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 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 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 technology]

[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 US Pat. No. 5,999,363. The 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 in which AR antagonism is desired. [ka]

[0003] US Pat. No. 5,399,633 discloses a process for the preparation of compounds of formula (1A) via intermediates of formulae (III), (IV) and (V) as shown in Scheme 1. [ka]

[0004] The compound of formula (III), i.e., 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-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 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 completion of the reaction, the solvent was evaporated almost to dryness and water was added to precipitate the compound of formula (III).

[0005] A similar process for preparing the compound of formula (III) is disclosed in US Pat. No. 5,399,663. The Suzuki reaction is carried out in the presence of homogeneous bis(triphenylphosphine)palladium(II) chloride catalyst, sodium carbonate base and phase transfer catalyst (TBAB) in THF-toluene-water solvent. The compound of formula (III) is isolated by adding water and evaporating the isolated organic phase to near dryness, followed by adding ethanol and filtering the crystalline product.

[0006] Finally, US Pat. No. 5,399,633 discloses a method for preparing the compound of formula (III), in which the Suzuki reaction is carried out in the presence of homogeneous Pd(OAc)2 catalyst, potassium carbonate base and triphenylphosphine in acetonitrile-water solvent. 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, followed by 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 palladium catalyst remain in the isolated product.

[0008] Thus, there is a need for more practical and economical processes suitable for the production of AR antagonist intermediates, such as the compound of formula (III), on a large scale. [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 Summary of the Invention

[0010] It has now been found that the compound of formula (III) can be produced on a large scale with high yields, high purity of the final product, and short reaction times by heterogeneous catalysis. The heterogeneous catalyst is fixed or supported on a solid support, and can therefore be easily recovered and recycled, thereby substantially reducing the production costs of the process. The level of catalyst residues found in the final product is also substantially reduced.

[0011] Thus, the present invention relates to a compound of formula (Ia) or (Ib) [ka] (Wherein, R1 and R2 are hydrogen, or R1 and R2 together are straight or branched chain C 2-6 forming an alkyl chain or a -C(O)-CH2-N(CH3)-CH2-C(O)- chain) with 4-bromo-2-chlorobenzonitrile of formula (II) [ka] 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. [ka] A method for the preparation of

[0012] In another aspect, the present invention provides a 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile of formula (V) [ka] A method for the manufacture of (a) A compound of formula (III) [ka] To obtain a compound of formula (Ia) or (Ib) [ka] (R1 and R2 are hydrogen or R1 and R2 together are straight or branched chain C 2-6 forming an alkyl chain or a -C(O)-CH2-N(CH3)-CH2-C(O)- chain) with 4-bromo-2-chlorobenzonitrile of formula (II) [ka] 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 a compound of formula (V) The present invention provides a method comprising:

[0013] In yet another aspect, the present invention provides a compound of formula (1A) [ka] A process for the manufacture of (a) A compound of formula (III) [ka] To obtain a compound of formula (Ia) or (Ib) [ka] (R1 and R2 are hydrogen or R1 and R2 together are straight or branched chain C 2-6 forming an alkyl chain or a -C(O)-CH2-N(CH3)-CH2-C(O)- chain) with 4-bromo-2-chlorobenzonitrile of formula (II) [ka] 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) A compound of formula (V) [ka] adding a base to obtain (d) A compound of formula (VII) [ka] to produce a compound of formula (VI) [ka] reacting with; (e) A compound of formula (IX) [ka] by reacting a compound of formula (VII) with a compound of formula (VIII) [ka] and (f) reducing the compound of formula (IX) to produce a compound of formula (1A). The present invention provides a process including: DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

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

[0016] Tautomerism: It will be recognized by those skilled in the art that formulas and chemical names disclosed herein that include hydrogen atoms on the pyrazole ring include tautomers of the compounds in question, as the hydrogen atoms on the pyrazole ring can exist in tautomeric equilibrium between positions 1 and 2. For example, the chemical name "2-chloro-4-(1H-pyrazol-3-yl)benzonitrile" and the corresponding formula (V) include the tautomer of the compound, i.e., "2-chloro-4-(1H-pyrazol-5-yl)benzonitrile."

[0017] According to the present invention, there is provided a 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] (Wherein, R1 and R2 are hydrogen, or R1 and R2 together are straight or branched chain C 2-6 forming an alkyl chain or a -C(O)-CH2-N(CH3)-CH2-C(O)- chain) with 4-bromo-2-chlorobenzonitrile of formula (II) [ka] in the presence of a heterogeneous palladium catalyst, a solvent and a base at elevated temperature.

[0018] According to a preferred embodiment of the present invention, the compound of formula (Ia) is [ka] is 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] The heterogeneous palladium catalyst used in the reaction is a palladium catalyst that is fixed or supported on a solid support. Examples of 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, from Evonik Industries Aktiengesellschaft under the trademark Noblyst®. Examples include Noblyst® P1064 (5% palladium on activated carbon), Noblyst® 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 moist free-flowing powders. In the process of the present invention, the amount of palladium used relative to the amount of 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%. It has been found that palladium ligands such as triphenylphosphine interfere with the reaction when using heterogeneous palladium catalysts, so 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 comprises dimethylsulfoxide (DMSO), either alone or, more preferably, in a mixture with water. Suitably, the ratio of water to DMSO is, by volume, about 0:100 to about 50:50, 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 including trialkylamines such as diisopropylethylamine (DIPEA), trimethylamine (TEA) or tributylamine (TBA). Trialkylamines are preferred, and diisopropylethylamine (DIPEA) is particularly preferably used 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, with tetrabutylammonium bromide and tetrabutylammonium chloride being particularly preferred.

