Technical field
The present invention relates to an improved process for the preparation of 2-
chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) which is
useful as an intermediate in the preparation of carboxamide structured androgen
10 receptor antagonists such as N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-
2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (1A).
15
Background of the invention
The compound N -( (S)-1-(3-(3-chloro-4-cyanophenyl)-1 H -pyrazol-1-yl )propan-
2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide of formula (1A) and
derivatives thereof have been disclosed in WO 20 11/051540. Compound of formula
(1A) and its derivatives are potent androgen receptor (AR) antagonists that are useful
in the treatment of cancer, particularly prostate cancer and other diseases where AR
20 antagonism is desired.
25
WO 2011/051540 discloses a process for the preparation of the compound of
formula (1A) via intermediates of formula (III), (IV) and (V) as shown in Scheme I:
5~> Suzuki
~B ClmN HC CI~NH CI~NH N
reaction Base 1'-':: N - I -..;::, N HCI I -..;::, N
6 ob NC
0 ob - CIOBr NC 0
NC 0
NC .& (IV) (V)
(I) (Ill)
(II)
SCHEME1
The compound of formula (III) or 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-
1H-pyrazol-5-yl)benzonitrile was prepared by reacting 1-(tetrahydro-2H-pyran-2-yl)-
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2
1H-pyrazole-5-boronic acid pinacol ester (I) with 4-bromo-2-chlorobenzonitrile (II)
in a Suzuki reaction. The Suzuki reaction is carried out in the presence of
homogeneous (soluble) bis(triphenylphosphine )palladium(II) chloride catalyst and
sodium carbonate base in THF -water solvent. After the reaction has completed the
5 solvents are distilled to almost dryness and water is added to precipitate the
compound of formula (III).
A similar process for preparing the compound of formula (III) is disclosed in
WO 2012/143599. The Suzuki reaction is carried out in the presence of
10 homogeneous bis( triphenylphosphine )palladium(II) chloride catalyst, sodium
carbonate base and phase transfer catalyst (TBAB) in THF-toluene-water solvent.
The isolation of the compound of formula (III) is carried out by adding water and
distilling the isolated organic phase close to dryness followed by adding ethanol and
filtering the crystalline product.
15
Finally, WO 2016/162604 describes a method for preparing the compound of
formula (III) wherein the Suzuki reaction is carried out in the presence of
homogeneous Pd(OAc )2 catalyst, potassium carbonate base and triphenylphosphine
in an acetonitrile-water solvent. Compound of formula (III) is isolated by removing
20 the water phase from the reaction mixture, adding ammonia water (25 %) and
cooling the reaction mixture followed by addition of water and isolating the
crystalline product.
The above mentioned processes have the drawback that the expensive soluble
25 palladium catalyst is disposed after the reaction contributing a significant part to the
production costs and that traces of the palladium catalyst remains in the isolated
product.
Thus, there is a need for a more practical and economical process that is
30 suitable for the manufacture of AR antagonist intermediates such as the compound of
formula (III) in a large scale.
35
Summary of the invention
It has now been found that the compound of formula (III) can be prepared in a
large scale by heterogeneous catalyst resulting in high yields, high purity of the end
5
10
15
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3
product and short reaction times. As the heterogeneous catalyst is immobilised or
supported on solid support, it can be easily recovered and recycled thereby
substantially reducing the production costs of the process. The levels of catalyst
residues found in the end product are also substantially reduced.
Thus the present invention provides a method for the preparation of 2-chloro-
4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile of formula (III)
Clm;N I~ N
NC /.- 6
(Ill)
comprising reacting a compound of formula (Ia) or (Ib)
or (I b)
wherein R1 and Rz are hydrogen, or R1 and Rz together form a straight or a
branched Cz-6 alkyl chain or a -C(O)-CHz-N(CH3)-CHz-C(O)- chain,
with 4-bromo-2-chlorobenzonitrile of formula (II)
CI~Br
NC~
(II)
at an elevated temperature in the presence of heterogeneous palladium
20 catalyst, a solvent and a base.
