Note: Descriptions are shown in the official language in which they were submitted.
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METHODS OF MAKING TNDAZOLES
'lTzis appncation claims the benefit of U.S. Provisional Patent Application
No.
60/295,430, filed June 1, 2001; and is incorporated in its entirety by
reference herein.
BACKGROUND OF THE INVENTION
The present invention relates to methods of making indazoles and more
particularly
relates to methods of making indazoles which avoid unwanted by-products and
results in
enantiomerically pure final pharmaceutically active products.
so WO 98/30548 (Yamanouchi) shows the utility of 1-(aminoalkyl)indazoles for
treating
CNS diseases. The route of synthesis involves the reaction of various
indazoles, having
substituents only in the benzene ring, with alkylating agents. It is well
known that such
alkylation of indazoles always gives about a 1:1 mixture of isomeric 1- and 2-
alkylindazoles.
See, generally, Song and Yee, Organic Letters, vol. 2, page 519 (2000).
Therefore about half
1 s of the reaction material is wasted due to the formation of the undesired 2-
alkylindazole which
must be separated by chromatography or other technique. The isolated 1-
alkylindazole is then
further modified to provide the target 1-(aminoalkyl)indazole.
Fischer and Tafel, Justus Liebigs Annalen der Chemie, vol. 227, p. 334 (1885)
report
nitrosation of 2'-ethylaminoacetophenone with sodium nitrite and the reduction
of the resulting
~o nitrosamine with zinc to yield 1-ethyl-3-methylindazole. Use of isoamyl
nitrite instead of
sodium nitrite for an analogous nitrosation is discussed in Applegate and
Turnbull, Synthesis, p.
1011 (1988). McGeachin, Canadian Journal of Chemistry, vol. 44, p. 2323 (1966)
reports
nitrosation of a 2-aminobenzaldehyde wherein the amino group is substituted
with a
nonhydroxylic C23H18N30 group, for the purpose of verification of chemical
structure. The
25 resulting nitrosamine was reduced with zinc forming a very specific
indazole, for the purpose of
further verification of chemical structure.
Monoalkylhydrazines react with benzophenones or acetophenones having o~tho
leaving
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groups (e.g., halide or mesylate) to give 1-alkylindazoles substituted at the
3-position as
reported in Caron and Vazquez, Synthesis, p. 588 (1999). The analogous
conversion of
benzaldehydes to 3-unsubstituted indazoles requires forcing conditions
unsuitable for scaleup.
See Halley and Sava, Synthetic Communications, vol. 27, p. 1199 (1997).
Suwinski and Walczak, Polish Journal of Chemistry, vol. 59, p. 521 (1985),
report
cyclization of 2-aminobenzaldoxime hemisulfate to give indazole. The inventors
attempted
to extend this method to a 2-alkylaminobenzaldoxime hemisulfate, but the
desired 1-
alkylindazole was not obtained and instead the unwanted nitrite or the free
oxime was
obtained. An analogous cyclization of oxime acetates, demonstrated only for
forming 3-
s o substituted indazoles, employs conditions poorly suited for scaleup as
shown in Brown et al.,
Journal of Medicinal Chemistry, vol. 35, p. 2419 (1992). Cyclization of 2-
acylaminobenzaldoxime derivatives yields 1-acylindazoles (von Auwers and
Frese, Justus
Liebigs Annalen der Chemie, vol. 450, p. 290 (1926)) but these do not provide
1-
alkylindazoles upon reduction, the 1-unsubstituted indazole being formed
instead. See Al-
Khamees and Grayshan, Journal of the Chemical Society, Perkin Trans. I, p.
2001 (1985). A
known synthesis of 1,3-dialkylindazoles from 1,3-dialkylindoles involves (1)
oxidative
cleavage of the 1,3-dialkylindazole to give the 2-(N-alkylformamido)aryl alkyl
ketone; (2)
ketoxime formation with concurrent N-deformylation; (3) O-acetylation; and (4)
heating the
resulting ketoxime acetate at 170-200 °C in the melt, under vacuum. See
Matassa et al., J.
2o Med. Chem., vol. 33, page 1781 (1990); and Brown et al., J. Med. Chem.,
vol. 35, page 2419
(1992). This method has not been demonstrated for aldoximes, required for the
synthesis of
3-unsubstituted indazoles. Furthermore, the in vacuo thermolysis step has been
reported on a
maximal 1.3-gram scale, and would present experimental difficulties on a
larger preparative
scale.
2 s Accordingly, there , is a need to provide processes to manufacture 1-
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(aminoalkyl)indazoles which avoid undesired isomers and which are capable of
producing
large quantities of the desired compound.
All patents, patent applications, and publications referenced in this
application are
incorporated in their entirety and form a part of the present application.
s SUMMARY OF THE PRESENT INVENTION
A feature of the present invention is to provide a method to make indazoles
such as
hydroxy indazoles.
A further feature of the present invention is to provide a method to make
indazoles in
large quantities and with avoiding large quantities of undesired isomers.
1 o Additional features and advantages of the present invention will be set
forth in part in
the description that follows, and in part will be apparent from the
description, or may be learned
by practice of the present invention. The objectives and other advantages of
the present
invention will be realized and attained by means of the elements and
combinations particularly
pointed out in the description and appended claims.
