Note: Descriptions are shown in the official language in which they were submitted.
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METHODS FOR PREPARING INDAZOLE COMPOUNDS
Field of the Invention
The present invention relates to methods for preparing indazole compounds, and
intermediates thereof, which are useful as modulators and/or inhibitors of
protein kinases.
Background of the Invention
The discussion of the background to the invention herein is included to
explain the
context of the invention. This is not to be taken as an admission that any of
the material referred
to was published, known or part of the common general knowledge in any country
as of the
priority date of any of the claims.
U.S. Patent Nos. 6,531,491 and 6,534,524, each of which are incorporated
herein by
reference in their entirety, are directed to indazole compounds that modulate
and/or inhibit the
activity of certain protein kinases such as VEGF-R (vascular endothelial cell
growth factor
receptor), FGF-R (fibroblast growth factor receptor), CDK (cyclin-dependent
kinase) complexes,
CHK1, LCK (also known as lymphocyte-specific tyrosine kinase), TEK (also known
as Tie-2),
FAK (focal adhesion kinase), and/or phosphorylase kinase. Such compounds are
useful for the
treatment of cancer and other diseases associated with angiogenesis or
cellular proliferation
mediated by protein kinases.
One group of indazole compounds discussed in the above-referenced U.S. Patents
is
represented by the formula shown below:
H
R9
H H 0 N&R10
N,N / Y I ~ ~ R1 H Rio
H
wherein:
Ri is a substituted or unsubstituted aryl or heteroaryl, or a group of the
formula CH=CHR3
or CH=NR3, where R3 is a substituted or unsubstituted alkyl, cycloalkyl,
heterocycloalkyl, aryl, or
heteroaryl;
Y is 0, S, C=CH2, C=O, S=O, SO2, CH2, CHCH3, -NH-, or -N(C1 to Ca alkyl);
R9 is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl,
aryl, heteroaryl,
alkoxyl, aryloxyl, cycloalkoxyl, -NH(Ci to C$ alkyl), -NH(aryl), -
NH(heteroaryl), -N=CH(alkyl),
-NH(C=O)R11, or -NH2, where R11 is independently selected from hydrogen,
substituted or
unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and
R10 is independently selected from hydrogen, halogen, and lower-alkyl; and
pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites,
and
pharmaceutically acceptable salts thereof.
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Although methods for preparing such compounds were previously referred to,
there
remains a need in the art for new synthetic routes that are efficient and cost
effective.
Summary of the Invention
In one aspect, the invention relates to methods for preparing a compound of
formula I:
H
H 0 N, R2
3
N1N S/ R
R1 R3
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R' is a group of the formula -CH=CHR4 or -CH=NR4, and R' is substituted with 0
to 4 R5
groups;
R2 is (Ci to C12) alkyl, (C3 to C12) cycloalkyl, (5 to 12-membered)
heterocycloalkyl, (Cs to
C12) aryl, (5 to 12-membered) heteroaryl, (Cl to C12) alkoxy, (Cs to C12)
aryloxy, (C3 to C12)
cycloalkoxy, -NH(C1 to C8 alkyl), -NH(C6 to C12 aryl), -NH(5 to 12-membered
heteroaryl),
-N=CH(Ci to C12 alkyl), -NH(C=O)H, -NH(C=O)R5, or -NH2, and R2 is substituted
with 0 to 4 R5
groups;
each R3 is independently hydrogen, halogen, or (C1 to C8) alkyl, and the (Cl
to C8) alkyl is
substituted with 0 to 4 R5 groups;
R4 is (Ci to C12) alkyl, (C3 to C12) cycloalkyl, (5 to 12-membered)
heterocycloalkyl, (C6 to
C12) aryl, or (5 to 12-membered) heteroaryl, and R4 is substituted with 0 to 4
R5 groups;
each R5 is independently halogen, (Ci to C8) alkyl, (C2 to C8) alkenyl, (C2 to
C8) alkynyl,
-OH, -NO2i -CN, -CO2H, -O(C1 to C8 alkyl), (C6 to C12) aryl, (Cs to C12) aryl
(Ci to C8) alkyl,
-CO2CH3a -CONH2, -OCH2CONH2, -NH2, -SO2NH2i halo substituted (C1 to C12)
alkyl, or -O(halo
substituted (Cl to C12) alkyl); comprising:
a) reacting a compound of formula II with a compound of formula III to provide
a
compound of formula IV:
N1 O NR2 w O N,R2
N I X+ HS
R/ R3 N,N S/ I R3
R1 3~ R' 1 ~ R3 ~
11 III IV
wherein the reaction occurs in the presence of a catalyst and a base; W is a
protecting group; X
is an activated substituent group; and R', R2, and R3 are as described above;
and
b) deprotecting the compound of formula IV to provide the compound of formula
I.
In another aspect, the invention relates to method for preparing a compound of
formula I,
wherein the catalyst is a palladium catalyst.
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In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein the catalyst is Pd(dppf)CI2-CH2CI2.
In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein the base is selected from the group consisting of potassium
carbonate, sodium
carbonate, cesium carbonate, sodium t-butoxide, potassium t-butoxide,
triethylamine, and
mixtures thereof.
In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein the base is cesium carbonate.
In another aspect, the invention relates to methods for preparing a compound
of formula
I, further comprising a solvent in the reaction between the compound of
formula II and the
compound of formula Ill.
In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein the solvent is N, N-dimethyl formamide.
In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein the reaction is carried out at about 80 C.
In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein W is a tetrahydropyran protecting group or a
trimethylsilyiethoxymethyl protecting
group.
In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein the activated substituent group X is chloride, bromide, or iodide.
In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein the activated substituent group X is iodide.
In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein the protecting group W is tetrahydropyran, and the process of
deprotecting comprises
reacting the compound of formula IV with an acid in an alcoholic solvent.
In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein the acid is methanesulfonic acid or is p-toluenesulfonic acid, and
the alcoholic solvent
is methanol, ethanol, n-propanol or isopropanol.
In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein the compound of formula II has formula V, and the compound of
formula Ill has formula
VI:
w
N'N I NCH
3
HS
+ ~I
v vi
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In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein the compound of formula IV has formula VII:
H
w -CH
,
NN S
N
VII
In another aspect, the invention relates to methods for preparing a compound
of formula
I, wherein the compound of formula I has formula VIII:
H
H -CH
3
N N S
N
VIII
In another aspect, the invention relates to methods for preparing a compound
of formula
II:
w
N.N x
R1
II
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R' is a group of the formula -CH=CHR4 or -CH=NR4, and R' is substituted with 0
to 4 R5
groups;
R4 is (Cl to C12) alkyl, (C3 to C12) cycloalkyl, (5 to 12-membered)
heterocycloalkyl, (C6 to
C12) aryl, or (5 to 12-membered) heteroaryl, and R4 is substituted with 0 to 4
R5 groups;
each R5 is independently halogen, (Ci to Ca) alkyl, (Cz to C8) alkenyl, (C2 to
Ca) alkynyl,
-OH, -NO2, -CN, -CO2H, -O(Ci to Ca alkyl), (Cs to C12) aryl, (C6 to C12) aryl
(Cl to C8) alkyl,
-CO2CH3i -CONH2, -OCH2CONH2, -NH2, -SO2NH2i halo substituted (Ci to C12)
alkyl, or -O(halo
substituted (Ci to C12) alkyl);
W is a protecting group; and
X is an activated substituent group;
comprising:
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a) reacting a compound of formula IX with a diazotizing agent to form a
diazonium salt;
and
b) treating the diazonium salt with a metal halide,
w w
N NH2 NN / I X
R' ~ R'
IX I I
wherein R1, W and X are as described above.
In another aspect, the invention relates to methods for preparing a compound
of formula
II, wherein the activated substituent group X is chloride, bromide, or iodide.
In another aspect, the invention relates to methods for preparing a compound
of formula
II, wherein the activated substituent group X is iodide.
In another aspect, the invention relates to methods for preparing a compound
of formula
II, wherein the diazotizing agent is sodium nitrite or t-butyl nitrite.
In another aspect, the invention relates to methods for preparing a compound
of formula
II, wherein the diazotizing agent is sodium nitrite, and the metal halide is
potassium iodide.
In another aspect, the invention relates to methods for preparing a compound
of formula
II, further comprising a catalytic amount of iodine.
In another aspect, the invention relates to methods for preparing a compound
of formula
II, wherein the compound of formula IX has formula X, and the compound of
formula II has
formula V:
W W
N.N NH2 N.N I
I
I N I N
x v
In accordance with a convention used in the art, is used in structural
formulas herein
to depict the bond that is the point of attachment of the moiety or
substituent to the core or
backbone structure. When the phrase, "optionally substituted with one or more
substituents" is
used herein, it is meant to indicate that the group in question may optionally
be substituted by one
or more of the substituents provided. The number of substituents a group in
the compounds of
the invention may have depends on the number of positions available for
substitution. For
example, an aryl ring in the compounds of the invention may contain from 1 to
5 additional
substituents, depending on the degree of substitution present on the ring. The
maximum number
of substituents that a group in the compounds of the invention may have can be
easily
determined.
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The terms "react", "reacted" and "reacting," as used herein, refers to a
chemical process
or processes in which two or more reactants are allowed to come into contact
with each other to
effect a chemical change or transformation. For example, when reactant A and
reactant B are
allowed to come into contact with each other to afford a new chemical
compound(s) C, A is said
to have "reacted" with B to produce C.
The terms "protect," "protected," and "protecting" as used herein, refers to a
process in
which a functional group in a chemical compound is selectively masked by a non-
reactive
functional group in order to allow a selective reaction(s) to occur elsewhere
on said chemical
compound. Such non-reactive functional groups are herein termed "protecting
groups." For
example, the term "nitrogen protecting group," as used herein refers to those
groups that are
capable of selectively masking the reactivity of a nitrogen (N) group. The
term "suitable
protecting group," as used herein refers to those protecting groups that are
useful in the
preparation of the compounds of the present invention. Such groups are
generally able to be
selectively introduced and removed using mild reaction conditions that do not
interfere with other
portions of the subject compounds. Protecting groups that are suitable for use
in the processes
and methods of the present invention are well known. The chemical properties
of such protecting
groups, methods for their introduction and their removal can be found, for
example, in T. Greene
and P. Wuts, Protective Groups in Organic Synthesis (3d ed.), John Wiley &
Sons, NY (1999),
herein incorporated by reference in its entirety. The terms "deprotect,"
"deprotected," and
"deprotecting," as used herein, are meant to refer to the process of removing
a protecting group
from a compound.
The term "leaving group," as used herein refers to a chemical functional group
that
generally allows a nucleophilic substitution reaction to take place at the
atom to which it is
attached. For example, in acid chlorides of the formula Cl-C(O)R, wherein R is
alkyl, aryl, or
heterocyclic, the -Cl group is generally referred to as a leaving group
because it allows
nucleophilic substitution reactions to take place at the carbonyl carbon.
Suitable leaving groups
are well known, and can include halides, aromatic heterocycles, cyano, amino
groups (generally
under acidic conditions), ammonium groups, alkoxide groups, carbonate groups,
formates, and
hydroxy groups that have been activated by reaction with compounds such as
carbodiimides. For
example, suitable leaving groups include, but are not limited to, chloride,
bromide, iodide, cyano,
imidazole, and hydroxy groups that have been allowed to react with a
carbodiimide such as
dicyclohexylcarbodiimide (optionally in the presence of an additive such as
hydroxybenzotriazole)
or a carbodiimide derivative.