In another aspect, the present invention provides a method for the preparation
of2-chloro-4-(1H-pyrazol-3-yl)benzonitrile of formula (V)
5
10
15
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4
Cl~c.--,NH
I~ N
NC 0
(V)
comprising the steps of
(a) reacting a compound of formula (Ia) or (Ib)
or (I b)
wherein R1 and Rz are hydrogen, or R1 and Rz together form a straight or a
branched Cz-6 alkyl chain or a -C(O)-CHz-N(CH3)-CHz-C(O)- chain,
with 4-bromo-2-chlorobenzonitrile of formula (II)
CI~Br
NC~
(II)
at an elevated temperature in the presence of heterogeneous palladium
catalyst, a solvent and a base to obtain a compound of formula (III)
ClIx~D ;N N
NC b ob
(Ill)
(b) treating the compound of formula (III) with HCl;
(c) adding a base to obtain the compound of formula (V).
In still another aspect, the present invention provides a process for the
20 preparation of the compound of formula (IA)
5
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5
comprising the steps of
(a) reacting a compound of formula (Ia) or (Ib)
or (I b)
wherein R1 and Rz are hydrogen, or R1 and Rz together form a straight or a
branched Cz-6 alkyl chain or a -C(O)-CHz-N(CH3)-CHz-C(O)- chain,
10 with 4-bromo-2-chlorobenzonitrile of formula (II)
15
20
CI~Br
NC~
(II)
at an elevated temperature in the presence of heterogeneous palladium
catalyst, a solvent and a base to obtain a compound of formula (III)
ClIm~ ;N N
NC /.- 6
(Ill)
(b) treating the compound of formula (III) with HCl;
(c) adding a base to obtain the compound of formula (V)
Cl~c.--,NH
I~ N
NC 0
(V)
(d) reacting a compound of formula (V) with a compound of formula (VI)
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6
to produce a compound of formula (VII);
j-NH2
Cl N
N
NC
(VII)
(e) reacting the compound of formula (VII) with a compound of formula
(VIII)
H
HO N-N
0~
5 (VIII) 0
to produce a compound of formula (IX); and
Nj-NH~ Cl N 0
NC (IX)
(f) reducing the compound of formula (IX) to produce the compound of
10 formula (1A).
Detailed description of the invention
15 The term "heterogeneous palladium catalyst", as used herein, refers to
20
25
palladium catalyst which is immobilized or supported on solid support such that the
catalyst can be readily removed from the reaction medium after completion of the
reaction, for example by filtering.
The term "mol-% of palladium", as used herein, refers to the percentage of
the amount of palladium (in moles) used in the reaction step in relation to the amount
of starting compound (in moles). For example, if 0.005 mol of palladium is used per
1 mol ofbromo-2-chlorobenzonitrile in the reaction, the mol-% of palladium used is
(0.005/1) *100 mol-%= 0.5 mol-%.
Tautomerism: As the hydrogen atom of the pyrazole ring may exist in
tautomeric equilibrium between the 1- and 2-position, it is recognized by the skilled
person that the formulas and chemical names disclosed herein comprising a hydrogen
5
10
15
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7
atom in the pyrazole ring are inclusive of the tautomer of the compound in question.
For example, the chemical name as "2-chloro-4-(IH-pyrazol-3-yl)benzonitrile" and
the corresponding formula (V) is inclusive of the tautomer of the compound, namely
"2-chloro-4-(IH-pyrazol-5-yl)benzonitrile".
In accordance with the present invention, 2-chloro-4-( 1-( tetrahydro-2Hpyran-
2-yl)-IH-pyrazol-5-yl)benzonitrile of formula (III)
Clm;N I~ N
NC /.- 6
(Ill)
is prepared by reacting a compound of formula (Ia) or (Ib)
or (I b)
wherein R1 and Rz are hydrogen, or R1 and Rz together form a straight or a
branched Cz-6 alkyl chain or a -C(O)-CHz-N(CH3)-CHz-C(O)- chain,
with 4-bromo-2-chlorobenzonitrile of formula (II)
CI~Br
NC~
(II)
at an elevated temperature in the presence of heterogeneous palladium
20 catalyst, a solvent and a base.
