Process for the preparation of ar antagonists trc-253

Abstract

The present application relates to a kind of preparation of prostate cancer drug TRC-253 intermediate and the method for TRC-253, comprising the following steps: (1) 2-chloro-5-nitro pyridine and piperidin-4-ol are reacted under alkaline condition, and compound 1, i.e. 5-nitro-2-(piperidin-4-yloxy) pyridine is obtained;(2) compound 1 is reduced to compound 2, i.e. 6-(piperidin-4-yloxy) pyridine-3-amine under the catalysis of Pd / C in hydrogen atmosphere;(3) compound 2 is reacted with trimethyl cyanosilane and cyclobutanone, and after reaction is completed, it is salted with HCl to obtain compound 3, i.e. 1-(6-(piperidin-4-yloxy) pyridine-3-yl) amino) cyclobutane-1-carbonitrile hydrochloride;(4) compound 3 is cyclized with 5-isothiocyanato-3-(trifluoromethyl) pyridine nitrile in solvent DMA or DMSO / ethyl acetate mixed system to obtain product TRC-253.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically a method for synthesizing a drug for treating prostate cancer. Background Technology

[0002] Prostate cancer (PCa) is a tumor caused by the malignant proliferation of prostate epithelial cells. It typically causes a range of problems, including abnormal urination, pelvic discomfort, and even erectile dysfunction. Clinically, it can be treated with surgical castration or androgen deprivation therapy (ADT). However, studies have found that 65% of PCa patients will develop castration-resistant prostate cancer (CRPC).

[0003] Androgen receptor antagonists (AR antagonists) are currently the main chemotherapeutic agents for the treatment of prostate cancer. Enzalutamide, apalutamide, and bicalutamide are already in clinical use. However, the AR F877L mutation, which has been found in patients treated with enzalutamide or apalutamide, leads to resistance to both drugs.

[0004] In response to this situation, the compound TRC-253 was developed. TRC-253 has been identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations. Therefore, TRC-253 is now being considered as a next-generation AR antagonist in clinical trials for the treatment of castration-resistant prostate cancer (CRPC). The structural formula of TRC-253 is as follows:

[0005]

[0006] Two synthetic routes for TRC-253 were disclosed in an article published in J. Med. Chem. 2021, 64, 909-924:

[0007] Route 1:

[0008] Using 5-aminopyridin-2-ol as a starting material, cyclobutanone was reacted with cyclobutanone via the Strecker reaction to yield 1-((6-hydroxypyridin-3-yl)amino)cyclobutane-1-onitrile 4, 5-isothiocyano-3-(trifluoromethyl)pyridinium, which was then reacted with compound 4 in DMA to yield 5-(5-(6-hydroxypyridin-3-yl)-8-oxo-6-thiooxo-5,7-diazaspiro[3.4]oct-7-yl)-3-(trifluoromethyl) 5. Pyridinium nitrile; Compound 5 reacts with tert-butyl 4-hydroxypiperidine-1-carboxylate via photoelectroporation to give tert-butyl 4-((5-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thiaoxo-5,7-diazaspiro[3.4]octan-5-yl)pyridin-2-yl)oxy)piperidine-1-carboxylate 6; Compound 6 is debonded in 1,4-dioxane hydrochloride to give product TRC-253.

[0009]

[0010] The above synthetic route has the following disadvantages: (1) The starting material 5-aminopyridine-2-ol cannot be obtained commercially and requires multiple steps to synthesize, resulting in low yield and high cost. (2) The step from compound 5 to compound 6 is obtained through photocatalytic reaction, which uses highly toxic triphenylphosphine. More troublesome is that its byproduct, triphenylphosphine oxide, is very difficult to remove completely. Recrystallization or column chromatography is insufficient to remove it completely, which may lead to its introduction into the next step of the reaction. (3) Each step in this route requires column chromatography purification to obtain the pure product, which is costly and time-consuming. Therefore, this route is not suitable for industrial production.