The term "activated substituent group," as used herein refers to a chemical
functional
group that generally allows a substitution reaction to take place at the atom
to which it is
attached. For example, in aryl iodides, the -I group is generally referred to
as an activated
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substituent group because it allows substitution reactions to take place at
the aryl carbon.
Suitable activated substituent groups are well known, and can include halides
(chloride, bromide,
iodide), activated hydroxyl groups (e.g., triflate, mesylate, and tosylate),
and diazonium salts.
As used herein, the term "alkyl" represents a straight- or branched-chain
saturated
hydrocarbon, containing 1 to 10 carbon atoms which may be unsubstituted or
substituted by one
or more of the substituents described below. Exemplary alkyl substituents
include, but are not
limited to methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-
butyl, and the like.
The term "alkenyl" represents a straight- or branched-chain hydrocarbon,
containing one
or more carbon-carbon double bonds and having 2 to 10 carbon atoms which may
be
unsubstituted or substituted by one or more of the substituents described
below. Exemplary
alkenyl substituents include, but are not limited to ethenyl, propenyl,
butenyl, allyl, pentenyl and
the like.
The term "phenyl," as used herein refers to a fully unsaturated 6-membered
carbocyclic
group. A"phenyP' group may also be referred to herein as a benzene derivative.
The term "heteroaryl," as used herein refers to a group comprising an aromatic
monovalent monocyclic, bicyclic, or tricyclic group, containing 5 to 18 ring
atoms, including 1 to 5
heteroatoms selected from nitrogen, oxygen and sulfur, which may be
unsubstituted or
substituted by one or more of the substituents described below. As used
herein, the term
"heteroaryl" is also intended to encompass the N-oxide derivative (or N-oxide
derivatives, if the
heteroaryl group contains more than one nitrogen such that more than one N-
oxide derivative
may be formed) of the nitrogen-containing heteroaryl groups described herein.
Illustrative
examples of heteroaryl groups include, but are not limited to, thienyl,
pyrrolyl, imidazolyl,
pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl,
pyrazinyl, pyrimidinyl,
pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl,
isobenzofuranyl, chromenyl,
xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl,
purinyl, isoquinolyl, quinolyl,
phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl,
benzimidazolyl,
tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl,
phenanthridinyl, acridinyl,
perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and
phenoxazinyl.
Illustrative examples of N-oxide derivatives of heteroaryl groups include, but
are not limited to,
pyridyl N-oxide, pyrazinyl N-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide,
triazinyl N-oxide,
isoquinolyl N-oxide, and quinolyl N-oxide. Further examples of heteroaryl
groups include the
following moieties:
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~ ~~ [/ ~ / \N QN O N ~O R S R
cQOOQL000
N N N N N
oRoo0(;c1o0(?ccs
i I\ QCNOOOT0()
\ N -N Ns \ ~N N/ ~N
N \ ~ \ I N O \ I N / \ I N /
R
wherein R is H, alkyl, hydroxyl or is a suitabie nitrogen protecting group.
The terms "halide," "halogen" and "halo" represent fluoro, chloro, bromo or
iodo
substituents.
If an inventive compound or an intermediate in the present invention is a
base, a desired
salt may be prepared by any suitable method known in the art, including
treatment of the free
base with an inorganic acid, such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid,
phosphoric acid, and the like, or with an organic acid, such as acetic acid,
maleic acid, succinic
acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,
glycolic acid, salicylic
acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-
hydroxy acid, such as
citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic
acid, aromatic acid, such
as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic
acid or ethanesulfonic
acid, or the like.
If an inventive compound or an intermediate in the present inventon is an
acid, a desired
salt may be prepared by any suitable method known to the art, including
treatment of the free
acid with an inorganic or organic base, such as an amine (primary, secondary,
or tertiary); an
alkali metal or alkaline earth metal hydroxide; or the like. Illustrative
examples of suitable salts
include organic salts derived from amino acids such as glycine and arginine;
ammonia; primary,
secondary, and tertiary amines; and cyclic amines, such as piperidine,
morpholine, and
piperazine; as well as inorganic salts derived from sodium, calcium,
potassium, magnesium,
manganese, iron, copper, zinc, aluminum, and lithium.
The compounds of the present invention may contain at least one chiral center
and may
exist as single stereoisomers (e.g., single enantiomers or single
diastereomers), any mixture of
stereoisomers (e.g., any mixture of enantiomers or diastereomers) or racemic
mixtures thereof. It
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is specifically contemplated that, unless otherwise indicated, all
stereoisomers, mixtures and
racemates of the present compounds are encompassed within the scope of the
present invention.
Compounds identified herein as single stereoisomers are meant to describe
compounds
that are present in a form that contains at least from at least about 90% to
at least about 99% of a
single stereoisomer of each chiral center present in the compounds. Where the
stereochemistry
of the chiral carbons present in the chemical structures illustrated herein
are not specified, it is
specifically contemplated that all possible stereoisomers are encompassed
therein. The
compounds of the present invention may be prepared and used in
stereoisomerically pure form or
substantially stereoisomerically pure form.
As used herein, the term "stereoisomeric" purity refers to the "enantiomeric"
purity and/or
"diastereomeric" purity of a compound. The term "stereoisomerically pure
form," as used herein,
is meant to encompass those compounds that contain from at least about 95% to
at least about
99%, and all values in between, of a single stereoisomer.
The term "substantially enantiomerically pure," as used herein is meant to
encompass
those compounds that contain from at least about 90% to at least about 95%,
and all values in
between, of a single stereoisomer.
The term "diastereomerically pure," as used herein, is meant to encompass
those
compounds that contain from at least about 95% to at least about 99%, and all
values in between,
of a single diastereoisomer.
The term "substantially diastereomerically pure," as used herein, is meant to
encompass
those compounds that contain from at least about 90% to at least about 95%,
and all values in
between, of a single diastereoisomer.
The terms "racemic" or "racemic mixture," as used herein, refer to a mixture
containing
equal amounts of stereoisomeric compounds of opposite configuration. For
example, a racemic
mixture of a compound containing one stereoisomeric center would comprise
equal amount of
that compound in which the stereolsomeric center is of the (S)- and (R)-
configurations.
The term "enantiomerically enriched," as used herein, is meant to refer to
those
compositions wherein one stereoisomer of a compound is present in a greater
amount than the
opposite stereoisomer.
Similarly, the term "diastereomerically enriched," as used herein, refers to
those
compositions wherein one diastereomer of compound is present in amount greater
than the
opposite diastereomer.
The compounds of the present invention may be obtained in stereoisomerically
pure (i.e.,
enantiomerically and/or diastereomerically pure) or substantially
stereoisomerically pure (i.e.,
substantially enantiomerically and/or diastereomerically pure) form. Such
compounds may be
obtained synthetically, according to the procedures described herein using
stereoisomerically
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pure or substantially stereoisomerically pure materials. Alternatively, these
compounds may be
obtained by resolution/separation of mixtures of stereoisomers, including
racemic and
diastereomeric mixtures, using known procedures. Exemplary methods that may be
useful for
the resolution/separation of stereoisomeric mixtures include derivitation with
stereochemically
pure reagents to form diastereomeric mixtures, chromatographic separation of
diastereomeric
mixtures, chromatographic separation of enantiomeric mixtures using chiral
stationary phases,
enzymatic resolution of covalent derivatives, and crystallization/re-
crystallization. Other useful
methods may be found in Enantiomers, Racemates, and Resolutions, J. Jacques,
et al., 1981,
John Wiley and Sons, New York, NY, the disclosure of which is incorporated
herein by reference.
Preferred stereoisomers of the compounds of this invention are described
herein.
Detailed Description of the Invention
The compounds of formula I can be prepared from 6-nitroindazole. The indazole
ring can
be substituted at the C-3 position with an R' group as described herein, using
commonly known
reagents and reactions. For example, the C-3 position of the indazole ring can
be functionalized
by reacting 6-nitroindazole with iodine (12) in the presence of a base such as
potassium carbonate
(K2CO3), and in a solvent such as DMF, to provide 3-iodo-6-nitro-indazole.
H NO
H DMF N 2
N N \6 N02 + 12 + K2CO3 N~ + ICI + KHCO3
\
3
The C-3 position of the indazole ring can then be elaborated to a desired R'
group using
known reactions, such as a Suzuki reaction or a Heck reaction.
Before elaboration of the C-3 R' group, however, the intermediates useful for
the
preparation of the compounds of formula I may require the use of protecting
groups. For
example, the nucleophilic indazole ring nitrogen (N-1) may require masking
through use of a
suitable protecting group. Furthermore, if the substituents on these
intermediates are themselves
not compatible with the synthetic methods of this invention, the substituents
may be protected
with suitable protecting groups that are stable to the reaction conditions
used in these methods.
The protecting groups may be removed at a suitable point in the reaction
sequence of the method
to provide a desired intermediate or target compound. Suitable protecting
groups and the
methods for protecting and de-protecting different substituents using such
suitable protecting
groups are well known, examples of which may be found in T. Greene and P.
Wuts, supra.
A suitable nitrogen protecting group, W, is one that is stable to the reaction
conditions in
which the compounds of formula II are allowed to react with the compounds of
formula III to
provide the compounds of formula IV. Furthermore, such a protecting group
should be chosen so
that it can be subsequently removed to provide the compounds of formula I.
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As indicated above, suitable nitrogen protecting groups are well known, and
any nitrogen
protecting group that is useful in the methods of preparing the compounds of
this invention or
may be useful in the protein kinase inhibitory compounds of this invention may
be used.
Exemplary nitrogen protecting groups include silyi, substituted silyl, alkyl
ether, substituted alkyl
ether, cycloalkyl ether, substituted cycloalkyl ether, alkyl, substituted
alkyl, carbamate, urea,
amide, imide, enamine, sulfenyl, sulfonyl, nitro, nitroso, oxide, phosphinyl,
phosphoryl, silyl,
organometallic, borinic acid and boronic acid groups. Examples of each of
these groups,
methods for protecting nitrogen moieties using these groups and methods for
removing these
groups from nitrogen moieties are disclosed in T. Greene and P. Wuts, supra.
Thus, suitable nitrogen protecting groups useful as W include, but are not
limited to, silyl
protecting groups (e.g., SEM: trimethylsilylethoxymethyl, TBDMS: tert-
butyidimethylsilyl); alkyl
ether protecting groups such as cycloalkyl ethers (e.g., THP:
tetrahydropyran); carbamate
protecting groups such as alkyloxycarbonyl (e.g., Boc: t-butyloxycarbonyl),
aryloxycarbonyl (e.g.,
Cbz: benzyioxycarbonyl, and FMOC: fluorene-9-methyloxycarbonyl),
alkyloxycarbonyl (e.g.,
methyloxycarbonyl), alkylcarbonyl or arylcarbonyl, substituted alkyl,
especially arylalkyl (e.g., trityl
(triphenylmethyl), benzyl and substituted benzyi), and the like.
