A process for the preparation of a pharmaceutical intermediate, 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile

Abstract

The application discloses a method for synthesizing 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile which is a prostate drug intermediate, and the method comprises the following steps: reacting a compound of formula VIII with a compound of formula IV under the action of an organic lithium reagent, a halogenated zinc reagent and a metal catalyst to obtain a compound of formula III: the method selects pyrazole as a starting material, adopts one-pot reaction for three-step reaction, optimizes reaction conditions, reduces the production cost of the overall reaction, improves the reaction yield, reduces the generation of impurities, and provides a more suitable industrial production method for the synthesis of prostate drugs.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceuticals and chemical synthesis, and more particularly to a method for preparing 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile, a drug intermediate for prostate cancer. Background Technology

[0002] Prostate cancer is the second most common malignant tumor among men worldwide. In 2018, approximately 1.2 million men worldwide were diagnosed with prostate cancer, and 358,000 died from the disease. Darlotamide, jointly developed by Bayer and Orion, is an oral nonsteroidal androgen receptor (AR) antagonist. It has a high affinity for the AR receptor and a strong antagonistic effect, inhibiting the receptor function and growth of prostate cancer cells. On July 30, 2019, the US FDA approved darlotamide for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). Subsequently, darlotamide was approved in the EU, Japan, and China for the treatment of non-metastatic castration-resistant prostate cancer.

[0003] Its chemical structure is as follows:

[0004]

[0005] Compound 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (Formula I) is a key intermediate in the synthesis of dallotamine, and its common preparation methods are mainly as follows:

[0006]

[0007] The first method is a preparation method of a key intermediate compound of dallotamine, Formula I, reported by Orion Corporation in PCT patent WO2011051540A1 / CN102596910B. This method involves reacting 4-bromo-2-chlorobenzonitrile with 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-boronic acid pinacol ester via the Suzuki reaction to prepare 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile, followed by hydrolysis to prepare 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (Formula I) or its hydrochloride salt.

[0008]

[0009] The second method is reported by Orion Corporation in PCT patent WO2016162604A1 / CN107428695B, which describes another method for preparing the key intermediate compound of dallotamine, formula I. This method first prepares 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole by sequentially lithiation, borate oxidation, and esterification reactions in the presence of n-butyllithium, triisopropyl borate, and pinacol. Then, it reacts with 4-bromo-2-chlorobenzonitrile via a Suzuki reaction to prepare 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-yl)benzonitrile. Finally, it prepares compound I by hydrolysis and alkalization.

[0010]

[0011] The third method, reported by Orion in PCT patent WO2021229145A1 / CN115605470A, involves the preparation of a key intermediate compound of dallotamine, compound I. This method first involves reacting borate esters such as 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-boronic acid pinacol ester with 4-bromo-2-chlorobenzonitrile via a Suzuki coupling reaction at high temperature in the presence of a heterogeneous palladium catalyst, a phase transfer catalyst, and a base to prepare 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile. Finally, compound I is prepared via hydrolysis and alkalization.

[0012]

[0013] All three methods involve expensive palladium catalysts such as bis(triphenylphosphine)palladium chloride, palladium acetate, and heterogeneous palladium catalysts. Furthermore, the preparation processes for some of the reactants, such as 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol esters, are complex and costly. These factors make it difficult to scale up the process for preparing the intermediate 2-chloro-4-(1H-pyrazole-3-yl)benzonitrile, making it unsuitable for industrial production. Therefore, it is essential to find a simple, safe, environmentally friendly, high-yield, high-purity, and low-cost method for the industrial preparation of this intermediate. Summary of the Invention

[0014] To address the problems existing in the prior art, this invention uses inexpensive and readily available pyrazole as a raw material, preferably a cheaper nickel catalyst, thereby reducing production costs. Furthermore, a condensation process has been developed, which shortens the synthesis route, increases the reaction yield, and reduces the generation of by-products. This is beneficial for improving the quality of 2-chloro-4-(1H-pyrazole-3-yl)benzonitrile, a key intermediate of darutalamine, and is suitable for scale-up production.

[0015] The technical solution adopted in this invention includes the following three aspects:

[0016] In a first aspect, the present invention provides a method for preparing a compound of formula III, wherein a compound of formula VIII and a compound of formula IV are reacted in the presence of an organolithium reagent, a zinc halide reagent, and a metal catalyst to obtain a compound of formula III:

[0017]

[0018] PG is selected from tetrahydro-2H-pyran-2-yl, methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl.

[0019] Furthermore, the reaction also includes the following intermediate process:

[0020]

[0021] Step a. The compound of formula VIII is subjected to a lithiation reaction in organic solvent 1 at a temperature of -80 to 0°C under the condition of an organolithium reagent to form the intermediate of formula VII;

[0022] Step b. The intermediate of formula VII is subjected to a metal exchange reaction at a temperature of -80 to 0°C under the conditions of a zinc halide reagent to form the intermediate of formula VI;

[0023] Step c. The intermediate of formula VI and the compound of formula IV are coupled together at 0–80 °C under the condition of a metal catalyst to form the compound of formula III.

[0024] Further, the organolithium reagent in step a is selected from at least one of n-butyllithium, isobutyllithium, sec-butyllithium, tert-butyllithium, diisopropylaminolithium, and bistrimethylsilylaminolithium; and the organic solvent 1 is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl tert-butyl ether, heptane, and hexane.

[0025] Further, the zinc halide reagent in step b is selected from at least one of anhydrous zinc chloride, anhydrous zinc bromide, anhydrous zinc iodide, zinc chloride tetrahydrofuran solution, zinc chloride 2-methyltetrahydrofuran solution, zinc chloride diethyl ether solution, zinc bromide tetrahydrofuran solution, zinc bromide 2-methyltetrahydrofuran solution, zinc bromide diethyl ether solution, zinc iodide tetrahydrofuran solution, zinc iodide 2-methyltetrahydrofuran solution, and zinc iodide diethyl ether solution, wherein X in the compound of formula VI is the corresponding Cl, Br, or I.

[0026] Furthermore, the metal catalyst is selected from at least one of nickel metal catalysts, palladium metal catalysts, or combinations of metal catalysts and ligands.

[0027] Further, the nickel metal catalyst is selected from at least one of (1,1'-bis(diphenylphosphine)ferrocene) nickel dichloride Ni(dppf)Cl2, 1,2-bis(diphenylphosphine)ethane nickel chloride Ni(dppe)Cl2, 1,3-bis(diphenylphosphine)propane nickel dichloride Ni(dppp)Cl2, bis(triphenylphosphine)nickel bromide Ni(PPh3)2Br2, bis(triphenylphosphine)nickel chloride Ni(PPh3)2Cl2, nickel acetylacetonate Ni(acac)2, ferrous acetylacetonate Fe(acac)2, nickel chloride dimethoxyethane NiCl2.DME, nickel acetate Ni(OAc)2, bis(tricyclohexylphosphine)nickel chloride (PCy3)2NiCl2, nickel bromide NiBr2, nickel chloride NiCl2, and nickel trifluoromethanesulfonate Ni(OTf)2.

[0028] The palladium metal catalyst is selected from at least one of the following: bis(triphenylphosphine)palladium dichloride Pd(PPh3)2Cl2, tetra(triphenylphosphine)palladium Pd(PPh3)4, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride Pd(dppf)Cl2, palladium acetate Pd(OAc)2, tris(diphenylacetone)palladium dichloride Pd2(dba)3, 1,3-bis(diphenylphosphine propane)palladium dichloride Pd(dppp)Cl2, 1,4-bis(diphenylphosphine butane)palladium dichloride Pd(dppb)Cl2, and bis(acetonitrile)palladium dichloride Pd(MeCN)2Cl2.

