Method for preparing androgen receptor antagonist and intermediate thereof

Abstract

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 a carboxamide-structured androgen receptor antagonist. The method comprises preparing compound (III) using a heterogeneous palladium catalyst.

Description

Technical Field

[0001] 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 carboxamide-structured androgen 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). Background Art

[0002] The compound of formula (1A), N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide 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 to treat cancer, especially prostate cancer, and other diseases requiring AR antagonism.

[0003]

[0004] WO 2011 / 051540 discloses a method for preparing a compound of formula (1A) via intermediates of formula (III), (IV) and (V), as shown in Scheme I:

[0005]

[0006] Process I

[0007] 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 the presence of a homogeneous (soluble) bis(triphenylphosphine)palladium chloride (II) catalyst and a sodium carbonate base in a THF-water solvent. After the reaction is complete, the solvent is distilled to almost dryness, and water is added to precipitate the compound of formula (III).

[0008] A similar method for preparing compounds of formula (III) is disclosed in WO 2012 / 143599. The Suzuki reaction is carried out in the presence of a homogeneous bis(triphenylphosphine)palladium chloride (II) catalyst, a sodium carbonate base and a phase transfer catalyst (TBAB) in a THF-toluene-water solvent. The compound of formula (III) is isolated by adding water and distilling the separated organic phase to near dryness, followed by adding ethanol and filtering the crystallized product.

[0009] Finally, WO 2016 / 162604 describes a method for preparing a 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 isolated by removing the aqueous phase from the reaction mixture, adding aqueous ammonia (25%) and cooling the reaction mixture, subsequently adding water and isolating the crystalline product.

[0010] The disadvantages of the above method are that the expensive soluble palladium catalyst is discarded after the reaction, which accounts for a considerable part of the production cost, and trace amounts of palladium catalyst remain in the separated product.

[0011] 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

[0012] It has been found that the compound of formula (III) can be prepared on a large scale by heterogeneous catalysts, resulting in high yield, high purity and short reaction time of the final product. Since the heterogeneous catalyst is fixed or supported on a solid support, it is easy to recover and recycle, thereby significantly reducing the production cost of the method. The level of catalyst residues found in the final product is also significantly reduced.

[0013] 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)

[0014]

[0015] The method comprises treating a compound of formula (Ia) or (Ib)

[0016]

[0017] Wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight or branched chain C 2-6 Alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)- chain,

[0018] With 4-bromo-2-chlorobenzonitrile of formula (II)

[0019]

[0020] The reaction is carried out at elevated temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base.

[0021] In another aspect, the present invention provides a method for preparing 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile of formula (V):

[0022]

[0023] The method comprises the following steps:

[0024] (a) a compound of formula (Ia) or (Ib)

[0025]

[0026] Wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight or branched chain C 2-6 Alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)- chain,

[0027] With 4-bromo-2-chlorobenzonitrile of formula (II)

[0028]

[0029] The reaction is carried out at high temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base to obtain a compound of formula (III)

[0030]

[0031] (b) treating the compound of formula (III) with HCl;

[0032] (c) adding a base to obtain a compound of formula (V).

[0033] In another aspect, the present invention provides a method for preparing a compound of formula (1A)

[0034]

[0035] The method comprises the following steps

[0036] (a) a compound of formula (Ia) or (Ib)

[0037]

[0038] Wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight or branched chain C 2-6 Alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)- chain,

[0039] With 4-bromo-2-chlorobenzonitrile of formula (II)

[0040]

[0041] The reaction is carried out at high temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base to obtain a compound of formula (III)

[0042]

[0043] (b) treating the compound of formula (III) with HCl;

[0044] (c) adding a base to obtain a compound of formula (V)

[0045]

[0046] (d) reacting the compound of formula (V) with the compound of formula (VI)

[0047]

[0048] Producing a compound of formula (VII);

[0049]

[0050] (e) reacting the compound of formula (VII) with the compound of formula (VIII)

[0051]

[0052] Produce a compound of formula (IX); then

[0053]

[0054] (f) reducing the compound of formula (IX) to obtain a compound of formula (1A). DETAILED DESCRIPTION

[0055] As used herein, the term "heterogeneous palladium catalyst" refers to a palladium catalyst that is immobilized or supported on a solid support so that it can be easily removed from the reaction medium after the reaction is complete, such as by filtration.

