A preparation method of apalutamide and intermediates

Abstract

The present invention discloses a preparation method of apalutamide and intermediates. Among them, the preparation method of apalutamide comprises the following steps: 4-bromo-2-fluorobenzoic acid (SM1) reacts with thionyl chloride and methylamine to generate N-methyl-4-bromo-2-fluorobenzamide. N-methyl-4-bromo-2-fluorobenzamide reacts with 1-aminocyclobutane-1-carboxylic acid hydrochloride to generate intermediate 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane carboxylic acid. 5-Amino-3-(trifluoromethyl)cyanopyridine reacts with phenyl chloroformate to generate intermediate phenyl (6-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamate. 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane carboxylic acid reacts with phenyl (6-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamate to generate crude apalutamide, and the crude product is purified to obtain the finished product of apalutamide. This synthetic route is short, with high yield and low cost. All operations in the process route are conventional operations, without high temperature, cryogenic temperature and other special production equipment. The materials and reagents used in this route are easily purchasable and inexpensive on the market.

Description

Technical Field

[0001] The present invention relates to the technical field of API synthesis and intermediate synthesis, and particularly relates to a preparation method of apalutamide. Background Art

[0002] Apalutamide is an androgen receptor (AR) inhibitor used for the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC).

[0003] The chemical name of apalutamide is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide, and its chemical structure is as Figure 1 shown.

[0004] The main synthetic methods of apalutamide are as follows:

[0005] Route 1, as Figure 2 shown: The route disclosed in the original research compound patent (WO2007126765). Fragment 1 uses 5-amino-3-(trifluoromethyl)cyanopyridine as the raw material, reacts with thiophosgene to obtain isothiocyanate. Fragment 2 uses 4-amino-2-fluoro-N-methylbenzamide and cyclobutanone as the raw materials, and generates Fragment 2 under the action of sodium cyanide. Fragment 1 and Fragment 2 are cyclized under acidic conditions to obtain apalutamide. This route requires microwave conditions, and sodium cyanide and thiophosgene are used in the reaction process. Sodium cyanide is a highly toxic substance, and thiophosgene has a strong odor. The entire route is not conducive to industrial scale-up.

[0006] Route 2, as Figure 3 shown: In the patent (WO2016100645A1), 3-fluoro-4-iodoaniline and cyclobutanone are used as the raw materials to obtain Intermediate 1 under the action of sodium cyanide. Intermediate 1 and 5-amino-3-(trifluoromethyl)cyanopyridine are cyclized to generate Intermediate 2. Intermediate 2 undergoes carbonylation insertion reaction with carbon dioxide, and finally reacts with methylamine to obtain apalutamide. The raw material iodide used in this route has a high cost and is not easily obtained. Cyanide and precious metal palladium or Grignard reagent are used in the process, and the total yield is about 37%, with a high cost.

[0007] Route 3, as Figure 4As shown: In patent document (WO2016100645A1), 5-amino-3-(trifluoromethyl)cyanopyridine is used as a raw material to undergo a condensation reaction with amino-protected 1-aminocyclobutanecarboxylic acid to obtain intermediate 1. After deprotection, it reacts with 4-bromo-2-fluoro-N-methylbenzamide to generate intermediate 3, and finally undergoes a ring-closure reaction with a sulfuric acid reagent to obtain apalutamide. The route is relatively short. However, it is found that due to the connection of multiple electron-withdrawing groups to 5-amino-3-(trifluoromethyl)cyanopyridine, the activity of the amino group is relatively low, and the condensation is difficult to carry out. The protection and deprotection processes are slightly lengthy. Finally, the ring-closure sulfur reagent 1,1'-thiobis-2(1H)-pyridone in the last step is not easily obtained.

