An apalutamide intermediate compound

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to an apalutamide intermediate compound. The application provides a new apalutamide intermediate, which is prepared from tert-butyl (1-aminocarbonylcyclobutyl) carbamate and phenyl chlorothioformate under alkaline conditions to obtain the new apalutamide intermediate. The preparation of apalutamide from the new intermediate avoids the Strecker reaction of N-methyl-2-fluoro-4-aminobenzamide and sodium cyanide (or trimethylsilyl cyanide), cyclobutanone, and the use of a highly toxic cyanide reagent in the prior art. Meanwhile, the application also solves the problems of high temperature and equivalent copper required in the Ullmann reaction, and the preparation process can avoid the generation of double-substituted impurities, is simple to operate, has a higher yield, and is more suitable for industrial mass production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and specifically relates to an apalutamide intermediate compound. Background Technology

[0002] Apalutamide is a second-generation nonsteroidal androgen receptor (AR) antagonist developed by Johnson & Johnson. It was first marketed in the United States in 2018 for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) and in Europe and Japan in 2019. Later that year, the FDA approved an expansion of the product's label to include the treatment of patients with metastatic androgen-sensitive prostate cancer (mCSPC); a supplemental application in Japan is currently under review to further approve this indication. In 2020, the EMA approved the product for use, with the following structural formula:

[0003]

[0004] Currently, the main reported methods for synthesizing apalutamide are as follows:

[0005] The original synthetic routes reported in WO2007126765, WO2008119015, etc. are shown below:

[0006]

[0007] The introduction of cyanide in this route requires large amounts of sodium cyanide or potassium cyanide, which can cause poisoning and other adverse effects on operators, and the wastewater generated poses a potential risk of environmental pollution. Furthermore, the initial raw material cyclobutanone used in this route is constrained by process safety, making commercial production difficult and resulting in high prices for downstream products. Both sodium cyanide and potassium cyanide are highly toxic raw materials, easily causing safety accidents. Additionally, this route uses microwave reaction equipment that is difficult to scale up. In summary, this route is unsuitable for industrial production.

[0008] Patent WO2016100645: The cyclobutanenitrile intermediate obtained by the Strecker reaction of 3-fluoro-4-iodoaniline with cyclobutanone and cyanide is condensed and cyclized with 2-cyano-3-trifluoromethyl-5-aminopyridine in the presence of a thiocarbonyl compound. Then, a carbonyl insertion reaction is carried out under the catalysis of the noble metal palladium to obtain a carboxylic acid ester intermediate, or a carboxylic acid (ester) intermediate is obtained by Grignard exchange followed by reaction with dry ice. Finally, amidation yields the final product apalutamide. This route not only uses highly toxic sodium cyanide but also a noble metal palladium catalyst, resulting in high industrial production costs. The synthetic route is shown below:

[0009]

[0010] Chinese patent applications CN107108507 and WO2016100652 describe a process using APAL-007 and 1-Boc-aminocyclobutane-1-carboxylic acid as raw materials. After amidation with N,N'-carbonyldiimidazole (CDI) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) catalysis, followed by deBoc removal with hydrogen chloride, 1-amino-N-(6-cyano-5-(trifluoromethyl)pyridin-3-)cyclobutane-1-carboxylic acid (APAL-022) is obtained. Compound 22 is then coupled with 2-fluoro-4-chloro-N-methylbenzamide (APAL-023) via potassium acetate / copper powder catalysis to obtain APAL-024. Compound 24 reacts with phenyl thiochloroformate under DMAP catalysis to yield apalutamide. Although this route avoids the use of highly toxic cyanides and heavy metal catalysts, the CDI condensation method is still too costly for industrial production. Furthermore, this route involves excessively long linear steps and cumbersome processes, resulting in high costs for industrial production. The synthetic route is shown below:

[0011]

[0012] Chinese patent application CN109988077 discloses a novel method for preparing apalutamide. Using 2-fluoro-4-bromo-N-methylbenzamide and 1-aminocyclobutylcarboxylic acid hydrochloride as starting materials, a substitution reaction is performed to prepare 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylic acid; subsequently, esterification yields 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylic acid ester; finally, a cyclization reaction is completed with 2-cyano-3-trifluoromethyl-5-isothiocyanopyridine to obtain apalutamide. The synthetic route is shown below:

[0013] This route also avoids the use of highly toxic cyanide and heavy metal catalysts, but the preparation of compound I requires a relatively high temperature (110°C) and a long reaction time (10-11 hours), and requires inert gas (argon) protection; the preparation of compound II requires the use of iodomethane or acetyl chloride, which poses safety hazards in industrial production.