If W is a silyl protecting group (e.g., SEM: trimethylsilylethoxymethyl,
TBDMS: tert-
butyldimethylsilyl), such groups may be applied and subsequently removed under
known
conditions. For example, such silyl protecting groups may be attached to
nitrogen moieties and
hydroxyl groups via their silyl chlorides (e.g., SEMCI:
trimethylsilylethoxymethyl chloride,
TBDMSCI: tert-butyldimethylsilyl chloride) in the presence of a suitable base
(e.g., potassium
carbonate), catalyst (e.g., 4-dimethylaminopyridine (DMAP)), and solvent (e.g,
N,N-dimethyl
formamide). Such silyl protecting groups may be cleaved by exposure of the
subject compound
to a source of fluoride ions, such as the use of an organic fluoride salt such
as a
tetraalkylammonium fluoride salt, or an inorganic fluoride salt. Suitable
fluoride ion sources
include, but are not limited to, tetramethylammonium fluoride,
tetraethylammonium fluoride,
tetrapropylammonium fluoride, tetrabutylammonium fluoride, sodium fluoride,
and potassium
fluoride. Alternatively, such silane protecting groups may be cleaved under
acidic conditions
using organic or mineral acids, with or without the use of a buffering agent.
For example, suitable
acids include, but are not limited to, hydrofluoric acid, hydrochloric acid,
sulfuric acid, nitric acid,
acetic acid, citric acid, and methanesulfonic acid. Such silane protecting
groups may also be
cleaved using appropriate Lewis acids. For example, suitable Lewis acids
include, but are not
limited to, dimethylbromo borane, triphenylmethyl tetrafluoroborate, and
certain Pd (II) salts.
Such silane protecting groups can also be cleaved under basic conditions that
employ
appropriate organic or inorganic basic compounds. For example, such basic
compounds include,
but are not limited to, sodium carbonate, potassium carbonate, sodium
bicarbonate, potassium
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bicarbonate, sodium hydroxide, and potassium hydroxide. The cleavage of a
silane protecting
group may be conducted in an appropriate solvent that is compatible with the
specific reaction
conditions chosen and will not interfere with the desired transformation.
Among such suitable
solvents are, for example, alkyl esters, alkylaryl esters, aryl esters, alkyl
ethers, aryl ethers,
alkylaryl esters, cyclic ethers, hydrocarbons, alcohols, halogenated solvents,
alkyl nitriles, aryl
nitriles, alkyl ketones, aryl ketones, alkylaryl ketones, or non-protic
heterocyclic compounds. For
example, suitable solvents include, but are not limited to, ethyl acetate,
isobutyl acetate, isopropyl
acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl
ether,
chlorobenzene, dimethyl formamide, dimethyl acetamide, propionitrile,
butyronitrile, t-amyl
alcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenyl ether,
methylphenyl ether,
tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, pentane, hexane,
heptane, methanol,
ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol,
dichloromethane, chloroform,
1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene,
toluene, anisole,
xylenes, and pyridine, or any mixture of the above solvents. Additionally,
water may be used as a
co-solvent in this transformation if necessary. Finally, such reactions may be
performed at an
appropriate temperature from -20 C to 100 C, depending on the specific
reactants used.
Further suitable reaction conditions may be found in T. Greene and P. Wuts,
supra.
If W is a cyclic ether protecting group (e.g., a tetrahydropyran (THP) group),
such groups
may be applied and subsequently removed under known conditions. For example,
such cyclic
ethers may be attached to nitrogen moieties and hydroxyl groups via their enol
ethers (e.g.,
dihydropyran (DHP)) in the presence of a suitable acid (e.g., para-
toluenesulfonic acid or
methanesulfonic acid), and solvent (e.g., dichloromethane). Such cyclic ether
groups may be
cleaved by treating the subject compound with organic or inorganic acids or
Lewis acids. The
choice of a particular reagent will depend upon the type of ether present as
well as the other
reaction conditions. Examples of suitable reagents include, but are not
limited to, hydrochloric
acid, sulfuric acid, nitric acid, para-toluenesulfonic acid, methanesulfonic
acid, or Lewis acids
such as boron trifluoride etherate.
These reactions may be conducted in solvents that are compatible with the
specific
reaction conditions chosen and will not interfere with the desired
transformation. Among such
suitable solvents are, for example, alkyl esters, alkylaryl esters, aryl
esters, alkyl ethers, aryl
ethers, alkylaryl esters, cyclic ethers, hydrocarbons, alcohols, halogehated
solvents, alkyl nitriles,
aryl nitriles, alkyl ketones, aryl ketones, alkylaryl ketones, or non-protic
heterocyclic compounds.
For example, suitable solvents include, but are not limited to, ethyl acetate,
isobutyl acetate,
isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, dimethoxyethane,
diisopropyl ether,
chlorobenzene, dimethyl formamide, dimethyl acetamide, propionitrile,
butyronitrile, t-amyl
alcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenyl ether,
methylphenyl ether,
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tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,
heptane, methanol,
ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol, 2-butanol,
dichloromethane, chloroform,
1,2-dichloroethane, acetonitrile, benzonitrile, acetone, 2-butanone, benzene,
toluene, anisole,
xylenes, and pyridine, or any mixture of the above solvents. Additionally,
water may be used as a
co-solvent in this transformation if necessary. Finally, such reactions may be
performed at an
appropriate temperature from -20 C to 100 C, depending on the specific
reactants used.
Further suitable reaction conditions may be found in T. Greene and P. Wuts,
supra.
Protection of the N-1 indazole ring nitrogen is accomplished by reacting 3-
iodo-6-
nitroindazole with 3,4-dihydro-2! / pyran and methanesulfonic acid in a
solvent, such as DMF,
tetrahydrofuran (THF), and methylene chloride (CH2CI2) to provide 3-iodo-6-
nitro-l-
(tetrahydropyran-2-yl)-1 H-indazole.
0
N \ N02 Methanesulfonic acid
N~ ~/ + , D N \ N02
N ~ I
The various substituents contemplated for the compounds of formula I, and
their
intermediates, such as when Ri is C1-C8 alkyl, -OH, -NO2, -CN, -CO2H, -O(Cl-Ca
alkyl), -aryl,
-aryl(Ci-C8 alkyl), -CO2CH3, -CONH2, -OCH2CONH2, -NH2, -SO2NH2i haloalkyl, or -
O(haloalkyl),
may require the use suitable protecting groups. The choice of a suitable
nitrogen protecting
group (described above), hydroxyl protecting group, carboxylic acid protecting
group, amide
protecting group, or sulfonamide protecting group, their application and their
subsequent removal,
is disclosed in T. Greene and P. Wuts, supra.
Suitable hydroxyl protecting groups that are useful in the present invention
include, but
are not limited to, alkyl or aryl esters, alkyl silanes, aryl silanes or
alkylaryl silanes, alkyl or aryl
carbonates, benzyl groups, substituted benzyl groups, ethers, or substituted
ethers. The various
hydroxyl protecting groups can be applied and suitably cleaved utilizing a
number of known
reaction conditions. The particular conditions used will depend on the
particular protecting group
as well as the other functional groups contained in the subject compound.
Furthermore, suitable
conditions include the use of an appropriate solvent that is compatible with
the reaction conditions
utilized and will not interfere with the desired transformation. Suitable
solvents useful in applying
the various protecting groups and their subsequent removal may include alkyl
esters, alkylaryl
esters, aryl esters, alkyl ethers, aryl ethers, alkylaryl esters, cyclic
ethers, hydrocarbons, alcohols,
halogenated solvents, alkyl nitriles, aryl nitriles, alkyl ketones, aryl
ketones, alkylaryl ketones, and
non-protic heterocyclic compounds. For example, suitable solvents include, but
are not limited to,
ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl
isobutyl ketone,
dimethoxyethane, diisopropyl ether, chlorobenzene, dimethyl formamide,
dimethyl acetamide,
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propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethyl ether,
methyl-t-butyl ether, diphenyl
ether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-
dioxane, pentane,
hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-
butanol, 2-butanol,
dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile,
acetone, 2-butanone,
benzene, toluene, anisole, xylenes, and pyridine, or any mixture of the above
solvents.
Additionally, water may be used as a co-solvent in these transformations if
necessary. Finally,
such reactions may be performed at an appropriate temperature from -20 C to
100 C,
depending on the specific reactants used. Further suitable reaction conditions
may be found in T.
Greene and P. Wuts, supra.
After functionalization of the C-3 position with Iodine, and protection of the
indazole ring
nitrogen (N-1) with a suitable nitrogen protecting group W, the C-3 position
of the indazole ring
can be elaborated to a desired R' group through a Suzuki or Heck reaction,
using the appropriate
catalyst, ligand, aryl, heteroaryl and/or olefinic species.
The Suzuki reaction is a palladium catalyzed coupling reaction in which the
reaction of an
optionally substituted aryl boronic acid or an optionally substituted
heteroaryl boronic acid is
coupled with a substituted aryl group or a substituted heteroaryl group, in
which the substituents
on the aryl group or the heteroaryl group are halide, triflate, or a diazonium
salt, which produces a
di-aryl species.
R'
U:111 Br / R\ /R,
+ ~,
R (HO)2B
Useful palladium catalysts for the Suzuki reaction includes but are not
limited to
Pd(C17H140)X, Pd(PPh3)4, and [Pd( Ac)2]3, and the like. A base such as an
inorganic base or an
organic base (e.g., organic amine) is also required to neutralize the
liberated acid. In general,
Suzuki coupling reactions require milder conditions than Heck reactions.
When R' is a substituted or unsubstituted aryl group, or is a substituted or
unsubstituted
heteroaryl group, the compounds of formula I can be prepared by a Suzuki
reaction between an
optionally substituted aryl or heteroaryl boronic acid and a substituted aryl
or heteroaryl group, in
which the substituents on the aryl or heteroaryl group are halide, triflate,
or a diazonium salt.
A Heck reaction involves the catalytic coupling of C-C bonds, where a vinylic
hydrogen is
replaced by a vinyl, aryl, or benzyl group, with the latter being introduced
as a halide, diazonium
salt, aryl triflate or hypervalent iodo compound.
R = vinyl, aryl, or benzyl
R-X + - -~ /~ + ~ X = anionlc Ieaving group
H R' \
Palladium in the form of Pd(II) salts or complexes and Pd(0), with 1-5% mole
concentration, is the most widely used metal catalyst for these types of
reactions. A base such
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as an inorganic base or an organic base (e.g., organic amine) is also required
to neutralize the
liberated acid. Typical catalysts for use in the Heck reaction include but are
not limited to
Pd(dppf)CI2/CH2CI2, [Pd(OAc)2]3, trans-PdCI2(CH3CN)2, Pd(C17H14O),,, and Pd(0)-
phosphine
complexes such as Pd(PPh3)4 and trans-PdCl2(PPh3)2 or in situ catalysts such
as Pd(OAc)2/PPh3,
and the like. Chelated phosphines with larger bite angles such as Cp2Fe(PPh2)2
and Ph2P(CH2)2_
4PPh2 are useful with catalysts such as Pd(OAc)2i (pi-allyl)Pd complexes,
Pd2(dba)3, Pd(dba)2
and PdCI2, and the like. The presence of phosphines "stabilize" these
catalysts. Generally, these
types of reactions are conducted in polar aprotic mediums (sigma donor type
solvents such as
acetonitrile, N,N-dimethyl formamide, dimethyl sulfoxide or
dimethylacetamide). The reaction
time and temperature depend on the nature of the organic halide to be
activated. lodo derivatives
are more reactive and hence auxiliary ligands (phosphines) may not be
required. In these cases
polar solvents such as N,N-dimethyl formamide, dimethylacetamide and N-
methylpyrrolidine in
combination with sodium acetate as a base are especially beneficial.