According to one preferred embodiment of the invention, the compound of
formula (Ia) is selected from the following compounds:
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8
0
f)-lH f)----~0) f)-o:o+ f)----~0)< f)-s0 ~N -
N-N OH N-N 0 N-N 0 N-N 0
N-N oy
b b b b (Jo
(I) (2) (3) (4) (5)
According to a particularly preferred embodiment of the invention, 4-bromo-
2-chlorobenzonitrile of formula (II) is reacted with the compound of formula (Ia)
5 which is 1-(tetrahydro-2H-pyran-2-yl)-5-( 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-
yl)-1H-pyrazole (3).
The heterogeneous palladium catalyst used in the reaction is a palladium
catalyst which is immobilized or supported on solid support. Examples of
10 heterogeneous palladium catalysts include palladium on carbon, palladium on barium
sulfate, palladium on metal oxides (such as alumina), palladium on silicon dioxide or
palladium on zeolites. Heterogeneous palladium catalysts are commercially
available, for example under trademark Noblyst® from Evonik Industries AG.
Examples include Noblyst® P1064 (5% palladium on activated carbon), Noblyst®
15 P1070 (10% palladium on activated carbon), Noblyst® P1090 (5% palladium on
activated carbon), Noblyst® P1092 (5% palladium on activated carbon), Noblyst®
P1093 (5% palladium on activated carbon) and Noblyst®P1095 (5% palladium on
activated carbon), which are available as a wet free-flowing powder. In the method
of the present invention, the amount of palladium used per amount of compound of
20 formula (II) is typically from about 0.2 to about 1 mol-%, preferably from about 0.4
to about 0.8, mol-%, for example 0.5 mol-%. The reaction is preferably conducted in
the absence of palladium ligands such as triphenylphosphine since such ligands were
found to disturb the reaction when heterogeneous palladium catalysis is used.
25 The reaction is carried out in a suitable solvent. Whereas any suitable solvent
30
can be used, the solvent preferably comprises dimethyl sulfoxide (DMSO) alone or,
more preferably, in a mixture with water. Suitably, the ratio of water to DMSO is
from about 0:100 to about 50:50, preferably from about 1:99 to about 35:65, more
preferably from about 5:95 to about 20:80, for example 10:90, by volume.
Particularly suitable bases for conducting the reaction are organic bases
including trialkylamines such as diisopropylethylamine (DIPEA), trimethylamine
5
10
15
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9
(TEA) or tributylamine (TBA). Trialkylamines are preferred and diisopropylethylamine
(DIPEA) in particular, which is suitably used in an amount of 1 to 2
molar equivalent, for example from 1.3 to 1.6 molar equivalent, in relation to
compound (II).
The reaction is preferably carried out in the presence of phase transfer catalyst
such as a quaternary ammonium salt. Tetrabutylammonium bromide and
tetrabutylammonium chloride are particularly preferred.
According to one particularly preferred embodiment of the invention, the
reaction is conducted in DMSO-water solvent in the presence of a base which is
diisopropylethylamine (DIPEA) and a phase transfer catalyst which is
tetrabutylammonium bromide or tetrabutylammonium chloride.
The compounds of formula (Ia), (Ib) and (II) are commercially available or
they can be prepared according to methods known in the art.
For carrying out the Suzuki reaction, the mixture of 4-bromo-2-chlorobenzonitrile
(II), compound of formula (Ia) or (Ib ), for example, 1-(tetrahydro-2H-pyran-2-
20 yl)-5-( 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-pyrazole (3), solvent, the
base and phase transfer catalyst, may be first stirred under nitrogen atmosphere. The
reaction is suitably carried out under nitrogen flow. The catalyst is added and the
mixture is heated to the temperature which is from about 60 oc to about 100 °C,
preferably from about 70 oc to about 80 °C, for example from about 72 oc to about
25 78 °C. The mixture is agitated until the reaction is complete, for example for about 1
to about 5 h, typically for about 2 to about 4 h. Thereafter, the mixture is suitably
cooled to about 50 - 70 oc and the heterogeneous palladium catalyst is removed, for
example, by filtration under nitrogen pressure. To facilitate the removal of the
heterogeneous palladium catalyst, such as palladium on carbon, from the reaction
30 mixture, ethanol may be added to the reaction mixture before filtration. It was found
that particles of palladium on carbon may form very fine dispersion in DMSO
hampering the complete removal of catalyst particles from the reaction mixture by
filtration. Addition of ethanol was found to result in aggregation of fine catalyst
particles into larger particles which are easier to remove by filtration. The ratio of
35 DMSO: ethanol before filtering is suitable from about 10:2 to about 10:10, more
typically from about 10:3 to about 10:5, for example about 10:4.