[0014]

[0015] Chinese patent application CN108383749 uses N-methyl-2-fluoro-4-halo-benzamide compound 1 and cyclobutine hydrochloride 2 as starting materials. The synthesis proceeds via Ullmann reaction condensation to obtain intermediate compound 3, followed by esterification to obtain intermediate compound 4. This intermediate compound 4 is then cyclized with thiocyanate to obtain compound 5. Finally, compound 5 is coupled with compound 6 to obtain apalutamide. This route avoids the use of highly toxic cyanides and heavy metal catalysts. The two Ullmann reactions (for the preparation of compound 3 and apalutamide 7) require high temperatures and long reaction times, and necessitate inert gas (nitrogen) protection. Furthermore, the use of thionyl chloride and potassium thiocyanate poses significant safety hazards in industrial production. The synthetic route is shown below:

[0016]

[0017] Therefore, in view of the shortcomings of the existing technology, there is an urgent need for a simple, industrially suitable, high-yield, and low-cost method for the synthesis of apalutamide to meet market demand. Summary of the Invention

[0018] To address the shortcomings of the above methods, this invention provides a novel apalutamide intermediate compound and its preparation method. Furthermore, this invention provides a method for preparing apalutamide using this novel intermediate. The preparation of apalutamide using this novel intermediate successfully avoids the use of highly toxic cyanide and heavy metal catalysts, reducing process costs. The operation is simple, the reaction conditions are mild, the safety is high, the pollution is low, and a high yield of the product can be obtained, making it more suitable for industrial scale-up.

[0019] The specific solution of this invention is as follows:

[0020] The first aspect of this invention provides a novel apalutamide intermediate compound, the structure of which is shown in Formula II:

[0021]

[0022] The second aspect of this invention provides a method for preparing a novel intermediate compound II of apalutamide. The method specifically includes the following steps: adding compound SM-1 and base A to organic solvent A, heating to T1, adding compound SM-2 and base B, maintaining the temperature and stirring until the reaction is complete, and then post-processing the reaction to obtain compound II. The synthetic route is as follows:

[0023]

[0024] Preferably, the organic solvent A is selected from one or a combination of N,N-dimethylformamide, n-hexane, n-heptane, ethyl acetate, isopropyl acetate, acetonitrile, and tetrahydrofuran, with N,N-dimethylformamide being particularly preferred.

[0025] Preferably, base A and base B are selected from organic or inorganic bases, wherein the inorganic base is selected from sodium carbonate, cesium carbonate, sodium hydroxide, and sodium bicarbonate; the organic base may be selected from 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, and N-methylmorpholine; wherein 4-dimethylaminopyridine is preferred.

[0026] Preferably, the molar ratio of compound SM-1, compound SM-2, base A, and base B is 1:1.5-2.5:1.8-2.5:1.8-2.5, and particularly preferably 1:2.0:2.0:2.0.

[0027] Preferably, the reaction temperature T1 is 40-80°C, more preferably 50-55°C.

[0028] In a preferred embodiment, the reaction requires post-treatment, specifically: adding 6M hydrochloric acid solution dropwise to the reaction system, stirring to induce crystallization, filtering, and drying to obtain compound II.

[0029] A third aspect of the present invention provides the use of a novel apalutamide intermediate compound II for the preparation of apalutamide.

[0030] The use of apalutamide's novel intermediate compound II in the preparation of apalutamide specifically includes the following steps:

[0031] Step 1: Add compound II to organic solvent B, add base C under ice bath, dissolve compound III in organic solvent and add it to the reaction solution. After the addition is complete, stir at room temperature until the reaction is finished to obtain compound IV.

[0032] Step 2: Add compound IV, dichloromethane, and trifluoroacetic acid to the reaction flask and stir at room temperature until the reaction is complete. After evaporating the solvent, add organic solvent C. Add base D in batches under ice bath conditions. Dissolve compound VI in organic solvent C under ice bath stirring and add it to the reaction solution. After the addition is complete, stir at room temperature until the reaction is complete to obtain apalutamide.

[0033] The synthesis route is as follows:

[0034]

[0035] Preferably, the organic solvent B in step 1 is selected from one or a combination of N,N-dimethylformamide, isopropyl acetate, acetonitrile, and tetrahydrofuran, with N,N-dimethylformamide being particularly preferred.