15 To achieve these and other advantages and in accordance with the purposes
of the
present invention, as embodied and properly described herein, the present
invention relates to a
method of making an indazole.involving:
a) the nitrosation of an aromatic aldehyde to form a nitroso aromatic
aldehyde; and
b) reacting said nitroso aromatic aldehyde with a reducing agent to form an
2 o indazole.
In the present invention, the method of making an indazole can further include
the steps
of reacting the indazole from step (b) above with a sulfonyl halide or
anhydride to form the
corresponding sulfonic ester. The method can then involve reacting this
corresponding sulfonic
ester with a metal azide to yield an azido indazole which can then be reacted
with a hydrogen
25 source and a catalyst to yield the desired aminoalkyl indazole.
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Also, the present invention relates to a method of making an indazole
involving:
a) nitrosating a 2-(hydroxyalkyl)aminobenzaldehyde to form a 2-
(hydroxyalkyl)nitrosaminobenzaldehyde; and
b) reacting said 2-(hydroxyalkyl)nitrosaminobenzaldehyde with a reducing agent
to
s form a 1-(hydroxyalkyl)indazole.
In this embodiment, the method of making an indazole can further include the
steps of
reacting the 1-(hydroxyalkyl)indazole from step (b) above with a sulfonyl
halide or sulfonic
anhydride to form the corresponding sulfonic ester. The method can then
involve reacting this
sulfonic ester with a metal azide to yield a 1-(azidoalkyl)indazole which can
then be reacted
1 o with a hydrogen source and a catalyst to yield the desired 1-
(aminoalkyl)indazole.
It is to be understood that both the foregoing general description and the
following
detailed description are exemplary and explanatory only and are intended to
provide a further
explanation of the present invention, as claimed.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
15 The present invention relates to methods of making indazoles. More
particularly, the
present invention involves making indazoles using aromatic aldehydes as the
starting material.
The indazoles that can be made following the methods of the present invention
are preferably
enantiomerically pure products which are preferably useful as
pharmacologically active
products such as in the treatment of glaucoma and/or are useful for lowering
and controlling
2 o normal or elevated intraocular pressure.
In the methods of the present invention, indazoles can be produced by taking
the starting
aromatic aldehyde and forming a nitroso aromatic aldehyde by the nitrosation
of the aromatic
aldehyde. This nitroso aromatic aldehyde can then be reacted with a reducing
agent to form an
indazole. This indazole can then be further reacted to form a desired indazole
which is
25 preferably enantiomerically pure and is preferably a pharmaceutically
active product. The
SUBSTITUTE SHEET (RULE 26)
3
(aminoalkyl)indazoles whic
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indazole forming from the reaction between the nitroso aromatic aldehyde and
reducing agent
can be reacted with a sulfonic hydride or anhydride to form a corresponding
sulfonic ester. This
sulfonic ester can be reacted with a metal azide to yield an azido indazole
which in turn is
reacted with a hydrogen source and a catalyst to yield an aminoalkyl indazole.
s The starting aromatic aldehyde which is subjected to nitrosation can be any
aromatic
aldehyde that is capable of converting to a nitroso aromatic aldehyde. For
instance, the aromatic
aldehyde can have the formula Ar(CHO)(NHR). In this formula, R is -OH, an
alkyl group, or
an aromatic group. Ar is a substituted or unsubstituted aromatic group such as
phenyl, aromatic
sulfide, aromatic nitro group, and the like.
z o The aromatic aldehyde which is used in the methods of the present
invention can be
prepared by any number of reaction schemes. For instance, the aromatic
aldehyde can be
formed from reacting an indole with ozone in an organic solvent followed by
addition of at least
one reducing agent to form a formyl aromatic aldehyde. The formyl aromatic
aldehyde can be
reacted with a base or acid in the presence of water andlor an organic solvent
to yield the
z 5 starting aromatic aldehyde. Alternatively, the aromatic aldehyde can be
formed by starting with
a benzonitrile fluorobenzonitrile which is reacted with a reactant that
permits the attachment of
desired substituents on the benzonitrile. For instance, fluorobenzonitrile can
be reacted with 1
amino-2 propanol in the presence of an organic solvent to yield the desired 2-
(hydroxypropyl)
aminobenzonitrile. The benzonitrile can then be reacted with a hydrogen source
and a catalyst
2 o to form the desired aromatic aldehyde.
Besides these reaction schemes, other reaction schemes can be used to form the
desired
starting aromatic aldehyde. Those skilled in the art, in view of the present
invention, can form a
variety of starting aromatic aldehydes for purposes of the present invention.
In the present invention, the method of making the desired indazole generally
can occur
2 s at any temperature above the freezing point of the reactants. For
instance, the method can occur
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at a temperature of from about 25°C to about -25°C.
As shown in the details of the preferred embodiment set forth below, the
nitrosation can
be accomplished by the addition of at least one organic nitrite or inorganic
nitrite preferably in
the presence of at least one organic solvent. Examples of suitable nitrites
include, but are not
s limited to, isoamyl nitrite or sodium nitrite. Preferred solvents include,
but are not limited to,
tetrahydrofuran, acetic acid, or an organic-aqueous solvent pair such as
acetic acid-water or
tetrahydrofuran-dilute aqueous HCI. Combinations or mixtures of two or more
nitrites can be
used. This would also be true with respect to the other reactants in that
combinations or
mixtures of various reactants can be used.
1 o Preferably, the reducing agent used above is a metal such as zinc. Other
reducing agents
known to those skilled in the art can be used. The catalyst that is used in
the methods of the
present invention is preferably palladium on charcoal in the presence of a
solvent which is an
organic solvent like ethanol. The hydrogen source can be any hydrogen source
such as an
ammonium formate. Another example of a suitable solvent is an acetic acid.