[0008] Route four, as Figure 5 As shown: Patent document (CN108069869A) reports that using 4-bromo-2-fluoro-N-methylbenzamide as a raw material, it undergoes a condensation reaction with 1-aminocyclobutanecarboxylic acid to obtain intermediate 1, and is methylated with methyl iodide to obtain intermediate 2, and finally undergoes a ring-closure reaction with isothiocyanate to obtain apalutamide; when methylating in the second step, highly toxic methyl iodide is used, and its boiling point is relatively low, especially inconvenient to operate in summer. At the same time, the isothiocyanate used in the last step is not very stable itself, has high activity, is prone to self-condensation and reacts with by-product methanol, and a relatively large amount is used. It is found that there is a relatively large residue of intermediate 2, the raw material of the last step reaction, and the yield is not high.

[0009] Route five, as Figure 6 As shown: In patent document ((CN108383749B), the first two steps are the same as those in route three. In the last step, potassium thiocyanate or sodium thiocyanate is used instead of isothiocyanate in route three for ring closure, and finally undergoes a condensation reaction with 5-bromo-3-(trifluoromethyl)cyanopyridine to obtain apalutamide. Thionyl chloride and methanol are used in the process instead of methyl iodide in the previous step for methylation. However, 5-bromo-3-(trifluoromethyl)cyanopyridine in the last step is not easily obtained on a large scale, and the route is relatively long.

[0010] Route six, as Figure 7 As shown: In patent document (CN107501237B), the first step is the same as that in route three. Instead of using highly toxic methyl iodide, it directly undergoes a condensation reaction with 5-amino-3-(trifluoromethyl)cyanopyridine to obtain intermediate 2, and finally undergoes a ring-closure reaction with thiophosgene to obtain apalutamide; similarly, due to the connection of multiple electron-withdrawing groups to 5-amino-3-(trifluoromethyl)cyanopyridine, the activity of the amino group is relatively low, and the condensation is difficult to carry out. In the last step, thiophosgene is used, which has a strong odor and relatively high environmental protection pressure.

[0011] Route seven, as Figure 8As shown: In patent document (WO2019229625A1), 4-amino-2-fluoro-N-methylbenzamide is used as a raw material to react with 1-bromocyclobutanecarboxylic acid to obtain intermediate 1, which is methylated with dimethyl carbonate to obtain intermediate 2, and then reacted with isothiocyanate to obtain apalutamide. Both 4-amino-2-fluoro-N-methylbenzamide and 1-bromocyclobutanecarboxylic acid are compounds with relatively high prices and difficult to obtain a large amount of supply in the market, which limits their large-scale industrial production. At the same time, when reacting with isothiocyanate finally, there are the same problems as in Route 3, and the yield of the last step is 72% - 73%.

[0012] Route eight, as Figure 9 shown: In patent document (CN112194633B), the yields of each step of this route are relatively high. The problems are high reaction temperature and long reaction time. The first step reacts at 185 - 195 °C for 4 h, the second step reacts at 165 - 170 °C for 30 h, and the third step reacts at 175 - 180 °C for 36 h. There are relatively large risks in actual operation, and there are certain problems with the large-scale supply of compound 31’ and 40.

[0013] In the above existing routes, the following defects exist:

[0014] ① Use highly toxic substances (sodium cyanide), relatively toxic reagents (methyl iodide), and reagents with strong odors (phosgene);

[0015] ② The raw materials are difficult to obtain and it is difficult to carry out large-scale industrial production;

[0016] ③ Use precious metal (palladium Pd) catalysts, with high costs;

[0017] ④ The reaction temperature is high and the time is long, with relatively high requirements for equipment;

[0018] ⑤ The route is long, the yield is low, and the cost is high. Summary of the Invention

[0019] In view of this, the purpose of the present invention is to provide a synthesis method for a preparation method of apalutamide and its intermediates, so as to solve one or more of the above-mentioned problems in the prior art.