[0029] The ligand is selected from at least one of 1,2-bis(diphenylphosphine)ethane DPPE, 1,3-bis(diphenylphosphine)propane DPPP, 1,1'-bis(diphenylphosphine)ferrocene DPPF, 1,4-bis(diphenylphosphine)butane DPPB, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene Xantphos, bis(2-diphenylphosphine) ether DPEphos, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine BINAP, and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl Ruphos.

[0030] Furthermore, the molar ratio of the compound of formula VIII to the ligand is 1:(0 to 0.200).

[0031] Furthermore, the molar ratio of compound VIII to compound IV is 1:(0.50-1.50); ​​the molar ratio of compound VIII to organolithium reagent is 1:(1.02-2.00); the molar ratio of compound VIII to zinc halide reagent is 1:(1.02-2.00); and the molar ratio of compound VIII to metal catalyst is 1:(0.005-0.200).

[0032] Furthermore, the coupling reaction temperature in step c is 0–80°C, and the coupling reaction time is 2–24 h.

[0033] Furthermore, the compound of formula VIII is prepared by an upprotection reaction of pyrazole with a protecting agent under acidic or alkaline conditions in organic solvent 2.

[0034]

[0035] The protecting reagent is selected from 3,4-dihydro-2H-pyran, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, ditert-butyl dicarbonate, benzyl chloroformate, benzyl bromide, benzyl chloride, p-methoxybenzyl bromide, p-methoxybenzyl chloride, 2,4-dimethoxybenzyl chloride, triphenylmethyl chloride, triphenylmethyl bromide, trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, hexamethyldisilazane, triethylchlorosilane, triethylbromosilane, triethyliodosilane, hexaethyldisilazane, tert-butyldimethylchlorosilane, and triisopropylchlorosilane.

[0036] Acid 1 is selected from one or any combination of p-trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and sulfuric acid.

[0037] Base 1 is selected from triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, sodium hydride, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, and tripotassium phosphate.

[0038] Organic solvent 2 is selected from one or any combination of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-butyl ether, isopropyl ether, heptane, and hexane, or without any solvent.

[0039] In a second aspect, the present invention provides a method for preparing the pharmaceutical intermediate 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile represented by Formula I, wherein the compound of Formula I is prepared by a deprotection reaction of the compound of Formula III, and the compound of Formula III is prepared by the method described in the first aspect.

[0040]

[0041] Thirdly, the present invention provides the use of the compound of formula I described in the second aspect in the preparation of a medicament for treating prostate cancer.

[0042] Compared with the prior art, the present invention has the following effects:

[0043] 1. This invention uses compound VIII to directly produce compound III in a one-pot process under the action of organolithium reagent, zinc halide and metal catalyst, instead of the 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol esters in the prior art, which reduces the production cost of materials, shortens the overall synthesis route and is suitable for large-scale production.

[0044] 2. This invention uses inexpensive and readily available pyrazole as a raw material to synthesize compound III, thereby reducing production costs;

[0045] 3. This invention preferably uses a cheaper nickel catalyst as the metal catalyst, which reduces production costs while producing a compound of formula III with a yield of over 80% and a purity of up to 99%, thereby improving the quality of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile and providing a more suitable preparation method for the industrial production of prostate cancer drugs such as dallotamid. Detailed Implementation

[0046] To make the invention's content and technical solutions clearer, the following description, in conjunction with embodiments, further illustrates the invention. It should be understood that the specific implementation methods described herein are merely illustrative of the invention and not intended to limit it. Unless otherwise specified, the embodiments and features described in this application can be combined with each other.

[0047] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0048] I. Preparation of Compounds of Formula VIII

[0049] Compound VIII is prepared by an upprotection reaction of pyrazole with a protecting agent under acidic or alkaline conditions in organic solvent 2.

[0050]

[0051] The aforementioned protection reaction is one of the following: addition, sulfonation, acylation, substitution, etc.

[0052] The protecting reagent is selected from 3,4-dihydro-2H-pyran, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, ditert-butyl dicarbonate, benzyl chloroformate, benzyl bromide, benzyl chloride, p-methoxybenzyl bromide, p-methoxybenzyl chloride, 2,4-dimethoxybenzyl chloride, triphenylmethyl chloride, triphenylmethyl bromide, trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, hexamethyldisilazane, triethylchlorosilane, triethylbromosilane, triethyliodosilane, hexaethyldisilazane, tert-butyldimethylchlorosilane, and triisopropylchlorosilane.

[0053] Acid 1 is selected from one or any combination of p-trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and sulfuric acid.

[0054] Base 1 is selected from triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, sodium hydride, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, and tripotassium phosphate.

[0055] Organic solvent 2 is selected from one or any combination of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-butyl ether, isopropyl ether, heptane, and hexane, or without any solvent.

[0056] The protecting reagent for the addition reaction is 3,4-dihydro-2H-pyran, and the addition reaction is carried out under acidic conditions at a reflux temperature of 30°C to reflux temperature. The acid 1 is preferably p-toluenesulfonic acid, and the organic solvent 2 is preferably dichloromethane. The molar ratio of the compound of formula XII to the protecting reagent is 1:(1.05 to 1.50), and the molar ratio of the compound of formula XII to the acid is 1:(0.10 to 0.50).

[0057] The protecting reagent for the sulfonation reaction is methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride, preferably p-toluenesulfonyl chloride; the sulfonation reaction is carried out under alkaline conditions at -10℃ to 30℃, wherein the base is preferably triethylamine, and the organic solvent 2 is preferably dichloromethane; the molar ratio of the compound of formula XII to the protecting reagent is 1:(1.05 to 5.00), and the molar ratio of the compound of formula XII to the base is 1:(1.05 to 5.00).

[0058] The protecting reagent for the acylation reaction is di-tert-butyl dicarbonate and benzyl chloroformate. The acylation reaction is carried out under alkaline conditions at -10℃ to 30℃. Triethylamine is preferred as the base, and dichloromethane is preferred as the organic solvent. The molar ratio of the compound of formula XII to the protecting reagent is 1:(1.05 to 5.00), and the molar ratio of the compound of formula XII to the base is 1:(1.05 to 5.00).

[0059] The protecting reagent for the substitution reaction is benzyl bromide, benzyl chloride, p-methoxybenzyl bromide, p-methoxybenzyl chloride, 2,4-dimethoxybenzyl chloride, triphenylmethyl chloride, triphenylmethyl bromide, trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, hexamethyldisilazane, triethylchlorosilane, triethylbromosilane, triethyliodosilane, hexaethyldisilazane, tert-butyldimethylchlorosilane, and triisopropylchlorosilane, preferably benzyl chloride or trimethylchlorosilane; the substitution reaction is carried out under alkaline conditions at -10℃ to 80℃, wherein the base is preferably potassium hydroxide or triethylamine, and the organic solvent 2 is preferably N,N-dimethylformamide or tetrahydrofuran; the molar ratio of the compound of formula XII to the protecting reagent is 1:(0.60~5.00), and the molar ratio of the compound of formula XII to the base is 1:(0.60~5.00).