[0011] Route 2:

[0012] Using 2-chloro-5-nitropyridine and tert-butyl 4-hydroxypiperidine-1-carboxylate as raw materials, a substitution reaction was carried out in the presence of a base to obtain tert-butyl 4-((5-nitropyridine-2-yl)oxy)piperidine-1-carboxylate 7. Compound 7 was then reduced by Pd / C to obtain compound 8. Compound 8 was reacted with cyclobutanone in the presence of trimethylcyanosilane via a Streck reaction to obtain tert-butyl 4-((5-((1-cyanocyclobutyl)amino)pyridine-2-yl)oxy)piperidine-1-carboxylate 9. Compound 9 was reacted with 5-isothiocyano-3-(trifluoromethyl)pyridinium nitrile in DMA to obtain compound 6. Compound 6 was debonded in 1,4-dioxane hydrochloride to obtain product TRC-253.

[0013]

[0014] The above synthetic route has the following disadvantages: (1) The route is long, and the amino group in the piperidine group needs to be protected and deprotected, which adds two steps to the reaction and leads to a decrease in the overall yield; (2) The product of each step of the reaction needs to be purified by column chromatography, which is costly and time-consuming. Therefore, this route is not suitable for industrial production. Summary of the Invention

[0015] The technical problem to be solved by this invention is to overcome the shortcomings of the prior art, provide a new synthetic route, enrich the synthetic means of TRC-253, and provide reference for laboratory and industrial production.

[0016] The synthesis method of the present invention includes the following steps:

[0017] (1) 2-Chloro-5-nitropyridine and piperidine-4-ol react under alkaline conditions to give compound 1, namely 5-nitro-2-(piperidine-4-yloxy)pyridine.

[0018] (2) Compound 1 was reduced to compound 2, namely 6-(piperidin-4-yloxy)pyridine-3-amine, under the catalysis of Pd / C in a hydrogen atmosphere.

[0019] (3) Compound 2 was reacted with cyclobutanone in the presence of trimethylcyanosilane. After the reaction was complete, HCl-ethanol solution was added to form a salt to obtain compound 3, namely 1-((6-(piperidin-4-yloxy)pyridin-3-yl)amino)cyclobutane-1-nitrile hydrochloride.

[0020] (4) React compound 3 with 5-isothiocyano-3-(trifluoromethyl)cyanopyridine in a DMA system or a DMSO / ethyl acetate system to obtain the product TRC-253.

[0021] The main advantage of this invention is that it provides a novel synthetic method for TRC-253, enriching the synthetic means of TRC-253. Furthermore, the post-processing of each reaction step in this route only requires recrystallization for purification, which is simpler, more economical, and less time-consuming than other purification methods such as column chromatography. Moreover, this route does not require highly toxic or corrosive chemical reagents, making it more suitable for industrial production. In addition to the objectives, features, and advantages described above, this invention also has other objectives, characteristics, and advantages. Detailed Implementation

[0022] According to the present invention, the following synthetic route is provided:

[0023]

[0024] In the first step of the reaction, the base that can be used is one of sodium ethoxide, sodium methoxide, sodium hydride, sodium tert-butoxide, and cesium carbonate, with sodium ethoxide being the most preferred. When using cesium carbonate, the reaction is carried out at a heating temperature, for example, at 60-90°C. When using other bases, the reaction can be carried out at room temperature. The organic solvent that can be used is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, or mixtures thereof, with THF being the most preferred. Using these preferred conditions yields higher yields.

[0025] In a typical embodiment, the base and piperidine-4-ol are first added to the solvent and stirred at room temperature for a period of time. Then, 2-chloro-5-nitropyridine is added, and the reaction is carried out at a suitable temperature. When using sodium alkoxide or sodium hydride, it is preferable to stir the reaction at room temperature.

[0026] After the reaction is complete, a saturated sodium bicarbonate solution is added to consume the generated hydrochloric acid. Then, extraction is performed using an organic solvent, such as ethyl acetate, diethyl ether, chloroform, or dimethyl carbonate. In a preferred embodiment of the invention, extraction is performed using ethyl acetate and petroleum ether, or a mixture of ethyl acetate and diethyl ether. The volume ratio of ethyl acetate to petroleum ether is preferably between 1:0.2 and 0.5, and the volume ratio of ethyl acetate to diethyl ether is preferably between 1:0.5 and 0.8. The extracted organic phase is dried with anhydrous sodium sulfate, and after removing the solvent under reduced pressure, it is recrystallized with ethanol or isopropanol. The filter cake obtained is compound 1. The preferred molar ratio of the three reactants, 2-chloro-5-nitropyridine, piperidin-4-ol, and sodium ethoxide, is between 1:1.20-1.50:1.5-1.8, preferably between 1:1.20-1.25:1.5-1.8.