15 Depending on the starting aromatic aldehyde, the desired indazoles such as
the
aminoalkyl indazole can be formed. As shown in the preferred embodiment and in
the
examples, the present invention essentially prevents the formation of unwanted
isomers thus
resulting in improved yields and a process that is less expensive. The process
of the present
invention can essentially start with racemic mixtures of the starting aromatic
aldehyde or can
a o start with optically pure starting materials such as (R) aromatic
aldehydes or (S) aromatic
aldehydes. Thus, the process of the present invention permits great
flexibility in the starting
aromatic aldehydes which further permits great flexibility in forming various
desired indazoles
such as aminoalkyl indazoles. The indazoles which can be formed using the
methods of the
present invention are useful in, for instance, treating glaucoma and/or
lowering or controlling
2 s elevated intraocular pressure. Examples of such uses for indazoles include
those set forth in
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International Published Application WO 98/30548 and other patents and
publications
mentioned herein.
The process of the present invention which permits the use of an aromatic
aldehyde
typically uses an amino group on the benzaldehyde. This amino group can be
substituted or
s unsubstituted and as shown in one of the preferred aromatic aldehyde
formulas, the amino group
can be NHR where the R is OH, alkyl group, or aromatic group. The ability to
have a
substituted amino group in such a reaction is a great benefit and unexpected
since those skilled
in the art might expect that the unprotected OH group would not survive
further processing.
However, as shown in the examples, the ability to have an unprotected OH group
on the
1 o benzaldehyde can be done and ultimately that hydroxy group can be present
for the ultimate end
product which is preferably an aminoalkyl indazole. Thus, the present
invention permits the
formation of various desirable indazoles, which previous to the present
process, were quite
difficult to form.
In a more specific and preferred embodiment, the present invention involves
making 1-
1 s (aminoalkyl)indazoles using 2-(hydroxyalkyl)aminobenzaldehydes as the
starting material. The
1-(aminoalkyl)indazoles that can be made following the methods of the present
invention are
preferably enantiomerically pure products which are preferably useful as
pharmacologically
active products such as in the treatment of glaucoma and/or are useful for
lowering and
controlling normal or elevated intraocular pressure.
2 o In a preferred embodiment of the present invention, indazoles can be
produced by
nitrosating a 2-(hydroxyalkyl)aminobenzaldehyde to form a 2-
(hydroxyalkyl)nitrosaininobenzaldehyde. This 2-
(hydroxyalkyl)nitrosaminobenzaldehyde can
be reacted with a reducing agent to form a 1-(hydroxyalkyl)indazole.
Preferably, the reducing
agent is a metal such as zinc. Other reducing agents known to those skilled in
the art can be
25 used. This 1-(hydroxyalkyl)indazole can then be further reacted to form a
desired 1-
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(aminoalkyl)indazole which is preferably enantiomerically pure and is
preferably a
pharmaceutically active product. The 1-(hydroxyalkyl)indazole can be reacted
with a sulfonyl
halide or sulfonic anhydride to form a corresponding sulfonic ester. This
sulfonic ester can be
reacted with a metal azide to yield a 1-(azidoalkyl)indazole which in turn is
reacted with a
s hydrogen source and a catalyst to yield a 1-(aminoalkyl)indazole. The
hydrogen source is
preferably ammonium formate and the catalyst is preferably palladium on
charcoal in the
presence of an organic solvent like ethanol.
Preferably, the 2-(hydroxyalkyl)aminobenzaldehyde has the formula
R~
H
R2
~O
R3 ~ 'NH
R4 R
1 o In this fornula, R is a C2 to C12 alkyl group substituted with at least
one OH group and
optionally substituted with phenyl, methoxyphenyl, (dimethylamino)phenyl, ORS,
OC(=O)R5,
OC(=O)ORS, N(RS)2, N(RS)C(=O)R5, N(R5)C(=O)ORS, or with one or more F atoms;
Rl, R2, R3
and R4 are independently H, F, Cl, Br, CF3, OH, ORS, OC(=O)R5, OC(=O)ORS,
N(RS)2,
N(RS)C(=O)R5, N(RS)C(=O)ORS, N02, CN, N3, SH, S(O)"R5, C(=O)R5, COOH, COORS,
15 CON(RS)2, C1 to C6 alkyl optionally substituted with phenyl, methoxyphenyl,
(dimethylamino)phenyl, C(=O)R5, COOH, COORS, CON(RS)~, CN, ORS, OC(=O)R5,
OC(=O)ORS, N(RS)2, N(RS)C(=O)R5, or N(RS)C(=O)ORS; or Rl and R2 as herein
defined taken
together form a ring, or R2 and R3 as herein defined taken together form a
ring, or R3 and R4 as
herein defined taken together fore a ring; RS is C1 to C6 alkyl optionally
substituted with phenyl,
2 o methoxyphenyl, (dimethylamino)phenyl, methoxy, ethoxy, benzyloxy, or with
one or more F
atoms, or R5 is phenyl, methoxyphenyl, or (dimethylamino)phenyl; and n = 0, l,
or 2.