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The temperature of the filtrate is then suitably adjusted to about 30 - 50 oc
and the precipitation of compound (III) is carried out by adding water slowly to the
cooled mixture. The amount of water to be added is suitably about 60- 120 %, for
5 example about 65 - 80 %, by volume of the solvent in which the reaction was
conducted. The resulting suspension can then be further cooled to about 15 - 25 oc
and stirred for a period needed to complete the precipitation of compound (III), for
example for about 3 to 12 h. The precipitated product can be isolated, for example by
filtering, and washed with water and dried, for example, at reduced pressure at about
10 40- 60 °C. The method typically affords compound (III) at a HPLC purity of99.5%
or higher, more typically about 99.8 %.
The conversion of the compound of formula (III) to the compound of formula
(V) can be carried out using the methods known in the art. For example, the
15 compound of formula (III) dissolved in methanol can be treated with a small amount
of 30% HCl (aqueous) suitably at lowered temperature, such as 0- 15 °C. The
mixture is stirred at this temperature for a time period necessary for the
tetrahydropyranyl ring detachment to occur, for example 2 h. A base, for example
ammonia water (25 % ), is then added to the mixture at the above temperature.
20 Thereafter, water is added gradually, for example at 10 - 20 oc followed by stirring
for example for a period of 6 to 24 h. The compound of formula (V) can be
precipitated by cooling the mixture, for example to about 0 - 5 °C, and stirring at this
temperature for a period of time sufficient to complete the precipitation, suitably
from for example from about 3 to about 5 h. The precipitated product can be isolated,
25 for example by filtering.
The compound of formula (1A) can be prepared from the compound of
formula (V), for example, using the methods described in WO 2011/051540 and WO
2012/143599. For example, according to one embodiment, the process for the
30 preparation of the compound of formula (1A) comprises the steps of
(d) reacting a compound of formula (V)
Cl:vC;...--,NH I -....::::: N
NC ~
(V)
5
10
15
20
wo 2021/229145
with a compound of formula (VI)
QH3 0 k HO - A ~N 0
H
(VI)
to produce a compound of formula (VII);
j-NH2
Cl N
N
NC
(VII)
PCT/FI2021/050343
11
(e) reacting the compound of formula (VII) with a compound of formula
(VIII)
H
HO N-N
0~
(VIII) 0
to produce a compound of formula (IX); and
Nj-NH~ Cl N 0
NC (IX)
(f) reducing the compound of formula (IX) to produce the compound of
formula (1A).
The reaction of step (d) can be carried out, for example, using the conditions
of the Mitsunobu reaction, for example at room temperature in the presence of
triphenylphosphine and DIAD ( diisopropylazodicarboxylate) in a suitable solvent,
for example THF or EtOAc, followed by Boc-deprotection by treatment with HCl
and finally with a base such as NaOH.
The reaction step (e) can be carried out at room temperature in the presence of
suitable activating and coupling agent system such as a combination ofDIPEA (N,Ndiisopropylethylamine
), EDCI ( 1-ethyl-3 -(3-dimethylaminopropyl)carbodiimide) and
anhydrous HOBt (1-hydroxy-benzotriazole) in a suitable solvent, for example DCM.
25 As an alternative to HOBt, HBTU (0-(benzotriazol-1-yl)-N,N,N',N' -tetramethyluroniumhexafluorophosphate
) can be used. Alternatively, a combination of DIPEA
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and T3P (1-propanephosphonic acid cyclic anhydride) can be used as an activating
and coupling agent system.