[0056] The term "mol% of palladium" as used herein refers to the percentage of the amount of palladium (in moles) used in the 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 the reaction, the mole% of palladium used is (0.005 / 1)*100 mole%=0.5 mole%.

[0057] Tautomerism: Since the hydrogen atoms of the pyrazole ring can exist in 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 hydrogen atoms in the pyrazole ring include tautomers of the compounds in question. For example, the chemical name "2-chloro-4-(1H-pyrazol-3-yl)benzonitrile" and the corresponding formula (V) include tautomers of the compound, i.e., "2-chloro-4-(1H-pyrazol-5-yl)benzonitrile".

[0058] According to the present invention, 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile of formula (III)

[0059]

[0060] By mixing the compound of formula (Ia) or (Ib)

[0061]

[0062] Wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight or branched chain C 2-6 Alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)- chain,

[0063] With 4-bromo-2-chlorobenzonitrile of formula (II)

[0064]

[0065] It is prepared by reacting at high temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base.

[0066] According to a preferred embodiment of the present invention, the compound of formula (Ia) is selected from the following compounds:

[0067]

[0068] 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).

[0069] The heterogeneous palladium catalyst used in the reaction is a palladium catalyst fixed or supported on a solid support. Examples of heterogeneous palladium catalysts include palladium / carbon, palladium / barium sulfate, palladium / metal oxide (e.g., aluminum oxide), palladium / silicon or palladium / zeolite. Heterogeneous palladium catalysts are commercially available, for example under the trademark Available 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 palladium ligands such as triphenylphosphine, because it is found that these ligands interfere with the reaction when heterogeneous palladium catalysis is used.

[0070] The reaction is carried out in a suitable solvent. Although any suitable solvent can be used, the solvent preferably only comprises dimethyl sulfoxide (DMSO), or more preferably comprises 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.

[0071] Particularly suitable bases for the reaction are organic bases, including trialkylamines, such as diisopropylethylamine (DIPEA), trimethylamine (TEA) or tributylamine (TBA). Preferred trialkylamines, especially diisopropylethylamine (DIPEA), are used in an appropriate amount of 1-2 molar equivalents, such as 1.3-1.6 molar equivalents, relative to compound (II).

[0072] The reaction is preferably carried out in the presence of a phase transfer catalyst such as a quaternary ammonium salt, particularly preferably tetrabutylammonium bromide or tetrabutylammonium chloride.

[0073] 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.

[0074] Compounds of formula (Ia), (Ib) and (II) are commercially available or they can be prepared according to methods known in the art.

[0075] To carry 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 may first be stirred under a nitrogen atmosphere. The reaction is suitably carried out under a stream of nitrogen. The 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, for example, about 72°C to about 78°C. The mixture is stirred until the reaction is complete, for example, for about 1 to about 5 hours, typically about 2 to about 4 hours, after which the mixture is suitably 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, for example, palladium on carbon, from the reaction mixture, ethanol may be added to the reaction mixture prior to filtration. It was found that the carbon-supported palladium particles can form a very fine dispersion in DMSO, preventing complete removal of the catalyst particles from the reaction mixture by filtration. It was found that the addition of ethanol causes the fine catalyst particles to aggregate into larger particles, which are more easily removed by filtration. A suitable ratio of DMSO:ethanol before filtration is from about 10:2 to about 10:10, more typically from about 10:3 to about 10:5, for example about 10:4.

[0076] The temperature of the filtrate is then 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 being reacted, for example, about 65-80% by volume. The resulting suspension is then further cooled to about 15-25°C, and stirred to complete the time required for compound (III) to precipitate, for example, about 3-12 hours. The precipitated product can be separated, for example, by filtration, then washed with water and dried, for example, dried under reduced pressure at about 40-60°C. The method generally obtains a HPLC purity of 99.5% or higher, more typically about 99.8% of compound (III).