[0060] II. Preparation method of compound III

[0061] The compound of formula VIII prepared by the aforementioned method reacts with the compound of formula IV in the presence of an organolithium reagent, a zinc halide reagent, and a metal catalyst to obtain the compound of formula III:

[0062]

[0063] PG is selected from tetrahydro-2H-pyran-2-yl, methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl.

[0064] The reaction also includes the following intermediate processes:

[0065]

[0066] Step a. The compound of formula VIII is subjected to a lithiation reaction in organic solvent 1 at a temperature of -80 to 0°C under the condition of an organolithium reagent to form the intermediate of formula VII;

[0067] Step b. The intermediate of formula VII is subjected to a metal exchange reaction at a temperature of -80 to 0°C under the conditions of a zinc halide reagent to form the intermediate of formula VI;

[0068] Step c. The intermediate of formula VI and the compound of formula IV are coupled together at 0–80 °C under the condition of a metal catalyst to form the compound of formula III.

[0069] The organolithium reagent in step a is selected from at least one of n-butyllithium, isobutyllithium, sec-butyllithium, tert-butyllithium, diisopropylaminolithium, and bis(trimethylsilylaminolithium), preferably n-butyllithium; the organic solvent 1 is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl tert-butyl ether, heptane, and hexane, preferably tetrahydrofuran or 2-methyltetrahydrofuran; the temperature of the lithiation reaction is -80 to 0°C, preferably -60 to -40°C, and the lithiation reaction time is 0.5 h to 24 h, preferably 0.5 h to 2 h.

[0070] The zinc halide reagent in step b is selected from at least one of anhydrous zinc chloride, anhydrous zinc bromide, anhydrous zinc iodide, zinc chloride tetrahydrofuran solution, zinc chloride 2-methyltetrahydrofuran solution, zinc chloride diethyl ether solution, zinc bromide tetrahydrofuran solution, zinc bromide 2-methyltetrahydrofuran solution, zinc bromide diethyl ether solution, zinc iodide tetrahydrofuran solution, zinc iodide 2-methyltetrahydrofuran solution, and zinc iodide diethyl ether solution, preferably anhydrous zinc chloride; the metal exchange reaction temperature is -80 to 0°C, preferably -60 to -40°C, and the metal exchange reaction time is 0.5 h to 24 h, preferably 0.5 h to 2 h.

[0071] In the compound of formula VI, X is the corresponding Cl, Br, or I.

[0072] In step c, the metal catalyst is selected from at least one of nickel metal catalyst, palladium metal catalyst, or a combination of metal catalyst and ligand.

[0073] The nickel metal catalyst is selected from (1,1'-bis(diphenylphosphine)ferrocene) nickel dichloride Ni(dppf)Cl2, 1,2-bis(diphenylphosphine)ethane nickel chloride Ni(dppe)Cl2, 1,3-bis(diphenylphosphine)propane nickel dichloride Ni(dppp)Cl2, bis(triphenylphosphine)nickel bromide Ni(PPh3)2Br2, bis(triphenylphosphine)nickel chloride Ni(PPh3)2Cl2, nickel acetylacetone Ni(acac)2, ferrous acetylacetone Fe(acac)2, nickel chloride dimethoxyethane NiCl2.DME, nickel acetate Ni(OAc)2, bis(tricyclohexylphosphine)nickel chloride (PCy3)2NiCl2, nickel bromide NiBr2, nickel chloride NiCl2, and nickel trifluoromethanesulfonate Ni(OTf)2. Preferred materials include bis(triphenylphosphine) nickel bromide Ni(PPh3)2Br2 and bis(triphenylphosphine) nickel chloride Ni(PPh3)2Cl2.

[0074] The palladium metal catalyst is selected from bis(triphenylphosphine)palladium dichloride Pd(PPh3)2Cl2, tetra(triphenylphosphine)palladium Pd(PPh3)4, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride Pd(dppf)Cl2, palladium acetate Pd(OAc)2, tris(dibenzylacetone)palladium dichloride Pd2(dba)3, 1,3-bis(diphenylphosphinepropane)palladium dichloride Pd(dppp)Cl2, 1,4-bis(diphenylphosphinebutane)palladium dichloride Pd(dppb)Cl2, and bis(acetonitrile)palladium dichloride Pd(MeCN)2Cl2. Palladium acetate Pd(OAc)2 is preferred.

[0075] The ligand is selected from 1,2-bis(diphenylphosphine)ethane DPPE, 1,3-bis(diphenylphosphine)propane DPPPP, 1,1'-bis(diphenylphosphine)ferrocene DPPF, 1,4-bis(diphenylphosphine)butane DPPB, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene Xantphos, bis(2-diphenylphosphine) ether DPEphos, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine BINAP, and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl Ruphos. Preferably, it is 1,2-bis(diphenylphosphine)ethane DPPE.

[0076] The molar ratio of compound VIII to compound IV is 1:(0.50-1.50), preferably 1:0.70-1.00; the molar ratio of compound VIII to organolithium reagent is 1:(1.02-2.00), preferably 1:(1.05-1.30); the molar ratio of compound VIII to zinc halide reagent is 1:(1.02-2.00), preferably 1:(1.05-1.35); the molar ratio of compound VIII to metal catalyst is 1:(0.005-0.200), preferably 1:(0.050-0.150); the molar ratio of compound VIII to ligand is (0-0.200), preferably 1:(0.050-0.150).

[0077] The coupling reaction temperature in step c is 0–80°C, preferably 30–60°C, and the coupling reaction time is 2–24 h, preferably 15–20 h.

[0078] III. Preparation of Compounds of Formula I

[0079] Compound of Formula I was prepared by deprotection reaction of the compound of Formula III obtained by the aforementioned method in organic solvent 3.

[0080]

[0081] The organic solvent 3 is selected from one or any combination of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, acetonitrile, and water.

[0082] The PG of compound III is tetrahydro-2H-pyran-2-yl and tert-butoxycarbonyl. The deprotection reaction is carried out in the presence of acid 2, followed by alkalization in the presence of base 2 to obtain compound I. Acid 2 is selected from one or any combination of hydrochloric acid aqueous solution, hydrochloric acid organic solvent mixture, sulfuric acid, acetic acid, and phosphoric acid, preferably hydrochloric acid aqueous solution or hydrochloric acid organic solvent mixture; the hydrochloric acid organic solvent mixture is selected from one or any combination of hydrochloric acid, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, and 1,4-dioxane; base 2 is selected from one or any combination of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, and tripotassium phosphate, preferably sodium hydroxide; the deprotection reaction temperature is 0–60°C, preferably 10–20°C; the alkalization reaction temperature is 0–30°C, preferably 10–20°C.

[0083] The PG of the compound of formula III is methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, or p-nitrobenzenesulfonyl. The deprotection reaction is carried out in the presence of base 3 to give the compound of formula I. The base 3 is selected from one or any combination of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, and tripotassium phosphate, preferably sodium hydroxide; the deprotection reaction temperature is 0–80°C, preferably 50–80°C.

[0084] The PG of the compound of formula III is benzyloxycarbonyl, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, and triphenylmethyl. The deprotection reaction is carried out in the presence of a palladium catalyst to obtain the compound of formula I. The deprotection reaction temperature is 20–100 °C, preferably 60–80 °C.

[0085] The PG of the compound of formula III is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl. The deprotection reaction is carried out in the presence of tetrabutylammonium fluoride to obtain the compound of formula I. The deprotection reaction temperature is 0–50°C, preferably 20–30°C.

[0086] This invention provides the use of the compound of formula I as described above in the preparation of a medicament for treating prostate cancer.

