Methods for producing androgen receptor antagonists and intermediates thereof

Abstract

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-structure androgen receptor antagonists. The process involves the preparation of compound (III) using a heterogeneous palladium catalyst.

Description

Technical Field

[0001] The present invention relates to an improved process for the production of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III), which is useful as an intermediate in the production of carboxamide structure 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-iphenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide and its derivatives are disclosed in Patent Document 1. The compounds of formula (1A) and their derivatives are potent androgen receptor (AR) antagonists useful in the treatment of cancer, particularly prostate cancer, and other diseases where AR antagonism is desired.

Chemical Formula

[0003] Patent Document 1 discloses a process for the production of the compound of formula (1A) via the intermediates of formula (III), (IV) and (V) as shown in Scheme 1.

Chemical Formula

[0004] The compound of formula (III), namely 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-yl)benzonitrile, was prepared by reacting 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (I) with 4-bromo-2-chlorobenzonitrile (II) in the 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 a sodium carbonate base. After the reaction is complete, the solvent is evaporated almost completely, and water is added to precipitate the compound of formula (III).

[0005] A similar process for producing the compound of formula (III) is disclosed in Patent Document 2. The Suzuki reaction is carried out in a THF-toluene-water solvent in the presence of a homogeneous bis(triphenylphosphine)palladium(II) chloride catalyst, a sodium carbonate base, and a phase transfer catalyst (TBAB). The compound of formula (III) is isolated by adding water, evaporating the isolated organic phase to near dryness, then adding ethanol, and filtering the crystalline product.

[0006] Finally, Patent Document 3 discloses a method for producing the compound of formula (III), in which the Suzuki reaction is carried out in an acetonitrile-aqueous 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%), cooling the reaction mixture, then adding water, and isolating the crystalline product.

[0007] The above process has the disadvantage that the expensive soluble palladium catalyst, which accounts for a significant portion of the production cost, is disposed of after the reaction, and trace amounts of the palladium catalyst remain in the isolated product.

[0008] Therefore, a more practical and economical process is needed that is suitable for the large-scale production of AR antagonist intermediates such as the compound of formula (III). [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] International Publication No. 2011 / 051540 [Patent Document 2] International Publication No. 2012 / 143599 [Patent Document 3] International Publication No. 2016 / 162604 [Overview of the Initiative]

[0010] It has now been found that the compound of formula (III) can be produced on a large scale with high yield, high purity of the final product, and short reaction time using a heterogeneous catalyst. Since the heterogeneous catalyst is immobilized or supported on a solid support, it can be easily recovered and recycled, thereby substantially reducing the production cost of the process. The level of catalyst residue observed in the final product is also substantially reduced.

[0011] Therefore, the present invention relates to compounds of formula (Ia) or (Ib). [ka] (In the formula, R1 and R2 are hydrogen, or R1 and R2 together form a straight or branched chain of carbon.) 2-6 (Forms alkyl chains or -C(O)-CH2-N(CH3)-CH2-C(O)-chains) , 4-bromo-2-chlorobenzonitrile of formula (II) [ka] And reacting under elevated temperature in the presence of a heterogeneous palladium catalyst, a solvent and a base, 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile of formula (III) [Chemical formula] provides a method for the production of.

[0012] In another aspect, the present invention relates to 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile of formula (V) [Chemical formula] A method for the production of, comprising (a) A compound of formula (III) [Chemical formula] To obtain a compound of formula (Ia) or (Ib) [Chemical formula] (where R1 and R2 are hydrogen, or R1 and R2 together form a straight-chain or branched-chain C 2-6 alkyl chain or -C(O)-CH2-N(CH3)-CH2-C(O)- chain) reacting with 4-bromo-2-chlorobenzonitrile of formula (II) [Chemical formula] in the presence of a heterogeneous palladium catalyst, a solvent and a base at elevated temperature; (b) treating the compound of formula (III) with HCl; (c) adding a base to obtain the compound of formula (V) provides a method comprising.