[0027] The structural formula of compound 1 is as follows:

[0028]

[0029] In the second step of the reaction, compound 1 is dissolved in a solvent, and then an appropriate amount of Pd / C is added to this solution. The reaction is carried out overnight under a hydrogen atmosphere at a temperature of 25-35 degrees Celsius. After the reaction is complete, the Pd / C in the solution is filtered off, and the solvent is removed under reduced pressure to obtain compound 2. The solvent that can be used here is ethanol, propanol, THF, pyridine, piperidine, acetone, or a mixture thereof, with ethanol being preferred.

[0030] The structural formula of compound 2 is as follows:

[0031]

[0032] In the third step of the reaction, compound 2 is dissolved in acetic acid, and then trimethylcyanosilane and cyclobutanone are added to this solution. The mixture is heated to 80 degrees Celsius, refluxed, and stirred overnight. After the reaction is complete, water is added to quench the reaction, followed by extraction with an organic solvent. The organic phase is dried with anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The resulting hydrochloride salt is prepared with HCl-ethanol solution, and then recrystallized with ethanol or isopropanol. The filter cake obtained by filtration is compound 3. The preferred molar ratio of the three reactants, compound 2, trimethylcyanosilane, and cyclobutanone, is 1:0.6-0.8:1.0-1.4, preferably 1:0.75:1.2-1.3. In this step, the extraction solvents that can be used are ethyl acetate, diethyl ether, chloroform, and dimethyl carbonate. In a preferred embodiment of the present invention, ethyl acetate and petroleum ether or a mixture of ethyl acetate and diethyl ether are used for extraction. The preferred volume ratio of ethyl acetate to petroleum ether is between 1:0.2 and 0.5, and the preferred volume ratio of ethyl acetate to diethyl ether is between 1:0.5 and 0.8.

[0033] The structural formula of compound 3 is as follows:

[0034]

[0035] In the fourth step of the reaction, compound 3 reacts with 5-isothiocyano-3-(trifluoromethyl)cyanopyridine in a DMA system or a DMSO / ethyl acetate system at a reaction temperature of 80 degrees Celsius. After the reaction is complete, water is added to quench the reaction, followed by extraction with an organic solvent. The organic phase is dried with anhydrous sodium sulfate, and the solvent is removed under reduced pressure. The product is then recrystallized with ethanol or isopropanol, and the resulting filter cake is the product TRC-253.

[0036] The present invention will be further described in detail below with reference to embodiments, but the present invention may be implemented in many different ways as defined and covered by the claims.

[0037] Example 1

[0038] (1) Synthesis of 5-nitro-2-(piperidin-4-yloxy)pyridine (compound 1)

[0039] 60 ml of THF was added to a 250 ml single-necked flask, followed by sodium ethoxide (5.2 g, 0.077 mol). After dissolution, piperidine-4-ol (6.54 g, 0.064 mol) was added, and the mixture was stirred for 30 minutes. Then, 2-chloro-5-nitropyridine (8.08 g, 0.051 mol) was added, and the mixture was stirred at room temperature for 24 hours. After the reaction was complete, sodium bicarbonate solution was added, followed by extraction with a mixed solvent of ethyl acetate and petroleum ether. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the resulting oily substance was recrystallized from ethanol. The solid obtained was 7.29 g of compound 1, with a yield of 64%.

[0040] (2) Synthesis of 6-(piperidin-4-yloxy)pyridine-3-amine (compound 2)

[0041] Compound 1 (4.46 g, 0.02 mol) and 30 mL of anhydrous ethanol were added to a 100 mL flask. Pd / C (200 mg) was then added to the solution. After purging the air from the flask with nitrogen, the reaction was carried out in a hydrogen atmosphere. The temperature was raised to 30 °C and the reaction was allowed to proceed overnight. After the reaction was completed, Pd / C was filtered off, and the solvent was removed under reduced pressure to obtain 3.67 g of compound 2, with a yield of 95%.