[0087] Drugs used to treat prostate cancer include dalotamide.

[0088] The following are specific examples:

[0089] Example 1

[0090]

[0091] Preparation of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole:

[0092] Add 150.0 g pyrazole (2.20 mol, 1.00 eq.), 241.0 g 3,4-dihydro-2H-pyran (2.86 mol, 1.30 eq.), and 750 mL dichloromethane (5 Vol.) to a 2 L reaction flask. Start stirring and slowly add 41.9 g p-toluenesulfonic acid monohydrate (0.22 mol, 0.10 eq.). After the addition is complete, purge with nitrogen three times, then heat to 45–55 °C and stir overnight.

[0093] After the reaction was complete, the mixture was cooled to room temperature, and 750 ml (5 vol.) of 5% sodium carbonate aqueous solution was added. The mixture was stirred for 0.5–1.0 hours, and the organic layer was separated. The aqueous layer was extracted with 300 ml of dichloromethane (2 vol.), and the organic layers were combined. The mixture was then washed with 750 ml (5 vol.) of 10% brine, and the organic layer was separated. The organic layer was concentrated under reduced pressure to obtain 300.4 g of a pale yellow liquid, yielding 89.6% and a purity of 99.41%. No further purification was required, and the mixture was used directly in the next reaction.

[0094] Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile:

[0095] Step a. Add 133.6 g of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0.88 mol, 1.00 eq.) and 2004 ml of tetrahydrofuran (15 vol.) to a 5 L reaction flask under a nitrogen atmosphere. After the addition is complete, start stirring and cool to -60 to -40 °C, maintaining the temperature ≤ -40 °C for about 1 hour. Then, slowly add 374 ml of n-butyllithium (2.5 M / L n-hexane solution, 0.94 mol, 1.07 eq.). After the addition is complete, maintain the temperature ≤ -40 °C and stir for about 1 hour.

[0096] Step b. Under a nitrogen atmosphere, with the temperature controlled at ≤-40℃, after about 1 hour, add dropwise a 2.0M tetrahydrofuran solution of zinc chloride (prepared under nitrogen protection, 131.8g anhydrous zinc chloride plus 485ml tetrahydrofuran, 0.97mol, 1.10eq.) to the above reaction solution. After the addition is complete, raise the temperature to 10~30℃ and keep the temperature and stir the reaction for 0.5~1h.

[0097] Step c. Under a nitrogen atmosphere, the temperature is controlled at 10–30 °C. 135.0 g of 4-bromo-2-chlorobenzonitrile (Formula IV, 0.62 mol, 0.71 eq.) and 46.10 g of metal catalyst Ni(PPh3)2Br2 (0.06 mol, 0.07 eq.) are added to the above reaction solution. After the addition is complete, the temperature is raised to 40–50 °C and the reaction is carried out for 15–20 h.

[0098] After the reaction was complete, the mixture was cooled to room temperature, and 668 ml of 10% saline solution (5 vol.) was added. The mixture was stirred for about 0.5 hours, the organic layer was separated, and the washing was repeated once. The organic layer was concentrated to dryness, and 535 ml of ethyl acetate (4 vol.) was added and the concentrate was dispersed by stirring. Then, 535 ml of n-heptane (4 vol.) was added, and a large amount of solid precipitated. After stirring and dispersing, another 535 ml of n-heptane (4 vol.) was added. After the addition was complete, the temperature was lowered to 0–10 °C, and the mixture was stirred at this temperature for 1–2 hours. The solid was filtered and then dried at 45–55 °C for 6–10 hours to obtain compound III, 144.8 g of white solid, with a yield of 80.70% (based on formula IV) and a purity of 99.31%.

[0099] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 1.59-1.73 (m, 3H), 1.85-1.89 (m, 1H), 1.99-2.00 (m, 1H), 2.38-2.48 (m, 1H), 3.62-3.68 (m, 1H),4.02-4.05(m,1H),5.33-5.36(dd,1H),6.77(d,1H),7.69(d,1H),7.76~7.79(dd,1H),7.97(d,1H),8.17-8.19(d,1H);

[0100] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 141.1, 139.5, 136.4, 136.3, 135.5, 129.8, 128.1, 116.3, 112.0, 108.8, 84.3, 66.9, 29.4, 25.0, 22.5.

[0101] Other examples for the preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile are shown in the table below:

[0102]

[0103]

[0104] Note: a) The amounts of organolithium reagents, zinc halogenates and metal catalysts are based on formula VIII;

[0105] b) The yield is calculated based on Equation IV;

[0106] c) Here, 0.08 eq. of the ligand 1,2-bis(diphenylphosphine)ethane DPPE was added.

[0107] Preparation of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile:

[0108] Add 100.0 g of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (0.35 mol, 1.00 eq.) and 500 ml of ethanol (5 Vol.) to a 2 L reaction flask. After the addition is complete, start stirring and maintain the temperature at 10–20 °C. Slowly add 174 ml of hydrochloric acid solution (12 M / L, 2.09 mol, 6.00 eq.). After the addition is complete, maintain the temperature at 10–20 °C and stir for 4–6 hours.

[0109] After the reaction was complete, the mixture was cooled to -5 to 5°C and stirred for 1 to 2 hours. The mixture was then filtered, and the filter cake was washed with 100 ml of cold ethanol (1 vol.). The filter cake was then suspended in 300 ml of ethanol (3 vol.) and the temperature was maintained at 10 to 20°C. 93.0 ml of a sodium hydroxide aqueous solution (30% by mass, 0.70 mol, 2.00 eq.) was slowly added. After the addition was complete, the mixture was stirred at 0 to 10°C for 3 to 4 hours. The mixture was then filtered, and the filter cake was washed with 120 ml of an ethanol aqueous solution. The mixture was dried at 50-60°C for 10-14 hours to obtain compound I, 65.6 g of white solid, with a yield of 92.7% and a purity of 99.8%.

[0110] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.00 (d, 1H), 7.88 (d, 1H), 7.99 (s, 2H), 8.16 (s, 1H);

[0111] 13 C NMR (101MHz, DMSO-d6) δ (ppm): 147.0, 140.0, 136.4, 135.4, 131.9, 126.2, 124.6, 116.7, 110.4, 104.1.

[0112] Example 2

[0113]

[0114] Preparation of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole:

[0115] Add 150.0 g pyrazole (2.20 mol, 1.00 eq.), 278.1 g 3,4-dihydro-2H-pyran (3.31 mol, 1.50 eq.), and 600 mL dichloromethane (4 Vol.) to a 2 L reaction flask. Start stirring and slowly add 125.5 g p-toluenesulfonic acid (0.66 mol, 0.30 eq.). After the addition is complete, purge with nitrogen three times, then heat to 30–40 °C and maintain the temperature with stirring for 6 hours.

[0116] After the reaction was complete, the mixture was cooled to room temperature, and 600 ml (4 vol.) of 5% sodium carbonate aqueous solution was added. The mixture was stirred for 0.5–1.0 hours, and the organic layer was separated. The aqueous layer was extracted with 300 ml of dichloromethane (2 vol.), and the organic layers were combined. The mixture was then washed with 600 ml (4 vol.) of 10% brine, and the organic layer was separated. The organic layer was concentrated under reduced pressure to obtain 294.5 g of a pale yellow liquid, with a yield of 87.8% and a purity of 99.35%. No further purification was required, and the mixture was used directly in the next reaction.