[0077] 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 period of time required for the tetrahydropyran ring to be separated, for example 2 hours. Then, a base such as ammonia (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, for example, 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, for example, suitably about 3 to about 5 hours. The precipitated product is separated, for example, by filtration.

[0078] 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:

[0079] (d) the compound of formula (V)

[0080]

[0081] Reaction with a compound of formula (VI)

[0082]

[0083] To generate a compound of formula (VII);

[0084]

[0085] (e) reacting the compound of formula (VII) with the compound of formula (VIII)

[0086]

[0087] To generate a compound of formula (IX); then

[0088]

[0089] (f) reducing the compound of formula (IX) to prepare the compound of formula (1A).

[0090] The reaction of step (d) can be carried out, for example, using Mitsunobu reaction conditions, for example in the presence of triphenylphosphine and DIAD (diisopropyl azodicarboxylate) in a suitable solvent such as THF or EtOAc at room temperature, followed by Boc-deprotection by treatment with HCl and finally treatment with a base such as NaOH.

[0091] 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 (e.g., DCM). As an alternative to HOBt, HBTU (O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) can be used. In addition, a combination of DIPEA and T3P (1-propanephosphonic acid cyclic anhydride) can be used as an activator and coupling agent system.

[0092] Reaction step (f) may be carried out at room temperature by treating a 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 aqueous HCl.

[0093] The present invention is further illustrated by the following non-limiting examples.

[0094] 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

[0095] 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 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) were added to a flask under nitrogen. The mixture was degassed by evacuating with vacuum followed by reintroduction of nitrogen while stirring vigorously. This process was repeated three times. Catalyst (5% palladium on carbon, water wet, 1.0 g dry weight, 0.005 molar equivalent) was added and the mixture was heated to 75° C. over 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 over 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 washed with cold ethanol (20 mL). The product was dried in vacuo at 50°C to obtain 24.5 g (92%) of the title compound (III) with a purity of 99.8a%.

[0096] 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

[0097] 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), water (7.5 mL) and diisopropylethylamine (6.1 mL, 1.5 molar equivalent) were added to a flask under nitrogen. The mixture was degassed by evacuating with vacuum followed by the introduction of nitrogen while stirring vigorously. This process was repeated three times. Catalyst (5% palladium / alumina, 0.37 g dry weight, 0.0075 molar equivalent) was added and the mixture was heated to 75° C. over 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 (5mL). The temperature of the filtrate was adjusted to 35°C. Water (40mL) was slowly added in 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 (25mL). The product was dried under vacuum at 50°C to obtain 6.4g (95%) of the title compound (III) with a purity of 99.8a%.

[0098] Example 3 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

[0099] 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), water (7.5 mL) and diisopropylethylamine (6.1 mL, 1.5 molar equivalent) were added to a flask under nitrogen. The mixture was degassed by evacuating with vacuum followed by the introduction of nitrogen while stirring vigorously. This process was repeated three times. Catalyst (5% palladium on carbon, water wet, 0.25 g dry weight, 0.005 molar equivalent) was added and the mixture was heated to 75° C. over 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 (5mL). The temperature of the filtrate was adjusted to 35°C. Water (40mL) was slowly added in 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 (25mL). The product was dried under vacuum at 50°C to obtain 6.2g (93%) of the title compound (III) with a purity of 99.8a%.

[0100] Example 4 Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) using palladium on carbon in acetonitrile / water solvent

[0101] 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) were added to a flask under nitrogen. The mixture was degassed by evacuating with vacuum and then reintroducing nitrogen while stirring vigorously. This process was repeated three times. 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. At this point, analysis 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 that the starting compound (3) was significantly decomposed.