[0042] (3) Synthesis of 1-((6-(piperidin-4-yloxy)pyridin-3-yl)amino)cyclobutane-1-nitrile hydrochloride (compound 3)

[0043] Compound 2 (7.73 g, 0.04 mol), cyclobutanone (3.7 g, 0.05 mol), trimethylcyanosilane (3.3 g, 0.03 mol), and acetic acid (30 ml) were added to a 100 ml flask and refluxed at 80 °C for 6 h. After the reaction was completed, the mixture was extracted with a mixed solvent of ethyl acetate and petroleum ether. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure. HCl-ethanol solution was added to form the hydrochloride salt, which was then recrystallized from isopropanol. The solution was filtered to give 6.40 g of compound 3, with a yield of 54%.

[0044] (4) Synthesis of 5-isothiocyano-3-(trifluoromethyl)cyanopyridine

[0045] Add 5.6 g (0.03 mol) of 5-amino-3-(trifluoromethyl)cyanopyridine to a 100 ml flask, dissolve in chloroform (35 ml), then add water (20 ml), and simultaneously add phosgene (6.88 g (0.06 mol) while stirring vigorously. React overnight. After the reaction is complete, extract with dichloromethane, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and wash 3-5 times with petroleum ether. Remove the petroleum ether under reduced pressure to obtain 5.86 g of 5-isothiocyano-3-(trifluoromethyl)cyanopyridine, yield 85.4%.

[0046] (5) Synthesis of TRC-253

[0047] Compound 3 (5.93 g, 0.02 mol) and 5-isothiocyano-3-(trifluoromethyl)pyridine nitrile (3.73 g, 0.016 mol) were added to a 250 mL flask and dissolved in DMA (40 mL). The mixture was heated to 60 °C and refluxed for 6 h. After the reactants had reacted completely, the mixture was cooled to room temperature. Methanol (30 mL) and hydrochloric acid (2 M, 30 mL) were added to this solution, and the mixture was heated to 80 °C and refluxed for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting oily substance was just dissolved in methanol, and then washed with a mixture of ethyl acetate and petroleum ether. The supernatant was collected, and the solvent was removed under reduced pressure. The product was recrystallized twice from isopropanol and filtered to obtain 4.53 g of TRC-253, with a yield of 42%. LCMS(API): mass calcd.for C 23 H 21 F3N6O2S·HCl,502.1; m / zfound,503.1[M+H]+; 1 H NMR (500MHz, DMSO): δ9.21 (d, J=2.0Hz, 1H), 8.92 (br s, 2H), 8.75 (d, J=2.0Hz, 1H), 8.22 (d, J=2.6Hz, 1H), 7.80 (dd, J=8.8, 2.6Hz, 1H), 7.09 (d, J=8.8Hz, 1H), 5.26-5.40 (m, Hz, 1H), 3.2 1-3.35(m,2H),3.04-3.20(m,2H),2.58-2.73(m,2H),2.34-2.48(m,2H),2.12-2.29(m,2H),1.87-2.04(m,3H),1.48-1.69(m,1H).

[0048] Example 2

[0049] (1) Synthesis of 5-nitro-2-(piperidin-4-yloxy)pyridine (compound 1)

[0050] 60 ml of THF was added to a 250 ml single-necked flask, followed by sodium methoxide (2.1 g, 0.039 mol). After dissolution, piperidine-4-ol (3.25 g, 0.032 mol) was added, and the mixture was stirred for 20-30 minutes. Then, 2-chloro-5-nitropyridine (4.12 g, 0.026 mol) was added under ice-water bath conditions. The mixture was stirred overnight at room temperature. After the reaction was complete, sodium bicarbonate solution was added, followed by extraction with a mixed solvent of ethyl acetate and petroleum ether. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the resulting oily substance was recrystallized from isopropanol. The resulting solid was filtered to obtain 3.25 g of compound 1, with a yield of 56%. Sodium methoxide was used as the base in this step, resulting in a lower yield than in Example 1.

[0051] (2) Synthesis of 6-(piperidin-4-yloxy)pyridine-3-amine (compound 2)

[0052] Compound 1 (2.23 g, 0.01 mol) and 15 mL of anhydrous methanol were added to a 100 mL flask. Pd / C (120 mg) was then added to this solution. After purging the air from the flask with nitrogen, the reaction was carried out in a hydrogen atmosphere at 30 °C overnight. After the reaction was complete, Pd / C was filtered off, and the solvent was removed under reduced pressure to obtain 1.64 g of compound 2, with a yield of 85%. Methanol was used as the solvent in this step, resulting in a lower yield than in Example 1.