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More preferably, R is a Cz to C6 alkyl group substituted with at least one OH
group and
optionally substituted with phenyl, ORS, N(RS)C(=O)R5, N(RS)C(=O)ORS, or with
one or more
F atoms; Rl, Rz, R3 and R4 are independently H, F, Cl, CF3, ORS, OC(=O)R5,
OC(=O)ORS,
N(RS)z, N(RS)C(=O)R5, N(RS)C(=O)ORS, NOz, CN, C(=O)R5, COORS, CON(RS)z, Cl to
C6
s alkyl optionally substituted with phenyl, C(=O)R5, COORS, CON(RS)z, CN, ORS,
OC(=O)R5,
OC(=O)ORS, N(RS)z, N(RS)C(=O)R5, or N(RS)C(=O)ORS; or Rl and Rz as herein
defined taken
together form a ring, or Rz and R3 as herein defined taken together form a
ring, or R3 and R4 as
herein defined taken together form a ring; RS is Cl to C6 alkyl optionally
substituted with phenyl,
methoxyphenyl, methoxy, benzyloxy, or with one or more F atoms, or RS is
phenyl or
~. o methoxyphenyl.
The 2-(hydroxyalkyl)aminobenzaldehyde which is preferably used in the methods
of the
present invention can be prepared by any number of reaction schemes. For
instance, the 2-
(hydroxyalkyl)aminobenzaldehyde can be formed by reacting a 1-
(hydroxyalkyl)indole with
ozone in an organic solvent followed by addition of at least one reducing
agent to form a 2-(N-
15 (hydroxyalkyl)formamido)benzaldehyde. The 2-(N-
(hydroxyalkyl)formamido)benzaldehyde
can be reacted with a base or acid in the presence of water and/or an organic
solvent to yield the
2-(hydroxyalkyl)aminobenzaldehyde. Alternatively, the 2-
(hydroxyalkyl)aminobenzaldehyde
can be formed by starting with a 2-fluorobenzonitrile. The 2-
fluorobenzonitrile can be reacted
with a (hydroxyalkyl)amine to yield a 2-(hydroxyalkyl)aminobenzonitrile. For
instance, a 2-
a o fluorobenzonitrile can be reacted with 1-amino-2-propanol in the presence
of an organic solvent
to yield the desired 2-(2-hydroxypropyl)aminobenzonitrile. The 2-(2-
hydroxypropyl)aminobenzonitrile can then be reacted with a hydrogen source and
a catalyst to
form the desired 2-(hydroxyalkyl)aminobenzaldehyde.
Besides these reaction schemes, other reaction schemes can be used to form the
desired
2 s starting 2-(hydroxyalkyl)aminobenzaldehyde. Those skilled in the art, in
view of the present
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invention, can form a variety of starting 2-(hydroxyalkyl)aminobenzaldehydes
for purposes of
the present invention.
As shown in the details of the preferred embodiment set forth below, the
nitrosation can
be accomplished by the addition of at least one organic nitrite or inorganic
nitrite preferably in
s the presence of at least one organic solvent. Examples of suitable nitrites
include, but are not
limited to, isoamyl nitrite or sodium nitrite. Preferred solvents include, but
are not limited to,
tetrahydrofuran, acetic acid, or an organic-aqueous solvent pair such as
acetic acid-water or
tetrahydrofuran-dilute aqueous HCI. Combinations or mixtures of two or more
nitrites can be
used. This would also be true with respect to the other reactants in that
combinations or
1 o mixtures of various reactants can be used.
Depending on the starting 2-(hydroxyalkyl)aminobenzaldehyde, desired indazoles
such
as 1-(aminoalkyl)indazoles can be formed. As shown in the preferred embodiment
and in the
examples, the present invention prevents the formation of unwanted isomers
thus resulting in
improved yields and a process that is less expensive. The process of the
present invention can
Start with a racemic 2-(hydroxyalkyl)aminobenzaldehyde, or can start with an
enantiomerically
enriched or enantiomerically pure 2-(hydroxyalkyl)aminobenzaldehyde of either
R or S
configuration. Thus, the process of the present invention permits great
flexibility in the starting
2-(hydroxyalkyl)aminobenzaldehyde, which further permits great flexibility in
forming various
desired indazoles such 1-(aminoalkyl)indazoles. The indazoles which can be
formed using the
2 o methods of the present invention are useful in, for instance, treating
glaucoma andlor lowering
or controlling elevated intraocular pressure.
The process of the present invention preferably uses a 2-
(hydroxyalkyl)aminobenzaldehyde. The ability to carry an unprotected hydroxy
group through
such a reaction sequence is a great benefit and unexpected since those skilled
in the art might
2 s expect that the hydroxy group would not survive the reaction sequence.
However, as shown in
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the examples, the hydroxy group can be present, without the need for a
protecting group, for use
in forming the end product which is preferably a 1-(aminoalkyl)indazole. Thus,
the present
invention permits the formation of various desirable indazoles, which previous
to the present
process, were quite difficult to form.
With respect to the preferred reactants and the preferred reaction schemes,
set forth
below and in Scheme 1 are preferred reaction schemes in the formation of a
preferred 2
(hydroxyalkyl)aminobenzaldehyde which is then subsequently subjected to
preferred reactions
in the formation of the indazole. While the preferred components are set forth
below, it is to be
recognized that the present invention embraces other reactants, which in view
of the present
z o application, can easily be used by those skilled in the art.
Sequence A:
Step 1. 6-Benzyloxyindole (1) (Batcho and Leimgruber, Organic Syntheses,
Collective Vol.