[0013] In yet another aspect, the present invention relates to a compound of formula (1A) [Chemical formula] A process for manufacturing, (a) Compounds of formula (III) [ka] To obtain the compound of formula (Ia) or (Ib), [ka] (R1 and R2 are hydrogen, or R1 and R2 together form a straight or branched chain of C 2-6 (Forms alkyl chains or -C(O)-CH2-N(CH3)-CH2-C(O)-chains) , 4-bromo-2-chlorobenzonitrile of formula (II) [ka] The process involves reacting the palladium catalyst, solvent, and base in the presence of a heterogeneous palladium catalyst under increasing temperature; (b) A step of treating the compound of formula (III) with HCl; (c) Compound of formula (V) [ka] A step of adding a base to obtain the desired result; (d) Compounds of formula (VII) [ka] To produce the compound of formula (V) and the compound of formula (VI) [ka] A process of reacting with; (e) Compounds of formula (IX) [ka] To produce the compound of formula (VII), and the compound of formula (VIII) [ka] A step of reacting with; and (f) A step of reducing the compound of formula (IX) to produce the compound of formula (1A). It provides a process that includes this. [Modes for carrying out the invention]

[0014] As used herein, the term “heterogeneous palladium catalyst” refers to a palladium catalyst that is immobilized or supported on a solid support so that the catalyst can be easily removed from the reaction medium after the completion of the reaction, for example by filtration.

[0015] As used herein, the term "molar % of palladium" refers to the percentage of moles of palladium used in the reaction relative to the moles of the starting compound. For example, if 0.005 moles of palladium are used in a reaction relative to 1 mole of bromo-2-chlorobenzonitrile, the molear % of palladium used is (0.005 / 1) × 100 mol% = 0.5 mol%.

[0016] Tautomerism: If the hydrogen atoms of the pyrazole ring can exist in a tautomeral equilibrium between the 1st and 2nd positions, it will be recognized by those skilled in the art that the formulas and chemical names disclosed herein that include the hydrogen atoms of the pyrazole ring include tautomerism of the compound in question. For example, the chemical name "2-chloro-4-(1H-pyrazole-3-yl)benzonitrile" and the corresponding formula (V) include tautomers of the compound, namely "2-chloro-4-(1H-pyrazole-5-yl)benzonitrile".

[0017] According to the present invention, 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile of formula (III) [ka] teeth, Compounds of formula (Ia) or (Ib) [ka] (In the formula, R1 and R2 are hydrogen, or R1 and R2 together form a straight or branched chain of carbon.) 2-6 (Forms alkyl chains or -C(O)-CH2-N(CH3)-CH2-C(O)-chains) , 4-bromo-2-chlorobenzonitrile of formula (II) [ka] It is produced by reacting a heterogeneous palladium catalyst, a solvent, and a base under elevated temperature.

[0018] According to a preferred embodiment of the present invention, the compound of formula (Ia) is the following compound [ka] Selected from.

[0019] According to a preferred embodiment of the present invention, 4-bromo-2-chlorobenzonitrile of formula (II) is reacted with a compound of formula (Ia), which is 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3).

[0020] Heterogeneous palladium catalysts used in reactions are palladium catalysts that are immobilized or supported on a solid support. Examples of heterogeneous palladium catalysts include palladium-carbon, barium sulfate-supported palladium, metal oxide (such as alumina)-supported palladium, silicon dioxide-supported palladium, or zeolite-supported palladium. Heterogeneous palladium catalysts are commercially available, for example, from Evonik Industries Aktchengesellschaft under the trademark Noblyst®. Examples include Noblyst® P1064 (5% palladium activated carbon), Noblyst® P1070 (10% palladium activated carbon), Noblyst® P1090 (5% palladium activated carbon), Noblyst® P1092 (5% palladium activated carbon), Noblyst® P1093 (5% palladium activated carbon), and Noblyst® P1095 (5% palladium activated carbon), which are available as wet, free-flowing powders. In the method of the present invention, the amount of palladium used relative to the amount of the compound of formula (II) is typically about 0.2 to about 1 mol%, preferably about 0.4 to about 0.8 mol%, for example 0.5 mol%. Since it has been found that palladium ligands such as triphenylphosphine interfere with the reaction when heterogeneous palladium catalysts are used, the reaction is preferably carried out in the absence of such ligands.

[0021] The reaction is carried out in a suitable solvent. Any suitable solvent can be used, but the solvent preferably contains dimethyl sulfoxide (DMSO) alone or more preferably in a mixture with water. Preferably, the ratio of water to DMSO is about 0:100 to about 50:50 by volume, preferably about 1:99 to about 35:65, more preferably about 5:95 to about 20:80, for example 10:90.