The reaction step (f) can be carried out at room temperature by treating the
5 compound of formula (IX) with a reduction agent, for example sodium borohydride,
in a suitable solvent, for example ethanol, followed by treating the mixture with
aqueous HCl.
10
The invention is further illustrated by the following non-limiting examples.
Example 1. Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazol-
5-yl)benzonitrile (III) in DMSO/water solvent using palladium on carbon
Into a flask under nitrogen was charged 4-bromo-2-chlorobenzonitrile (II) (20
15 g, 1 molar equivalent), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole (3) (28.4 g, 1.05 molar equivalent), tetrabutylammonium
bromide (1.49 g 0.05 molar equivalent), dimethyl sulfoxide (87.5 mL),
water (12.5 mL) and diisopropylethylamine (24.1 mL, 1.5 molar equivalent). The
mixture was degassed by evacuating using vacuum followed by reintroduction of
20 nitrogen while vigorously stirring. The procedure was repeated three times. The
catalyst ( 5 % palladium on carbon, water wet, 1. 0 g by dry weight, 0. 005 molar
equivalent) was added and the mixture was heated to 75 oc over 2 h. The mixture
was agitated until the reaction was complete (2-3 h) after which the mixture was
cooled to 65 °C. Celite (2 g) and ethanol (40 mL) were added and the mixture was
25 further agitated for about an hour. The catalyst was removed by filtration under
nitrogen pressure and the filter cake was washed with dimethyl sulfoxide (10 mL).
The temperature of the filtrate was adjusted to 45 °C. Water (67 mL) was slowly
added over about 30 minutes. The resulting suspension was cooled to 20 oc and the
product was collected by filtration. The cake was washed with water ( 40 mL)
30 followed by chilled ethanol (20 mL). The product was dried under vacuum at 50 oc
to afford 24.5 g (92 %) of the title compound (III) at 99.8 a-% purity.
35
Example 2. Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazol-
5-yl)benzonitrile (III) in DMSO/water solvent using palladium on alumina
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Into a flask under nitrogen was charged 4-bromo-2-chlorobenzonitrile (II) (5
g, 1 molar equivalent), 1-(tetrahydro-2H-pyran-2-yl)-5-( 4,4,5,5-tetramethyl-1 ,3,2-
dioxaborolan-2-yl)-1H-pyrazole (3) (7.1 g, 1.05 molar equivalent), tetrabutylammonium
bromide (0.37 g, 0.05 molar equivalent), dimethyl sulfoxide (42.5 mL),
5 water (7.5 mL) and diisopropylethylamine (6.1 mL, 1.5 molar equivalent). The
mixture was degassed by evacuating using vacuum followed by reintroduction of
nitrogen while vigorously stirring. The procedure was repeated three times. The
catalyst (5% palladium on alumina, 0.37g by dry weight, 0.0075 molar equivalent)
was added and the mixture was heated to 75 oc over 30 min. The mixture was
10 agitated until the reaction was complete (2-3 h) after which the mixture was cooled
to 50 °C. The catalyst was removed by filtration under nitrogen pressure and the
filter cake was washed with dimethyl sulfoxide (5 mL). The temperature of the
filtrate was adjusted to 35 °C. Water (40 mL) was slowly added over about 30
minutes. The resulting suspension was cooled to 20 oc and the product was collected
15 by filtration. The cake was washed with water (25 mL). The product was dried under
vacuum at 50 octo afford 6.4 g (95 %) of the title compound (III) at 99.8 a-% purity.