[0024] According to one particularly preferred embodiment of the invention, the reaction is carried out in a 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.

[0025] Compounds of formula (Ia), (Ib) and (II) are either commercially available or can be prepared 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 suitably 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 reaction is stirred until completion, for example, for about 1 to about 5 hours, typically for about 2 to about 4 hours. The mixture is then cooled, suitably to about 50 to 70°C, and the heterogeneous palladium catalyst is removed, for example, by filtration under nitrogen pressure. Ethanol may be added to the reaction mixture prior to filtration to facilitate removal of heterogeneous palladium catalysts, such as palladium on carbon, from the reaction mixture. It has been found that particles of palladium on carbon can form very fine dispersions in DMSO that prevent complete removal of the catalyst particles from the reaction mixture by filtration. It has been found that the addition of ethanol causes agglomeration of the fine catalyst particles into larger particles that are easier to remove by filtration. A ratio of DMSO:ethanol prior to filtration of about 10:2 to about 10:10, more typically about 10:3 to about 10:5, for example about 10:4, is suitable.

[0027] The temperature of the filtration is then suitably adjusted to about 30-50° C., and 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, for example about 65-80% by volume, of the solvent in which the reaction is carried out. The resulting suspension may then be further cooled to about 15-25° C. and stirred for the period required to complete the precipitation of compound (III), 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 results in compound (III) having a purity of 99.5% or more by HPLC, more typically about 99.8%.

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

[0029] The compound of formula (1A) can be prepared from the compound of formula (V) using the methods described, for example, in US Pat. No. 5,399,623 and US Pat. No. 5,499,623. For example, according to one embodiment, the process for the preparation of the compound of formula (1A) comprises: (d) A compound of formula (VII) [ka] To produce a compound of formula (V) [ka] with a compound of formula (VI) [ka] reacting with; (e) A compound of formula (IX) [ka] to produce a compound of formula (VII) [ka] and (f) reducing the compound of formula (IX) to produce a compound of formula (1A). Includes.

[0030] 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 with a base such as NaOH.

[0031] The reaction of step (e) can be carried out at room temperature in a suitable solvent, such as DCM, in the presence of a suitable activating and coupling reagent system, such as a combination of DIPEA (N,N-diisopropylethylamine), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) and anhydrous HOBt (1-hydroxy-benzotriazole). As an alternative to HOBt, HBTU (O-(benzotriazol-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 activating and coupling reagent system.

[0032] The reaction of step (f) can be carried out by treating a compound of formula (IX) with a reducing agent, such as sodium borohydride, in a suitable solvent, such as ethanol, and treating the mixture with aqueous HCl at room temperature.

[0033] The invention is further illustrated by the following non-limiting examples.

[0034] Example 1. Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) in DMSO / water solvent using palladium on carbon A flask under nitrogen was charged with 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), dimethylsulfoxide (87.5 mL), water (12.5 mL) and diisopropylethylamine (24.1 mL, 1.5 molar equivalent). The mixture was degassed by applying a vacuum and reintroducing nitrogen with vigorous stirring. This procedure 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 stirred at 37°C for 1 hour. Over two hours 75℃ to The mixture was stirred until the reaction was complete (2-3 hours), after which the mixture was cooled to 65°C. Celite (2 g) and ethanol (40 mL) were added and the mixture was stirred for about an additional 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 added and stirred for about 30 minutes. Over 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 chilled ethanol (20 mL). The product was dried in vacuum at 50° C. to give 24.5 g (92%) of the title compound (III) with 99.8 a-% purity.

[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 palladium supported on alumina A flask under nitrogen was charged with 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), dimethylsulfoxide (42.5 mL), water (7.5 mL) and diisopropylethylamine (6.1 mL, 1.5 molar equivalent). The mixture was degassed by applying a vacuum and reintroducing nitrogen with vigorous stirring. This procedure was repeated three times. The catalyst (5% palladium on alumina, 0.37 g dry weight, 0.0075 molar equivalent) was added and the mixture was stirred at 37°C for 1 hour. Over 30 minutes 75℃ to The mixture was stirred until the reaction was complete (2-3 hours), 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 added for approximately 30 minutes. Over The mixture was added slowly. 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 dried in vacuum at 50° C. to give 6.4 g (95%) of the title compound (III) with 99.8 a-% purity.

[0036] Example 3. Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) in DMSO / water solvent using palladium on carbon A flask under nitrogen was charged with 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), dimethylsulfoxide (42.5 mL), water (7.5 mL) and diisopropylethylamine (6.1 mL, 1.5 molar equivalent). The mixture was degassed by applying a vacuum and reintroducing nitrogen with vigorous stirring. This procedure 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 stirred at 37°C for 1 hour. Over 30 minutes 75℃ to The mixture was stirred until the reaction was complete (2-3 hours), 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 added for approximately 30 minutes. Over The mixture was added slowly. 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 dried in vacuum at 50° C. to give 6.2 g (93%) of the title compound (III) with 99.8 a-% purity.

[0037] reference Example 4. Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (III) in acetonitrile / water solvent using palladium on carbon A flask under nitrogen was charged with 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 mixture was degassed by applying a vacuum and reintroducing nitrogen with vigorous stirring. This procedure was repeated three times. Catalyst (palladium on carbon, 1.0 g dry weight, 0.02 molar equivalent) was added along with triphenylphosphine (0.49 g, 0.08 equiv.) and the mixture was heated to near reflux, approximately 74° C. The mixture was stirred for 2 hours. At this point, analysis showed 14.4% conversion of 4-bromo-2-chlorobenzonitrile with complete consumption of starting compound (3), indicating significant decomposition 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 1:99 to 50:50 by volume.

5. 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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