[0022] Particularly suitable bases for carrying out the reaction are organic bases containing trialkylamines such as diisopropylethylamine (DIPEA), trimethylamine (TEA), or tributylamine (TBA). Trialkylamines are preferred, and diisopropylethylamine (DIPEA) is particularly suitable in an amount of 1 to 2 molar equivalents, for example, 1.3 to 1.6 molar equivalents, relative to compound (II).

[0023] 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.

[0024] According to one particularly preferred embodiment of the present invention, the reaction is carried out in a DMSO-aqueous solvent in the presence of a base, diisopropylethylamine (DIPEA), and a phase transfer catalyst, tetrabutylammonium bromide or tetrabutylammonium chloride.

[0025] The compounds of formulas (Ia), (Ib), and (II) are commercially available or can be manufactured according to methods known in the art.

[0026] To carry out the Suzuki reaction, a mixture of 4-bromo-2-chlorobenzonitrile(II), a compound of formula (Ia) or (Ib), such as 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 preferably carried out under a nitrogen stream. 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 for about 1 to about 5 hours, typically about 2 to about 4 hours, until the reaction is complete. The mixture is then preferably cooled to about 50 to 70°C, and the heterogeneous palladium catalyst is removed, for example, by filtration under nitrogen pressure. To facilitate the removal of heterogeneous palladium catalysts, such as palladium-carbon, from the reaction mixture, ethanol may be added to the reaction mixture before filtration. It has been found that palladium-carbon particles can form very fine dispersions in DMSO, which prevent complete removal of catalyst particles from the reaction mixture by filtration. The addition of ethanol has been found to cause aggregation of fine catalyst particles into larger particles that are easier to remove by filtration. The DMSO:ethanol ratio before filtration is preferably about 10:2 to about 10:10, more typically about 10:3 to about 10:5, for example, about 10:4.

[0027] The filtration temperature is preferably 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 preferably about 60–120% by volume of the solvent in which the reaction is carried out, for example, about 65–80% by volume. The resulting suspension is then further cooled to about 15–25°C and may be stirred for the period required for the precipitation of compound (III) to be completed, for example, about 3–12 hours. The precipitated product may be isolated, for example by filtration, washed with water, and dried, for example, under reduced pressure at about 40–60°C. The method typically yields a purity of compound (III) of 99.5% or higher, more typically about 99.8%, by HPLC.

[0028] 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 can be treated with a small amount of 30% HCl (aqueous solution) at a cooling temperature, preferably 0 to 15°C. The mixture is stirred at this temperature for the time required for the tetrahydropyranyl ring to detach, for example, 2 hours. A base, for example, aqueous ammonia (25%), is then added to the mixture at the above temperature. Water is then slowly added, for example, at 10 to 20°C, and the mixture is stirred for a period of, for example, 6 to 24 hours. The compound of formula (V) can be precipitated by cooling the mixture to, for example, about 0 to 5°C and stirring at this temperature for a time sufficient to complete the precipitation, preferably for example, about 3 to about 5 hours. The precipitated product can be isolated, for example, by filtration.

[0029] The compound of formula (1A) can be produced from the compound of formula (V) using, for example, the methods described in Patent Documents 1 and 2. For example, according to one embodiment, the process for producing the compound of formula (1A) is: (d) Compounds of formula (VII) [ka] To produce the compound of formula (V), [ka] The compound of formula (VI) [ka] A process of reacting with; (e) Compounds of formula (IX) [ka] To produce the compound of formula (VII) and the compound of formula (VIII) [ka] A step of reacting with; and (f) A step of reducing the compound of formula (IX) to produce the compound of formula (1A). Includes.

[0030] The reaction in step (d) can be carried out, for example, under the conditions of the Mitsunobu reaction, for example, at room temperature in a suitable solvent, such as THF or SiO, in the presence of triphenylphosphine and DIAD (diisopropyl azodicarboxylate), and then Boc-deprotection is performed by treatment with HCl and finally with a base such as NaOH.