[0053] (3) Synthesis of 1-((6-(piperidin-4-yloxy)pyridin-3-yl)amino)cyclobutane-1-nitrile hydrochloride (compound 3)

[0054] Compound 2 (3.86 g, 0.02 mol), cyclobutanone (1.8 g, 0.03 mol), trimethylcyanosilane (1.6 g, 0.015 mol), and acetic acid (18 ml) were added to a 100 ml flask and refluxed at 80 °C for 6 h. After the reaction was completed, the mixture was extracted with a mixed solvent of ethyl acetate and petroleum ether. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure. HCl-ethanol solution was added to form the hydrochloride salt, which was then recrystallized from isopropanol. The solution was filtered to give 3.46 g of compound 3, with a yield of 56%.

[0055] (4) Synthesis of TRC-253

[0056] Compound 3 (2.97 g, 0.01 mol) and 5-isothiocyano-3-(trifluoromethyl)pyridine nitrile (1.9 g, 0.008 mol) were added to a 250 mL flask and dissolved in DMA (20 mL). The mixture was heated to 60 °C and refluxed for 6 h. After the reaction was complete, the mixture was cooled to room temperature. Methanol (15 mL) and hydrochloric acid (2 M, 15 mL) were added to the solution, and the mixture was heated to 80 °C and refluxed for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting oily substance was just dissolved in methanol. The mixture was then washed with a mixture of ethyl acetate and petroleum ether. The supernatant was collected and the solvent was removed under reduced pressure. The mixture was recrystallized twice with isopropanol and filtered to obtain 2.3 g of TRC-253, with a yield of 42%.

[0057] Example 3

[0058] (1) Synthesis of 5-nitro-2-(piperidin-4-yloxy)pyridine (compound 1)

[0059] Add 60 ml of THF to a 250 ml single-necked flask, then add cesium carbonate (19.2 g, 0.059 mol). After it dissolves, add piperidine-4-ol (4.8 g, 0.048 mol), stir for 20-30 minutes, then add 2-chloro-5-nitropyridine (6.0 g, 0.038 mol). Stir overnight at room temperature. After the reaction is complete, add sodium bicarbonate solution and extract with a mixed solvent of ethyl acetate and petroleum ether. Wash with saturated brine and dry with anhydrous sodium sulfate. Remove the solvent under vacuum. Recrystallize the resulting oily substance with ethanol or isopropanol. Filter to obtain 3.9 g of solid, compound 1, with a yield of 46%. This step uses cesium carbonate as a base, resulting in a lower yield than in Examples 1 and 2, and requires a larger amount of cesium carbonate.

[0060] (2) Synthesis of 6-(piperidin-4-yloxy)pyridine-3-amine (compound 2)

[0061] Compound 1 (3.0 g, 0.013 mol) and 20 mL of anhydrous ethanol were added to a 100 mL flask. Pd / C (180 mg) was then added to the solution. After purging the air from the flask with nitrogen, the reaction was carried out in a hydrogen atmosphere. The temperature was raised to 30 °C and the reaction was allowed to proceed overnight. After the reaction was completed, Pd / C was filtered off, and the solvent was removed under reduced pressure to obtain 2.4 g of compound 2, with a yield of 93%.

[0062] (3) Synthesis of 1-((6-(piperidin-4-yloxy)pyridin-3-yl)amino)cyclobutane-1-nitrile hydrochloride (compound 3)

[0063] Compound 2 (5.15 g, 0.027 mol), cyclobutanone (2.5 g, 0.03 mol), trimethylcyanosilane (2.2 g, 0.02 mol), and acetic acid (20 ml) were added to a 100 ml flask and refluxed at 80 °C for 6 h. After the reaction was completed, the mixture was extracted with a mixed solvent of ethyl acetate and petroleum ether. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure. HCl-ethanol solution was added to form the hydrochloride salt, which was then recrystallized from isopropanol. The solution was filtered to give 4.56 g of compound 3, with a yield of 55%.