When R' is a group of the formula CH=CHR4 or CH=NR4, wherein R4 is as
described
herein, the compounds of formula I can be prepared by a Heck reaction between
a compound
containing a vinylic hydrogen and a compound containing a vinyl, aryl, or
benzyl group which is
substituted with a halide, halide, diazonium salt, aryl triflate or
hypervalent iodo compound.
A Heck reaction between 3-iodo-6-nitro-l-(tetrahydropyran-2-yl)-1H-indazole
and 2-vinyl
pyridine is accomplished by heating these reactants in the presence of a
catalyst such as
palladium(II) acetate (Pd(OAc)2), a ligand such as tri-o-tolylphosphine, a
suitable base such as
N,N-diisopropylethyl-amine, and a solvent such as DMF to provide 6-nitro-3-
((E)-2-pyridin-2-yl-
vinyl)-1-(tetrahydropyran-2-yl)-1 H-indazole.
qo
O ~ I I _ N N 2
lN INO2+ ~N + /~N"/ Pd(OAc)z N" I + ~N
N I ~/ P(o-tolyl)3 )
HI
DMF
6-N
The compounds of formula I contain an indazole ring and phenyl ring that are
bridged by
a sulfide group. Such sulfide linked ring structures are obtained by coupling
an indazole
derivative which is substituted with an activated substituent group X
(compound of formula II) with
a thiophenol derivative (compound of formula III). Suitable activated
substituent groups for X
include but are not limited to halides (e.g., chloride, bromide, iodide),
hydroxyl derivatives (e.g.,
triflate, mesylate, and tosylate groups), and diazonium salts.
Derivatization of the 6-nitroindazole ring compounds described above, with an
activated
substituent X group can be accomplished by reduction of the 6-nitro group to
the 6-amino
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indazole compound, followed by diazotization, and optionally, displacement of
N2 with a
nucleophile such as a halide, water, or aqueous base.
6-nitroindazole ring compounds can be converted to 6-amino indazole compounds
by a
reduction. The reduction of nitro groups to amino groups are well known.
Metals, such as Fe
(iron), Zn (zinc), Sn (tin) and In (indium) can be used with a H+ source to
reduce a nitro group to
an amino group by a sequence of single electron transfer (SET)/protonation
reactions.
6-nitro-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole is
reduced to the 6-
amino compound by treatment with iron metal in the presence of an aqueous
solution of
ammonium chloride to provide 6-amino-3-(E)-2-pyridin-2-yl-vinyl)-1-
(tetrahydropyran-2-yl)-1H-
indazole.
qo qo
N NO 2 N NH2
N ~ Ammonium chloride N ~
+ 12 H20 + 6 Fe + 6 Fe(OH)3
\ N \ N
Diazotizing reagents useful for converting an amino group to a diazonium salt
include but
are not limited to sodium nitrite and tert-butyl nitrite. These diazotizing
reactions require the
presence of a strong acid such as hydrochloric acid to convert the amino group
into the
diazonium salt. Alkali metal halides, such as lithium, sodium and potassium
halides are a
convenient source of nucleophilic halide anions. Hydroxyl groups are easily
converted into
triflate, mesylate and tosylate groups using standard procedures.
Treatment of 6-amino-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-
indazole with
a diazotizing reagent, such as sodium nitrite in hydrochloric acid, provides
the intermediate C-6
diazonium salt. Addition of a metal halide, such as potassium iodide (KI ) and
iodine (12) (12 is
employed as a catalyst to facilitate the iodination process) provides 6-iodo-3-
(E)-2-pyridin-2-yl-
vinyl)-1-(tetrahydropyran-2-yl)-1 H-indazole.
O 1. NaNO2, O
N \ NH2 2. HOAc N ~ I
N~ ~/ 3. HCI (2 equiv.)
4. CH2CI2
5. KI/12
~N
~ / N
The coupling reaction between the compounds of formula II and the compounds of
formula III to provide the compounds of formula IV is accomplished in the
presence of a catalyst,
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a base, and optionally, one or more solvents. The catalyst may be either a
palladium or a copper
catalyst. Methods that use palladium or copper catalysts to couple aryl
sulfides to aryl
compounds containing an activated substituent X are well known. For example,
palladium
catalysts which are useful in the above coupling reaction include but are not
limited to
Pd(dppf)CI2-CH2CI2, [Pd(Pt-Bu3)( -Br)]2, Pd(PCy3)2CI2, Pd(P(o-tolyl)3)2CI2,
[Pd(P(OPh-2,4-t-
Bu))2CI]2, FibreCat 1007 (PCy2-fibre/Pd(OAc)2), FibreCat 1026 (PCy2-
fibre/PdCI2/CH3CN),
FibreCat@ 1001(PPh2-fibre/Pd(OAc)2), Pd(dppf)CI2, Pd(dppb)C12, Pd(dppe)C12,
Pd(PPh3)4,
Pd(PPh3)CI2, and the like. Other useful catalysts for the above transformation
include those
where one or more ligands, especially phosphine ligands, additionally
complexes to the palladium
catalyst, for example: Pd2(dba)3 complexed to a phospine ligand such as 2-
(tert-butyl2-
phosphino)biphenyl; Pd(dba)2 complexed to P(t-Bu)3; Pd(OAc)2 complexed to (o-
biphenyl)P(t-
Bu)2; and Pd2(dba)3 complexed to (o-biphenyl)P(t-Cy)2. Copper catalysts which
are useful in the
above coupling reaction include those catalysts in which the copper is
complexed with one or
more ligands, including but not limited to Cul/ethylene glycol complex;
CuBr/DBU complex,
Cu(PPh3)Br; and Cu(PPh3)Br additionally complexed to 1,10-phenanthroline or
neocuproine (e.g.,
Cu(phen) (PPh3)Br and Cu(neocup)(PPh3)Br, respectively), and the like.
Bases which are useful in the above coupling reaction include but are not
limited to
potassium carbonate, sodium carbonate, cesium carbonate, sodium tert-butoxide,
potassium tert-
butoxide, potassium phenoxide, triethylamine, and the like, or mixtures
thereof. Solvents may be
used in such coupling reactions including but not limited to toluene, xylenes,
diglyme,
tetrahydrofuran, dimethylethyleneglycol, and the like, or mixtures thereof.
In general, the activated substituent X in the compounds of formula III should
be such
that it provides sufficient reactivity to react with the compounds of formula
II to provide the
compounds of formula IV. Compounds of formula III that contain such activated
substituents may
be prepared, isolated and/or purified, and subsequently reacted with the
compounds of formula II.
Alternatively, compounds of formula III with suitable activated substituents
may be
prepared and further reacted without isolation or further purification with
the compounds of
formula II to afford the compounds of formula IV. Among suitable activated
substituent groups for
X are halogens (e.g., Cl, Br, and I); derivatized hydroxyl groups (e.g.,
triflate, mesylate, and
tosylate); and diazonium salts. Other suitable activated substituent groups
are known and may
be found, for example, in U.S. Patent No. 5,576,460 and in Humphrey, J.M.;
Chamberlin, A.R.
Chem. Rev. 1997, 97, 2243; Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon:
New York, (1991); Vol. 6, pp 301-434; and Comprehensive Organic
Transformations; Larock, R.
C.; VCH: New York, (1989), Chapter 9.
6-iodo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1H-indazole is
reacted with a
catalytic amount of Pd(dppf)CIz-CH2CI2, cesium carbonate and 2-mercapto-N-
methylbenzamide
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in DMF at 80 C to provide 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-
yl-vinyl)-1-
(tetrahydropyroan-2-yl)-1 H-indazole.
OQ IQ CONHCH3
fl CONHCH3 N ~ S HS Pd(dppf)2CI2=CH2CI2 N~ ~/ + I / CS2CO3 ~
\ N
Other suitably functionalized indazole compounds that are substituted with an
X group,
especially an iodide group, would be expected to react similarly with a
thiophenol compound to
provide a coupled product.
The choice of suitable reagents and reaction conditions for deprotecting the N-
1 indazole
ring nitrogen group, W, are well known. For example, when W is a
tetrahydropyran protecting
group, suitable reagents include, but are not limited to, hydrochloric acid,
sulfuric acid, nitric acid,
para-toluenesulfonic acid, methanesulfonic acid, or Lewis acids such as boron
trifluoride etherate.
These reactions may be conducted in solvents that are compatible with the
specific reaction
conditions chosen and will not interfere with the desired transformation.
Deprotection of 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-
1-
(tetrahydropyroan-2-yl)-1 H-indazole using para-toluenesulfonic acid (p-TsOH)
in methanol/water
provides 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-H-
indazole.
CONHCH3
O CONHCH3 H S
NN I~ S ~~ ::0+
O
N
~ N
\ ~
When a palladium catalyst is used in any of the above reaction steps, removal
of residual
palladium is an important objective. Such palladium removal can be
accomplished using 10%
cysteine-silica as discussed in a U.S. provisional patent application entitled
Methods for the
Removal of Heavy Metals, attorney docket number PC032215, filed on November 1,
2004, and is
hereby incorporated by reference in its entirety. Palladium removal can also
be combined with
conditions that allow crystallization of the synthesized compounds in various
polymorphic forms.
For example, when a compound of formula I is prepared where R1 is 2-vinyl
pyridine, R2 is
methyl, and R3 are each hydrogen, the polymorphic form designated as Form IV
can be
produced by refluxing in tetrahydrofuran, N,N-dimethyl formamide, and
methanol, followed by the
addition of acetic acid and xylenes. The formation and characterization of
Form IV, as well as
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other polymorphs, is discussed in more detail in a U.S. provisional patent
application entitled
Polymorphic Forms of 6-[2-(methylcarboamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-
yl)ethenyl]-
indazole, attorney docket number PC019171, fiied on November 1, 2004, and is
hereby
incorporated by reference in its entirety. This palladium removal process and
polymorph control
step is also described in greater detail in the Examples provided below.
2-mercapto-N-methylbenzamide can be prepared as follows. 2,2'-dithiosalicylic
acid is
treated with reagents such as thionyl chloride or oxalyl chloride in the
presence of a suitable base
such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium
bicarbonate,
sodium hydroxide, potassium hydroxide, a trialkylamine, triethylamine for
example, or a
heteroaromatic base such as pyridine to provide the 2,2'-dithiosalicylic acid
dichloride. Treatment
of the dichloride compound with 2 M methylamine in THF provides 2,2'-dithio-N-
methylbenz-
amide. Reduction of the disulfide linkage with sodium borohydride in ethanol
provides 2
equivalents of 2-mercapto-N-methylbenzamide.
C02R CO2R O.C=NHCH3
/
S-S , -- 2 HS /
~ I ~ I ~ ~
R=H
R=C1
R = NHCH3
The specific reaction conditions chosen will depend on the specific subject
compound
and reagents chosen. Other suitably functionalized thiophenol compounds may be
generated
using appropriately functionalized disulfides as starting materials. The
resulting sulfides
(compounds of formula III) should be protected from light to prevent disulfide
formation. These
sulfides may be isolated and further reacted with the compounds of formula II
or they may be
reacted with the compounds of formula II without isolation or further
purification.