[0036] Preferably, the base C and base D mentioned in steps 1 and 2 are selected from sodium hydride, sodium hydroxide, lithium tert-butoxide, sodium tert-butoxide, sodium bis(trimethylsilyl)aminosodium, and lithium diisopropylamino, with sodium hydride being particularly preferred.

[0037] Preferably, the molar ratio of compound II, compound III and base C in step 1 is 1.0:1.0~1:8:2.5~3.5, and particularly preferably 1.0:1.05:2.8.

[0038] Preferably, the organic solvent C in step 2 is selected from one or a combination of N,N-dimethylformamide, acetonitrile, and tetrahydrofuran.

[0039] Preferably, the molar ratio of compound IV, compound VI, trifluoroacetic acid, and base D in step 2 is 1.0:1.0-1.8:2.0:2.2-3.0, with a particularly preferred ratio of 1:1.05:2.0:2.7.

[0040] In a preferred embodiment, the reaction requires post-processing. The post-processing of step 1 is as follows: after the reaction is completed by TLC monitoring, the reaction solution is added to water, filtered to obtain a crude product, and the crude product is recrystallized from ethanol to obtain compound IV. The post-processing of step 2 is as follows: after the reaction is completed by TLC monitoring, the reaction solution is added to water, filtered to obtain a crude product, and the crude product is dried and recrystallized from isopropanol to obtain apalutamide.

[0041] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0042] 1. This invention provides a novel apalutamide intermediate compound. The preparation method of this novel intermediate has few reaction steps, mild reaction conditions, simple post-reaction processing, and is easy to operate.

[0043] 2. The preparation of apalutamide using this new intermediate can avoid the use of highly toxic reagents such as sodium cyanide, reduce waste emissions, is environmentally friendly, and is suitable for industrial production;

[0044] 3. The preparation method provided by this invention can avoid the generation of apalutamide disubstituted impurities, resulting in a high purity final product. Detailed Implementation

[0045] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the invention and not for limiting the invention. Therefore, simple improvements to the present invention under the premise of the method of the present invention are all within the scope of protection of the present invention.

[0046] Confirmation of the structure of the compound obtained in this invention:

[0047] Structural characterization of compound II

[0048]

[0049] High-resolution mass spectrometry of compound II: ESI-HRMS: m / z = 257.0923 [M+H] +; 1 H-NMR(DMSO-d6,600MHz)δ2.25(2H,m),2.06(2H,m),1.72(1H,m),1.60(1H,m),1.43(9H,s). 13 CNMR(DMSO-d6,150MHz)δ181.5,172.0,154.9,83.9,76.7,31.8(2C),29.4(3C).

[0050] Structural characterization of compound IV

[0051]

[0052] ESI-HRMS: m / z=427.1005[M+1] + ; 1 H-NMR(DMSO-d6,600MHz)δ8.58(1H,s),8.49(1H,s),

[0053] 2.25(2H,m),2.06(2H,m),1.72(1H,m),1.60(1H,m). 13 CNMR(DMSO-d6,150MHz)181.5,179.4,154.9,140.4,140.0,138,2,130.3,121.5,118.5,117.0,83.9,74.7,32.3(2C),29.4(3C),13.3.

[0054] Structural characterization of compound I

[0055]

[0056] ESI-HRMS (m / z): 478.1300 [M+H] + ; 1 H NMR (600MHz, CDCl3) δ9.12(d,J=2.1Hz,1H),8.36(d,J=2.1Hz,1H),8.34(m,1H),7.28(m,1H),7.1 8(m,1H),6.75(m,1H),3.09(d,J=4.6Hz,3H),2.73(m,2H),2.57(m,2H),2.27(m,1H),1.71(m,1H); 13CNMR (150MHz, CDCl3) δ177.0,170.8,160.0,146.2,139.9,137.7 132.4,130.3,129.5,124.6,123.4,121.9,121.8,121.3,117.3,115.9,82.4,32.3(2C),27.3,13.9

[0057] Preparation of Compound II

[0058] Example 1

[0059] 4-Dimethylaminopyridine (2.44 g, 20 mmol), tert-butyl (1-carbamoylcyclobutyl)carbamate (2.14 g, 10 mmol), and N,N-dimethylformamide (20 mL) were added to a reaction flask. The temperature was raised to 50℃~55℃, and phenyl thiochloroformate (3.45 g, 20 mmol) and triethylamine (2.78 g, 20 mmol) were added. The reaction was maintained at this temperature for 5 h. 6 mol / L hydrochloric acid solution was added dropwise to the reaction system, and the mixture was stirred to induce crystallization. The crystals were filtered and dried to obtain compound II with a yield of 94.5% and an HPLC purity of 99.92%.