[0117] Preparation of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile:

[0118] Step a. Add 133.5 g of 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0.88 mol, 1.00 eq.) and 1602 ml of 2-methyltetrahydrofuran (12 Vol.) to a 5 L reaction flask under a nitrogen atmosphere. After the addition is complete, start stirring and cool to -80 to -60 °C, maintaining the temperature ≤ -60 °C for approximately 1 hour. Then, slowly add 386 ml of n-butyllithium (2.5 M / L n-hexane solution, 0.97 mol, 1.10 eq.). After the addition is complete, maintain the temperature ≤ -60 °C and stir for approximately 1 hour.

[0119] Step b. Under a nitrogen atmosphere, with the temperature controlled at ≤-40℃, after about 1 hour, add dropwise a 2.0M zinc chloride 2-methyltetrahydrofuran solution (prepared under nitrogen protection, 137.5g anhydrous zinc chloride plus 505ml 2-methyltetrahydrofuran, 1.01mol, 1.15eq.) to the above reaction solution. After the addition is complete, raise the temperature to 10~30℃ and keep the temperature and stir the reaction for 0.5~1 hour.

[0120] Step c. Under a nitrogen atmosphere, the temperature is controlled at 10–30 °C. 157.6 g of 4-bromo-2-chlorobenzonitrile (Formula IV, 0.62 mol, 0.83 eq.) and 9.93 g of metal catalyst Pd(OAc)2 (0.04 mol, 0.05 eq.) are added to the above reaction solution. After the addition is complete, the temperature is raised to 40–50 °C and the reaction is carried out for 15–20 hours.

[0121] After the reaction was complete, the mixture was cooled to room temperature, and 668 ml of 10% saline solution (5 vol.) was added. The mixture was stirred for about 0.5 hours, the organic layer was separated, and the washing was repeated once. The organic layer was concentrated to dryness, and 400 ml of ethyl acetate (3 vol.) was added and the concentrate was dispersed by stirring. Then, 400 ml of n-heptane (3 vol.) was added, and a large amount of solid precipitated. After stirring and dispersing, another 400 ml of n-heptane (3 vol.) was added. After the addition was complete, the temperature was lowered to 0–10 °C, and the mixture was stirred at this temperature for 1–2 hours. The solid was filtered and then dried at 45–55 °C for 6–10 hours to obtain compound III, 165.5 g of white solid, yield 79.0% (based on formula IV), with a purity of 98.25%.

[0122] Preparation of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile:

[0123] Add 100.0 g of 2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (0.35 mol, 1.00 eq.) and 400 ml of ethyl acetate (4 Vol.) to a 2 L reaction flask. After the addition is complete, start stirring and maintain the temperature at 20–30 °C. Slowly add 522 ml of ethyl acetate hydrochloride solution (4 M / L, 2.09 mol, 6.00 eq.). After the addition is complete, maintain the temperature at 20–30 °C and stir for 6–8 hours.

[0124] After the reaction was complete, the mixture was cooled to 0–10 °C and stirred for 1–2 hours. The mixture was then filtered, and the filter cake was washed with 100 ml of cold ethyl acetate (1 vol.). The filter cake was then suspended in 350 ml of methanol (3.5 vol.) and the temperature was maintained at 0–10 °C. 93.0 ml of sodium hydroxide aqueous solution (30% by mass, 2.00 eq.) was slowly added. After the addition was complete, the mixture was stirred at 0–10 °C for 3–4 hours. The mixture was then filtered, and the filter cake was washed with 120 ml of methanol aqueous solution. The mixture was dried at 50–60 °C for 10–14 hours to obtain compound I, 64.4 g of white solid, with a yield of 91.0% and a purity of 99.7%.

[0125] Example 3

[0126]

[0127] Preparation of 1-[(4-methylphenyl)sulfonyl]-1H-pyrazole:

[0128] Add 150.0 g pyrazole (2.20 mol, 1.00 eq.), 445.9 g triethylamine (4.40 mol, 2.00 eq.), and 1200 ml dichloromethane (8 vol.) to a 2 L reaction flask. Start stirring, maintain the temperature between 0 °C and 10 °C, and slowly add 630.1 g p-toluenesulfonyl chloride (3.31 mol, 1.50 eq.). After the addition is complete, raise the temperature to 20–30 °C and maintain the temperature with stirring for 2 hours.

[0129] After the reaction was complete, 900 ml (6 ol.) of 15% sodium hydroxide aqueous solution was slowly added, and the mixture was stirred for 0.5–1.0 h. The organic layer was separated, and the aqueous layer was extracted with 450 ml of dichloromethane (3 ol.). The organic layers were combined, and then washed with 750 ml (5 ol.) of 10% brine. The organic layer was separated again, and the organic layer was concentrated under reduced pressure to obtain compound VⅢ, 417.7 g of yellow solid, with a yield of 85.3% and a purity of 98.74%. No further purification was required, and the compound was used directly in the next reaction.

[0130] Preparation of 2-chloro-4-[1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl)benzonitrile:

[0131] Step a. Add 197.0 g of 1-[(4-methylphenyl)sulfonyl]-1H-pyrazole (0.89 mol, 1.00 eq.) and 1970 ml of tetrahydrofuran (10 vol.) to a 5 L reaction flask under a nitrogen atmosphere. After the addition is complete, start stirring and cool to -60 to -40 °C, maintaining the temperature ≤ -40 °C for about 1 hour. Then, slowly add 390 ml of n-butyllithium (2.5 M / L n-hexane solution, 0.94 mol, 1.10 eq.). After the addition is complete, maintain the temperature ≤ -40 °C and stir for about 1 hour.

[0132] Step b. Under a nitrogen atmosphere, with the temperature controlled at ≤-40℃, after about 1 hour, add dropwise a 2.0M tetrahydrofuran solution of zinc chloride (prepared under nitrogen protection, 132.9g anhydrous zinc chloride plus 485ml tetrahydrofuran, 0.97mol, 1.10eq.) to the above reaction solution. After the addition is complete, raise the temperature to 10~30℃ and keep the temperature and stir the reaction for 0.5~1h.

[0133] Step c. Under a nitrogen atmosphere, the temperature is controlled at 10–30 °C. 153.5 g of 4-bromo-2-chlorobenzonitrile (Formula IV, 0.71 mol, 0.80 eq.) and 46.10 g of metal catalyst Ni(PPh3)2Br2 (0.06 mol, 0.07 eq.) are added to the above reaction solution. After the addition is complete, the temperature is raised to 40–50 °C and the reaction is carried out for 15–20 h.

[0134] After the reaction was complete, the mixture was cooled to room temperature, and 985 ml of 10% saline solution (5 vol.) was added. The mixture was stirred for about 0.5 hours, the organic layer was separated, and the washing was repeated once. The organic layer was concentrated to dryness, and 788 ml of ethyl acetate (4 vol.) was added and the concentrate was dispersed by stirring. Then, 788 ml of n-heptane (4 vol.) was added, and a large amount of solid precipitated. After stirring and dispersing, another 788 ml of n-heptane (4 vol.) was added. After the addition was complete, the temperature was lowered to 0–10 °C, and the mixture was stirred at this temperature for 1–2 hours. The solid was filtered and then dried at 45–55 °C for 6–10 hours to obtain compound III, 194.7 g of off-white solid, with a yield of 76.73% (based on formula IV) and a purity of 98.63%.