7, p. 34 (1990)) is reacted with (~)-propylene oxide and a base in an organic
solvent to yield
15 (~)-1-(2-hydroxypropyl)-6-benzyloxyindole (2). Preferably the base is
sodium hydride and
the solvent is tetrahydrofuran. The temperature is 0 °C to 25
°C, preferably about 10 °C.
Preferably an inert atmosphere, e.g., nitrogen or argon, is maintained.
Alternatively, compound 1 is reacted with (R)-propylene oxide according to the
foregoing method to yield (R)-1-(2-hydroxypropyl)-6-benzyloxyindole (R-2).
Alternatively,
2 o compound 1 is reacted with (~-propylene oxide according to the foregoing
method to yield
(S~-1-(2-hydroxypropyl)-6-benzyloxyindole (S 2).
Step 2. Compound 2 is reacted with ozone in an organic solvent, preferably
dichloromethane, at -80 to -40 °C, preferably -55 to -70 °C,
followed by addition of a
reducing agent, preferably dimethyl sulfde. The temperature is then allowed to
increase to
25 about 25 °C, to yield (~)-4-benzyloxy-2-(N-(2-
hydroxypropyl)formamido)benzaldehyde (3).
Alternatively, compound R-2 is reacted according to the foregoing method to
yield
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(R)-4-benzyloxy-2-(N-(2-hydroxypropyl)formamido)benzaldehyde (R-3).
Alternatively,
compound S-2 is reacted according to the foregoing method to yield (~-4-
benzyloxy-2-(N-(2-
hydroxypropyl)formamido)benzaldehyde (S 3).
Step 3. Compound 3 is reacted with a base or an acid in the presence of water
and an organic
solvent, to yield (~)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzaldehyde (6).
Preferably,
base is used and the preferred base is sodium hydroxide or potassium hydroxide
and the
preferred solvent is tetrahydrofuran and the temperature is 0 to 35 °C,
preferably 20 to 25 °C.
Preferably, an inert atmosphere, e.g., nitrogen or argon, is maintained.
Alternatively, compound R-3 is reacted according to the foregoing method to
yield
l o (R)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzaldehyde (R-6). Alternatively,
compound S 3
is reacted according to the foregoing method to yield (Sj-4-benzyloxy-2-(2-
hydroxypropyl)aminobenzaldehyde (S-6).
Sequence B:
Step 1. 4-Benzyloxy-2-fluorobenzonitrile (4) is reacted with (~)-1-amino-2-
propanol in an
Z5 organic solvent, to yield (~)-4-benzyloxy-2-(2-
hydroxypropyl)aminobenzonitrile (5). At least
two molar equivalents of 1-amino-2-propanol are used, as one molar equivalent
is consumed
as the amine hydrofluoride. Alternatively an auxiliary base is employed, for
example a
tertiary amine such as triethylamine or N,N-disopropylethylamine, an alkali
metal carbonate
such as sodium carbonate or potassium carbonate, or basic alumina. When the
auxiliary base
2o is employed, less than two molar equivalents of (~)-1-amino-2-propanol can
be used,
preferably about 1.5 molar equivalents. Preferably an auxiliary base is
employed, most
preferably basic alumina. The solvent is preferably a dipolar apxotic solvent,
for example
dimethyl sulfoxide or N-methylpyrrolidone. The temperature is 80 to 140
°C, preferably 100
to 120 °C. Optionally, a drying agent, e.g., zeolite molecular sieves,
is present.
2s Alternatively, compound 4 is reacted with (R)-1-amino-2-propanol according
to the
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foregoing method to yield (R)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzonitrile
(R-5).
Alternatively, compound 4 is reacted with (S~-1-amino-2-propanol according to
the foregoing
method to yield (~-4-benzyloxy-2-(2-hydroxypropyl)aminobenzonitrile (S-5).
Step 2. Compound 5 is reacted with a hydrogen source and a catalyst in a
solvent
s mixture containing water, an acidic component and an organic solvent, to
yield (~)-4-
benzyloxy-2-(2-hydroxypropyl)aminobenzaldehyde (6). The organic solvent can be
formic
acid, which also serves as the acidic component and hydrogen source, or acetic
acid, which
also serves as the acidic component. Optionally an organic co-solvent can be
used, for
example pyridine. The hydrogen source can be, for example, hydrogen gas,
hypophosphorous
1 o acid, or an inorganic hypophosphite salt such as sodium hypophosphite.
Preferably the
solvent is a mixture of pyridine, acetic acid, and water in a ratio of about
2:1:1 parts by
volume. Preferably, the hydrogen source is sodium hypophosphite and preferably
the catalyst
is Raney nickel. The temperature is 20 to 60 °C, preferably 40 to 45
°C.
[This method is generally described in Fieser and Fieser, Reagents for Organic
Synthesis,
15 Volume 1, page 726 (1967).]
Alternatively, compound R-5 is reacted according to the foregoing method to
yield
(R)-4-benzyloxy-2-(2-hydroxypropyl)aminobenzaldehyde (R-6). Alternatively,
compound S 5
is reacted according to the foregoing method to yield (S~-4-benzyloxy-2-(2-
hydroxypropyl)aminobenzaldehyde (S 6).