Another synthetic route to the compounds of formula I is provided in the
Examples
section below.
Examples
The following processes illustrate the preparation of indazole compounds of
formula I
which are useful as modulators and/or inhibitors of protein kinases. These
compounds, prepared
by the methods of the present invention, are useful as anti-angiogenesis
agents and as agents for
modulating and/or inhibiting the activity of protein kinases, thus providing
treatments for cancer or
other diseases associated with cellular proliferation mediated by protein
kinases.
Unless otherwise indicated, variables according to the following processes are
as defined
above. Starting materials, the synthesis of which are not specifically
described herein or provided
with reference to published references, are either commercially available or
can be prepared
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using methods that are well known. Certain synthetic modifications may be done
according to
methods familiar to those of ordinary skill in the art.
In the examples described below, unless otherwise indicated, all temperatures
in the
following description are in degrees Celsius ( C) and all parts and
percentages are by weight,
unless indicated otherwise.
Various starting materials and other reagents were purchased from commercial
suppliers,
such as Aldrich Chemical Company or Lancaster Synthesis Ltd., and used without
further
purification, unless otherwise indicated.
The reactions set forth below were performed under a positive pressure of
nitrogen,
argon or with a drying tube, at ambient temperature (unless otherwise stated),
in anhydrous
solvents. Analytical thin-layer chromatography was performed on glass-backed
silica gel 60 F
254 plates (Analtech (0.25 mm)) and eluted with the appropriate solvent ratios
(v/v). The
reactions were assayed by high-pressure liquid chromotagraphy (HPLC) or thin-
layer
chromatography (TLC) and terminated as judged by the consumption of starting
material. The
TLC plates were visualized by UV, phosphomolybdic acid stain, or iodine stain.
1H-NMR spectra were recorded on a Bruker instrument operating at 300 MHz and
13C-NMR spectra were recorded at 75 MHz. NMR spectra are obtained as DMSO-d6
or CDCI3
solutions (reported in ppm), using chloroform as the reference standard (7.25
ppm and 77.00
ppm) or DMSO-d6 (2.50 ppm and 39.52 ppm). Other NMR solvents were used as
needed. When
peak multiplicities are reported, the following abbreviations are used: s =
singlet, d = doublet, t =
triplet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet
of triplets. Coupling
constants, when given, are reported in Hertz.
Infrared spectra were recorded on a Perkin-Elmer FT-IR Spectrometer as neat
oils, as
KBr pellets, or as CDCI3 solutions, and when reported are in wave numbers (cm
1). The mass
spectra were obtained using LC/MS or APCI. All melting points are
uncorrected.All final products
had greater than 95% purity (by HPLC at wavelengths of 220nm and 254nm).
In the following examples and preparations, "DMF" means N,N-dimethyl
formamide, "THF" means
tetrahydrofuran, "Et" means ethyl, "Ac" means acetyl, "Me" means methyl, "Ph"
means phenyl,
"HCI" means hydrochloric acid, "EtOAc" means ethyl acetate, "Na2CO3" means
sodium
carbonate, "NaHCO3" means sodium hydrogen carbonate (sodium bicarbonate),
"NaOH" means
sodium hydroxide, "Na2S2O3" means sodium thiosulfate, "NaCI" means sodium
chloride, "Et3N"
means triethylamine ,"H2O" means water, "KOH" means potassium hydroxide,
"K2C03" means
potassium carbonate, "MeOH" means methanol, "i-PrOAc" means isopropyl acetate,
"MgSO4"
means magnesium sulfate, "DMSO" means dimethylsulfoxide, "AcCI" means acetyl
chloride,
"CH2CI2" means methylene chloride, "MTBE" means methyl t-butyl ether, "SOCI2"
means thionyl
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chloride, "H3PO4" means phosphoric acid, "CH3SO3H" means methanesulfonic acid,
"Ac20"
means acetic anhydride, "CH3CN" means acetonitrile, "DHP" means 3,4-dihydro-2H-
pyran.
Example 1: Preparation of 3-iodo-6-nitroindazole
H N02
H al;ZZ~6 N02
DMF N N N + i2 + K2C03 N+ KI + KHCO3
\ 3 i
6-Nitroindazole (45.08 Kg) is dissolved in DMF (228 Kg) and powdered potassium
carbonate (77 Kg) is added while the solution temperate is maintained at <_ 30
C. A solution of
iodine (123 Kg) dissolved in DMF (100 Kg) is added over 5 to 6 hours while the
reaction
temperature is maintained <_ 35 C. (Caution: the reaction is exothermic). The
reaction mixture is
agitated for 1 to 5 hours at 22 C (until the reaction is complete by HPLC).
The mixture is then
added to a solution of sodium thiosulfate (68 Kg) and potassium carbonate
(0.46 Kg) dissolved in
water (455 Kg) while the solution temperature is maintained <_ 30 C. The
mixture is agitated for
1.5 hours at 22 C. Water (683 Kg) is added which precipitates solids and the
slurry is agitated for
1 to 2 hours at 22 C. The solids are filtered, washed with water (2 x 46 Kg),
and dried in a
vacuum oven for 24 to 48 hours (50 C and 25 mm Hg) to provide 74.7 Kg of 3-
iodo-6-
nitroindazole as a yellow white solid (93.6% yield with a purity of 86% by
HPLC; KF is 0.2%).
Example 2: Preparation of 3-iodo-6-nitro-l-(tetrahydropyran-2-yl)-1 H-indazole
0
N I~ NO~ Methanesulfonic acid
N + 0_'O N / N N02
/
3-iodo-6-nitroindazole (74.6 Kg) is dissolved in methylene chloride (306 Kg)
and THF
(211 L), and methanesulfonic acid (3.0 Kg) is carefully added. (Caution:
residual sodium
bicarbonate may cause CO2 to be evolved. Monitor the pressure in the reactor).
A solution of
DHP (55 Kg) in methylene chloride (97 Kg) is added over 5 to 6 hours while the
reaction
temperature is maintained at 5 22 C. The mixture is agitated at 22 C for 2 to
6 hours (until the
reaction is complete by HPLC). The mixture is then carefully added to an
aqueous solution of
10% NaHCO3 (37 Kg of NaHCO3 dissolved in 370 Kg water) while the solution
temperature is
maintained at 22 C. (Caution: CO2 is evolved. Monitor the pressure in the
reactor). The mixture
is agitated for 1 hour at 22 C and the layers separated. The organic layer is
washed with an
aqueous solution of 10% NaCI (407 Kg) and the layers separated. The organic
layer is
concentrated at 55 C and atmospheric pressure to cut the volume to half (ca.
500 L), then under
reduced pressure to remove the remaining solvents. The concentrate (ca.138 L)
is co-
evaporated with acetonitrile (1 x 224 Kg, 1 x 75 Kg, 1 x 60 Kg) at 55 C under
reduced pressure
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until the final volume is ca. 80 L. The resulting slurry is diluted with
acetonitrile (60 Kg) and is
agitated for 8 hours at -5 C. The slurry is filtered, and the solids are
rinsed with cold acetonitrile
(15 Kg). The solids are dried at room temperature under reduced pressure to
provide 77.6 Kg of
3-iodo-6-nitro-1-(tetrahydropyran-2-yl)-1 H-indazole (80.5% yield with a
purity of 95% by HPLC).
Example 3: Preparation of 6-nitro-3-((E)-2-pyridin-2-yl-vinyl)-1-
(tetrahydropyran-2-yl)-1 H-indazole
qo
N N02
Pd(OAc)2 N ~ ~/
N ~ QNO2 + N + +
N' i ~ P(o-toiyi)3 Hi
\ / DMF ~
~ N
\ !
3-iodo-6-nitro-l-(tetrahydropyran-2-yl)-1H-indazole (77 Kg) is added to a
solution of 2-
vinyl pyridine (31 Kg), N,N-diisopropylethylamine (51 Kg), and tri-o-
tolylphosphine (5.414 Kg) in
DMF (163 Kg). Pd(OAc)2 (1.503 Kg) is added and the mixture is agitated for 12
to 18 hours at
100 C (until the reaction is complete by HPLC). The mixture is then cooled to
45 C and
isopropanol (248 Kg) is added. The mixture is agitated for 30 minutes at 45 C,
diluted with water
(1,238 L), and the mixture is agitated at 22 C for 1 to 2 hours. The resulting
slurry is filtered,
rinsed with water (77 L), and the solids are combined with isopropanol (388
Kg). The mixture is
agitated for 30 to 90 minutes at 55 C, then for 30 to 90 minutes at 10 C,
filtered, and the solids
are washed with coid (ca. 10 C) isopropanol (2 x 30 L). The solids are dried
in a vacuum oven
for 24 to 48 hours (50 C and 25 mm Hg) to provide 61.8 Kg of 6-nitro-3-((E)-2-
pyridin-2-yl-vinyl)-
1-(tetrahydropyran-2-yl)-1 H-indazole (85% yield with a purity of 88% by
HPLC).
Example 4: Preparation of 6-amino-3-(E)-2-pyridin-2-yl-vinvi)-1-
(tetrahydropyran-2-yl)-1H-
indazole
Qo Qo
N02 N ~ NH2
NN I ~ Ammonium chloride
+ 12 H20 + 6 Fe N I/ + 6 Fe(OH)3
N 6-N
6-nitro-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole (61.4
Kg) is
dissolved in an aqueous solution of ammonium chloride (71.4 Kg of NH4CI in 257
Kg water) and
ethanol (244 Kg) is added. Iron powder (39 Kg) is added and the mixture is
agitated for 2 to 8
hours at 50 C (until the reaction is complete by HPLC). (Add more iron powder
(ca. 9.8 Kg) if the
reaction is not complete after 8 hours). The mixture is then cooled to 22 C
and THF (1,086 Kg) is
added. The mixture is agitated for 1 hour at 22 C, and filtered through
diatomaceous earth (ca. 5
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Kg). The cake is rinsed with THF (214 Kg), and the filtrate is concentrated at
50 C under reduced
pressure to a volume of ca. 305 L. The concentrate is cooled to 22 C, diluted
with water (603
Kg), and agitated at 22 C for 1 hour. The mixture is filtered, rinsed with
heptanes (62 Kg), dried
in a vacuum oven for 24 to 48 hours (50 C and 25 mm Hg) to provide 51.5 Kg of
6-amino-3-((E)-
2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole (91.8% yield with a
purity of 95% by
HPLC).