[0135] Preparation of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile:

[0136] Add 100.0 g of 2-chloro-4-[1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl)benzonitrile (0.28 mol, 1.00 eq.), 55.9 g of sodium hydroxide (1.40 mol, 5.00 eq.), and 500 ml of methanol (5 Vol.) to a 2 L reaction flask. After the addition is complete, start stirring and maintain the temperature at 60–70 °C for 2–3 hours.

[0137] After the reaction was complete, the mixture was cooled to 0–10 °C, and 800 ml of ethyl acetate (8 vol.) and 300 ml of water (3 vol.) were slowly added. The mixture was stirred for about 0.5 hours, and the organic layer was separated. The aqueous layer was extracted with 300 ml of ethyl acetate (3 vol.), and the organic layers were combined. The mixture was then washed with 500 ml (5 vol.) of 10% brine, and the organic layer was separated. The organic layer was concentrated under reduced pressure to dryness to obtain compound I, 49.1 g of off-white solid, with a yield of 86.3% and a purity of 99.3%.

[0138] Example 4

[0139]

[0140] Preparation of 1H-pyrazole-1-carboxylic acid tert-butyl ester:

[0141] Add 150.0 g pyrazole (2.20 mol, 1.00 eq.), 334.4 g triethylamine (3.30 mol, 1.50 eq.), and 750 ml dichloromethane (5 vol.) to a 2 L reaction flask. Start stirring, maintain the temperature at 20–30 °C, and slowly add 577.0 g di-tert-butyl dicarbonate (2.64 mol, 1.20 eq.). After the addition is complete, keep the mixture warm and stir overnight.

[0142] After the reaction was complete, the mixture was cooled to room temperature, and 750 ml (5 vol.) of 10% sodium bicarbonate aqueous solution was added. The mixture was stirred for 0.5–1.0 h, and the organic layer was separated. The aqueous layer was extracted with 300 ml of dichloromethane (2 vol.), and the organic layers were combined. The mixture was then washed with 750 ml (5 vol.) of 10% brine, and the organic layer was separated. The organic layer was concentrated under reduced pressure to obtain 338.0 g of compound VⅢ, a pale yellow liquid with a yield of 91.2% and a purity of 98.92%. No further purification was required, and the mixture was used directly in the next reaction.

[0143] Preparation of 5-(3-chloro-4-cyanophenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester:

[0144] Step a. Add 159.8 g of 1H-pyrazole-1-carboxylic acid tert-butyl ester (0.95 mol, 1.00 eq.) and 1598 ml of tetrahydrofuran (10 vol.) to a 5 L reaction flask under a nitrogen atmosphere. After the addition is complete, start stirring and cool to -60 to -40 °C, maintaining the temperature ≤ -40 °C for about 1 hour. Then, slowly add 456 ml of n-butyllithium (2.5 M / L n-hexane solution, 1.14 mol, 1.20 eq.). After the addition is complete, maintain the temperature ≤ -40 °C and stir for about 1 hour.

[0145] Step b. Under a nitrogen atmosphere, with the temperature controlled at ≤-40℃, after about 1 hour, add dropwise a 2.0M tetrahydrofuran solution of zinc chloride (prepared under nitrogen protection, 161.9g anhydrous zinc chloride plus 595ml tetrahydrofuran, 1.19mol, 1.25eq.) to the above reaction solution. After the addition is complete, raise the temperature to 10~30℃ and keep the temperature and stir the reaction for 0.5~1h.

[0146] Step c. Under a nitrogen atmosphere, the temperature is controlled at 10–30 °C. 153.5 g of 4-bromo-2-chlorobenzonitrile (Formula IV, 0.71 mol, 0.80 eq.) and 46.10 g of metal catalyst Ni(PPh3)2Br2 (0.06 mol, 0.07 eq.) are added to the above reaction solution. After the addition is complete, the temperature is raised to 40–50 °C and the reaction is carried out for 15–20 h.

[0147] After the reaction was complete, the mixture was cooled to room temperature, and 799 ml of 10% saline solution (5 vol.) was added. The mixture was stirred for about 0.5 hours, the organic layer was separated, and the washing was repeated once. The organic layer was concentrated to dryness, and 640 ml of ethyl acetate (4 vol.) was added and the concentrate was dispersed by stirring. Then, 640 ml of n-heptane (4 vol.) was added, and a large amount of solid precipitated. After stirring and dispersing, another 640 ml of n-heptane (4 vol.) was added. After the addition was complete, the temperature was lowered to 0–10 °C, and the mixture was stirred at this temperature for 1–2 hours. The solid was filtered and then dried at 45–55 °C for 6–10 hours to obtain compound III, 223.6 g of off-white solid, with a yield of 77.48% (based on formula IV) and a purity of 98.82%.

[0148] Preparation of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile:

[0149] Add 100.0 g of 5-(3-chloro-4-cyanophenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (0.33 mol, 1.00 eq.) and 500 ml of ethyl acetate (5 Vol.) to a 2 L reaction flask. After the addition is complete, start stirring and maintain the temperature at 10–20 °C. Slowly add 247 ml of ethyl acetate hydrochloride solution (4 M / L, 0.99 mol, 3.00 eq.). After the addition is complete, maintain the temperature at 10–20 °C and stir for 4–6 hours.

[0150] After the reaction was complete, the mixture was cooled to 0–10 °C and stirred for 1–2 hours. The mixture was then filtered, and the filter cake was washed with 100 ml of cold ethyl acetate (1 vol.). The filter cake was then suspended in 300 ml of methanol (3 vol.) and the temperature was maintained at 10–20 °C. 88.0 ml of sodium hydroxide aqueous solution (30% by mass, 0.66 mol, 2.00 eq.) was slowly added. After the addition was complete, the mixture was stirred at 0–10 °C for 3–4 hours. The mixture was then filtered, and the filter cake was washed with 120 ml of methanol aqueous solution. The mixture was dried at 50–60 °C for 10–14 hours to obtain compound I, 58.5 g of white solid, with a yield of 87.3% and a purity of 99.4%.

[0151] Example 5

[0152]

[0153] Preparation of 1-benzyl-1H-pyrazole:

[0154] Add 150.0 g pyrazole (2.20 mol, 1.00 eq.), 185.4 g potassium hydroxide (3.30 mol, 1.50 eq.), 71.0 g tetrabutylammonium bromide (0.22 mol, 0.10 eq.), and 900 ml N,N-dimethylformamide (6 Vol.) to a 2 L reaction flask. Start stirring, maintain the temperature at 10–20 °C, and slowly add 126.6 g benzyl chloride (2.64 mol, 1.20 eq.). After the addition is complete, raise the temperature to 60–80 °C and stir the mixture overnight.

[0155] After the reaction was complete, the mixture was cooled to room temperature. 450 ml (3 ol.) of water and 900 ml (6 ol.) of dichloromethane were added to dilute the reaction solution. The mixture was stirred for 0.5–1.0 h. The organic layer was separated, and the aqueous layer was extracted with 450 ml (3 ol.) of dichloromethane. The organic layers were combined, and the mixture was washed with 750 ml (5 ol.) of 10% saline solution. The organic layer was then separated again and concentrated under reduced pressure to obtain compound VⅢ, yielding 286.9 g of a yellow liquid with a yield of 82.3% and a purity of 97.62%. No further purification was required, and the compound was used directly in the next reaction.

