-4618 (1999), Shiau, et al., Cell 95:
927-937 (1998)]. In addition, the technique of phage display has been used to
Identify peptides that interact with estrogen receptors in the presence of different
ligands [Paige, et al., Proceedings of the National Academy of Sciences of the United
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WO 2006/096624 PCT/US2006/007887
States of America 96:3999-4004 (1999)]. For example, a peptide was identified that
distinguished between ERa bound to the full estrogen receptor agonists 17b-estradiol
and diethylstilbesterol. A different peptide was shown to distinguish between
clomiphene bound to ERa and ERb. These data indicate that each ligand potentially
places the receptor in a unique and unpredictable conformation that is likely to have
distinct biological activities.
As mentioned above, estrogens affect a panoply of biological processes. In
addition, where gender differences have been described (e.g. disease frequencies,
responses to challenge, etc), it is possible that the explanation involves the difference
in estrogen levels between males and females.
U.S. Pat No. 6,794,403, incorporated herein by reference in its entirety,
describes the preparation of substituted benzoxazole ERb selective ligands having
the Formula I, infra. Given the importance of these compounds as potential
therapeutics, it can be seen that Improved processes for their purification are of great
value. This invention is directed to these, as well as other, important ends.
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SUMMARY OF THE INVENTION
In one aspect, the present invention provides processes for the purification of
compounds of Formula I:

wherein;
R1 is alkenyl of 2-7 carbon atoms; wherein the alkenyl moiety is optionally substituted
with one or more substituents which may be the same or different and are
selected from hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -COR5, -
CO2R5, -NO2, CONR6R6, NR5R6 and N(R5)COR6;
R2 and R2a are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6
carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms,
alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or
trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl, alkenyl, or alkynyl
moieties are optionally substituted with one or more substituents which may
be the same or different and are selected from hydroxyl, -CN, halogen,
trifluoroalkyl, trifluoroalkoxy, -COR5, -CO2R5, -NO2, CONR5R6, NR5R6 and
N(R5)COR6,-
R3, and R3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of
2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-4 carbon
atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon
atoms; wherein the alkyl, alkenyl, or alkynyl moieties are optionally
substituted with one or more substituents which may be the same or different
and are selected from hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -
COR5, -CO2R5, -NO2, CONR5R6, NR5R6 and N(R5)COR6;
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R5, R6 are each, independently, hydrogen, alkyl of 1-6 carbon abms, aryl of 6-10
carbon atoms;
X is O, S, or NR7; and
R7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, -COR5, -CO2R5
or-SO2R5;
from a mixture comprising the compound and at least one impurity. In some
embodiments, the processes include the steps of:
a) recrystallizing said compound from a solution comprising acetone and
acetonitrile to provide a crude purified product;
b) dissolving said crude purified product in a solution comprising ethyl
acetate;
c) treating said solution comprising ethyl acetate with a clarifying agent
to form a clarified solution;
d) optionally concentrating said clarified solution to form a concentrated
clarified solution or slurry;
e) adding a nonpolar solvent to said clarified solution or said clarified
concentrated solution or slurry to form a mixed solvent solution or slurry; and
f) collecting the purified compound from said mixed solvent solution or
slurry.
In some embodiments of the methods of the invention X is O. In further such
embodiments, X is O and R1 is alkenyl of 2-3 carbon atoms, which is optionally
substituted with hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -COR5, -CO2R5,
-NO2, CONR5R6, NR5R6 or N(R5)COR6. In still further such embodiments, the
compound is 2-(3-fluoro-4-hydroxyphenyl)-7-vinyl 1,3-benzoxazol-5-ol.
The optionally substituted alkyl, alkenyl and alkynyl moieties are optionally
substituted with one or more substltuents which may be the same or different.
