Process for preparation of androgen receptor antagonists and intermediates thereof

Abstract

The invention relates to a method for preparing androgen receptor antagonists and intermediates thereof, in particular to an improved method for preparing 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl) benzonitrile (III), and the 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl) benzonitrile (III) can be used as the intermediate for preparing the androgen receptor antagonists of the carboxamide structure. The process comprises preparing compound (III) using a heterogeneous palladium catalyst. # imgabs0 #

Description

[0001] This application is a divisional application of the international application with the application number PCT / FI2021 / 050343 and the invention title "Method for Preparing Androgen Receptor Antagonists and Intermediates Thereof", filed on May 10, 2021. This international application entered the Chinese national phase on November 10, 2022, with the application number 202180034327.9. Technical Field

[0002] The present invention relates to an improved method for preparing 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III), which can be used as an intermediate for preparing androgen receptor antagonists having a formamide structure 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). Background Art

[0003] The compound N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide of formula (1A) and its derivatives are disclosed in WO 2011 / 051540. The compound of formula (1A) and its derivatives are effective androgen receptor (AR) antagonists that can be used for treating cancer, especially prostate cancer and other diseases requiring AR antagonism.

[0004]

[0005] WO 2011 / 051540 discloses a method for preparing the compound of formula (1A) via the intermediates of formula (III), (IV) and (V), as shown in Scheme I:

[0006]

[0007] Scheme I

[0008] The compound of formula (III) or 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile is prepared by reacting 1-(tetrahydro-2H-pyran-2-yl)-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 a THF-water solvent in the presence of a homogeneous (soluble) bis(triphenylphosphine)palladium(II) chloride catalyst and sodium carbonate base. After the reaction is completed, the solvent is distilled to near dryness, and water is added to precipitate the compound of formula (III).

[0009] A similar method for preparing the compound of formula (III) is disclosed in WO 2012 / 143599. The Suzuki reaction is carried out in a THF-toluene-water solvent in the presence of a homogeneous bis(triphenylphosphine)palladium(II) chloride catalyst, sodium carbonate base, and a phase transfer catalyst (TBAB). The separation of the compound of formula (III) is carried out by adding water and distilling the separated organic phase to near dryness, followed by adding ethanol and filtering the crystalline product.

[0010] Finally, WO 2016 / 162604 describes a method for preparing the compound of formula (III), wherein the Suzuki reaction is carried out in an acetonitrile-water solvent in the presence of a homogeneous Pd(OAc)2 catalyst, potassium carbonate base, and triphenylphosphine. The compound of formula (III) is separated by removing the aqueous phase from the reaction mixture, adding ammonia water (25%), cooling the reaction mixture, then adding water and separating the crystalline product.

[0011] The disadvantages of the above methods are that the expensive soluble palladium catalyst is discarded after the reaction, which accounts for a significant part of the production cost, and there are trace amounts of palladium catalyst residues in the separated product.

[0012] Therefore, there is a need for a more practical and economical method suitable for large-scale preparation of AR antagonist intermediates such as the compound of formula (III). SUMMARY OF THE INVENTION

[0013] It has now been found that the compound of formula (III) can be prepared on a large scale by a heterogeneous catalyst, resulting in a high yield, high purity, and short reaction time of the final product. Since the heterogeneous catalyst is immobilized or supported on a solid carrier, it is easy to recover and recycle, thus significantly reducing the production cost of the method. The level of catalyst residues found in the final product is also significantly reduced.

[0014] Therefore, the present invention provides a method for preparing 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile of formula (III)

[0015]

[0016] The method comprises reacting a compound of formula (Ia) or (Ib)

[0017]

[0018] wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight-chain or branched C 2-6 alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)- chain,

[0019] with 4-bromo-2-chlorobenzonitrile of formula (II)

[0020]

[0021] The reaction is carried out at a high temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base.

[0022] On the other hand, the present invention provides a method for preparing 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile of formula (V)

[0023]

[0024] The method comprises the following steps:

[0025] (a) reacting a compound of formula (Ia) or (Ib)

[0026]

[0027] wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight-chain or branched C 2-6 alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)- chain,

[0028] with 4-bromo-2-chlorobenzonitrile of formula (II)

[0029]

[0030] in the presence of a heterogeneous palladium catalyst, a solvent and a base at a high temperature to obtain a compound of formula (III)

[0031]

[0032] (b) treating the compound of formula (III) with HCl;

[0033] (c) adding a base to obtain a compound of formula (V).