Example 5: Preparation of 6-iodo-3-((E)-2-pyridin-2-yl-vinyl)-1-
(tetrahydropyroan-2-yl)-1H-
indazole
P o
1. NaNO2,
N N \ NH2 2. HOAc N I
N~ ~/ 3. HCI (2 equiv.) N~
\ 4. CH2CI2
5. KI/12
~ /N N
6-amino-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole (1
Kg) dissolved
in acetic acid (6.5 L) is added over 1.5 hours to a solution of sodium nitrite
(350 g) dissolved in
water (3.0 L) at 0 C. The mixture is stirred for 1 hour at 0 C, and a solution
of hydrochloric acid
(560 mL diluted in 1 L of water) at 0 C is added over 15 minutes. The mixture
is stirred for 1 hour
at 0 C. The formation of the diazonium salt is monitored by HPLC. Methylene
chloride (4 L) at
0 C is added over 10 minutes to the diazonium salt solution at 0 C, and a
solution of potassium
iodide (1.062 Kg) and iodine (396 g) dissolved in water (3 L) at 0 C is added
over 1.5 hours. The
reaction mixture is agitated for 3 hours at 0 C (until complete by HPLC). The
mixture is then
poured into a solution of 20% aqueous sodium hydrogen sulfite (2 Kg sodium
thiosulfate in 10 L
water) and methylene chloride (4 L) at 0 C, agitated, and the layers
separated. The aqueous
layer is extracted with methylene chloride (2 x 4 L) at 0 C and combined. A
solution of 3 M
aqueous sodium hydroxide (17 L) at 0 C is added over 40 minutes to the
combined organic
layers until the aqueous phase is basic (pH = 9 to 12). The phase separation
is not clear due to
the formation of an emulsion. A solution of 28% aqueous ammonium hydroxide (1
L) and water
(2 L) is added, and the mixture is agitated for 30 minutes at 10 C, and
allowed to settle for 24
hours to afford a clear phase separation. The layers are separated and the
aqueous layer is
extracted with methylene chloride (2 x 6 L). The combined organic layers (ca.
35 L) are loaded
onto a glass fritted column (7 in. ID and 20 in. length) containing silica gel
(4 Kg) and are eluted
under nitrogen pressure with methylene chloride (8 L). The filtration is
collected in three carboys
and labeled as fractions 1, 2 and 3, respectively. The column is then eluted
with 5% ethyl acetate
in methylene chloride (32 L) and the filtration was collected in three carboys
and labeled as
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fractions 4, 5 and 6, respectively. The column is further eluted with 10%
ethyl acetate in
methylene chloride (24 L) and the filtration was collected in three carboys
and labeled as fractions
7 and 8, respectively. Fractions 1 to 6 are combined, concentrated under
reduced pressure, and
dried in a vacuum oven for 24 to 48 hours (40 C and 25 mm Hg) to provide 1,110
g of 6-iodo-3-
((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1 H-indazole (75% yield
with a purity of 97%).
Example 6: Preparation of 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-
yl-vinyl)-1-
(tetrahydropyroan-2-yl)-1 H-indazole
O CONHCH3
NN C NHCH3 Pd(dppf)2CI2=CH2CI2 N N I~ S I~
J\'Ir
C'iS2('; g N 6-iodo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1 H-
indazole (34.3 Kg)
dissolved in DMF (162 Kg) is added to [1,1'-bis(diphenyl-
phosphino)ferrocene]dichloro-palladium
(II) complex with dichloromethane (Pd(dppf)2CI2=CH2CI2) (2.9 Kg), and cesium
carbonate (38.8
Kg). 2-mercapto-N-methylbenzamide (17.2 Kg) is added and the mixture is
agitated for 4 to 16
hours at 80 C (until the reaction is complete by HPLC). The mixture is then
cooled to 22 C and
ethyl acetate (412 Kg) is added and the mixture is agitated for 1 hour at 22
C. Water (686 Kg) is
added and the mixture is agitated at 22 C for 2 hours. The mixture is filtered
and the solids are
washed with ethyl acetate (62 Kg), water (137 Kg), and ethyl acetate (62 Kg).
The solids are
dissolved in THF (93.3 Kg) and methylene chloride (686 Kg), and the solution
is eluted through a
column containing sand (25 Kg, at the bottom of the column), Florisil (453 Kg,
in the middle of the
column) and sand (97.8 Kg, on the top of the column), with a solution of THF
(15.4 Kg) and
methylene chloride (113 Kg) 35 C, followed by five portions of THF (31 Kg) and
methylene
chloride (226 Kg) 35 C. The fractions containing the product are collected and
concentrated
under reduced pressure to a volume of ca. 103 L. Ethyl acetate (206 Kg) is
added, and the
solution is concentrated under reduced pressure to a volume of ca. 172 L.
Water (69 g) is added
and the solution is agitated for 2 hours at 22 C. The solids are filtered,
vvashed with ethyl acetate
(62 Kg), and dried in a vacuum oven for 24 to 48 hours (55 C and 25 mrn Hg) to
provide 20.2 Kg
of 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-
(tetrahydropyroan-2-yl)-1 H-
indazole as a light brown solid (54% yield with a purity of 98%). The metal
contents are 17.3 ppm
for palladium and 42.5 ppm for iron. The product is light-sensitive and should
be stored in the
dark at 0 C.
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Example 7: Preparation of 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-
yl-vinyl)-1-H-
indazole
H CONHCH3
O CONHCH3 N ~ g
N S
N\ i/ ::0+
~ N
N \ ~
~
6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-
(tetrahydropyroan-2-yl)-
1 H-indazole (20.2 Kg), p-toluene sulfonic acid monohydrate (40 Kg), methanol
(111 Kg) and
water (20 Kg) are combined and agitated for 1 to 5 hours at 64 C (until the
deprotection is
complete by HPLC analysis). The mixture is then cooled to 22 C and
concentrated under
reduced pressure to volume of ca. 90 L. Methanol (111 Kg) is added and the
rnixture is agitated
for 1 hour at 64 C. Water (71 Kg) is added and the mixture is cooled to 22 C
and concentrated
under reduced pressure to a volume of ca. 100 L. The process is repeated to
drive the reaction
to completion by evaporation of the side-product (DHP) with water. Methanol
(111 Kg) is added
and the mixture is agitated for 1 hour at 64 C, diluted with water (71 Kg) and
the mixture is
agitated for 1 hour at 0 C. The mixture is filtered and the solids are washed
vvith cold methanol
(61 Kg). The solids are transferred to a reactor and ethyl acetate (61 Kg) is
added. The mixture
is agitated for 30 minutes at 65 C, cooled to 3 C, and the solids are filtered
and washed with cold
ethyl acetate (61 Kg). This sequence removes any residual methanol since trace
amounts of
methanol may prevent the formation of the desired polymorph form III during
the neutralization
step. The solids are transferred to a reactor, diluted with ethyl acetate (82
Kg), agitated for 3
minutes at 0 C, and neutralized by addition of 5% aqueous sodium bicarbonate
solution (175 Kg)
(aqueous phase pH _ 7). Caution: carbon dioxide is evolved. The slurry is
agitated for 2 hours at
22 C and a sample is withdrawn (60 mL) to check the pH and to test for
polymorph form. If the
DSC indicates that the conversion of polymorph form VI to polymorph form III (-
'/~ ethyl acetate
solvate) is not complete, continue the agitation at 22 C and check DSC every 4
hours until the
formation of polymorph form I II is confirmed. A long period of agitation (ca.
7 6 hours) may be
required for the complete polymorph conversion. Once the DSC indicates the
formation of form
III, the solids are filtered, washed with ethyl acetate (61 Kg), water (61
Kg), and ethyl acetate (61
Kg), and dried in a vacuum oven for 24 to 48 hours (40 C and 25 mm Hg) to
provide 17.8 Kg of 6-
(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-H-indazole (98%
yield with a purity
of 98.8% by HPLC). The product is light sensitive and should be stored in the
dark at 0 C.
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Example 8: Polymorph Control of 6-(2-mercapto-N-methylbenzamide)-3-((E)-
2pyridin-2-yi-vinyl)
1 -H-indazole
If 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-H-indazc>
le from
Example 7 is an off-white solid (polymorph III), then proceed with Example 8a.
If 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-H-indazole
from
Example 7 is a pink solid (polymorph ??), then proceed with Example 8b.
a. Conversion of Polymorph III to Polymorph IV
6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-H-indazole
(polymorph
III, 17.6 Kg) is added to acetic acid (115 Kg) and methanol (189.4 Kg) and the
mixture is agitated
for 1 hour at 68 C to dissolve the solids. The solution is filtered, diluted
with xyienes (193 Kg),
and concentrated at 68 C under reduced pressure to ca. 81 L. The addition of
xylenes and
subsequent concentration is repeated until the desired polymorph form IV is
confirmed by an in-
process DSC check. In some cases, additional agitation (ca. 16 hours) is
needed for the
complete conversion of polymorph form III to form IV. After conversion of
polymorph form III to
polymorph form IV, the solution is cooled to 50 C, the solids are filtered and
rinsed with heptanes
(44 Kg) and dried in a vacuum oven at 75 C for 24 hours to provide 13.4 Kg of
6-(2-mercapto-N-
methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-H-indazole polymorph form IV
as an off-white
solid (84% yield with a purity of 99% by HPLC). This product is light
sensitive and should be
stored in the dark at 0 C.
b. Color Removal and Polymorph Control
6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-H-indazole
Cpink tint,
2.423 Kg) is added to methanol (75 L) and the mixture is agitated for 1.5
hours at 1 5 to 25 C.
The slurry is filtered, and the solids are washed with methanol (12.5 L) and
dried in a vacuum
oven at room temperature for 24 hours. The dried solids are added to a
solution of acetic acid
(100 L) at ca. 35 C, and the mixture is agitated for 45 minutes at ca. 35 C
until a clear solution is
obtained. The solution is cooled to room temperature and activated carbon
(Darco G-60, 2.5 Kg)
is added. The mixture is stirred at room temperature for 2 to 3 hours,
filtered through Celite (3.0
Kg), and the filtrate is concentrated at 70 C under reduced pressure to a
volume of 25 L. The
solution is cooled to 25 C and xylenes (25 L) are added. The solution is
heated to 70 C, and
concentrated at 70 C under reduced pressure to a volume of 25 L. This
procedure is repeated
four times until solids appear. The slurry is cooled to room temperature,
filtered, washed with
xylenes (25 L) and heptanes (25 L), and the solids are dried in a vacuum oven
for 24- hours (40
C and 25 mm Hg) to provide 1.988 Kg of 6-(2-mercapto-N-methylbenzamide)-3-((E)-
2-pyridin-2-
yl-vinyl)-1-H-indazole as an off-white solid (79.5% yield with a purity of >
99% by HPLC'.
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Example 9: Preparation of 2,2' -dithiosalicylic acid dichloride
CO2H CO2H COCI COCI
S-S b \ S-S
2,2'-dithiosalicylic acid (421 g) is dissolved in toluene (1.7 L) and thionyl
chloride (212
mL) and DMF (7 mL) are added, and the mixture is agitated for 20 hours at 82
C. The mixture is
then cooled to 70 C and hexanes (2 L) are added. Further cooling to 10 C
provides a solid
precipitate. The solids are filtered, washed with hexanes (2 x 250 mL), and
dried in a vacuum
oven for 24 hours (55 C and 25 mm Hg) to provide 390 g of 2.2' -
dithiosalicylic acid dichloride
(97% yield with a purity of 80% by'H NMR/DMSO).
Example 10: Preparation of 2,2'-dithio-N-methylbenzamide
COCI COCI CONHCH3 CONHCH3
S-S \ I _. \ I S-S
2,2'-dithiosalicylic acid dichloride (90 g) dissolved in THF (500 mL) is added
to a solution
of 2 M methyl amine in THF (655 mL) in over 40 minutes at 0 C, and agitated at
room
temperature for 16 hours. The mixture is then diluted with water (200 mL) and
the resulting slurry
is filtered. The solids are washed with water (2x 50 mL), dried in a vacuum
oven for 16 hours
(55 C and 25 mm Hg) to provide 50 g of 2,2'-dithio-N-methylbenzamide (65%
yield with a purity
of 86% by HPLC).