[0060] Example 2

[0061] Triethylamine (2.02 g, 20 mmol), tert-butyl (1-carbamoylcyclobutyl)carbamate (2.14 g, 10 mmol), and N,N-dimethylformamide (20 mL) were added to a reaction flask. The temperature was raised to 50℃~55℃, and phenyl thiochloroformate (2.59 g, 15 mmol) and 4-dimethylaminopyridine (2.44 g, 20 mmol) were added. The reaction was maintained at this temperature for 5 h. 6 mol / L hydrochloric acid solution was added dropwise to the reaction system, and the mixture was stirred to induce crystallization. The crystals were filtered and dried to obtain compound II with a yield of 91.6% and an HPLC purity of 99.61%.

[0062] Example 3

[0063] Sodium carbonate (2.12 g, 20 mmol), tert-butyl (1-carbamoylcyclobutyl)carbamate (2.14 g, 10 mmol), and N,N-dimethylformamide (20 mL) were added to a reaction flask. The temperature was raised to 50℃~55℃, and phenyl thiochloroformate (4.32 g, 25 mmol) and diisopropylethylamine (2.58 g, 20 mmol) were added. The reaction was maintained at this temperature for 5 h. 6 mol / L hydrochloric acid solution was added dropwise to the reaction system, and the mixture was stirred to induce crystallization. The crystals were filtered and dried to obtain compound II with a yield of 90.1% and an HPLC purity of 99.54%.

[0064] Example 4

[0065] 4-Dimethylaminopyridine (2.20 g, 18 mmol), tert-butyl (1-carbamoylcyclobutyl)carbamate (2.14 g, 10 mmol), and n-hexane (20 mL) were added to a reaction flask. The temperature was raised to 40℃~45℃, and phenyl thiochloroformate (3.45 g, 20 mmol) and N-methylmorpholine (2.02 g, 20 mmol) were added. The reaction was maintained at this temperature for 5 h. 6 mol / L hydrochloric acid solution was added dropwise to the reaction system, and the mixture was stirred to induce crystallization. The crystals were filtered and dried to obtain compound II with a yield of 90.5% and an HPLC purity of 99.71%.

[0066] Example 5

[0067] 4-Dimethylaminopyridine (3.05 g, 25 mmol), tert-butyl (1-carbamoylcyclobutyl)carbamate (2.14 g, 10 mmol), and n-heptane (20 mL) were added to a reaction flask. The temperature was raised to 75℃~80℃, and phenyl thiochloroformate (3.45 g, 20 mmol) and sodium carbonate (2.12 g, 20 mmol) were added. The reaction was maintained at this temperature for 5 h. 6 mol / L hydrochloric acid solution was added dropwise to the reaction system, and the mixture was stirred to induce crystallization. The crystals were filtered and dried to obtain compound II with a yield of 91.2% and an HPLC purity of 99.55%.

[0068] Example 6

[0069] Cesium carbonate (6.52 g, 20 mmol), tert-butyl (1-carbamoylcyclobutyl)carbamate (2.14 g, 10 mmol), and ethyl acetate (20 mL) were added to a reaction flask. The mixture was heated to 50 °C–55 °C, and phenyl thiochloroformate (3.45 g, 20 mmol) and triethylamine (1.82 g, 18 mmol) were added. The mixture was kept at this temperature for 5 h. 6 mol / L hydrochloric acid solution was added dropwise to the reaction system, and the mixture was stirred to induce crystallization. The crystals were filtered and dried to obtain compound II with a yield of 90.0% and an HPLC purity of 99.65%.

[0070] Example 7

[0071] Sodium hydroxide (0.80 g, 20 mmol), tert-butyl (1-carbamoylcyclobutyl)carbamate (2.14 g, 10 mmol), and acetonitrile (20 mL) were added to a reaction flask. The temperature was raised to 50 °C–55 °C, and phenyl thiochloroformate (3.45 g, 20 mmol) and triethylamine (2.53 g, 25 mmol) were added. The reaction was maintained at this temperature for 5 h. 6 mol / L hydrochloric acid solution was added dropwise to the reaction system, and the mixture was stirred to induce crystallization. The crystals were filtered and dried to obtain compound II with a yield of 89.0% and an HPLC purity of 99.65%.