[0034] On the other hand, the present invention provides a method for preparing a compound of formula (1A)

[0035]

[0036] The method comprises the following steps

[0037] (a) reacting a compound of formula (Ia) or (Ib)

[0038]

[0039] wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight-chain or branched C 2-6 alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)- chain,

[0040] 4-bromo-2-chlorobenzonitrile of formula (II)

[0041]

[0042] react at high temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base to obtain a compound of formula (III)

[0043]

[0044] (b) Treat the compound of formula (III) with HCl;

[0045] (c) Add a base to obtain a compound of formula (V)

[0046]

[0047] (d) React the compound of formula (V) with a compound of formula (VI)

[0048]

[0049] to form a compound of formula (VII);

[0050]

[0051] (e) React the compound of formula (VII) with a compound of formula (VIII)

[0052]

[0053] to form a compound of formula (IX); then

[0054]

[0055] (f) Reduce the compound of formula (IX) to prepare a compound of formula (1A). Detailed Description

[0056] As used herein, the term "heterogeneous palladium catalyst" refers to a palladium catalyst that is fixed or supported on a solid carrier and can thus be easily removed from the reaction medium, for example by filtration, after the reaction is complete.

[0057] As used herein, the term "mol% of palladium" refers to the percentage of the amount of palladium (in moles) used in a reaction step relative to the amount of the starting compound (in moles). For example, if 0.005 moles of palladium are used per 1 mole of bromo-2-chlorobenzonitrile in a reaction, the mol% of palladium used is (0.005 / 1)*100 mol% = 0.5 mol%.

[0058] Tautomerism: Since the hydrogen atom of the pyrazole ring can exist in a tautomeric equilibrium between the 1- and 2-positions, those skilled in the art recognize that the chemical formulas and chemical names disclosed herein that contain a hydrogen atom in the pyrazole ring include the tautomers of the compounds under discussion. For example, the chemical name "2-chloro-4-(1H-pyrazol-3-yl)benzonitrile" and the corresponding formula (V) include the tautomers of this compound, namely "2-chloro-4-(1H-pyrazol-5-yl)benzonitrile".

[0059] According to the present invention, 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile of formula (III)

[0060]

[0061] By reacting a compound of formula (Ia) or (Ib)

[0062]

[0063] wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight-chain or branched C 2-6 alkyl chain or a -C(O)-CH2-N(CH3)-CH2-C(O)- chain,

[0064] with 4-bromo-2-chlorobenzonitrile of formula (II)

[0065]

[0066] The reaction is carried out at a high temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base to prepare.

[0067] According to a preferred embodiment of the present invention, the compound of formula (Ia) is selected from the following compounds:

[0068]

[0069] According to a particularly preferred embodiment of the present invention, 4-bromo-2-chlorobenzonitrile of formula (II) is reacted with a compound of formula (Ia), namely 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3).

[0070] The heterogeneous palladium catalyst used in the reaction is a palladium catalyst fixed or supported on a solid carrier. Examples of heterogeneous palladium catalysts include palladium / carbon, palladium / barium sulfate, palladium / metal oxide (such as alumina), palladium / silicon or palladium / zeolite. The heterogeneous palladium catalyst is commercially available, for example, under the trade mark Purchased from Evonik Industries AG. Examples include P1064 (5% palladium / activated carbon), P1070 (10% palladium / activated carbon), P1090 (5% palladium / activated carbon), P1092 (5% palladium / activated carbon), P1093 (5% palladium / activated carbon) and P1095 (5% palladium / activated carbon), which can be obtained in the form of a wet free-flowing powder. In the process of the present invention, the amount of palladium used relative to the amount of the compound of formula (II) is generally about 0.2 to about 1 mol%, preferably about 0.4 to about 0.8 mol%, for example 0.5 mol%. The reaction is preferably carried out in the absence of a palladium ligand such as triphenylphosphine, because it has been found that these ligands interfere with the reaction when heterogeneous palladium catalysis is used.

[0071] The reaction is carried out in a suitable solvent. Although any suitable solvent can be used, the solvent preferably contains only dimethyl sulfoxide (DMSO), or more preferably contains a mixture of dimethyl sulfoxide and water. Suitably, the volume 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.