2 o Compound 6 is reacted with an organic nitrite, e.g., isoamyl nitrite, in
an organic
solvent (e.g., tetrahydrofuran), or with an inorganic nitrite, e.g., sodium
nitrite, in an organic
solvent (e.g., acetic acid), or organic-aqueous solvent pair (e.g., acetic
acid-water;
tetrahydrofuran -dilute aqueous HCl) to yield (~)-4-benzyloxy-2-(2-
hydroxypropyl)nitrosaminobenzaldehyde (7). Preferably the nitrite is sodium
nitrite and the
2s solvent is acetic acid-water. Preferably the temperature is kept between
about 0 °C and 35
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14
°C. Preferably an inert atmosphere, e.g., nitrogen or argon, is
maintained. The preferred
method is to react 6 with about 1.2 molar equivalents of NaN02 in acetic acid-
water (about
4:I parts by volume) at 15 to 25 °C. The resulting compound 7 can be
isolated, but it is
preferable instead to convert 7 without isolation to 8 e.g., by a one-flask
method as described
s herein.
Alternatively, compound R-6 is reacted according to the foregoing method to
yield
(R)-4-benzyloxy-2-(2-hydroxypropyl)nitrosaminobenzaldehyde (R-7).
Alternatively,
compound S 6 is reacted according to the foregoing method to yield (~-4-
benzyloxy-2-(2-
hydroxypropyl)nitrosaminobenzaldehyde (S 7).
1 o Compound 7 is reacted with a reducing agent in an organic solvent
optionally
containing water to yield (~)-6-benzyloxy-1-(2-hydroxypropyl)indazole (8).
Preferably the
reducing agent is zinc and the solvent is a mixture of acetic acid and water
in a ratio of about
4:1 parts by volume. Most preferably, the reduction is carried out by adding
zinc to the
reaction mixture in which compound 7 was prepared from compound 6, without
isolation of
z 5 compound 7.
The desired reduction-cyclization reaction of 7 to 8 can be accompanied by a
competing denitrosation reaction to regenerate 6. When zinc dust is used as
the reducing
agent, the ratio of 8 to 6 is about 5:1. The nitrosation-reduction sequence
can be repeated on
the crude reaction mixture to effect nearly complete conversion of 6 to 8.
Alternatively,
2 o removal of 6 from the crude product can be effected by chromatography.
Alternatively, 6 is
removed as a water-soluble hydrazone derivative which is formed by treating
the crude
product with, e.g., Guard's Reagent T or Guard's Reagent P. Alternatively, 6
is removed as a
polymer-bound hydrazone derivative by treating the crude product with a
polymer-bound
arenesulfonylhydrazide resin.
2s Alternatively, compound R-7 is reacted according to the foregoing method to
yield
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(R)-6-benzyloxy-1-(2-hydroxypropyl)indazole (R-8). Alternatively, compound S 7
is reacted
according to the foregoing method to yield (~-b-benzyloxy-1-(2-
hydroxypropyl)indazole (S-
8).
Compound 8 is ,reacted with an alkanesulfonyl halide or anhydride, or with an
5 arenesulfonyl halide or anhydride, in an organic solvent in the presence of
a base, to form the
corresponding sulfonic ester. Preferably an alkanesulfonyl halide is used,
most preferably
methanesulfonyl chloride. The organic solvent can be pyridine which also
serves as the base.
Preferably the solvent is dichloromethane and the base is triethylamine.
Preferably an inert
atmosphere, e.g., nitrogen or argon, is maintained. The sulfonic ester thus
obtained is reacted
so with an alkali metal azide ' in an organic solvent, to yield (~)-1-(~,-
azidopropyl)-6-
benzyloxyindazole (9). Preferably the alkali metal azide is sodium azide and
the solvent is
preferably a Bipolar aprotic solvent, most preferably N,N-dimethylformamide.
The
temperature can be 25 to 80 °C; preferably about 60 °C, and
other temperatures are possible.
Alternatively, compound R-8 is reacted according to the foregoing method to
yield
1s (S)-1-(2-azidopropyl)-6-benzyloxyindazole (S 9). Alternatively, eompound S
8 is reacted
according to the foregoing method to yield (R)-1-(2-azidopropyl)-6-
benzyloxyindazole (R-9).
Compound 9 is reacted with a hydrogen source and a catalyst in an organic
solvent, to
yield (~)-1-(2-aminopropyl)-6-hydroxy indazole (10). Preferably the hydrogen
source is
ammonium formate, the catalyst is palladium on charcoal and the solvent is
ethanol.
2 o Alternatively, compound S 9 is reacted according to the foregoing method
to yield
(~-1-(2-aminopropyl)-6-hydroxy indazole (S-10). Alternatively, compound R-9 is
reacted
according to the foregoing method to yield (R)-1-(2-aminopropyl)-6-hydroxy
indazole (R-10).
The following examples are given to illustrate the preparation of compounds
that are
the subject of this invention but should not be construed as implying any
limitations to the
2 5 claims.
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E~~AMPLES
Preparation of (~)-6-benzyloxy-1-(2-hydroxypropyl)indole (2). To a stirred,
cooled (10
°C) suspension of NaH (80.7 g of a 60% dispersion in mineral oil, 2.02
mol) in anhydrous
THF (1.9 L) was added a solution of 6-benzyloxyindole (1) (375 g, 1.68 mol) in
anhydrous
s THF (1.9 L) keeping the temperature below 25 °C. After 2 h at 10
°C, (~)-propylene oxide
(140 mL, 2.0 mol) was added dropwise keeping the temperature below 25
°C. After 48 h at
°C, (~)-propylene oxide (71 mL, 1.0 mol) was added. After 96 h at 10
°C , saturated
aqueous KH2P04 (3.8 L) and ethyl acetate (3.8 L) were carefully added, the
layers were
separated and the aqueous solution was extracted with 3.8 L of ethyl acetate.