20
Example 3. Preparation of 2-chloro-4-( 1-( tetrahydro-2H-pyran-2-yl )-1 Hpyrazol-
5-yl)benzonitrile (III) in DMSO/water solvent using palladium on carbon
Into a flask under nitrogen was charged 4-bromo-2-chlorobenzonitrile (II) (5
g, 1 molar equivalent), 1-(tetrahydro-2H-pyran-2-yl)-5-( 4,4,5,5-tetramethyl-1 ,3,2-
dioxaborolan-2-yl)-1H-pyrazole (3) (7.1 g, 1.05 molar equivalent), tetrabutylammonium
chloride (0.32 g 0.05 molar equivalent), dimethyl sulfoxide (42.5 mL),
25 water (7.5 mL) and diisopropylethylamine (6.1 mL, 1.5 molar equivalent). The
mixture was degassed by evacuating using vacuum followed by reintroduction of
nitrogen while vigorously stirring. The procedure was repeated three times. The
catalyst (5% palladium on carbon, water wet 0.25 g by dry weight, 0.005 molar
equivalent) was added and the mixture was heated to 75 oc over 30 min. The mixture
30 was agitated until the reaction was complete (2-3 h) after which the mixture was
cooled to 50 °C. The catalyst was removed by filtration under nitrogen pressure and
the filter cake was washed with dimethyl sulfoxide (5 mL). The temperature of the
filtrate was adjusted to 35 °C. Water (40 mL) was slowly added over about 30
minutes. The resulting suspension was cooled to 20 oc and the product was collected
35 by filtration. The cake was washed with water (25 mL). The product was dried under
vacuum at 50 octo afford 6.2 g (93 %) of the title compound (III) at 99.8 a-% purity.
5
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14
Example 4. Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazol-
5-yl)benzonitrile (III) in acetonitrile/water solvent using palladium on
carbon
Into a flask under nitrogen was charged 4-bromo-2-chlorobenzonitrile (II) (5
g, 1 molar equivalent), 1-(tetrahydro-2H-pyran-2-yl)-5-( 4,4,5,5-tetramethyl-1 ,3,2-
dioxaborolan-2-yl)-1H-pyrazole (3) (7.1 g, 1.05 molar equivalent), acetonitrile (27
mL), water (18 mL) and potassium carbonate (4.5 g, 1.4 molar equivalent). The
10 mixture was degassed by evacuating using vacuum followed by reintroduction of
nitrogen while vigorously stirring. The procedure was repeated three times. The
catalyst (palladium on carbon, 1.0 g by dry weight, 0.02 molar equivalent) together
with triphenylphosphine (0.49 g, 0.08 eq.) were added and the mixture was heated to
near reflux, about 74 °C. The mixture was agitated for 2 h. At this point analysis
15 indicated 14.4% conversion of 4-bromo-2-chlorobenzonitrile together with complete
consumption of 1-(tetrahydro-2H-pyran-2-yl)-5-( 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-
2-yl)-1H-pyrazole (3) indicating significant decomposition of the starting
compound (3).
5
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15
Claims
1. A method for the preparation of2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-
1H-pyrazol-5-yl)benzonitrile of formula (III)
Clm;N I~ N
NC /.- 6
(Ill)
comprising reacting a compound of formula (Ia) or (Ib)
or (I b)
10 wherein R1 and Rz are hydrogen, or R1 and Rz together form a straight or a branched
Cz-6 alkyl chain or a -C(O)-CHz-N(CH3)-CHz-C(O)- chain,
15
with 4-bromo-2-chlorobenzonitrile of formula (II)
CI~Br
NC~
(II)
at an elevated temperature in the presence of heterogeneous palladium
catalyst, a solvent and a base.
2. A method according to claim 1, wherein the heterogeneous palladium
20 catalyst is palladium on carbon, palladium on barium sulfate, palladium on metal
oxides, palladium on silicon dioxide or palladium on zeolites.
25
3. A method according to claim 2, wherein palladium on metal oxides is
palladium on alumina.
4. A method according to any of preceding claims, wherein the solvent
comprises dimethyl sulfoxide (DMSO).
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16
5. A method according to claim 4, wherein the solvent comprises a mixture of
dimethyl sulfoxide (DMSO) and water.
5 6. A method according to claim 5, wherein the ratio of water to DMSO is
from about 0:100 to about 50:50, preferably from about 1:99 to about 35:65, more
preferably from about 5:95 to about 20:80, for example 10:90, by volume.
7. A methd according to any of the preceding claims, wherein the
10 base is diisopropylethylamine (DIPEA).
15
20
25
8. A method according to any of the preceding claims, wherein the
reaction is carried out in the presence of phase transfer catalyst.
9. A method according to claim 8, wherein phase transfer catalyst is a
quaternary ammonium salt.