[0072] Example 8

[0073] Sodium bicarbonate (1.26 g, 15 mmol), tert-butyl (1-carbamoylcyclobutyl)carbamate (2.14 g, 10 mmol), and tetrahydrofuran (20 mL) were added to a reaction flask. The temperature was raised to 35 °C–40 °C, and phenyl thiochloroformate (2.07 g, 12 mmol) and triethylamine (1.52 g, 15 mmol) were added. The reaction was maintained at this temperature for 5 h. 6 mol / L hydrochloric acid solution was added dropwise to the reaction system, and the mixture was stirred to induce crystallization. The crystals were filtered and dried to obtain compound II with a yield of 84.5% and an HPLC purity of 98.82%.

[0074] Example 9

[0075] N-methylmorpholine (2.83 g, 28 mmol), tert-butyl (1-carbamoylcyclobutyl)carbamate (2.14 g, 10 mmol), and N,N-dimethylformamide (20 mL) were added to a reaction flask. The temperature was raised to 80℃~85℃, and phenyl thiochloroformate (4.66 g, 27 mmol) and triethylamine (2.73 g, 27 mmol) were added. The reaction was maintained at this temperature for 5 h. 6 mol / L hydrochloric acid solution was added dropwise to the reaction system, and the mixture was stirred to induce crystallization. The crystals were filtered and dried to obtain compound II with a yield of 85.1% and an HPLC purity of 98.61%.

[0076] Preparation of compound IV

[0077] Example 10

[0078] 20 mL of N,N-dimethylformamide was added to a 100 mL three-necked flask. Intermediate II (4.61 g, 18 mmol) was added sequentially with stirring. The mixture was cooled to 0–5 °C in an ice-water bath. Sodium hydride (1.20 g, 50 mmol) was added in portions. After the addition was complete, stirring was continued in the ice-water bath for 30 min. 3-Trifluoromethyl-5-bromophenylcyanopyridine (4.72 g, 18.9 mmol) was dissolved in 12 mL of DMF and slowly added dropwise to the reaction mixture, maintaining the internal temperature at 0–5 °C. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 4 h. The reaction was monitored for completion by TLC. The reaction mixture was added to 100 mL of water, filtered to obtain the crude product, and recrystallized from ethanol (10 mL) to give compound IV, with a yield of 95.1% and an HPLC purity of 99.91%.

[0079] Example 11

[0080] 20 mL of N,N-dimethylformamide was added to a 100 mL three-necked flask. Intermediate II (4.61 g, 18 mmol) was added sequentially with stirring. The mixture was cooled to 0–5 °C in an ice-water bath. Sodium hydroxide (2.0 g, 50 mmol) was added in portions. After the addition was complete, stirring was continued in the ice-water bath for 30 min. 3-Trifluoromethyl-5-bromophenylcyanopyridine (4.52 g, 18 mmol) was dissolved in 12 mL of DMF and slowly added dropwise to the reaction mixture, maintaining the internal temperature at 0–5 °C. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 4 h. The reaction was monitored for completion by TLC. The reaction mixture was added to 100 mL of water, filtered to obtain the crude product, and recrystallized from ethanol (10 mL) to give compound IV, with a yield of 92.6% and an HPLC purity of 99.63%.

[0081] Example 12

[0082] 20 mL of isopropyl acetate was added to a 100 mL three-necked flask. Intermediate II (4.61 g, 18 mmol) was added sequentially with stirring. The mixture was cooled to 0–5 °C in an ice-water bath. Lithium tert-butoxide (4.00 g, 50 mmol) was added in portions. After the addition was complete, stirring was continued in the ice-water bath for 30 min. 3-Trifluoromethyl-5-bromophenylcyanopyridine (8.10 g, 32.4 mmol) was dissolved in 12 mL of isopropyl acetate and slowly added dropwise to the reaction mixture, maintaining the internal temperature at 0–5 °C. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 4 h. The reaction was monitored for completion by TLC. The reaction mixture was added to 100 mL of water, filtered to obtain the crude product, and recrystallized from ethanol (10 mL) to give compound IV, with a yield of 91.8% and an HPLC purity of 99.53%.