The combined
Z o organic extracts were dried over sodium sulfate and concentrated in vacuo
to yield 2 (520 g,
110%, contains mineral oil).
Preparation of (~)-4-Benzyloxy-2-(N-(2-hydroxypropyl)formamido)benzaldehyde
(3). A
solution of 172 g of 2 in 1.5.L of dichloromethane was cooled to 78 °C
and ozonized (4%
ozone in oxygen). Excess ozone was displaced with oxygen for 5 min, followed
by addition
s5 of 78 mL of dimethyl sulfide and warming to 25 °C. The solution was
concentrated to half
volume, eluted through Florisil rinsing with ethyl ether-ethyl acetate and
concentrated in
vacuo. One additional run on 172 g scale and three runs on 58-g scale were
performed. The
combined products were eluted through silica (2.5 kg) with a gradient of 10%-
80% ethyl
acetate-hexane to yield, after concentration in vacuo, 3 (351 g, 70%) as an
oil.
2 o Preparation of (~)-4-Benzyloxy-2-(2-hydroxypropyl)aminobenzaldehyde (6).
An ice-
cooled solution of 3 (298 g, 0.95 mol) in THF (3 L) was treated with 1M aq
NaOH (1.95 L,
1.9 mol) keeping the temperature below 8° C. After 3 was consumed, the
mixture was
diluted with brine and extracted twice with ethyl ether. The organic solution
was washed
with water until neutral and with brine, dried over sodium sulfate, treated
with charcoal and
25 eluted through silica (1 kg) with ether and with 1:1 ethyl acetate-hexane
to yield, after
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concentration in vacuo, 6 (207 g, 76%) as a yellow solid.
Preparation of 4-Benzyloxy-2-fluorobenzonitrile (4). Benzyl bromide (467 mL,
3.93 mol)
and potassium carbonate (1.4 kg, 10.1 mol) were added to a solution of 2-
fluoro-4-
hydroxybenzonitrile (490 g, 3.57 mol) in 3.4 L of acetone. The stirred mixture
was heated at
60 °C for 20 h, then cooled and filtered. The filtrate was concentrated
and the resulting solid
was triturated with 10% ethyl acetate-hexane (5 L) and vacuum dried at 35
°C to yield 4 (787
g, 97%).
Preparation of (R)-4-Benzyloxy-2-(2-hydroxypropyl)aminobenzonitrile (R-5). A
solution
of (R)-(-)-1-amino-2-propanol (389 g, 5.19 mol) in DMSO (600 mL) was added to
a solution
of 4 (786 g, 3.46 mol), basic alumina (786 g), and 4A molecular sieves (131
g). The stirred
mixture was heated at 110-140 °C for 24 h, cooled and filtered through
Celite, washing with
10 L of 4:1 ether-ethyl acetate followed by 4 L of 3:2 ethyl acetate-hexane.
The organic
washes were extracted with water (5 L) and the aqueous phase was extracted
with four 2-L
portions of 25% ethyl acetate-hexane. The combined organic phases were washed
with water
s5 and brine, dried over sodium sulfate, concentrated to about 4 L and allowed
to stand for 48 h.
The precipitated solid was collected by filtration, washed with hexane and
vacuum dried to
provide R-5 (first crop 613 g, second crop, 86 g). The concentated supernatant
was applied to
a 5 kg silica gel pad and eluted with a gradient of 10-50% ethyl acetate-
hexane to give, after
concentration in vacuo, 119 g of 5, for a total yield of 791 g (81 %) of R-5.
2 o Preparation of (R)-4-Benzyloxy-2-(2-hydroxypropyl)aminobenzaldehyde (R-6).
Sodium
hypophosphite hydrate (986 g, 11.2 mol) and Raney nickel (500 g of a 50%
aqueous
suspension) were added to a solution of R-5 (790 g, 2.8 mol) in 7 L of 2:1:1
pyridine-acetic
acid-water. The mixture was stirred at 45 °C for 7 h, then cooled to 25
°C overnight and
filtered through Celite rinsing with water and ethyl acetate. The filtrate was
washed with
2 s saturated Na2HP04 to pH 5, with water and brine, dried over sodium sulfate
and
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concentrated. During concentration, 4 L of heptane was added to azeotropically
remove
pyridine. After 8 L of solvent had been removed the product solidified.
Heptane (5 L) was
added and the solid was triturated, isolated by filtration and vacuum dried at
35 °C to yield R-
6 (722 g, 90%).
Preparation of (R)-6-benzyloxy-1-(2-hydroxypropyl)indazole (R-8). Sodium
nitrite (209 g,
3.03 mol) was added over 25 min to a stirred solution of R-6 (720 g, 0.2.53
mol) in acetic
acid (5.6 L) and water (1.4 L), keeping the temperature below 25° C.
The resulting solution
of nitrosamine R-7 was cooled in ice, and zinc dust (595 g, 9.10 mol) was
added in 25-g
portions over 3.5 h, keeping the temperature below 35°C. Ethyl acetate
(7 L) was added and
1 o the thick suspension was filtered on a sintered glass funnel, washing with
ethyl acetate (7.5
L). To the filtrate containing a 5:1 mixture of R-8 and regenerated R-6 was
added Girard's
Reagent T (98 g, 0.58 mol). After stirring at 25° C for 1 day, another
150 g (0.90 mol) of
Girard's Reagent T was added. After 3 more days R-6 was consumed. The mixture
was
extracted twice with water, with aqueous Na2HP0~. to remove acetic acid, with
water and
brine, dried over sodium sulfate, filtered through Florisil and concentrated.