[0156] Preparation of 2-chloro-4-(1-benzyl-1H-pyrazole-5-yl)benzonitrile:

[0157] Step a. Add 158.2 g of 1-benzyl-1H-pyrazole (1.00 mol, 1.00 eq.) and 1582 ml of tetrahydrofuran (10 vol.) to a 5 L reaction flask under a nitrogen atmosphere. After the addition is complete, start stirring and cool to -60 to -40 °C, maintaining the temperature ≤ -40 °C for about 1 hour. Then, slowly add 440 ml of n-butyllithium (2.5 M / L n-hexane solution, 1.10 mol, 1.10 eq.). After the addition is complete, maintain the temperature ≤ -40 °C and stir for about 1 hour.

[0158] Step b. Under a nitrogen atmosphere, with the temperature controlled at ≤-40℃, after about 1 hour, add dropwise a 2.0M tetrahydrofuran solution of zinc chloride (prepared under nitrogen protection, 156.7g anhydrous zinc chloride plus 575ml tetrahydrofuran, 1.15mol, 1.15eq.) to the above reaction solution. After the addition is complete, raise the temperature to 10~30℃ and keep the temperature and stir the reaction for 0.5~1h.

[0159] Step c. Under a nitrogen atmosphere, the temperature is controlled at 10–30 °C. 162.3 g of 4-bromo-2-chlorobenzonitrile (Formula IV, 0.75 mol, 0.75 eq.) and 45.66 g of metal catalyst Ni(PPh3)2Br2 (0.06 mol, 0.07 eq.) are added to the above reaction solution. After the addition is complete, the temperature is raised to 40–50 °C and the reaction is carried out for 15–20 h.

[0160] After the reaction was complete, the mixture was cooled to room temperature, and 791 ml of 10% saline solution (5 vol.) was added. The mixture was stirred for about 0.5 hours, the organic layer was separated, and the washing was repeated once. The organic layer was concentrated to dryness, and 633 ml of ethyl acetate (4 vol.) was added and the concentrate was dispersed by stirring. Then, 633 ml of n-heptane (4 vol.) was added, and a large amount of solid precipitated. After stirring and dispersing, another 633 ml of n-heptane (4 vol.) was added. After the addition was complete, the temperature was lowered to 0–10 °C, and the mixture was stirred at this temperature for 1–2 hours. The solid was filtered and then dried at 45–55 °C for 6–10 hours to obtain compound III, 160.0 g of white solid, with a yield of 72.64% (based on formula IV) and a purity of 99.31%.

[0161] Preparation of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile:

[0162] Add 100.0 g of 2-chloro-4-(1-benzyl-1H-pyrazol-5-yl)benzonitrile (0.34 mol, 1.00 eq.), 3.9 g of trifluoroacetic acid (0.03 mol, 0.10 eq.), 10.0 g of 10% palladium on carbon (0.10 w / w), and 500 ml of ethanol (5 vol.) to a 2 L reaction flask. After the addition is complete, purge the mixture three times with nitrogen, start stirring, and hydrogenate the mixture under pressure at 60–80 °C for 12–16 hours.

[0163] After the reaction was complete, the mixture was cooled to 20–30°C, filtered, and the filter cake was washed with 200 ml of ethanol (2 vol.). The filtrate was concentrated to dryness under reduced pressure at 40–50°C. The filter cake was then suspended in 300 ml of ethanol (3 vol.) and the temperature was controlled at 10–20°C. 55.0 ml of sodium hydroxide aqueous solution (30% by mass, 0.41 mol, 1.20 eq.) was slowly added. After the addition was complete, the mixture was kept at 0–10°C and stirred for 3–4 hours. The mixture was then filtered, and the filter cake was washed with 120 ml of ethanol aqueous solution. The mixture was dried at 50–60°C for 10–14 hours to obtain compound I, 60.2 g of white solid, with a yield of 86.8% and a purity of 99.6%.

[0164] Example 6

[0165]

[0166] Preparation of 1-(trimethylsilyl)-1H-pyrazole:

[0167] Add 150.0 g pyrazole (2.20 mol, 1.00 eq.), 556.5 g triethylamine (5.50 mol, 2.50 eq.), and 600 ml tetrahydrofuran (4 Vol.) to a 2 L reaction flask. Start stirring and maintain the temperature at 0℃~10℃. Slowly add 358.5 g trimethylchlorosilane (3.30 mol, 1.50 eq.). After the addition is complete, raise the temperature to 50~60℃ and maintain the temperature with stirring for 10~12 hours.

[0168] After the reaction was complete, the mixture was cooled to room temperature. 450 ml (3 ol.) of water and 900 ml (6 ol.) of dichloromethane were added to dilute the reaction solution. The mixture was stirred for 0.5–1.0 h. The organic layer was separated, and the aqueous layer was extracted with 450 ml (3 ol.) of dichloromethane. The organic layers were combined, and the mixture was washed with 750 ml (5 ol.) of 10% saline solution. The organic layer was then separated again and concentrated under reduced pressure to obtain 294.5 g of a pale yellow liquid, yielding 95.3% and a purity of 96.78%. No further purification was required, and the mixture was used directly in the next reaction.

[0169] Preparation of 2-chloro-4-(1-trimethylsilyl-1H-pyrazol-5-yl)benzonitrile:

[0170] Step a. Add 145.5 g of 1-(trimethylsilyl)-1H-pyrazole (1.04 mol, 1.00 eq.) and 1746 ml of tetrahydrofuran (12 Vol.) to a 5 L reaction flask under a nitrogen atmosphere. After the addition is complete, start stirring and cool to -60 to -40 °C, maintaining the temperature ≤ -40 °C for about 1 hour. Then, slowly add 456 ml of n-butyllithium (2.5 M / L n-hexane solution, 1.14 mol, 1.10 eq.). After the addition is complete, maintain the temperature ≤ -40 °C and stir for about 1 hour.

[0171] Step b. Under a nitrogen atmosphere, with the temperature controlled at ≤-40℃, after about 1 hour, add dropwise a 2.0M tetrahydrofuran solution of zinc chloride (prepared under nitrogen protection, 162.6g anhydrous zinc chloride plus 595ml tetrahydrofuran, 1.19mol, 1.15eq.) to the above reaction solution. After the addition is complete, raise the temperature to 10~30℃ and keep the temperature and stir the reaction for 0.5~1h.

[0172] Step c. Under a nitrogen atmosphere, the temperature is controlled at 10–30 °C. 168.4 g of 4-bromo-2-chlorobenzonitrile (Formula IV, 0.78 mol, 0.75 eq.) and 53.96 g of metal catalyst Ni(PPh3)2Br2 (0.07 mol, 0.07 eq.) are added to the above reaction solution. After the addition is complete, the temperature is raised to 40–50 °C and the reaction is carried out for 15–20 h.

[0173] After the reaction was complete, the mixture was cooled to room temperature, and 728 ml of 10% saline solution (5 vol.) was added. The mixture was stirred for about 0.5 hours, the organic layer was separated, and the washing was repeated once. The organic layer was concentrated to dryness, and 582 ml of ethyl acetate (4 vol.) was added and the concentrate was dispersed by stirring. Then, 582 ml of n-heptane (4 vol.) was added, and a large amount of solid precipitated. After stirring and dispersing, another 582 ml of n-heptane (4 vol.) was added. After the addition was complete, the temperature was lowered to 0–10 °C, and the mixture was stirred at this temperature for 1–2 hours. The solid was filtered and then dried at 25–35 °C for 6–10 hours to obtain compound III, 146.7 g of off-white solid, with a yield of 68.37% (based on formula IV) and a purity of 98.23%.