Examples include mono, di and tri substituted groups.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides processes for the purification of a compound
of Formula I:
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WO 2006/096624 PCT/US2006/007887
PCT/US2006/007887

wherein:
R1 is alkenyl of 2-7 carbon atoms; wherein the alkenyl moiety is optionally substituted
with one or more substituents which may be the same or different and are
selected from hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -COR5, -
CO2R5, -NO2, CONR5R6, NR5R6, and N(R5)COR5,
R2 and R2a are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6
carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms,
aikynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or
trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl, alkenyl, or aikynyl
moieties are optionally substituted with one or more substituents which may
be the same or different and are selected from hydroxyl, -CN, halogen,
trifluoroalkyi, trifluoroalkoxy, -COR5, -CO2R5, -NO2, CONR5R6, NR5R6 and
N(R5)COR6;
R3, and R3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of
2-7 carbon atoms, aikynyl of 2-7 carbon atoms, halogen, alkoxy of 1-4 carbon
atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon
atoms; wherein the alkyl, alkenyl, or aikynyl moieties are optionally
substituted with one or more substituents which may be the same or different
and are selected from hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -
COR5, -CO2R5, -NO2, CONR5R6, NR5R6 and N(R5)COR6;
R5, R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10
carbon atoms;
X is 0, S, or NR7; and
R7 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, -COR5, -CO2R5
or-SO2R5;
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WO 2006/096624 PCT/US2006/007887
from a mixture comprising said compound and at least one impurity, comprising the
steps of:
a) recrystallizing said compound from a solution comprising acetone and
acetonitriie to provide a crude purified product;
b) dissolving said crude purified product in a solution comprising ethyl
acetate;
c) treating said solution comprising ethyl acetate with a clarifying agent
to form a clarified solution;
d) optionally concentrating said clarified solution to form a concentrated
clarified solution or slurry;
e) adding a nonpolar solvent to said clarified solution or said clarified
concentrated solution or slurry to form a mixed solvent solution or slurry; and
f) collecting the purified compound from said mixed solvent solution or
slurry.
In some embodiments of the methods of the invention X is 0. In further such
embodiments, X is O and R1 is alkenyl of 2-3 carbon atoms, which is optionally
substituted with hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -COR5, -CO2R5,
-NO2, CONR5R6, NR5R6 or N(R5)COR6. In still further such embodiments, the
compound has the Formula:

In some embodiments, R1 is suitably an optionally substituted alkene of 2-3
carbon atoms. In some embodiments, R1 is vinyl. In some embodiments, R2, R2a,
R3, R3a are each independently suitably hydrogen. In certain embodiments R2, R2a,
R3 and R3a are all hydrogen.
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The processes described herein are useful for the purification of compounds
of Formula 1, and especially for the purification of 2-(3-fluoro-4-hydroxyphenyl)-7-
vinyl-1,3-benzoxazol-5-ol. Generally, the processes will be applied to a crude
preparation of the compound, for example a crude synthetic preparation, which
contains one or more impurities.
In accordance with the present processes, the crude product is first
recrystallized from a solution containing acetone and acetonitrile as the two major
solvent components of the solution. In some embodiments, the solution is composed
of acetone and acetonitrile.
In one nonlimiting embodiment, the crude compound is dissolved in acetone
to form a solution; and acetonitriie is added to the solution to form a second solution
from which the compound is to be crystallized. The dissolving of the crude
compound in the acetone solution is beneficially accomplished at an elevated
temperature, generally greater than about 25°C, preferably greater than about 50°C,
for example from about 50°C to about 60°C. Although any convenient amount of
acetone can be employed that is sufficient to dissolve the compound, generally,
about 0.75 to about 0.9 liters of acetone, preferably about 0.82 liters of acetone, is
employed for each 100 grams of dry crude compound. Thus, about 1.6 to about 2.0
liters of acetone, preferably about 1.8 liters of acetone, would be employed for each
219 grams of dry crude compound.
After the compound is dissolved, in the acetone solution, a solution including
acetonitrile as its major component is added. In some preferred embodiments, neat
acetonitrile is added. Any convenient amount of acetonitrile can be added to the
solution that is effective to provide an acceptable yield. In some preferred
embodiments, the volume of acetonitriie added is from about 30% to about 70%, or
about 40% to about 65%, or from about 48% to about 55%, of the volume of the
solution of the compound dissolved in acetone. More preferably, the volume of
acetonitrile added is about equal to the volume of the acetone solution.
Preferably, the addition of the acetonitrile solution is performed while
maintaining the elevated temperature. The addition can be performed over any
convenient time, for example over about 30 minutes.
In some embodiments, the resulting solution containing acetone, acetonitrile
and the dissolved compound is then concentrated, preferably to about one half its
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WO 2006/096624 PCT/US2006/007887
volume, and also preferably while maintaining the elevated temperature. Any
convenient means can be used to concentrate the solution, for example distillation at
atmospheric pressure.
The resulting concentrated solution is then cooled to crystallize the product.