[0083] Example 13

[0084] 20 mL of acetonitrile was added to a 100 mL three-necked flask. Intermediate II (4.61 g, 18 mmol) was added sequentially with stirring. The mixture was cooled to 0–5 °C in an ice-water bath. Sodium hydride (1.08 g, 45 mmol) was added in portions. After the addition was complete, stirring was continued in the ice-water bath for 30 min. 3-Trifluoromethyl-5-bromophenylcyanopyridine (4.72 g, 18.9 mmol) was dissolved in 12 mL of acetonitrile and slowly added dropwise to the reaction mixture, maintaining the internal temperature at 0–5 °C. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 4 h. The reaction was monitored for completion by TLC. The reaction mixture was added to 100 mL of water, filtered to obtain the crude product, and recrystallized from ethanol (10 mL) to give compound IV, with a yield of 92.1% and an HPLC purity of 99.66%.

[0085] Example 14

[0086] 20 mL of acetonitrile was added to a 100 mL three-necked flask. Intermediate II (4.61 g, 18 mmol) was added sequentially with stirring. The mixture was cooled to 0–5 °C in an ice-water bath. Sodium hydride (1.51 g, 63 mmol) was added in portions. After the addition was complete, stirring was continued in the ice-water bath for 30 min. 3-Trifluoromethyl-5-bromophenylcyanopyridine (4.72 g, 18.9 mmol) was dissolved in 12 mL of acetonitrile and slowly added dropwise to the reaction mixture, maintaining the internal temperature at 0–5 °C. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 4 h. The reaction was monitored for completion by TLC. The reaction mixture was added to 100 mL of water, filtered to obtain the crude product, and recrystallized from ethanol (10 mL) to give compound IV, with a yield of 93.0% and an HPLC purity of 99.59%.

[0087] Example 15

[0088] 20 mL of acetonitrile was added to a 100 mL three-necked flask. Intermediate II (4.61 g, 18 mmol) was added sequentially with stirring. The mixture was cooled to 0–5 °C in an ice-water bath. Sodium bis(trimethylsilyl)amino (7.33 g, 40 mmol) was added in portions. After the addition was complete, stirring was continued in the ice-water bath for 30 min. 3-Trifluoromethyl-5-bromophenylcyanopyridine (4.72 g, 18.9 mmol) was dissolved in 12 mL of acetonitrile and slowly added dropwise to the reaction mixture, maintaining the internal temperature at 0–5 °C. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 4 h. The reaction was monitored for completion by TLC. The reaction mixture was added to 100 mL of water, filtered to obtain the crude product, and recrystallized from ethanol (10 mL) to give compound IV, with a yield of 85.6% and an HPLC purity of 98.72%.

[0089] Example 16

[0090] 20 mL of acetonitrile was added to a 100 mL three-necked flask. Intermediate II (4.61 g, 18 mmol) was added sequentially with stirring. The mixture was cooled to 0–5 °C in an ice-water bath. Diisopropylaminolithium (7.31 g, 67 mmol) was added in portions. After the addition was complete, stirring was continued in the ice-water bath for 30 min. 3-Trifluoromethyl-5-bromophenylcyanopyridine (4.72 g, 18.9 mmol) was dissolved in 12 mL of acetonitrile and slowly added dropwise to the reaction mixture, maintaining the internal temperature at 0–5 °C. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 4 h. The reaction was monitored for completion by TLC. The reaction mixture was added to 100 mL of water, filtered to obtain the crude product, and recrystallized from ethanol (10 mL) to give compound IV, with a yield of 84.2% and an HPLC purity of 97.98%.

[0091] Preparation of apalutamide

[0092] Example 17

[0093] Compound IV (2.56 g, 6 mmol), dichloromethane (10 mL), and trifluoroacetic acid (0.89 mL, 12 mmol) were added to a reaction flask. The mixture was stirred at 25 °C for 2 h. After removing the solvent by rotary evaporation, 10 mL of N,N-dimethylformamide was added. The mixture was cooled in an ice-water bath, and sodium hydride (0.39 g, 16 mmol) was added in portions. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min. 2-Fluoro-4-bromobenzoylmide (1.46 g, 6.3 mmol) was dissolved in 3 mL of N,N-dimethylformamide and slowly added dropwise to the reaction solution, maintaining the internal temperature at 0-5 °C. After the addition was complete, the mixture was brought back to room temperature and stirred for 5 h. The reaction was monitored for completion by TLC. The reaction solution was added to 50 mL of water and filtered to obtain the crude product. After drying, it was recrystallized from isopropanol (20 mL) to give apalutamide, with a yield of 97.6% and an HPLC purity of 99.92%.