[0174] Preparation of 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile:

[0175] Add 100.0 g of 2-chloro-4-(1-trimethylsilyl-1H-pyrazol-5-yl)benzonitrile (0.36 mol, 1.00 eq.) and 500 ml of tetrahydrofuran (5 Vol.) to a 2 L reaction flask. After the addition is complete, start stirring and maintain the temperature at 10–20 °C. Slowly add 1080 ml of tetrabutylammonium fluoride tetrahydrofuran solution (1 M / L, 1.08 mol, 3.00 eq.). After the addition is complete, keep the temperature at 20–30 °C and stir for 2–3 hours.

[0176] After the reaction was complete, 500 ml of saturated ammonium chloride aqueous solution (5 vol.) was added, and the mixture was stirred for about 0.5 hours. The organic layer was separated and concentrated to dryness. Then, 300 ml of ethanol (3 vol.) was added, and the temperature was controlled at 10–20 °C. 96.0 ml of sodium hydroxide aqueous solution (mass fraction 30%, 0.72 mol, 2.00 eq.) was slowly added. After the addition was complete, the mixture was kept at 0–10 °C and stirred for 3–4 hours. The mixture was filtered, and the filter cake was washed with 120 ml of ethanol aqueous solution. The mixture was dried at 50–60 °C for 10–14 hours to obtain compound I, 62.7 g of off-white solid, with a yield of 84.9% and a purity of 99.2%.

Claims

1. A method for preparing a compound represented by Formula III, characterized in that, Compound VIII and compound IV are reacted in the presence of an organolithium reagent, a zinc halide reagent, and a metal catalyst to give compound III: PG is selected from tetrahydro-2H-pyran-2-yl, methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl.

2. The preparation method according to claim 1, characterized in that, The reaction also includes the following intermediate processes: Step a. The compound of formula VIII is subjected to a lithiation reaction in organic solvent 1 at a temperature of -80 to 0°C under the condition of an organolithium reagent to form the intermediate of formula VII; Step b. The intermediate of formula VII is subjected to a metal exchange reaction at a temperature of -80 to 0°C under the conditions of a zinc halide reagent to form the intermediate of formula VI; Step c. The intermediate of formula VI and the compound of formula IV are coupled together at 0–80 °C under the condition of a metal catalyst to form the compound of formula III.

3. The preparation method according to claim 2, characterized in that, The organolithium reagent in step a is selected from at least one of n-butyllithium, isobutyllithium, sec-butyllithium, tert-butyllithium, diisopropylaminolithium, and bis(trimethylsilylaminolithium); the organic solvent 1 is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, methyl tert-butyl ether, heptane, and hexane.

4. The preparation method according to claim 3, characterized in that, The zinc halide reagent in step b is selected from at least one of anhydrous zinc chloride, anhydrous zinc bromide, anhydrous zinc iodide, zinc chloride tetrahydrofuran solution, zinc chloride 2-methyltetrahydrofuran solution, zinc chloride diethyl ether solution, zinc bromide tetrahydrofuran solution, zinc bromide 2-methyltetrahydrofuran solution, zinc bromide diethyl ether solution, zinc iodide tetrahydrofuran solution, zinc iodide 2-methyltetrahydrofuran solution, and zinc iodide diethyl ether solution.

5. The preparation method according to claim 4, characterized in that, The metal catalyst is selected from at least one of nickel metal catalysts, palladium metal catalysts, or combinations of metal catalysts and ligands.

6. The preparation method according to claim 5, characterized in that, The nickel metal catalyst is selected from at least one of the following: (1,1'-bis(diphenylphosphine)ferrocene) nickel dichloride Ni(dppf)Cl2, 1,2-bis(diphenylphosphine)ethane nickel chloride Ni(dppe)Cl2, 1,3-bis(diphenylphosphine)propane nickel dichloride Ni(dppp)Cl2, bis(triphenylphosphine)nickel bromide Ni(PPh3)2Br2, bis(triphenylphosphine)nickel chloride Ni(PPh3)2Cl2, nickel acetylacetone Ni(acac)2, ferrous acetylacetone Fe(acac)2, nickel chloride dimethoxyethane NiCl2.DME, nickel acetate Ni(OAc)2, bis(tricyclohexylphosphine)nickel chloride (PCy3)2NiCl2, nickel bromide NiBr2, nickel chloride NiCl2, and nickel trifluoromethanesulfonate Ni(OTf)2.

7. The preparation method according to claim 5, characterized in that, The palladium metal catalyst is selected from at least one of the following: bis(triphenylphosphine)palladium dichloride Pd(PPh3)2Cl2, tetra(triphenylphosphine)palladium Pd(PPh3)4, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride Pd(dppf)Cl2, palladium acetate Pd(OAc)2, tris(diphenylacetone)palladium dichloride Pd2(dba)3, 1,3-bis(diphenylphosphine propane)palladium dichloride Pd(dppp)Cl2, 1,4-bis(diphenylphosphine butane)palladium dichloride Pd(dppb)Cl2, and bis(acetonitrile)palladium dichloride Pd(MeCN)2Cl2.

8. The preparation method according to claim 5, characterized in that, The ligand is selected from at least one of 1,2-bis(diphenylphosphine)ethane DPPE, 1,3-bis(diphenylphosphine)propane DPPP, 1,1'-bis(diphenylphosphine)ferrocene DPPF, 1,4-bis(diphenylphosphine)butane DPPB, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene Xantphos, bis(2-diphenylphosphine) ether DPEphos, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine BINAP, and 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl Ruphos.

9. The preparation method according to claim 8, characterized in that, The molar ratio of the compound of formula VIII to the ligand is 1:(0 to 0.200).

10. The preparation method according to claim 6, 7 or 9, characterized in that, The molar ratio of compound VIII to compound IV is 1:(0.50-1.50); ​​the molar ratio of compound VIII to organolithium reagent is 1:(1.02-2.00); the molar ratio of compound VIII to zinc halide reagent is 1:(1.02-2.00); and the molar ratio of compound VIII to metal catalyst is 1:(0.005-0.200).

11. The preparation method according to claim 9, characterized in that, The coupling reaction temperature in step c is 0–80°C, and the coupling reaction time is 2–24 h.

12. The preparation method according to claim 10, characterized in that, The compound of formula VIII is prepared by an upprotection reaction of pyrazole with a protecting agent under acidic or alkaline conditions in organic solvent 2. The protecting reagent is selected from 3,4-dihydro-2H-pyran, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, ditert-butyl dicarbonate, benzyl chloroformate, benzyl bromide, benzyl chloride, p-methoxybenzyl bromide, p-methoxybenzyl chloride, 2,4-dimethoxybenzyl chloride, triphenylmethyl chloride, triphenylmethyl bromide, trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, hexamethyldisilazane, triethylchlorosilane, triethylbromosilane, triethyliodosilane, hexaethyldisilazane, tert-butyldimethylchlorosilane, and triisopropylchlorosilane. Acid 1 is selected from one or any combination of p-trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, and sulfuric acid; Base 1 is selected from one or any combination of triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, sodium hydride, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, and tripotassium phosphate. Organic solvent 2 is selected from one or any combination of dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, ethanol, n-butyl ether, isopropyl ether, heptane, and hexane, or without any solvent.

13. A method for preparing the pharmaceutical intermediate 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile of Formula I, characterized in that, The compound of formula I is prepared from the compound of formula III via a deprotection reaction, and the compound of formula III is prepared by the method according to any one of claims 1-12:

14. Use of the compound of formula I as described in claim 13 in the preparation of a medicament for treating prostate cancer.

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