The residue was
eluted through 5 kg of silica withl:l ethyl acetate-hexane. Clean fractions
were concentrated
and 4 L of heptane was added to precipitate R-8. The solid was collected by
filtration,
washed with 1:1 ethyl acetate-hexane and vacuum dried at 35°C to yield
(417 g, 58%) of a
yellow solid, composed of 96.7% R-8, 0.3% S-8 and 3% R-6 by HPLC.
Concentration of the
2 o supernatant afforded an additional 14I g (20%) of R-8.
Preparation of (~)-6-benz~loxy-1-(2-hydroxypropyl)indazole (8). The procedure
described for R-8 was followed, beginning with (~)-6 (202.7 g, 0.71 mol).
After nitrosamine
7 had been converted to a mixture of 8 and 6 (5:1), sodium nitrite (29.5 g,
0.43 mol) was
added to renitrosate 6. Zinc dust (84 g, 1.28 mol) was then added in portions
with cooling as
described above. When the formation of 8 was complete, the reaction mixture
was worked
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up as described above and combined with the product from another run that
started with 176
g of 6. The combined crude product was purified by chromatography on a Biotage
I~iloprep-
250 instrument, eluting with ethyl acetate-hexane, to yield 8 (226 g, 60%) of
99% HPLC
purity.
s Preparation of (S)-1-(2-Azidopropyl)-6-benzyloa~yindazole (S 9). A solution
of R-8 (415
g, 1.47 mol) in dichloromethane (4 L) was treated with triethylamine (224 mL,
1.6 mol) and
cooled to 0 °C. Methanesulfonyl chloride (125 mL, 1.6 mol) was added
keeping the
temperature below 25 °C. The mixture was stirred at 25 °C until
complete and was then
quenched with water (4 L) and stirred vigorously. The layers were separated
and the aqueous
s o layer was extracted with an additional 4 L of dichloromethane. The
combined organic
solutions were dried over sodium sulfate and concentrated in vacuo. The
residue was
dissolved in DMF (4 L), sodium azide (191 g, 2.94 mol) was added and the
mixture was
stirred and heated to 70 °C for, l6 h, then allowed to cool to 25
°C. Water (16 L) and diethyl
ether (5.5 L) were added, the xnixture was stirred vigorously and the layers
were allowed to
s 5 separate. The aqueous layer was extracted with diethyl ether (2x7 L), and
the combined
organic solutions were concentrated and the residue was eluted through silica
(6 kg) with 1:3
..
ethyl acetate/hexane. Product containing fractions were concentrated in vacuo
to yield S 9
(380 g, 84%) as an oil.
Preparation of (S)-1-(2-Aminopropyl)-6-hydroa~yindazole (S-10). Ammonium
formate
20 (312 g, 4.96 mol) and 10% Pd(C) (38 g) were added to a stirred solution ofS
9 (380 g, 1.24
mol) in 4 L of EtOH. After 2 h, another 38 g of 10% Pd(C) was added. The
mixture was
stirred for 2 h, then filtered through Celite, rinsing with EtOH, and the
filtrate was
concentrated. The residue was partitioned between saturated NaHC03 (4 L) and
1:1 ethyl
acetate-THF (5 L). The aqueous phase was treated with 200 g of NaCI and
extracted .with 2:1
2 s ethyl acetate-THF (3 x 4 L). The combined organic extracts were dried over
sodium sulfate,
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filtered and concentrated in vacuo. The solid residue was suspended in ethyl
acetate (3 L),
stirred for 0.5 h and filtered to give 200 g of a solid. This material was
suspended in THF (1
L) and the mixture was stirred for several minutes and filtered to give a
solid, which was
washed with cold THF (200 mL), air dried, and then dried for 16 h in vacuo at
45 °C to yield
5 S 10 (183 g, 77%).
SCHEME 1
j I % cN
O H O F
~Ph 1 ~Ph 4
O HO
~CH3 ~NHZ
NaH, THF CHa
Ah03, DMSO
CN
l~ I~
O / N O / NICH
'OH ' 'OH
Ph 2 Ph fY5
CH3 CH3
03, CH~Ch NaH~P02
Raney Ni
Me2S Py-HOAc-
H~O
CHO NaOH ~ CHO
_ NaNOz
( / .H HOA O
CHO TH I /
O N
N. O
O
~Ph 3 Y OH ~ph g ~OH
I
CH3 CH3
CHO
Zn ~ N MsCI, Et3N;
NO ~ /
N~ HOAc-H20N NaN3
O
'ph ' /OH ~OH
~ ~P ~'h
'
7 $ CH3
C
H3
NH40CH0
O I / N N pd~C~ HO I / N N
EtOH
~N3 ' 'NHZ
~P ~' ~'h
g CH3 10 CH3
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Other embodiments of the present invention will be apparent to those skilled
in the art
from consideration of the present specification and practice of the present
invention disclosed
herein. It is intended that the present specification and examples be
considered as exemplary
only, with a true scope and spirit of the invention being indicated by the
following claims and
equivalents thereof.
SUBSTITUTE SHEET (RULE 26)