Example 11: Preparation of 2-mercapto-N-methylbenzamide
CONHCH3 CONHCH3 CONHCH3
S-S 2 HS22,2'-dithio-N-methylbenzamide (967.2 g) is suspended in ethanol (9.0
L) and cooled to
0 C. Sodium borohydride (253 g) is added in portions over 4 hours, and the
mixture is agitated
for 5 hours at 0 C. 3 M hydrochloric acid (3.15 L) is then added to the
mixture in over 15 minutes
which adjusted the pH to 1.73. The mixture is concentrated under reduced
pressure and 45 C to
remove the ethanol. The concentrate is diluted with ethyl acetate (8 L) and
water (4 L) and
agitated for 20 minutes. The layers are allowed to separate (30 minutes), and
the aqueous layer
is removed. Solids and an emulsion remain in the organic layer. Water (1 L) is
added to the
organic layer and the mixture is agitated for 20 minutes. The aqueous layer is
removed and a
solution of saturated aqueous sodium chloride (3 L) is added to the organic
layer. The mixture is
agitated and the layers are separated. The organic layer is dried over sodium
sulfate, filtered,
and evaporated to a volume of -4L before solids began to form. Heptanes (2 L)
are added to the
concentrate and the mixture is evaporated to provide 701.3 g of 2-mercapto-N-
methylbenzamide
(72% yield with a purity of 95% by HPLC). HPLC of this material showed only 1%
of the disulfide
present. Avoid exposure to air as this material readily forms the disulfide.
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Example 12: Preparation of 6-(2-(methylcarbamoyl)phenylsulfanyll-3-E-f2-
(pyridine-2-
yl)ethenyllindazole
N '
/ N
~ S N"N Pd(OAc)2, P(o-Tol)3 I
C:~ I I
S N'N
CONHCH3 H Proton Sponge, LiBr CONHCH3 H
DMA, 110 C
2-(3-lodo-1 H-indazol-6-ylsulfanyl)-N-methyl-benzamide (239.19 g), 2-
vinylpyridine (75.7
mL, 702 Mmol), Pd(OAc)2 (6.56 g), P(o-Tol)3 (23.12 g), Proton Sponge (187.82
g), LiBr (314.59
g), and DMA (3.1L, 3.5 mUg) were added to a 5 L 3-neck flask, equipped with a
mechanical
stirrer and a temperature probe. The mixture was degassed three times by
alternately connecting
to house vacuum and nitrogen. The mixture was then heated to 110 C in one
hour and the
temperature was maintained at 110 C for 24 hours, at which time all of the 2-
(3-lodo-1 H-indazol-
6-ylsulfanyl)-N-methyl-benzamide was consumed (HPLC). After cooling, the
mixture was
transferred to a 22 L extractor and followed by the addition of 5.5 L of
CH2CI2, 5.5 L of water and
275 mL of 37% aqueous HCI. After agitation and partitioning, the organic phase
was extracted
twice with 2.0 L of water and 100 mL of 37% HCI. At this stage, the organic
phase (HPLC) did
not contain any significant amount of the final product (HPLC), and was
discarded. The
combined aqueous layers were treated with 2.2 L of toluene, followed by the
addition of 1.05 L of
28% NH4OH over 45 minutes of time (via addition funnel). A thick precipitate
formed at this
stage. The resulting mixture was allowed to stir for approximately 48 hours.
The mixture was
then filtered and sucked dry. The cake was triturated with 3.5 L of toluene,
stirred overnight,
filtered and sucked dry. The cake was then transferred to a glass dish and
dried at 50 C under
house vacuum overnight to afford 160.20 g of the final product.
Example 13: Preparation of 2-(3-lodo-1 H-indazol-6-ylsulfanyl)-N-methyl-
benzamide
(~SH
CONHCH3 I
-N Pd2(dba)3 N
H Xantphos CONHCH3 H
CsOH
DMF, 70 C
3,6-diiodoindazole (250.00 g), 2-mercapto-N-methylbenzamide (118.48 g),
Pd2(dba)3
(9.28 g), Xantphos (11.73 g), DMF (2.5 L, 10 mUg), followed by CsOH were added
sequentially
to a 5 L four-neck flask equipped with a mechanical stirrer and a temperature
probe. The
reaction mixture was then stirred. The dark mixture was degassed three times
by alternately
connecting to house vacuum and then nitrogen. The mixture was heated to 70 C
over a period
of 30 minutes and maintained at the same temperature for fours, at which time
HPLC of the
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aliquot indicated that the 3,6-diiodoindazole was less than 3%. After cooling,
the mixture was
poured into a mixture of 7.5 L of water, 1.25 L of toluene and 1.25 L of
CH2CI2 in a 22 L extractor.
The mixture was allowed to stir at ambient temperature overnight. A thick
precipitate formed
overnight. The mixture was filtered and the cake was sucked dry. The cake was
further dried at
35 C under house vacuum for six hours to afford 216 g of the final product.
The mother liquor
was then extracted with 1.5 L of EtOAc. After partitioning, the aqueous layer
was discarded. The
organic layer was washed twice each with 2 L of water and concentrated. The
residue was
treated with 250 mL of CH2CI2 and stored overnight. A thick precipitate formed
overnight. The
mixture was filtered and the cake was sucked dry. The cake was dried at 35 C
under house
vacuum overnight to afford 24.71 g of the final product. The combined yield
was 241 g of the final
product. The material showed satisfactory purity and was used in the next step
without further
purification. 'H NMR 300MHz, DMSO ppm: 13.53 (s, 1H), 8.35 (q, J=4.7 Hz, 1H),
7.56 (s, 1H),
7.51-7.40 (m, 2H), 7.36-7.23 (m, 3H), 7.13 (dd, J=8.5, 1.3 Hz, 1H), 7.06-7.01
(m, 1H), 2.76 (d,
J=4.7 Hz, 3H).
Example 14: Preparation of 3,6-diodoindazole
N 12 /KOH
I
.
N DMF, 0 G I N
H H
An aqueous solution of NaHSO3 was prepared by adding 13.6 g of solid NaHSO3
into
250 mL of DI water with strong stirring. 6-iodoindazole (30.0 g), followed by
DMF (60 mL) were
added to a 500 mL three-neck flask that was fitted with a mechanical stirrer,
a temperature probe,
and a 100 mL dropping funnel. After the stirring had begun, the flask was
immersed in an
ice/water bath. After 30 mintues, KOH was added in one portion, and the
resulting mixture was
stirred for an additional 30 minutes. A solution of 54.3g of 12 in 55 mL of
DMF (total volume was
71 mL) was added to the dropping funnel and the run-in started. After 30
minutes, 42 mL of the
solution had been added to the reaction mixture. The addition was stopped and
an aliquot
sample was taken and analyzed with HPLC (TFASH method), which indicated that
there was still
6-iodoindazole present. After an additional 10 mL of the iodine/DMF solution
was added, the
second aliquot sample showed that all the starting 6-iodoindazle was consumed.
A solution of
13.6g of NaHSO3 in DI water was added slowly to the reaction mixture. At this
stage the dark
solution became a yellow suspension. After stirring for one hour, the mixture
was filtered and the
cake was washed with 200 mL of water and 200 mL of hexanes. The cake was
sucked dry and
further dried in a vacuum oven (25 inch vacuum/60 C) for 18 hours to afford
38.60 g of the final
product as a tan solid. iH NMR 300MHz, DMSO ppm: 7.96 (s, 1H), 7.46 (d, J=8.4
Hz, 1H), 7.24
(d, J=8.4 Hz, 1 H), 3.33 (s, 1 H).
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Example 15: Final deprotection step to produce 6-r2-
(methylcarbamoyl)phenylsulfanyll-3-E-[2-
(pyridine-2-yl)ethenyllindazole
N
P l TsOH I ~
S<N.N p N.N
CONHCH3 THP CONHCH3 H
N-1 THP 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-
yl)ethenyl]indazole
(355 g) was suspended in 2,485 mL of methanol, after which p-toluenesulfonic
acid monohydrate
(718 g) was added. The mixture was then heated to 65 C (hard reflux) for 4
hours under argon
while the reaction was monitored by HPLC (gluco method). Heating continued
until less than 1%
of the N-1 THP protected starting material persisted. The heating was then
removed and the
reaction was cooled to room temperature. The solid was filtered and the wet
cake was washed
with methanol (2 volumes, 710 mL) then the solids were rinsed with ethyl
acetate (2 volumes,
710 mL). The wet cake was transferred to a reactor containing sodium
bicarbonate (126.84 g),
deionized water (1800 mL), and ethyl acetate (975 mL), which was then stirred
for 2 hours at
C. The solids were filtered and washed with 5 volumes of deionized water (1800
mL), then
with 2 volumes of ethyl acetate (760 mL), and then dried in a vacuum oven at
40 C for 16 hours.
The isolated yield for the reaction was 92.5% (274 g). The isolated material
was identified as
20 crystalline Form III free base (0.5 ethyl acetate solvate). 1H NMR, 300
MHz, (DMSO-D6), ppm;
13.35 (1 H, s), 8.60 (1 H, d, J=3.8 Hz), 8.39 (1 H, m), 8.23 (1 H, d, J=8.5
Hz), 7.95 (1 H, d, J=16.4
Hz), 7.82 (1 H, ddd, J=7.7, 7.6, 1.8 Hz), 7.67 (1 H, d, J=7.8 Hz), 7.60 (a H,
s), 7.57 (1 H, d,
J=16.4 Hz), 7.49 (1 H, dd, J=7.1, 1.6 Hz), 7.35-7.26 (3 H, m), 7.19 (1 H, d,
J=8.4 Hz), 7.04 (1 H,
d, J=7.8 Hz), 2.77 (3 H, d, J=4.6 Hz). 13C NMR, 75 MHz, (DMSO-D6) ppm: 168.23,
155.18,
149.81, 142.35, 142.22, 137.31, 136.00, 132.89, 130.64, 130.36, 129.51,
128.14, 126.50, 125.93,
124.08, 123.01, 122.85, 122.12, 120.642, 115.08, 26.45.
Example 16: Preparation of 6-[2-(methylcarbamoyl)phenylsulfanyll-3-E-[2-
(pyridine-2-
Lrl)ethenyllindazole using the tetrahydropyranyl protectin aq roup
I N-
PL i J p-
S~ N N Pd(OAc)2, P(o-Tol)3 N
CONHCH3 THP (/S
-Pr)2NEt I
CONHCH3 THP
DMF, 10@C
N-1 THP 2-(3-Iodo-1 H-indazol-6-ylsulfanyl)-N-methyl-benzamide (21.77 g), 2-
vinylpyridine (5.92 mL, 54.9 Mmol), Pd(OAc)2 (0.96 g), P(o-Tol)3 (3.42 g), (i-
Pr)2NEt (11.3 mL,
64.9 Mmol), and N,N-dimethylformamide (550 mL) were added to a 1 L 3-neck
flask, equipped
with a mechanical stirrer and a temperature probe. The mixture was then
degassed three times
by alternately connecting to house vacuum and nitrogen. The mixture was heated
to 100 C and
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the temperature was maintained at 100 C overnight, at which time all the
starting material was
consumed (HPLC). After cooling, the mixture was poured into 800 mL of
saturated NaHCO3 and
400 mL of EtOAc was added. The mixture was stirred for half an hour at which
time a thick
precipitate formed. The solid was filtered off and the filtrate was allowed to
partition. After
partitioning, the aqueous layer was extracted twice with 300 mL of EtOAc. The
combined organic
layers were washed twice with water, dried over MgSO4 and concentrated. The
residue
crystallized on standing at room temperature. The solid was treated with 20 mL
of EtOAc and
filtered. The cake was allowed to air-dry overnight and afforded 17.66 g of
the final product.