[0072] Particularly suitable bases for carrying out the reaction are organic bases, including trialkylamines, such as diisopropylethylamine (DIPEA), trimethylamine (TEA) or tributylamine (TBA). Trialkylamines are preferred, especially diisopropylethylamine (DIPEA), and its appropriate amount is 1-2 molar equivalents relative to compound (II), for example 1.3-1.6 molar equivalents.

[0073] The reaction is preferably carried out in the presence of a phase transfer catalyst such as a quaternary ammonium salt. Tetrabutylammonium bromide and tetrabutylammonium chloride are particularly preferred.

[0074] According to a particularly preferred embodiment of the present invention, the reaction is carried out in a DMSO-water solvent, in the presence of a base and a phase transfer catalyst, the base is diisopropylethylamine (DIPEA), and the phase transfer catalyst is tetrabutylammonium bromide or tetrabutylammonium chloride.

[0075] The compounds of formula (Ia), (Ib) and (II) are commercially available, or they can be prepared according to methods known in the art.

[0076] For carrying out the Suzuki reaction, a mixture of 4-bromo-2-chlorobenzonitrile (II), a compound of formula (Ia) or (Ib) (e.g., 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3)), a solvent, a base, and a phase transfer catalyst can be first stirred under a nitrogen atmosphere. The reaction is preferably carried out under a nitrogen stream. A catalyst is added, and the mixture is heated to a temperature of about 60 °C to about 100 °C, preferably about 70 °C to about 80 °C, e.g., about 72 °C to about 78 °C. The mixture is stirred until the reaction is complete, e.g., about 1 to about 5 hours, usually about 2 to about 4 hours, and then the mixture is appropriately cooled to about 50 - 70 °C, and the heterogeneous palladium catalyst is removed, for example, by filtration under nitrogen pressure. To facilitate the removal of the heterogeneous palladium catalyst from the reaction mixture, e.g., palladium on carbon, ethanol can be added to the reaction mixture before filtration. It has been found that palladium on carbon particles can form a very fine dispersion in DMSO, hindering the complete removal of the catalyst particles from the reaction mixture by filtration. The addition of ethanol has been found to cause the fine catalyst particles to aggregate into larger particles, which are more easily removed by filtration. The appropriate ratio of DMSO:ethanol before filtration is about 10:2 to about 10:10, more typically about 10:3 to about 10:5, e.g., about 10:4.

[0077] Then the temperature of the filtrate is appropriately adjusted to about 30 - 50 °C, and the precipitation of compound (III) is carried out by slowly adding water to the cooled mixture. The amount of water added is suitably about 60 - 120% by volume of the solvent used for the reaction, e.g., about 65 - 80% by volume. Then the resulting suspension is further cooled to about 15 - 25 °C, and stirred for the time required to complete the precipitation of compound (III), e.g., about 3 - 12 hours. The precipitated product can be separated, for example, by filtration, then washed with water and dried, e.g., under reduced pressure at about 40 - 60 °C. This method generally gives compound (III) with an HPLC purity of 99.5% or higher, more usually about 99.8%.

[0078] The conversion of the compound of formula (III) to the compound of formula (V) can be carried out using methods known in the art. For example, the compound of formula (III) dissolved in methanol is treated with a small amount of 30% HCl (aqueous solution) at a suitable low temperature, such as 0 - 15 °C. The mixture is stirred at this temperature for a time required for the tetrahydropyran ring to cleave off, e.g., 2 hours. Then a base, such as ammonia water (25%), is added to the mixture at the above temperature. Then, water is gradually added at, for example, 10 - 20 °C, and then stirred for, e.g., 6 - 24 hours. The compound of formula (V) is precipitated by cooling the mixture, for example, to about 0 - 5 °C, and then stirred at this temperature for a time sufficient to complete the precipitation, e.g., suitably about 3 to about 5 hours. The precipitated product is separated, for example, by filtration.

[0079] 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 method for preparing the compound of formula (1A) comprises the following steps:

[0080] (d) reacting the compound of formula (V)

[0081]

[0082] with a compound of formula (VI)

[0083]

[0084] to produce a compound of formula (VII);

[0085]

[0086] (e) reacting the compound of formula (VII) with a compound of formula (VIII)

[0087]

[0088] to produce a compound of formula (IX); and then

[0089]

[0090] (f) reducing the compound of formula (IX) to prepare the compound of formula (1A).

[0091] The reaction of step (d) can be carried out, for example, using Mitsunobu reaction conditions, for example, at room temperature in the presence of triphenylphosphine and DIAD (diisopropyl azodicarboxylate) in a suitable solvent such as THF or EtOAc, followed by Boc-deprotection by treatment with HCl and finally treatment with a base such as NaOH.