Claims

1. Method for preparing 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile of formula (III) The method comprises treating a compound of formula (Ia) or (Ib) Wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight or branched chain C 2-6 Alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)- chain, With 4-bromo-2-chlorobenzonitrile of formula (II) The reaction is carried out at high temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base, wherein the heterogeneous palladium catalyst is palladium carbon, palladium / barium sulfate, palladium / metal oxide, palladium / silica or palladium / zeolite, and the solvent is a mixture of dimethyl sulfoxide and water.

2. The method of claim 1, wherein the palladium / metal oxide is palladium / aluminum oxide.

3. The method according to claim 1, wherein the volume ratio of water to dimethyl sulfoxide is 1:99 to 35:

65.

4. The method according to claim 1, wherein the volume ratio of water to dimethyl sulfoxide is 5:95 to 20:

80.

5. The method according to claim 1, wherein the volume ratio of water to dimethyl sulfoxide is 10:

90.

6. The method according to claim 1, wherein the base is diisopropylethylamine.

7. The method according to claim 1, wherein the reaction is carried out in the presence of a phase transfer catalyst.

8. The method of claim 7, wherein the phase transfer catalyst is a quaternary ammonium salt.

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

10. The method according to claim 1, wherein the reaction is carried out in a dimethyl sulfoxide-water solvent in the presence of a base and a phase transfer catalyst, the base is diisopropylethylamine, and the phase transfer catalyst is tetrabutylammonium bromide or tetrabutylammonium chloride. The method according to claim 1 , wherein the reaction temperature is 60° C. to 100° C.

12. The method according to claim 1, wherein the reaction temperature is 70°C to 80°C.

13. The method according to claim 1, wherein the reaction temperature is 72-78°C.

14. The method according to claim 1, wherein the amount of the palladium catalyst used is 0.2 mol% to 1 mol% relative to the amount of the compound of formula (II).

15. The process according to claim 1, wherein the amount of the palladium catalyst used is 0.4 mol% to 0.8 mol% relative to the amount of the compound of formula (II).

16. The method according to claim 1, wherein the reaction is carried out under a nitrogen atmosphere and the reaction time is 1-5 hours.

17. The method according to claim 16, wherein the reaction time is 2-4 hours.

18. The method according to claim 1, further comprising the steps of: (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).

19. The method of claim 18, further comprising the step of adding ethanol to the reaction mixture prior to removing the catalyst from the reaction mixture.

20. The process according to claim 18 or 19, wherein the separation of the compound of formula (III) is carried out at 10-30°C.

21. The process according to claim 18 or 19, wherein the separation of the compound of formula (III) is carried out at 15-25°C.

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

23. The method of claim 22, 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)-1H-pyrazole (3).

24. A method for preparing 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile of formula (V) The method comprises the following steps: (a) a compound of formula (Ia) or (Ib) Wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight or branched chain C 2-6 Alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)-chain-, With 4-bromo-2-chlorobenzonitrile of formula (II) The reaction is carried out at high temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base to obtain a compound of formula (III), wherein the heterogeneous palladium catalyst is palladium carbon, palladium / barium sulfate, palladium / metal oxide, palladium / silica or palladium / zeolite, and the solvent is a mixture of dimethyl sulfoxide and water, (b) treating the compound of formula (III) with HCl; (c) adding a base to obtain a compound of formula (V).

25. Method for preparing the compound of formula (1A) The method comprises the following steps: (a) a compound of formula (Ia) or (Ib) Wherein R1 and R2 are hydrogen, or R1 and R2 together form a straight or branched chain C 2-6 Alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)- chain, With 4-bromo-2-chlorobenzonitrile of formula (II) The reaction is carried out at high temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base to obtain a compound of formula (III), wherein the heterogeneous palladium catalyst is palladium carbon, palladium / barium sulfate, palladium / metal oxide, palladium / silica or palladium / zeolite, and the solvent is a mixture of dimethyl sulfoxide and water, (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 the compound of formula (VI) To generate a compound of formula (VII); (e) reacting the compound of formula (VII) with the compound of formula (VIII) To generate a compound of formula (IX); then (f) reducing the compound of formula (IX) to obtain a compound of formula (1A).

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