[0094] Example 18

[0095] Compound IV (2.56 g, 6 mmol), dichloromethane (10 mL), and trifluoroacetic acid (0.89 mL, 12 mmol) were added to a reaction flask. The mixture was stirred at 25 °C for 2 h. After removing the solvent by rotary evaporation, 10 mL of N,N-dimethylformamide was added. The mixture was cooled in an ice-water bath, and sodium hydroxide (0.64 g, 16 mmol) was added in portions. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min. 2-Fluoro-4-bromobenzoylmide (1.39 g, 6 mmol) was dissolved in 3 mL of N,N-dimethylformamide and slowly added dropwise to the reaction solution, maintaining the internal temperature at 0-5 °C. After the addition was complete, the mixture was brought back to room temperature and stirred for 5 h. The reaction was monitored for completion by TLC. The reaction solution was added to 50 mL of water and filtered to obtain the crude product. After drying, the product was recrystallized from isopropanol (20 mL) to give apalutamide, with a yield of 93.2% and an HPLC purity of 99.64%.

[0096] Example 19

[0097] Compound IV (2.56 g, 6 mmol), dichloromethane (10 mL), and trifluoroacetic acid (0.89 mL, 12 mmol) were added to a reaction flask. The mixture was stirred at 25 °C for 2 h. After removing the solvent by rotary evaporation, 10 mL of N,N-dimethylformamide was added. The mixture was cooled in an ice-water bath, and lithium tert-butoxide (1.28 g, 16 mmol) was added in portions. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min. 2-Fluoro-4-bromobenzoylmide (2.50 g, 10.8 mmol) was dissolved in 3 mL of N,N-dimethylformamide and slowly added dropwise to the reaction mixture, maintaining the internal temperature at 0-5 °C. After the addition was complete, the mixture was brought back to room temperature and stirred for 5 h. The reaction was monitored for completion by TLC. The reaction mixture was added to 50 mL of water and filtered to obtain the crude product. After drying, it was recrystallized from isopropanol (20 mL) to give apalutamide, with a yield of 94.0% and an HPLC purity of 99.55%.

[0098] Example 20

[0099] Compound IV (2.56 g, 6 mmol), dichloromethane (10 mL), and trifluoroacetic acid (0.89 mL, 12 mmol) were added to a reaction flask. The mixture was stirred at 25 °C for 2 h. After removing the solvent by rotary evaporation, 10 mL of N,N-dimethylformamide was added. The mixture was cooled in an ice-water bath, and sodium tert-butoxide (1.44 g, 15 mmol) was added in portions. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min. 2-Fluoro-4-bromobenzoylmide (1.46 g, 6.3 mmol) was dissolved in 3 mL of N,N-dimethylformamide and slowly added dropwise to the reaction solution, maintaining the internal temperature at 0-5 °C. After the addition was complete, the mixture was brought back to room temperature and stirred for 5 h. The reaction was monitored for completion by TLC. The reaction solution was added to 50 mL of water and filtered to obtain the crude product. After drying, the product was recrystallized from isopropanol (20 mL) to give apalutamide, with a yield of 93.8% and an HPLC purity of 99.71%.

[0100] Example 21

[0101] Compound IV (2.56 g, 6 mmol), dichloromethane (10 mL), and trifluoroacetic acid (0.89 mL, 12 mmol) were added to a reaction flask. The mixture was stirred at 25 °C for 2 h. After removing the solvent by rotary evaporation, 10 mL of acetonitrile was added. The mixture was cooled in an ice-water bath, and sodium hydride (0.51 g, 21 mmol) was added in portions. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min. 2-Fluoro-4-bromobenzoylmide (1.46 g, 6.3 mmol) was dissolved in 3 mL of acetonitrile and slowly added dropwise to the reaction mixture, maintaining an internal temperature of 0-5 °C. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 5 h. The reaction was monitored for completion by TLC. The reaction mixture was added to 50 mL of water and filtered to obtain the crude product. After drying, it was recrystallized from isopropanol (20 mL) to give apalutamide, with a yield of 94.2% and an HPLC purity of 99.55%.