For example, the solution can be cooled to about-10°C to about 10°C, preferably
from -3°C to about 3°C. It is generally advantageous to hold the solution at the cool
temperature for a period of time after the cooling is complete, to afford maxima! yield
of product Generally, holding the solution at -10oC to about 10"C, preferably from -
3°C to about 3°C, for about an hour or longer, for example about 90 minutes, is
sufficient.
In some embodiments, is can be advantageous to cool the solution In more
than one stage. For example, In some embodiments, the concentrated solution is
first cooled to an intermediate temperature, for example from about 45°C to about
50oC, and is then held at that temperature for a period of time, before cooling to
lower temperature as described above. Generally, holding the solution at the
intermediate temperature for about ten minutes or longer, about twenty minutes or
longer, about thirty minutes or longer, or about 45 minutes or longer, is sufficient.
Preferably, the solution is held at an intermediate temperature of from about 50°C to
about 60°C, more preferably from about 45°C to about 50°C, for about thirty minutes.
After coding is complete, the crude purified product can be collected by any
convenient means, for example by filtering the solution. The crude purified product
can then be washed (for example with one or more treatments with precooled
acetonitrile), and then dried by standard procedures, for example at 55°C to about
60°C, under vacuum.
The crude purified product obtained from the recrystallization is then
dissolved in a suitable solvent, and the resulting solution is clarified by treatment with
a clarifying agent; Le., a clarifying agent is added to the solution, and then physically
removed, for example by filtration. Any of the many such agents that are known to
be useful for adsorbing impurities In synthetic purification regimes can be employed.
In one preferred embodiment, the clarifying agent is charcoal.
Generally, the crude purified product is dissolved in ethyl acetate to form an
ethyl acetate solution. Generally, the crude purified product is dissolved in about 18
to about 28 volumes of ethyl acetate, preferably about 23 volumes of ethyl acetate,
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WO 2006/096624 PCT/US2006/007887
preferably at elevated temperature, for example from about 70 °C to about 90oC,
preferably from about 75oC to about 80°C.
In some embodiments, the ethyl acetate solution is cooled back to a lower
temperature, for example to about 25 °C to about 45 °C before the clarifying'agent is
added.
Generally the clarifying agent, preferably charcoal, is added to the ethyl
acetate solution in an amount of about 4 to about 5 grams per liter of ethyl acetate
solution, preferably about 4.4 grams per liter of ethyl acetate solution. The mixture is
stirred for about 0.5 hour, and the mixture ls then filtered to yield a clarified solution.
In some embodiments, the clarified solution is then concentrated, preferably
to about 5 volumes to about 10 volumes relative to the volume of the crude purified
product. The clarified solution can be concentrated by a variety of standard
procedures. Preferably, the concentration is performed at atmospheric pressure, for
example by distillation. During the concentration, the compound can start to
precipitate out of solution, forming a slurry.
A nonpolar solvent is then added to the concentrated solution or slurry to form
a mixed solvent solution or slurry. Preferably, the nonpolar solvent is added in an
amount that is about 4 to about 8 volumes relative to the volume of the crude purified
product. Preferably, the nonpolar solvent is added while maintaining the solution or
slurry at elevated temperature, for example about 75°C to about 85°C. A variety of
nonpolar solvents can be employed, including hydrocarbon solvents of suitable
boiling point, for example heptane, and ethers. One preferred solvent is heptane.
The purified product is then collected from the mixed solvent solution or slurry
by cooling and physical separation of the solid product form the solution. Generally,
the mixed solvent solution or slurry is then cooled to complete crystallization of the
product. For example, the solution can be cooled to about 0°C to about 5oC. It is
generally advantageous to hold the solution at the cool temperature for a period of
time after the cooling is complete, to afford maximal yield of product Generally,
holding the solution at 0°C to about 5°C, for about an hour or longer, for example up
to about 90 minutes, is sufficient
In some embodiments, is can be advantageous to cool the solution in more
than one stage. For example, in some embodiments, the mixed solvent solution or
slurry is first cooled to an intermediate temperature, for example from about 45°C to
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about 50°C, and is then held at that temperature for a period of time, before cooling
to lower temperature as described above. Generally, holding the solution atthe
intermediate temperature for about ten minutes or longer, about twenty minutes or
longer, about thirty minutes or longer, or about 45 minutes or longer is sufficient.