[0064] (4) Synthesis of TRC-253

[0065] Compound 3 (3.6 g, 0.013 mol) and 5-isothiocyano-3-(trifluoromethyl)pyridinenitrile (2.5 g, 0.01 mol) were added to a 250 mL flask and dissolved in DMSO (1 mL) and ethyl acetate (10 mL). The mixture was heated to 85 °C and refluxed for 6 h. After the reaction was complete, the mixture was cooled to room temperature. Methanol (20 mL) and hydrochloric acid (2 M, 20 mL) were added to this solution, and the mixture was heated to 80 °C and refluxed for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting oily substance was just dissolved in methanol and washed with a mixture of ethyl acetate and petroleum ether. The supernatant was collected and the solvent was removed under reduced pressure. The product was recrystallized twice from isopropanol and filtered to obtain 2.6 g of TRC-253, with a yield of 36%. In this step, DMSO and ethyl acetate were used as solvents, and the yield was significantly lower than that in Example 1.

[0066] Example 4

[0067] (1) Synthesis of 5-nitro-2-(piperidin-4-yloxy)pyridine (compound 1)

[0068] 60 ml of THF was added to a 250 ml single-necked flask, followed by sodium hydride (0.92 g, 0.0385 mol). After dissolution, piperidine-4-ol (3.2 g, 0.032 mol) was added, and the mixture was stirred for 30 minutes. Then, 2-chloro-5-nitropyridine (4.0 g, 0.025 mol) was added, and the mixture was stirred at 80°C for 24 hours. After the reaction was complete, sodium bicarbonate solution was added, followed by extraction with a mixed solvent of ethyl acetate and petroleum ether. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the resulting oily substance was recrystallized from ethanol or isopropanol. The resulting solid was filtered to obtain 3.1 g of compound 1, with a yield of 55%. In this step, sodium hydride was used as the base, resulting in a lower yield than in Example 1.

[0069] (2) Synthesis of 6-(piperidin-4-yloxy)pyridine-3-amine (compound 2)

[0070] Compound 1 (4.5 g, 0.02 mol) and 30 mL of anhydrous ethanol were added to a 100 mL flask. Pd / C (300 mg) was then added to the solution. After purging the air from the flask with nitrogen, the reaction was carried out in a hydrogen atmosphere. The temperature was raised to 30 °C and the reaction was allowed to proceed overnight. After the reaction was completed, Pd / C was filtered off, and the solvent was removed under reduced pressure to obtain 3.6 g of compound 2, with a yield of 94%.

[0071] (3) Synthesis of 1-((6-(piperidin-4-yloxy)pyridin-3-yl)amino)cyclobutane-1-nitrile hydrochloride (compound 3)

[0072] Compound 2 (2.51 g, 0.013 mol), cyclobutanone (1.19 g, 0.017 mol), trimethylcyanosilane (1.1 g, 0.01 mol), and acetic acid (10 ml) were added to a 100 ml flask and refluxed at 80 °C for 6 h. After the reaction was completed, the mixture was extracted with a mixed solvent of ethyl acetate and petroleum ether. The organic phase was dried with anhydrous sodium sulfate and the solvent was removed under reduced pressure. HCl-ethanol solution was added to form the hydrochloride salt, which was then recrystallized from isopropanol. The solution was filtered to give 2.28 g of compound 3, with a yield of 54%.

[0073] (4) Synthesis of TRC-253

[0074] Compound 3 (1.8 g, 0.07 mol) and 5-isothiocyano-3-(trifluoromethyl)pyridine nitrile (1.27 g, 0.005 mol) were added to a 250 mL flask and dissolved in DMA (13 mL). The mixture was heated to 60 °C and refluxed for 6 h. After the reaction was complete, the mixture was cooled to room temperature. Methanol (10 mL) and hydrochloric acid (2 M, 10 mL) were added to the solution, and the mixture was heated to 80 °C and refluxed for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting oily substance was just dissolved in methanol. The mixture was then washed with a mixture of ethyl acetate and petroleum ether. The supernatant was collected and the solvent was removed under reduced pressure. The mixture was recrystallized twice with isopropanol and filtered to obtain 1.43 g of TRC-253, with a yield of 40.2%.

[0075] Example 5

[0076] (1) Synthesis of 5-nitro-2-(piperidin-4-yloxy)pyridine (compound 1)

[0077] 60 ml of DMF was added to a 250 ml single-necked flask, followed by cesium carbonate (25 g, 0.077 mol). After dissolution, piperidine-4-ol (6.54 g, 0.064 mol) was added, and the mixture was stirred for 30 minutes. Then, 2-chloro-5-nitropyridine (8.08 g, 0.051 mol) was added, and the mixture was stirred at 70°C for 24 hours. After the reaction was complete, sodium bicarbonate solution was added, followed by extraction with a mixed solvent of ethyl acetate and diethyl ether. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the resulting oil was recrystallized from ethanol or isopropanol. The resulting solid was filtered to obtain 4.67 g of compound 1, with a yield of 41%. DMF was used as the solvent in this step, resulting in a lower yield than in Example 3.