[0020] To achieve the above purpose,

[0021] On the one hand, a preparation method for an apalutamide intermediate provided by the present invention includes the following steps:

[0022] 5-Amino-3-(trifluoromethyl)cyanopyridine and a reaction solvent are added to a reaction system, and then phenyl chloroformate is added. The temperature is raised to 0°C to 120°C. Preferably, the reaction is carried out at 60 - 70°C for 2 h. After the reaction is completed, tetrahydrofuran is concentrated off, n-heptane is added, the temperature is raised to 0°C to 120°C. Preferably, the reaction is carried out at 60°C to 70°C for 2 h, and then the temperature is lowered to 20°C to 30°C. After filtration and drying, the phenyl (6-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamate is obtained.

[0023] In some embodiments, the reaction solvent is selected from ethyl acetate, dichloromethane, n-heptane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, 2-methyltetrahydrofuran, and tetrahydrofuran. Preferably, the reaction solvent is tetrahydrofuran.

[0024] In some embodiments, the reaction system further includes an alkali solution, and the alkali solution is selected from triethylamine, N,N-diisopropylethylamine, pyridine, or potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate.

[0025] On the other hand, the apalutamide intermediate provided by the present invention is prepared by the above method, and the apalutamide intermediate has the following structural formula:

[0026]

[0027] On still another aspect, a method for preparing apalutamide provided by the present invention includes the following steps: 4-Bromo-2-fluorobenzoic acid (SM1) reacts with thionyl chloride and methylamine to form N-methyl-4-bromo-2-fluorobenzamide. The N-methyl-4-bromo-2-fluorobenzamide reacts with 1-aminocyclobutane-1-carboxylic acid hydrochloride to form the intermediate 1-((3-fluoro-4-(methylaminocarbonyl)phenyl)amino)cyclobutane carboxylic acid. 5-Amino-3-(trifluoromethyl)cyanopyridine reacts with phenyl chloroformate to form the intermediate phenyl (6-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamate. The 1-((3-fluoro-4-(methylaminocarbonyl)phenyl)amino)cyclobutane carboxylic acid reacts with the phenyl (6-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamate to form the crude apalutamide, and the crude product is purified to obtain the apalutamide finished product.

[0028] In some embodiments, the N-methyl-4-bromo-2-fluorobenzamide is prepared by the following steps:

[0029] 4-Bromo-2-fluorobenzoic acid and methanol are added to the reaction system. The temperature is lowered to below 20°C, and thionyl chloride is added dropwise. After the addition is complete, the temperature is raised to reflux and stirred. Then the temperature is lowered to 30°C, and aqueous methylamine solution is added dropwise. After the addition is complete, the mixture is stirred at 30-40°C for 2 h. The temperature is lowered to 20-30°C, and water is added dropwise. After the addition is complete, the mixture is stirred for 2 h, filtered, and dried to obtain the N-methyl-4-bromo-2-fluorobenzamide.

[0030] In some embodiments, the 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutanecarboxylic acid is prepared by the following steps:

[0031] N-Methyl-4-bromo-2-fluorobenzamide, 1-aminocyclobutane-1-carboxylic acid hydrochloride, potassium carbonate, N,N-dimethylacetamide, and water are added to the reaction system. The system is purged with an inert gas three times. Cuprous chloride and 2-acetylcyclohexanone are added. After the addition is complete, the temperature is raised to 110°C and the reaction is carried out for 16 h. The aqueous phase is separated. Hydrochloric acid is added dropwise to the aqueous phase to adjust the pH value to 1-2. The mixture is filtered and dried to obtain the 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutanecarboxylic acid.

[0032] In some embodiments, the apalutamide crude product is prepared by the following steps:

[0033] The 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutanecarboxylic acid and phenyl (6-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamate are added to the reaction system. Then N,N-dimethylacetamide and triethylamine are added. The temperature is raised to 70-80°C and the mixture is stirred for 2 h. The temperature is lowered to 10-20°C. Dimethylaminopyridine and isopropyl acetate are added. Phenyl chloroformate and triethylamine are added dropwise. After the addition is complete, the temperature is raised to 50°C - 60°C and the reaction is carried out for 2 h. After the reaction is completed, the temperature is lowered to 0°C - 10°C. 4 mol / L hydrochloric acid is added dropwise to adjust the pH to 1-2. The organic phase is washed with water twice. The organic phase is concentrated to remove half of the solvent. The temperature is raised to 50°C - 60°C and n-heptane is added dropwise. After the addition is complete, the temperature is lowered to 20°C - 30°C and the mixture is stirred for 1 h. The mixture is filtered and suction-dried. Isopropanol and water are added to the filter cake. The temperature is raised to 50°C - 60°C and n-heptane is added dropwise. After the addition is complete, the temperature is lowered to 20°C - 30°C and the mixture is stirred for 1 h. The mixture is filtered and dried to obtain the apalutamide crude product.

[0034] In some embodiments, the purification method of the apalutamide finished product includes the following steps:

[0035] The apalutamide crude product and ethyl acetate are added to the reaction system. The temperature is raised to 70-80°C and stirred until clear. N-heptane is added dropwise. After the addition is complete, the temperature is lowered to 20-30°C and the mixture is stirred for 1-2 h. The mixture is filtered and dried to obtain the apalutamide finished product.

[0036] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0037] This synthetic route is short, with high yield and low cost. All operations in the process route are conventional, without high temperature, cryogenic conditions and other special production equipment. Moreover, the materials and reagents used in this route are easily purchasable and inexpensive on the market. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 It is the chemical structural formula of apalutamide in the background art of the present invention;

[0039] Figure 2 It is Synthetic Route 1 of apalutamide in the background art of the present invention;

[0040] Figure 3 It is Synthetic Route 2 of apalutamide in the background art of the present invention;

[0041] Figure 4 It is Synthetic Route 3 of apalutamide in the background art of the present invention;

[0042] Figure 5 It is Synthetic Route 4 of apalutamide in the background art of the present invention;

[0043] Figure 6 It is Synthetic Route 5 of apalutamide in the background art of the present invention;

[0044] Figure 7 It is Synthetic Route 6 of apalutamide in the background art of the present invention;

[0045] Figure 8 It is Synthetic Route 7 of apalutamide in the background art of the present invention;

[0046] Figure 9 It is Synthetic Route 8 of apalutamide in the background art of the present invention;

[0047] Figure 10 It is the synthetic route of apalutamide in Example 1 of the present invention;

[0048] Figure 11 It is the HPLC chromatogram of apalutamide in Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0049] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0050] Example 1:

[0051] Preparation of 1N-Methyl-4-bromo-2-fluoro-benzamide (IM-1)

[0052] At room temperature, 10 g (45.7 mmol, 1.0 eq) of 4-bromo-2-fluorobenzoic acid and 30 mL (3V) of methanol were added to a reaction flask. The temperature was lowered below 20 °C, and 3.26 g (27.4 mmol, 0.6 eq) of thionyl chloride was added dropwise. After addition, the temperature was raised to reflux and stirred for 2 h. The temperature was lowered to 30 °C, and 17.73 g (228.3 mmol, 5 eq) of aqueous methylamine solution was added dropwise. After addition, it was stirred at 30 °C - 40 °C for 2 h. The temperature was lowered to 20 °C - 30 °C, 45 mL (4.5V) of water was added dropwise, and then it was stirred for 2 h. It was filtered and dried to obtain 9.6 g of a white solid, with a yield of 90.6%. Ms: 233.9 (M++1), 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 7.66 (q, 1H), 7.57 (t, 1H), 7.50 (q, 1H), 2.77 (d, 3H).