Preferably, the solution is held at an intermediate temperature of from about 50°C to
about 60oC, more preferably from about 45°C to about 50°C, for about thirty minutes.
After cooling is complete, the crude purified product can be collected by any
convenient means, for example by filtering the solution. The crude purified product
can then be dried by standard procedures, for example at 55°C to about 65°C, under
vacuum, to afford the purified compound.
The processes of the invention provide products of high purity, for example
purity of about 99.0% or greater, about 99.2% or greater, or about 99.4% or greater.
The processes of the invention typically provide recoveries of compound
(relative to the crude product starting material) of 80% or greater, 83% or greater,
86% or greater, or 89% or greater.
The present invention also provides products of the process of the described
herein, having purity of about 99.0% or greater, about 99.2% or greater, or about
99.4% or greater.
As used herein, the term "alkyl" or "alkylene" is meant to refer to a saturated
hydrocarbon group which is straight-chained or branched. Example alkyl groups
include methyl (Me), ethyl (Et), propyl {e.g., n-propyl and isopropyl), butyl (e.g., n-
butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl) and the
like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to
about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3
carbon atoms.
As used herein, "alkenyl" refers to an alkyl group having one or more double
carbon-carbon bonds. Example alkenyl groups include ethenyl, propenyl, butenyl,
pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like.
As used herein, "alkynyl" refers to an alkyl group having one or more triple
carbon-carbon bonds. Example alkynyl groups include ethynyl, propynyl, butynyl,
pentynyl, and the like.
As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
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As used herein, "alkoxy" refers to an -O-alkyl group. Example alkoxy groups
include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the
tike.
As used herein, "aryl" refers to a 6 to 10 membered mono or bicyclic aromatic
group including phenyl and naphthyl.
As used herein, "trifluoroalkyf refers to an alky) group substituted by three
fluorine atoms. A triftuoroalkyl group can contain from 1 to about 20, from 2 to about
20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or
from 1 to about 3 carbon atoms. One example of trifluoroalkyl is trifluoromethyl.
As used herein, "trifluoroalkoxy" refers to an alkoxy group substituted by three
fluorine atoms. A trifluoroalkoxy group can contain from 1 to about 20, from 2 to
about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4,
or from 1 to about 3 carbon atoms. One example of trifluoroalkoxy is
trifluoromethoxy.
At various places in the present specification substituenis of compounds of
the invention are disclosed in groups or in ranges. It is specifically intended that the
invention include each and every individual subcombination of the members of such
groups and ranges. For example, the term "C1-6 alkyl" is specifically intended to
Individually disclose methyl, ethyl, C3 alkyl, C4 alky!, C5 alkyl and C6 alkyl.
The compounds of the present invention can contain an asymmetric atom,
and some of the compounds can contain one or more asymmetric atoms or centers,
which can thus give rise to optical isomers (enantiomers) and diastereomers. The
present invention includes such optical isomers (enantiomers) and diastereomers
(geometric isomers); as well as the racemic and resolved, enantiomerically pure R
and S stereoisomers; as well as other mixtures of the R and S stereoisomers and
pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure
form by standard procedures known to those skilled in the art, and include, but are
not limited to, diastereorneric salt formation, kinetic resolution, and asymmetric
synthesis. It is also understood that this invention encompasses all possible
regioisomers, and mixtures thereof, which can be obtained in pure form by standard
separation procedures known to those skilled in the art, and include, but are not
Dmited to, column chromalography, thin-layer chromatography, and high-
performance liquid chromatography.
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The processes described herein can be carried out in air or under an inert
atmosphere. Typically, the processes are carried out in air.
It is appreciated that certain features of the invention, which are, for clarity,
described in the context of separate embodiments, can also be provided in
combination in a single embodiment Conversely, various features of the invention
which are, for brevity, described in the context of a single embodiment, can also be
provided separately or in any suitable subcombination.
The processes of this invention are suitable for the purification of compounds
Formula I on any convenient scale, for example greater than about 0.01 mg, 0.10
mg, 1 mg, 10 mg, 100 mg, 1g, 10g, 100g, 1kg, 10 kg or more. The processes are
particularly advantageous for the large scale (e.g., greater than about ten gram)
purification.
The invention will be described in greater detail by way of specific examples.
The following examples are offered for illustrative purposes, and are not intended to
limit the invention in any manner. Those of skill in the art will readily recognize a
variety of noncritical parameters which can be changed or modified to yield
essentially the same results.