Example 17: Preparation of N-1 THP-protected 2-(3-lodo-1 H-indazol-6-
ylsulfanyl)-N-methyl-
benzamide
lrl N DHP
CONHCH3 H TsOH, EtOAc
CONHCH3 THP
A mixture of 2-(3-lodo-1 H-indazol-6-ylsulfanyl)-N-methyl-benzamide (24.65 g),
dihydropyran (5.50 mL, 60.3 Mmol), and TsOH=H20 (1.146 g) in 600 mL of EtOAc
was heated at
60 C overnight. After cooling, the mixture was diluted with 500 mL of EtOAc,
washed with
NaHCO3 (200 mL), dried over MgSO4 and then concentrated in vacuo. The residue
was pre-
adsorbed onto silica gel and subjected to flash chromatography, using
hexanes/EtOAc (2:1, 1:1,
1:2, 1:3) to yield 21.77 g of the final product.
Example 18: Preparation of 6-f2-(methylcarbamoyl)phenylsulfanyll-3-E-f2-
(pyridine-2-
yl)ethenyllindazole using the tert-butoxvcarbonyl protecting aroup
N-
i i I~ 1)\ \/ / , - N
N ~
S N 2) Pd(OAc)2, P(o-ToI)3 S N"
CONHCH3 Boc I
DMF, 1oo C CONHCH3 H
3) TFA
N-1 Boc 2-(3-Iodo-1 H-indazol-6-ylsulfanyl)-N-methyl-benzamide (510 mg), and 2-
vinylpyridine (0.14 mL, 1.3 Mmol) were added to a 100 mL 3-neck flask,
equipped with a stirring
bar and a temperature probe. The mixture was then degassed three times by
alternately
connecting to house vacuum and nitrogen. The mixture was allowed to stir for
two hours, after
which an aliquot indicated that only the starting material was present (HPLC).
Initially, Pd[P(t-
Bu)3]2 was used as a catalyst (9.28 g), along with 20 mL of DMF, and 124 mL of
Cy2NMe (711
Mmol) at room temperature for 2 hours, but the reaction did not work.
Subsequently, it was found
that when Pd(OAc)2 was used as the catalyst, along with P(o-Tol)3, the
reaction worked.
However, the role of the Pd[P(t-Bu)3]2 catalyst in the overall reaction could
not be excluded.
Accordingly, 22 mg of Pd(OAc)2 and 91 mg of P(o-Tol)3 were then added to the
flask and the
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mixture was degassed again by alternately connecting to house vacuum and
nitrogen three
times. The mixture was heated to 100 C and the temperature was maintained at
100 C
overnight, at which time all the starting material was consumed (HPLC). TFA
(1.0 mL, 13.0
Mmol) was added to remove the Boc protecting group. After cooling, the mixture
was poured into
a mixture of 100 mL of water and 100 mL of EtOAc. After partitioning, the
aqueous layer was
extracted twice with 50 mL of EtOAc. The combined organic layers were washed
twice with
water, dried over MgSO4 and concentrated. The residue was pre-adsorbed onto
silica and
subjected to gradient flash chromatography (Hexanes/EtOAc, 1:3, 1:4, EtOAc,
EtOAc/MeOH,
100:1, 50/1) to yield 155 mg of the final product.
Example 19: Preparation of N-1 Boc 2-(3-lodo-1 H-indazol-6-ylsulfanyl)-N-
methyl-benzamide
' I ~ ~ N (Boc)20
~ ~S ~ NeN
H DMAP, DMF
CONHCH3 CONHCH3 Boc
(Boc)20 (1.18 g) was added in small portions to a solution of 2-(3-lodo-1 H-
indazol-6-
ylsulfanyl)-N-methyl-benzamide (2.20 g), dimethylamino pyridine (66 mg), and
N,N-
dimethylformamide (22 mL), which was chilled in an ice-water bath. At the
completion of the
addition, HPLC of the aliquot indicated that all the 2-(3-lodo-1 H-indazol-6-
ylsulfanyl)-N-methyl-
benzamide was consumed. The reaction mixture was poured into a mixture of 100
mL of EtOAc
and 100 mL of water. After partitioning, the aqueous layer was extracted two
more times with 50
mL of EtOAc. The combined organic layers were washed twice with water, dried
over MgSO4
and concentrated. The residue was chromatographed using Hexanes/EtOAc (1:1,
1:2, 1:4, 0:1)
to afford 1.35 g of the final product.
Example 20: Preparation of 6-f2-(methylcarbamoyl)ghenylsulfanyll-3-f2-
(pyridine-2-
yl)ethynyllindazole
N
I N P-S i
N.N Pd(PPh3)2CI2/Cu ~ N.N
CONHCH3
DMF CONHCH3 H
2-(3-lodo-1 H-indazol-6-ylsulfanyl)-N-methyl-benzamide (2.30 g), 2-
ethynylpyridine (0.25
mL), Pd(PPh3)2CIz (128 mg), Cul (64 mg), (i-Pr)2NEt (0.50 mL), and N,N-
dimethylformamide (15
mL) were added to a 50 mL 3-neck flask, equipped with a stirring bar and a
temperature probe.
The mixture was degassed by alternately connecting to house vacuum and
nitrogen three times,
and heated at 66 C for one hour. To the warm mixture was added 0.16 mL of 2-
ethynylpyridine
and 0.30 mL of (i-Pr)2NEt. The resulting mixture was allowed to stir at 66 C
overnight, at which
time HPLC indicated that all the starting material was consumed. After
cooling, the mixture was
diluted with 100 mL of dichloromethane and washed with water. To the organic
layer was added
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10 g of silica and agitated vigorously. The mixture was then filtered and the
filtrate was
discarded. The silica was then washed with tetrahydrofuran/dichloromethane
(discarded) and
followed by pure tetrahydrofuran. The tetrahydrofuran solution was
concentrated in vacuo to
yield 0.95 g of the final product.
Example 21: Preparation of 6-[2-(methylcarbamoyl)phenylsuifanyll-3-Z-[2-
(pyridine-2-
yl)ethenyllindazole
HZNNH2
S' NN
'
S N'N Phenyliodide diacetate CONHCH3
CONHCH3 H DCM
To a 100 mL 3-neck flask containing a solution of 0.95 g of 6-[2-
(methylcarbamoyl)phenylsulfanyl]-3-[2-(pyridine-2-yl)ethynyl]indazole was
added 2.5 g of
phenyliodide diacetate followed by 1.0 mL of H2NNH2-H20. After the bubbling
had settled, more
phenyliodide diacetate and H2NNH2-H20 were added in small portions, until
LC/MS indicated the
disappearance of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-[2-(pyridine-2-
yl)ethynyl]indazole and
the formation of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-Z-[2-(pyridine-2-
yl)ethenyl]indazole.
Example 22: Palladium removal and polymorph control of 6-[2-
(methylcarbamoyl)phenylsulfanyll-
3-E-[2-(pyridine-2-yl)ethenyllindazole
- N - N
N 1) 10% Cysteine-silica/DMA/THF P N
S N" 2) 10% Cysteine-silica/DMA/THF S N"
CONHCH3 3 3) THF/DMF, reflux C NHCH3 H
4) MeOH, reflux
5) HOAc/Xylenes Polymorph Form IV
To a 12 L 3-neck flask, equipped with a mechanical stirrer, was added 160.20 g
of 6-[2-
(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole and
1.6 L of DMA and
1.6 L of THF. After stirring for 20 minutes, the mixture became homogeneous.
To the clear
solution was added 800.99 g of 10% cysteine-silica and the resulting mixture
was allowed to stir
at room temperature overnight.
The mixture was filtered through a medium sintered glass fritted funnel, and
the cake was
washed with a solution of 500 mL of DMA and 500 mL of THF. The cake was
further washed
with 2.0 L of THF and the filtrate was collected into a separate flask. The
volatile parts in the
latter filtrate were removed in vacuo and the residue was combined with the
main filtrate. The
combined filtrate was recharged back into the 12 L flask, followed by 800 g of
10% cysteine-silica.
The flask was equipped with a mechanical stirrer and stirred over the weekend
at room
temperature.
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The mixture was then filtered through a medium sintered glass fritted funnel
and the silica
was washed with a mixture of solvents of 500 mL of DMA and 500 mL of THF,
followed by 3.0 L
of THF. The volatile parts in the filtrate were removed in vacuo and the
remaining solution was
transferred to a 22 L 3-neck flask and treated with 12 L of water (added over
a 20 minute period
of time), a thick precipitate formed at this stage. After stirring overnight,
the mixture was filtered
and the cake was washed with 2.0 L of water and sucked dry.
The cake was charged to a 5 L 3-neck flask, followed by 1.6 L of THF and 160
mL of
DMF. The flask was equipped with a mechanical stirrer, a reflux condenser and
the mixture was
heated at reflux for 8 hours. After cooling overnight, the mixture was
filtered through sharkskin
filter paper and sucked dry.
The cake was charged to a 5 L 3-neck flask and 1.6 L of MeOH was added. The
flask
was equipped with a mechanical stirrer, a water condenser and the contents
were heated at
reflux for 6 hours. After cooling overnight, the mixture was filtered through
sharkskin filter paper
and sucked dry.
The cake was dissolved into 1.6 L of HOAc with the assistance of gentl'e
heating in the
water bath of a rotary evaporator. The solution was filtered through #3 filter
paper and the total
volume of the filtrate was reduced to -500 mL in volume on the rotary
evaporator at 60 C/60
mmHg. At this stage, the bulk of the mixture remained a yellow solution and a
small amount of
precipitate formed. To the flask was charged 500 mL of xylenes (precipitate
formed) and the total
volume was reduced to -500 mL in volume on the rotary evaporator at 60 C/60
mmHg. The
process was repeated two more times. After cooling, the mixture was filtered,
the cake was
washed with 500 mL of xylenes and sucked dry. The cake was transferred to a
glass dish and
further dried at 80 C/27 inch vacuum overnight.
The cake was off-white in color and weighed 108.38g. X-ray powder diffraction
analysis
indicated that a crystalline form was present, which was characterized as Form
IV by a powder X-
ray diffraction pattern comprising peaks at the following approximate
diffraction angles (26): 8.9,
12.0, 14.6, 15.2, 15.7, 17.8, 19.2, 20.5, 21.6, 23.2, 24.2, 24.8, 26.2, and
27.5.
While the invention has been illustrated by reference to specific and
preferred
embodiments, those skilled in the art will recognize that variations and
modifications may be
made through routine experimentation and practice of the invention. Thus, the
invention is
intended not to be limited by the foregoing description, but to be defined by
the appended claims
and their equivalents.