[0031] The reaction in step (e) can be carried out at room temperature in a suitable solvent, such as DCM, in the presence of a suitable activation and conjugation reagent system, such as a combination of DIPEA (N,N-diisopropylethylamine), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), and anhydrous HOBt (1-hydroxybenzotriazole). As an alternative to HOBt, HBTU (O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) can be used. Alternatively, a combination of DIPEA and T3P (1-propanephosphonic acid cyclic anhydride) can be used as the activation and conjugation reagent system.

[0032] The reaction in step (f) can be carried out at room temperature by 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 solution of HCl.

[0033] The present invention can be further described by the following non-limiting embodiments.

[0034] Example 1. Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) in DMSO / aqueous solvent using palladium carbon. In a flask 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 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 placed. The mixture was degassed by creating a vacuum using a vacuum pump, and nitrogen was reintroduced while vigorously stirring. This procedure was repeated three times. A catalyst (5% palladium carbon, water-wetted, 1.0 g dry weight, 0.005 molar equivalent) was added, and the mixture was heated to 75°C for more than 2 hours. The mixture was stirred until the reaction was complete (2-3 hours), and then cooled to 65°C. Celite (2 g) and ethanol (40 mL) were added, and the mixture was stirred for a further 1 hour. The catalyst was removed by filtration under nitrogen pressure, and the filtrate 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 approximately 30 minutes. The resulting suspension was cooled to 20°C, and the product was collected by filtration. The cake was washed with water (40 mL), and then with cooled ethanol (20 mL). The product was vacuum-dried at 50°C to obtain 24.5 g (92%) of the title compound (III) with a purity of 99.8a-%.

[0035] Example 2. Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) in DMSO / water solvent using alumina-supported palladium. In a flask 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 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 placed. The mixture was degassed by creating a vacuum using a vacuum pump, and nitrogen was reintroduced while vigorously stirring. This procedure was repeated three times. A catalyst (5% alumina-supported palladium, 0.37 g dry weight, 0.0075 molar equivalent) was added, and the mixture was heated to 75°C for more than 30 minutes. The mixture was stirred until the reaction was complete (2-3 hours), and then cooled to 50°C. The catalyst was removed by filtration under nitrogen pressure, and the filtrate 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 approximately 30 minutes. The resulting suspension was cooled to 20°C, and the product was collected by filtration. The cake was washed with water (25 mL). The product was vacuum-dried at 50°C to obtain 6.4 g (95%) of the title compound (III) with a purity of 99.8a-%.

[0036] Example 3. Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) in DMSO / aqueous solvent using palladium carbon. In a flask 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 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 placed. The mixture was degassed by creating a vacuum using a vacuum pump, and nitrogen was reintroduced while vigorously stirring. This procedure was repeated three times. A catalyst (5% palladium carbon, water-wetted, 0.25 g dry weight, 0.005 molar equivalent) was added, and the mixture was heated to 75°C for more than 30 minutes. The mixture was stirred until the reaction was complete (2-3 hours), and then cooled to 50°C. The catalyst was removed by filtration under nitrogen pressure, and the filtrate 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 approximately 30 minutes. The resulting suspension was cooled to 20°C, and the product was collected by filtration. The cake was washed with water (25 mL). The product was vacuum-dried at 50°C to obtain 6.2 g (93%) of the title compound (III) with a purity of 99.8a-%.

[0037] Example 4. Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) in acetonitrile / aqueous solvent using palladium carbon. In a flask 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 equivalent), acetonitrile (27 mL), water (18 mL), and potassium carbonate (4.5 g, 1.4 molar equivalent) were placed. The mixture was degassed by creating a vacuum using a vacuum pump, and nitrogen was reintroduced while vigorously stirring. This procedure was repeated three times. The catalyst (palladium carbon, 1.0 g dry weight, 0.02 molar equivalent) was added together with triphenylphosphine (0.49 g, 0.08 equivalent), and the mixture was heated under reflux to approximately 74°C. The mixture was stirred for 2 hours. At this point, the analysis showed a 14.4% conversion of 4-bromo-2-chlorobenzonitrile, along with the complete consumption of the starting compound (3), which showed significant degradation of 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3).