EXAMPLES
EXAMPLE 1
Preparation of 2-(3-Fluoro-4-hydroxyphenyl)-7-vinylbenzooxazol-5-ol
A 2 gallon hydrogenator was charged with 2-(3-Fluoro-4-hydroxyphenyl)-7-
bromobenzooxazol-5-ol (300 g, 0.926 mole), tri-o-tolylphosphine (9.1 g, 3.3%),
palladium diacetate (2.1 g 1 %), acetonitrile (4.5 L), and triethylamine (375g, 4 eq).
The hydrogenator was flushed with nitrogen, and with ethylene; and then the
pressure was adjusted to 50 psi. The reaction mixture was heated to 75 °C and held
for 16 hours, at which time HPLC sampling indicated 0.2% of starting material
remaining. The mixture was cooled to 35-40oC and filtered through a 0.2m cartridge,
and washed with 1,2-diethoxyethane (1.2 L). The filtrate was concentrated under
vacuum to 1.2 L, and water (1.5 L) and 1,2-diethoxyethane (1.2 L) were added. The
pH was adjusted to 11-12 by adding 1.4L of 2N NaOH at 15-20°C. The phases were
separated, and the organic phase was extracted with water (300 ml), and 2 N NaOH
(20 mL). The combined aqueous phase was washed with 1,2-diethoxyethane (2 x
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WO 2006/096624 PCT/US2006/007887
900 mL). The pH was adjusted to 2.5-3.5 by adding 500 mL of 4N HCI at 15-20 °C.
After holding for 4 hours, the solid was filtered off and washed with water (3 x 200
mL).
The wet cake was suspended In acetone (1822 mL) and heated to 54-60°C
then held for complete solution. While maintaining at 54-60°C acetonitrile was added
(1822 mL) over 0.5 hour. The solution was concentrated by distilling at atmospheric
pressure to a volume of 1.8-2.0 L, then the concentrate was cooled to 45-50°C and
held for 0.5 hour; then cooled to -3 to 3°C and held for 1 hour. The solid was filtered
off and washed with precooled acetonitrile (2 x 200 mL); then dried in a vacuum oven
at 55-65°C and 5-10 mm Hg for 24 hours to give 180 g (71.5% yield) of product.
The product from above was dissolved in ethyl acetate (23 volumes) at 75-
80oC. The resulting solution was cooled back to 25-45°C and treated with charcoal.
The filtrate was then concentrated at atmospheric pressure to 7 volumes, and to the
slurry was added heptane (6 volumes) while maintaining at 75-80°C. The solution
was then cooled to 45-50°C, held for 0.5 hour, then cooled to 0-5oC, and held for 1
hour. The solid was filtered off, dried at 55-65°C, 5-10 mmHg, to afford an 87%
recovery and 99.4% purity.
As those skilled in the art will appreciate, numerous changes and
modifications may be made to the preferred embodiments of the invention without
departing from the spirit of the invention.
It is intended that all such variations fall within the scope of the invention. It is
intended that each of the patents, applications, and printed publications including
books mentioned in this patent document be hereby incorporated by reference in
their entirety.

WO 2006/096624 PCT/US2006/2007887
What is claimed is:
1. A process for purifying a compound of Formula I:

wherein:
R1 is alkenyl of 2-7 carbon atoms; wherein the alkenyl moiety is optionally substituted
with one or more substituents which may be the same or different and are
selected from hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -COR5, -
CO2R5, -NO2, CONR5R6 NR5R6 and N(R5)COR6;
R2 and R2a are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6
carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms,
alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or
trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl, alkenyl, or alkynyl
moieties are optionally substituted with one or more substituents which may
be the same or different and are selected from hydroxyl, -CN, halogen,
trifluoroalkyl, trifluoroalkoxy, -COR5, -CO2R6, -NO2, CONR5R6, NR5R6 and
N(R5)COR6;
R3, and R3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of
2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-4 carbon
atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon
atoms; wherein the alkyl, alkenyl, or alkynyl moieties are optionally
substituted with one or more substituents which may be the same or different
and are selected from hydroxyl, -CN, halogen, trifluoroalkyl, trifluoroalkoxy, -
COR5, -CO2R5, -NO2, CONR5R6, NR5R6 and N(R5)COR6;
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WO 2006/096624 PCT/US2006/007887
R5, R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10
carbon atoms;
Xis O, S,or NR7; and
R7 Is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, -COR5, -CO2R5
or -SO2R6;
from a mixture comprising said compound and at least one impurity, comprising the
steps of:
a) recrystallizing said compound from a solution comprising acetone and
acetonitrile to provide a crude purified product;
b) dissolving said crude purified product in a solution comprising ethyl
acetate;
c) treating said solution comprising ethyl acetate with a clarifying agent
to form a clarified solution;
d) optionally concentrating said clarified solution to form a concentrated
clarified solution or slurry;
e) adding a nonpolar solvent to said clarified solution or said clarified
concentrated solution or slurry to form a mixed solvent solution or slurry; and
f) collecting the purified compound from said mixed solvent solution or
slurry.