[0102] Example 22

[0103] Compound IV (2.56 g, 6 mmol), dichloromethane (10 mL), and trifluoroacetic acid (0.89 mL, 12 mmol) were added to a reaction flask. The mixture was stirred at 25 °C for 2 h. After removing the solvent by rotary evaporation, 10 mL of tetrahydrofuran was added. The mixture was cooled in an ice-water bath, and sodium bis(trimethylsilyl)amino (2.42 g, 13.2 mmol) was added in portions. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min. 2-Fluoro-4-bromobenzoylmethylamine (1.46 g, 6.3 mmol) was dissolved in 3 mL of tetrahydrofuran and slowly added dropwise to the reaction mixture, maintaining the internal temperature at 0-5 °C. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 5 h. The reaction was monitored for completion by TLC. The reaction mixture was added to 50 mL of water and filtered to obtain the crude product. After drying, it was recrystallized from isopropanol (20 mL) to give apalutamide, with a yield of 88.9% and an HPLC purity of 98.85%.

[0104] Example 23

[0105] Compound IV (2.56 g, 6 mmol), dichloromethane (10 mL), and trifluoroacetic acid (0.89 mL, 12 mmol) were added to a reaction flask. The mixture was stirred at 25 °C for 2 h. After removing the solvent by rotary evaporation, 20 mL of tetrahydrofuran was added. The mixture was cooled in an ice-water bath, and lithium diisopropylamino (2.40 g, 22.0 mmol) was added in portions. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min. 2-Fluoro-4-bromobenzoylmethylamine (2.78 g, 12 mmol) was dissolved in 5 mL of tetrahydrofuran and slowly added dropwise to the reaction mixture, maintaining the internal temperature at 0-5 °C. After the addition was complete, the mixture was allowed to return to room temperature and stirred for 5 h. The reaction was monitored for completion by TLC. The reaction mixture was added to 50 mL of water and filtered to obtain the crude product. After drying, it was recrystallized from isopropanol (30 mL) to give apalutamide, with a yield of 89.2% and an HPLC purity of 98.66%.

Claims

1. A method for preparing apalutamide, characterized in that, The preparation method includes the following steps: Add 2.44 g of 4-dimethylaminopyridine, 2.14 g of (1-carbamoylcyclobutyl)carbamate tert-butyl ester, and 20 mL of N,N-dimethylformamide to a reaction flask. Heat the mixture to 50℃~55℃, add 3.45 g of phenyl thiochloroformate and 2.78 g of triethylamine, and maintain the temperature for 5 h. Add 6 mol / L hydrochloric acid solution dropwise to the reaction system, stir to induce crystallization, filter, and dry to obtain compound II. 20 mL of N,N-dimethylformamide was added to a 100 mL three-necked flask. While stirring, 4.61 g of intermediate II was added sequentially. The mixture was cooled to 0-5 °C in an ice-water bath. 1.20 g of sodium hydride was added in portions. After the addition was complete, the mixture was stirred in an ice-water bath for 30 min. 4.72 g of 3-trifluoromethyl-5-bromophenylcyanopyridine was dissolved in 12 mL of DMF and slowly added dropwise to the reaction mixture, maintaining an internal temperature of 0-5 °C. After the addition was complete, the mixture was brought back to room temperature and stirred for 4 h. The reaction was monitored by TLC until completion. The reaction mixture was added to 100 mL of water, filtered to obtain the crude product, and recrystallized from 10 mL of ethanol to obtain compound IV. 2.56 g of compound IV, 10 mL of dichloromethane, and 0.89 mL of 12 mmol trifluoroacetic acid were added to a reaction flask. The mixture was stirred at 25 °C for 2 h. After removing the solvent by rotary evaporation, 10 mL of N,N-dimethylformamide was added. N,N-dimethylformamide was added in portions under an ice-water bath with 0.39 g of sodium hydride. After the addition was complete, the mixture was stirred in the ice-water bath for 30 min. 1.46 g of 2-fluoro-4-bromobenzoylmethane was dissolved in 3 mL of N,N-dimethylformamide and slowly added dropwise to the reaction solution while maintaining the internal temperature at 0-5 °C. After the addition was complete, the mixture was brought back to room temperature and stirred for 5 h. The reaction was monitored by TLC until it was complete. The reaction solution was added to 50 mL of water, filtered, and the crude product was dried and recrystallized from 20 mL of isopropanol to obtain apalutamide. The synthesis route is as follows: ； 。

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