Claims

1. Compounds of formula (Ia) or (Ib) 【Chemistry 1】 (In the formula, R 1 and R 2 is hydrogen, or R 1 and R 2 Together with linear or branched C 2-6 Alkyl chain or -C(O)-CH 2 -N(CH 3 )-CH 2 forming a -C(O)- chain) with 4-bromo-2-chlorobenzonitrile of formula (II) 【Chemistry 2】 with 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile of formula (III) in the presence of a heterogeneous palladium catalyst, a solvent and a base at elevated temperature. 【Chemistry 3】 5. A method for the preparation of a compound according to claim 1, wherein the solvent comprises dimethylsulfoxide (DMSO).

2. 2. The process of claim 1, wherein the heterogeneous palladium catalyst is palladium on carbon, palladium on barium sulfate, palladium on a metal oxide, palladium on alumina, palladium on silicon dioxide or palladium on a zeolite.

3. 3. The method of claim 1 or 2, wherein the solvent comprises a mixture of dimethylsulfoxide (DMSO) and water.

4. 4. The method of claim 3, wherein the ratio of water to DMSO is from 0:100 to 50:50 by volume.

5. The method of claim 4, wherein the ratio of water to DMSO is from 5:95 to 20:80 by volume.

6. The process according to any one of claims 1 to 5, wherein the base is diisopropylethylamine (DIPEA).

7. The process according to any one of claims 1 to 6, wherein the reaction is carried out in the presence of a phase transfer catalyst.

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

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

10. 2. The process of claim 1, wherein the reaction is carried out 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.

11. The method according to any one of claims 1 to 10, wherein the reaction temperature is from 60°C to 100°C.

12. The process according to any one of claims 1 to 11, wherein the amount of palladium catalyst used relative to the amount of compound of formula (II) is from 0.2 to 1 mol %.

13. The process according to any one of claims 1 to 12, wherein the reaction is carried out under a nitrogen atmosphere.

14. The process according to any one of claims 1 to 13, wherein the reaction time is from 1 to 5 hours.

15. (b) removing the catalyst from the reaction mixture; (c) adding water to cool the reaction mixture; and d) isolating the precipitated compound of formula (III). The method of any one of claims 1 to 14, further comprising:

16. 16. The method of claim 15, further comprising adding ethanol to the reaction mixture before the catalyst is removed from the reaction mixture.

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

18. The compound of formula (Ia) is 【Chemistry 4】 The method according to any one of claims 1 to 17, selected from the group consisting of

19. The method according to claim 18, 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).

20. 2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile of formula (V) 【Chemistry 5】 A method for the manufacture of (a) A compound of formula (III) 【Chemistry 6】 To obtain a compound of formula (Ia) or (Ib) 【Chemistry 7】 (R 1 and R 2 is hydrogen, or R 1 and R 2 Together with linear or branched C 2-6 Alkyl chain or -C(O)-CH 2 -N(CH 3 )-CH 2 forming a -C(O)- chain) with 4-bromo-2-chlorobenzonitrile of formula (II) 【Chemistry 8】 with a palladium catalyst, a solvent and a base at elevated temperature, wherein the solvent comprises dimethylsulfoxide (DMSO); (b) treating the compound of formula (III) with HCl; (c) adding a base to obtain a compound of formula (V) The method includes:

21. Compound of formula (1A) 【Chemistry 9】 A method for the manufacture of (a) A compound of formula (III) 【Chemistry 10】 To obtain a compound of formula (Ia) or (Ib) 【Chemistry 11】 (R 1 and R 2 is hydrogen, or R 1 and R 2 Together with linear or branched C 2-6 Alkyl chain or -C(O)-CH 2 -N(CH 3 )-CH 2 forming a -C(O)- chain) with 4-bromo-2-chlorobenzonitrile of formula (II) 【Chemistry 12】 with a palladium catalyst, a solvent and a base at elevated temperature, wherein the solvent comprises dimethylsulfoxide (DMSO); (b) treating the compound of formula (III) with HCl; (c) a compound of formula (V) 【Chemistry 13】 adding a base to obtain (d) A compound of formula (VII) 【Chemistry 14】 to produce a compound of formula (V) 【Chemistry 15】 reacting with (e) A compound of formula (IX) 【Chemistry 16】 To produce a compound of formula (VII), a compound of formula (VIII) 【Chemistry 17】 and (f) reducing the compound of formula (IX) to produce a compound of formula (1A). The method includes:

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