2. The process for claim 1 wherein said compound has the Formula I:

3. The process of claim 1 or claim 2 wherein step (a) comprises:
(i) dissolving said compound from said mixture in acetone to form a
solution;
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WO 2006/096624 PCT/US2006/007887
(ii) adding acetonitrile to the solution of step (i) to form a second solution;
and
(iii) cooling the second solution.
4. The process of claim 3 wherein said dissolving of said step (i) is
performed at a temperature greater than about 50°C.
5. The process of claim 3 or claim 4 wherein in step (ii):
the volume of acetonitrile added to said solution is from about 40% to about
65% of the volume of said solution; and
the acetonitrile is added to said solution while said solution is maintained at a
temperature of greater than about 50°C.
6. The process as claimed in any one of claims 3 to 5, wherein step (ii)
further comprises concentrating said second solution to about one half its volume.
7. The process as claimed in any one of claims 3 to 6, wherein step (iii)
further comprises:
cooling said second solution to a temperature of from about 45°C to about
50°C, and maintaining said second solution at about that temperature for a period of
time; and
further cooling of said second solution to a temperature of from about -10°C
to about 10oC, and maintaining said second solution at about that temperature for a
further period of time.
8. The process of claim 7 further comprising:
filtering said second solution to collect a crude purified product; and
washing and optionally drying said crude purified product.
9. The process of claim 3 wherein:
said dissolving of said step (i) is performed at temperature of greater than
about 50°C;
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WO 2006/096624 PCT/US2006/007887
in step (ii), the volume of acetonitrile added to said solution is from about 40%
to about 65% of the volume of said solution;
in step (ii), the acetonitrile is added to said solution while said solution is
maintained at a temperature of greater than about 50°C;
step (ii) further comprises concentrating said second solution to about one
half its volume;
step (iii) further comprises cooling said second solution to a temperature of
from about 45°C to about 50°C, and maintaining said second solution at about that
temperature for up to about 45 minutes, and further cooling said second solution to a
temperature of from about -10°C to about 10°C, and maintaining said second solution
at about that temperature for up to about 90 minutes;
and wherein said process further comprises filtering said second solution to
collect a crude purified product, and optionally washing and optionally drying said
crude purified product
10. The process as claimed in any one of claims 1 to 9 wherein:
in step (b), said crude purified product is dissolved in about 18 to about 28
volumes of ethyl acetate at a temperature of from about 70 °C to about 90 °C to form
an ethyl acetate solution.
11. The process as claimed in any one of claims 1 to 10 wherein said
treating of step (c) comprises-.
contacting said solution comprising ethyl acetate with charcoal at elevated
temperature to form a mixture, and filtering said mixture to provide said clarified
solution; and
concentrating said clarified solution to about 5 volumes to about 10 volumes
relative to said crude purified product to form a concentrated clarified solution or
slurry.
12. The process as claimed in any one of claims 1 to 11 wherein said
adding of said nonpolar solvent of step (e) comprises adding from about 4 to about 8
volumes of said nonpolar solvent at a temperature of from about 65°C to about 90°C
to said concentrated clarified solution or slurry.
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WO 2006/096624 PCT/US2006/007887
13. The process as claimed in any one of claims 1 to 12 wherein said
nonpolar solvent of step (e) comprises heptane.
14. The process as claimed in any one of claims 1 to 11 wherein said
• collecting of step (e) comprises cooling said mixed solvent solution or slurry to a
temperature of from about 45°C to about 50°C;
maintaining said temperature for a period of time;
further cooling said mixed solvent solution or slurry to a lower temperature of
from about -10°C to about 10°C to form a cooled mixed solvent slurry; and
maintaining said lower temperature for a period of time.