10. A method according to claim 9, wherein the quaternary ammonium salt is
tetrabutylammonium bromide or tetrabutylammonium chloride.
11. A method according to claim 1, wherein the reaction is conducted in
DMSO-water solvent in the presence of a base which is diisopropylethylamine
(DIPEA) and a phase transfer catalyst which is tetrabutylammonium bromide or
tetrabutylammonium chloride.
12. A method according to any of the preceding claims, wherein the reaction
temperature is from about 60 oc to about 100 °C, preferably from about 70 oc to
about 80 °C, for example 72 -78 °C.
30 13. A method according to any of the preceding claims, wherein the amount
of palladium catalyst used per amount of compound of formula (II) is from about 0.2
to about 1 mol-%, preferably from about 0.4 to about 0.8, mol-%.
14. A method according to any of the preceding claims, wherein the reaction
35 is carried out under nitrogen atmosphere.
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17
15. A method according to any of the preceding claims, wherein the reaction
time is 1 - 5 h, preferably 2 - 4 h.
16. A method according to any of the preceding claims, further comprising
5 the steps of
10
15
(b) removing the catalyst from the reaction mixture;
(c) adding water to the cooled reaction mixture; and
d) isolating the precipitated compound of formula (III).
17. A method according to claim 16, further comprising adding ethanol to the
reaction mixture before removing the catalyst from the reaction mixture.
18. A method according to 16 or 17, wherein the isolation of the compound of
formula (III) is carried out at 10- 30 °C, preferably at 15-25 °C.
19. A method according to any of the preceding claims, wherein the
compound of formula (Ia) is selected from the following compounds:
(1) (2) (4)
20 20. A method according to claim 19, wherein the compound of formula (Ia) is
1-(tetrahydro-2H-pyran-2-yl)-5-( 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1Hpyrazole
(3).
21. A method for the preparation of 2-chloro-4-( 1 H-pyrazol-3-yl) benzonitrile
25 of formula (V)
Cl:vC;...--,NH I -....::::: N
NC ~
(V)
comprising the steps of
(a) reacting a compound of formula (Ia) or (Ib)
30
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18
or (I b)
wherein R1 and Rz are hydrogen, or R1 and Rz together form a straight or a
branched Cz-6 alkyl chain or a -C(O)-CHz-N(CH3)-CHz-C(O)- chain,
5 with 4-bromo-2-chlorobenzonitrile of formula (II)
10
15
CI~Br
NC~
(II)
at an elevated temperature in the presence of heterogeneous palladium
catalyst, a solvent and a base to obtain a compound of formula (III)
ClIx "-'D:: ;NN
NC b ob
(Ill)
(b) treating the compound of formula (III) with HCl;
(c) adding a base to obtain the compound of formula (V).
22. A method for the preparation of the compound of formula (IA)
comprising the steps of
20 (a) reacting a compound of formula (Ia) or (Ib)
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19
or (I b)
wherein R1 and Rz are hydrogen, or R1 and Rz together form a straight or a
branched Cz-6 alkyl chain or a -C(O)-CHz-N(CH3)-CHz-C(O)- chain,
5 with 4-bromo-2-chlorobenzonitrile of formula (II)
10
15
CI~Br
NC~
(II)
at an elevated temperature in the presence of heterogeneous palladium
catalyst, a solvent and a base to obtain a compound of formula (III)
ClIx "-'D:: ;N N
NC b ob
(Ill)
(b) treating the compound of formula (III) with HCl;
(c) adding a base to obtain the compound of formula (V)
Cl:vC;...--,NH I -....::::: N
NC ~
(V)
(d) reacting a compound of formula (V) with a compound of formula (VI)
QH3 0 k HO - A ~N 0
H
(VI)
to produce a compound of formula (VII);
j-NH2
Cl N
N
NC
(VII)
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(e) reacting the compound of formula (VII) with a compound of formula
(VIII)
H
HO N-N
0~
(VIII) 0
to produce a compound of formula (IX); and
N_)-NH~ Cl N 0
NC (IX)
(f) reducing the compound of formula (IX) to produce the compound of
formula (IA).