[0078] (2) Synthesis of 6-(piperidin-4-yloxy)pyridine-3-amine (compound 2)

[0079] The operation is the same as in Example 1.

[0080] (3) Synthesis of 1-((6-(piperidin-4-yloxy)pyridin-3-yl)amino)cyclobutane-1-nitrile hydrochloride (compound 3)

[0081] The operation is the same as in Example 1.

[0082] (4) Synthesis of TRC-253

[0083] Compound 3 (5.94 g, 0.02 mol) was added to a 250 mL flask, followed by 5-isothiocyano-3-(trifluoromethyl)pyridinenitrile (3.73 g, 0.016 mol). DMA (40 mL) was added to dissolve the compound, and the mixture was heated to 60 °C and refluxed for 6 h. After the reaction was complete, the mixture was cooled to room temperature, and methanol (30 mL) and hydrochloric acid (2 M, 30 mL) were added to the solution. The mixture was heated to 80 °C and refluxed for 2 h. After the reaction was complete, the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting oily substance was just dissolved in methanol, and then washed with a mixture of ethyl acetate and petroleum ether. The supernatant was collected, and the solvent was removed under reduced pressure. The mixture was recrystallized twice with ethanol, and 5.4 g of TRC-253 was obtained by filtration, with a yield of 50%. The recrystallization solvent used in this step was ethanol, and the yield was significantly higher than that in Example 1.

Claims

1. A method for preparing an AR antagonist TRC-253, the compound having the structure of Formula I, the method comprising the following steps: Formula 1; (1) 2-chloro-5-nitropyridine and piperidine-4-ol react in the presence of a strong base to give compound 1, namely 5-nitro-2-(piperidine-4-yloxy)pyridine; (2) Compound 1 was reduced to compound 2, namely 6-(piperidin-4-yloxy)pyridine-3-amine, under the catalysis of Pd / C in a hydrogen atmosphere; (3) Compound 2 was reacted with cyclobutanone in the presence of trimethylcyanosilane. After the reaction was complete, HCl was added to form a salt to give compound 3, namely (1-(6-(piperidin-4-yloxy)pyridin-3-yl)amino)cyclobutane-1-nitrile hydrochloride). (4) React compound 3 with 5-isothiocyano-3-(trifluoromethyl)cyanopyridine to obtain the product TRC-253.

2. The method as described in claim 1, characterized in that, In step (1), the strong base is selected from the group consisting of sodium ethoxide, sodium methoxide, sodium hydride and cesium carbonate.

3. The method as described in claim 1, characterized in that, In step (1), the molar ratio of 2-chloro-5-nitropyridine, piperidine-4-ol, and sodium ethoxide is 1:1.20-1.50:1.5-1.

8.

4. The method as described in claim 2, characterized in that, In step (1), the organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran or a mixture thereof.

5. The method as described in claim 2 or 3, characterized in that, In step (1), the base and piperidine-4-ol are added to the organic solvent and stirred for 15-30 minutes before 2-chloro-5-nitropyridine is added.

6. The method as described in claim 1, characterized in that, In step (2), ethanol is used as the solvent and the amount of Pd / C is 8-15% of the mass of compound 1.

7. The method as described in claim 1, characterized in that... In steps (1) and (3), the recrystallization solvent is selected from ethanol, isopropanol or a mixture thereof.

8. The method as described in claim 1, characterized in that... In steps (1) and (3), the solvent used for extraction is a mixture of petroleum ether and ethyl acetate.

9. The method as described in claim 1, characterized in that, The solvent used in step (4) is N,N-dimethylacetamide, and preferably, the recrystallization solvent used in step (4) is ethanol.

10. The method as described in claim 1, characterized in that, The synthesis of isothiocyano-3-(trifluoromethyl)pyridine nitrile is obtained by reacting 5-amino-3-(trifluoromethyl)cyanopyridine with phosgene in a two-phase system of water and chloroform.

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