15. The process of claim 14 further comprising filtering said cooled mixed
solvent slurry to collect said purified compound; and optionally washing and
optionally drying said purified compound.
16. A process of purifying a compound of Formula I:

from a mixture comprising said compound and at least one impurity, comprising the
steps of:
a) dissolving said compound from said mixture in acetone at elevated
temperature to form a first solution;
b) adding to said first solution an amount of acetonitrile that is from about
40% to about 65% of the volume of said first solution, while maintaining said elevated
temperature, to form a second solution;
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WO 2006/096624 PCT/US2006/007887
c) concentrating said second solution to form a concentrated second
solution;
d) cooling said concentrated second solution to form a precipitate of
crude purified product;
e) collecting said crude purified product;
f) optionally washing and optionally drying said crude purified product;
g) dissolving said crude product in ethyl acetate at elevated temperature
to form a third solution;
h) contacting said third solution with charcoal to form a mixture;
i) filtering said mixture to provide a clarified solution;
j) concentrating said clarified solution to form a concentrated clarified
solution or slurry;
k) adding heptane to said concentrated clarified solution or slurry at
elevated temperature;
1) cooling the concentrated clarified solution or sturry to form a mixed
solvent solution or slurry; and
m) collecting the purified compound from the cooled further solution or
slurry.
17. The process of claim 16, wherein:
the elevated temperature in step (a) is greater than about 50 °C;
in step (c), the second solution is concentrated to about half its volume; and
in step (d), the concentrated second solution is cooled said second solution to
a temperature of from about 45°C to about 50°C, and said second solution is
maintained at about that temperature for a period of time; and the concentrated
second solution is further cooled to a temperature of from about -10oc to about 10°C,
and said second solution is maintained at about that temperature for a further period
of time;
18. The process of claim 16, wherein:
in step (g), said crude product is dissolved In about 18 to about 28 volumes of
ethyl acetate at elevated temperature;
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WO 2006/096624 PCT/US2006/007887
in step (h), said third solution is contacted with said charcoal at a temperature
of up to about 50°C to form said mixture;
in step (j), said clarified solution is concentrated to about 5 to about 7 volumes
relative to said crude purified product at atmospheric pressure, to form said
concentrated clarified solution or slurry;
in step (k), about 4 to about 8 volumes of heptane is added to said
concentrated clarified solution or slurry, at a temperature of up to about 90°C; and
in step (I), said cooling of said concentrated clarified solution or slurry
comprises:
i) cooling said mixed solvent solution or slurry to a temperature
of from about 45°C to about 50°C and maintaining said temperature for up to about
45 minutes after said cooling is complete; and
ii) further cooling said mixed solvent solution or slurry to a
temperature of from about -10°C to about 10°C and maintaining said temperature for
up to about 90 minutes after said cooling is complete.
19. The process as claimed in any one of claims 1 to 18 wherein the purity
of said purified compound Is about 99.0% or greater.
20. The process as claimed in any one of claims 1 to 18 wherein the purity
of said purified compound is about 99.2% or greater.
21. The process as claimed in any one of claims 1 to 18 wherein the purity
of said purified compound is about 99.4% or greater.
22. The process as claimed in any one of claims 1 to 21 wherein the
recovery of said compound from said mixture is about 80% or greater.
23. The process as claimed in any one of claims 1 to 21 wherein the
recovery of said compound from said mixture is about 83% or greater.
24. The process as claimed in any one of claims 1 to 21 wherein the
recovery of said compound from said mixture is about 86% or greater.
22

WO 2006/096624 PCT/US2006/007887
25. The process as claimed in any one of claims 1 to 21 wherein the.
recovery of said compound from said mixture is about 89% or greater.
26. A product of the process of any of claims 1-25, wherein said product
has a purity of about 99.4% or greater.
27. A product obtainable by the process defined in any one of claims. 1 to
25 wherein the product has a purity of about 99.4% or greater.
23

The present invention
provides processes for the purification of
substituted benzoxazole compounds of
formla (I), and in particular 2-(3-fluoro-4-hydroxy-phenyl)
-7-vinyl-benzooxazol-5-ol.
The processes include recrystallizing the
compound from a solution comprising
acetone and acetonitrile; treating the crude
purified product with a clarifying agent in
a solution comprising ethyl acetate, and
precipitating or triturating the compound
from a mixed solvent system.