[0092] The reaction step (e) can be carried out at room temperature, in the presence of a suitable activator and coupling agent system such as a combination of DIPEA (N,N-diisopropylethylamine), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) and anhydrous HOBt (1-hydroxy-benzotriazole), in a suitable solvent (such as DCM). As an alternative to HOBt, HBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) can be used. Additionally, a combination of DIPEA and T3P (1-propane phosphonic acid cyclic anhydride) can be used as the activator and coupling agent system.

[0093] Reaction step (f) can be carried out at room temperature, i.e., treating the compound of formula (IX) with a reducing agent such as sodium borohydride in a suitable solvent such as ethanol, and then treating the mixture with an aqueous HCl solution.

[0094] The present invention is further illustrated by the following non-limiting examples.

[0095] Example 1 . Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) using palladium on carbon in DMSO / water solvent

[0096] Under nitrogen, 4-bromo-2-chlorobenzonitrile (II) (20 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 equivalents), 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 equivalents) were added to a flask. The mixture was degassed by using vacuum evacuation followed by introduction of nitrogen again, while stirring vigorously. This process was repeated three times. The catalyst (5% palladium on carbon, water-wetted, 1.0 g dry weight, 0.005 molar equivalent) was added, and the mixture was heated to 75 °C within 2 hours. The mixture was stirred until the reaction was complete (2 - 3 hours), and then the mixture was cooled to 65 °C. Celite (2 g) and ethanol (40 mL) were added, and the mixture was further stirred for about 1 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 within about 30 minutes. The resulting suspension was cooled to 20 °C and the product was collected by filtration. The filter cake was washed with water (40 mL) and then with cold ethanol (20 mL). The product was dried in vacuo at 50 °C to give 24.5 g (92%) of the title compound (III) with a purity of 99.8a%.

[0097] Example 2 . Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) using palladium / aluminum oxide in DMSO / water solvent

[0098] Under nitrogen, 4-bromo-2-chlorobenzyl cyanide (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 equivalents), tetrabutylammonium bromide (0.37 g, 0.05 molar equivalent), dimethyl sulfoxide (42.5 mL), water (7.5 mL) and diisopropylethylamine (6.1 mL, 1.5 molar equivalents) were added to a flask. The mixture was degassed by using vacuum evacuation followed by introduction of nitrogen while stirring vigorously. This process was repeated three times. A catalyst (5% palladium / alumina, 0.37 g dry weight, 0.0075 molar equivalent) was added and then the mixture was heated to 75 °C within 30 minutes. The mixture was stirred until the reaction was complete (2 - 3 hours), then the mixture was cooled to 50 °C and the catalyst was removed by filtration under nitrogen pressure. 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 within about 30 minutes. The resulting suspension was cooled to 20 °C and the product was collected by filtration. The filter cake was washed with water (25 mL). The product was dried in vacuo at 50 °C to give 6.4 g (95%) of the title compound (III) with a purity of 99.8a%.

[0099] Example 3 . Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzyl cyanide (III) using palladium on carbon in DMSO / water solvent

[0100] Under nitrogen, 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 equivalents), tetrabutylammonium chloride (0.32 g, 0.05 molar equivalent), dimethyl sulfoxide (42.5 mL), water (7.5 mL), and diisopropylethylamine (6.1 mL, 1.5 molar equivalents) were added to a flask. The mixture was degassed by using vacuum evacuation followed by introduction of nitrogen again while stirring vigorously. This process was repeated three times. A catalyst (5% palladium on carbon, water-wetted, 0.25 g dry weight, 0.005 molar equivalent) was added, and then the mixture was heated to 75 °C within 30 minutes. The mixture was stirred until the reaction was complete (2 - 3 hours), then 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 within about 30 minutes. The resulting suspension was cooled to 20 °C and the product was collected by filtration. The filter cake was washed with water (25 mL). The product was dried in vacuo at 50 °C to give 6.2 g (93%) of the title compound (III) with a purity of 99.8a%.

[0101] Example 4 . Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) using palladium on carbon in an acetonitrile / water solvent

[0102] Under nitrogen, 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 equivalents), acetonitrile (27 mL), water (18 mL), and potassium carbonate (4.5 g, 1.4 molar equivalents) were added to a flask. The mixture was degassed by using vacuum evacuation followed by introduction of nitrogen again while stirring vigorously. This process was repeated three times. A catalyst (palladium on carbon, 1.0 g dry weight, 0.02 molar equivalent) and triphenylphosphine (0.49 g, 0.08 equivalent) were added and the mixture was heated to near reflux (about 74 °C). The mixture was stirred for 2 hours. Analysis at this point showed that the conversion of 4-bromo-2-chlorobenzonitrile was 14.4%, while 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3) was completely consumed, indicating significant decomposition of the starting compound (3).

Claims

1. Process for preparing 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile of formula (III) The process comprises reacting a compound of formula (Ia) or (Ib) wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight-chain or branched C 2-6 alkyl chain or a -C(O)-CH2-N(CH3)-CH2-C(O)- chain, with 4-bromo-2-chlorobenzonitrile of formula (II) at elevated temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base, wherein the solvent comprises dimethyl sulfoxide (DMSO).

2. The process according to claim 1, wherein the heterogeneous palladium catalyst is palladium on carbon, palladium / barium sulfate, palladium / metal oxide, palladium / silica or palladium / zeolite.

3. The process according to claim 2, wherein the palladium / metal oxide is palladium / alumina.

4. The process according to any one of the preceding claims, wherein the solvent comprises a mixture of dimethyl sulfoxide (DMSO) and water.

5. The process according to claim 4, wherein the volume 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, such as 10:

90.

6. The process according to any one of the preceding claims, wherein the base is diisopropylethylamine (DIPEA).

7. The process according to any one of the preceding claims, wherein the reaction is carried out in the presence of a phase transfer catalyst.

8. The process according to claim 7, wherein the phase transfer catalyst is a quaternary ammonium salt.

9. The process according to claim 8, wherein the quaternary ammonium salt is tetrabutylammonium bromide or tetrabutylammonium chloride.

10. The process according to claim 1, wherein the reaction is carried out in a DMSO-water solvent in the presence of a base and a phase transfer catalyst, the base being diisopropylethylamine (DIPEA) and the phase transfer catalyst being tetrabutylammonium bromide or tetrabutylammonium chloride.

11. The process according to any one of the preceding claims, wherein the reaction temperature is from about 60 °C to about 100 °C, preferably from about 70 °C to about 80 °C, such as 72 - 78 °C.

12. The process according to any one of the preceding claims, wherein the amount of palladium catalyst used relative to the amount of the compound of formula (II) is from about 0.2 mol% to about 1 mol%, preferably from about 0.4 mol% to about 0.8 mol%.

13. The process according to any one of the preceding claims, wherein the reaction is carried out under a nitrogen atmosphere and the reaction time is 1 - 5 hours, preferably 2 - 4 hours.

14. The process according to any one of the preceding claims, the process further comprising the following steps: (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).

15. The process according to claim 14, further comprising the step of adding ethanol to the reaction mixture before removing the catalyst from the reaction mixture.

16. The process according to claim 14 or 15, wherein the isolation of the compound of formula (III) is carried out at 10 - 30 °C, preferably 15 - 25 °C.

17. The method according to any one of the preceding claims, wherein the compound of formula (Ia) is selected from the following compounds:

18. The method according to claim 17, wherein the compound of formula (Ia) is 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (3).

19. A method for preparing 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile of formula (V) The method comprises the following steps: (a) reacting a compound of formula (Ia) or (Ib) wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight-chain or branched C 2-6 alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)- chain-, with 4-bromo-2-chlorobenzonitrile of formula (II) at a high temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base to obtain a compound of formula (III), wherein the solvent comprises dimethyl sulfoxide (DMSO) (b) treating the compound of formula (III) with HCl; (c) adding a base to obtain a compound of formula (V).

20. A method for preparing a compound of formula (1A) The method comprises the following steps: (a) reacting a compound of formula (Ia) or (Ib) wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight-chain or branched C 2-6 alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)- chain, with 4-bromo-2-chlorobenzonitrile of formula (II) at a high temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base to obtain a compound of formula (III), wherein the solvent comprises dimethyl sulfoxide (DMSO) (b) treating the compound of formula (III) with HCl; (c) adding a base to obtain a compound of formula (V) (d) reacting the compound of formula (V) with a compound of formula (VI) to generate a compound of formula (VII); (e) reacting the compound of formula (VII) with a compound of formula (VIII) to generate a compound of formula (IX); and then (f) reducing the compound of formula (IX) to obtain a compound of formula (1A).

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