[0053] Preparation of 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutanecarboxylic acid (IM-2)

[0054] At room temperature, 10 g (43.1 mmol, 1.0 eq) of N-methyl-4-bromo-2-fluorobenzamide, 7.84 g (51.7 mmol, 1.2 eq) of 1-aminocyclobutane-1-carboxylic acid hydrochloride, 11.91 g (86.2 mmol, 2.0 eq) of potassium carbonate, 50 mL (5V) of N,N-dimethylacetamide and 10 mL (1V) of water were added to a reaction flask. It was replaced with an inert gas 3 times, 0.85 g (8.6 mmol, 0.2 eq) of copper(I) chloride and 1.21 g (8.6 mmol, 0.2 eq) of 2-acetylcyclohexanone were added. After addition, the temperature was raised to 110 °C and reacted for 16 h. After the reaction was completed, the temperature was lowered to 20 °C - 30 °C, filtered, 800 mL (8V) of water was added to the filtrate, and it was extracted with isopropyl acetate 2 times. The aqueous phase was separated, hydrochloric acid was added dropwise to the aqueous phase to adjust the pH to 1 - 2, filtered, and dried to obtain 9.4 g of an off-white to light yellow solid, with a yield of 81.9%. Ms: 267.0 (M++1), 1H NMR (400 MHz, DMSO) δ 12.60 (s, 1H), 7.64 (t, 1H), 7.46 (t, 1H), 7.16 (s, 1H), 6.23 (d, 1H), 6.01 (d, 1H), 2.72 (d, 2H), 2.61 (m, 2H), 2.17 (m, 2H), 2.00 (m, 2H).

[0055] Preparation of phenyl (6-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamate (IM-3)

[0056] At room temperature, 10 g (53.4 mmol, 1.0 eq) of 5-amino-3-(trifluoromethyl)cyanopyridine and 50 mL (5V) of tetrahydrofuran were added to a reaction flask. Then, 11.07 g (64.1 mmol, 1.2 eq) of phenyl chloroformate was added. The temperature was raised to 60 °C - 70 °C and the reaction was carried out for 2 h. After the reaction was completed, tetrahydrofuran was concentrated off. 50 mL (5V) of n-heptane was added, and the temperature was raised to 60 °C - 70 °C and the reaction was carried out for 2 h. The temperature was lowered to 20 °C - 30 °C, filtered, and dried to obtain 15.59 g of a white solid with a yield of 95%. Ms: 308.0 (M++1), 1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 9.00 (s, 1H), 8.48 (s, 1H), 7.47 (m, 2H), 7.31 (m, 3H).

[0057] Preparation of Apatamide Crude

[0058] At room temperature, 5 g (18.8 mmol, 1.0 eq) of IM-2 and 6.35 g (20.7 mmol, 1.1 eq) of IM-3 were added to a reaction flask. Then, 25 mL (5V) of N,N-dimethylacetamide and 2.28 g (22.5 mmol, 1.2 eq) of triethylamine were added. The temperature was raised to 70 °C - 80 °C and stirred for 2 h. The temperature was lowered to 10 °C - 20 °C. 3.44 g (28.2 mmol, 1.5 eq) of 4-dimethylaminopyridine and 50 mL (10V) of isopropyl acetate were added. A solution of 4.86 g (28.2 mmol, 1.5 eq) of phenyl thiocarbonochloridate and 2.85 g (28.2 mmol, 1.5 eq) of triethylamine was added dropwise. After addition, the temperature was raised to 50 °C - 60 °C and the reaction was carried out for 2 h. After the reaction was completed, the temperature was lowered to 0 °C - 10 °C, and 4 mol / L hydrochloric acid was added dropwise to adjust the pH to 1 - 2. The organic phase was washed with water twice. The organic phase was concentrated to half of the solvent. 50 mL (10V) of n-heptane was added dropwise at 50 °C - 60 °C. After addition, the temperature was lowered to 20 °C - 30 °C and stirred for 1 h, filtered, suction-dried. 25 mL (5V) of isopropyl alcohol and 25 mL (5V) of water were added to the filter cake. 50 mL (10V) of n-heptane was added dropwise at 50 °C - 60 °C. After addition, the temperature was lowered to 20 °C - 30 °C and stirred for 1 h, filtered, and dried to obtain 47.5 g of a white solid with a yield of 95%. Ms: 478.2 (M++1), 1H NMR (400 MHz, DMSO) δ 9.25 (d, 1H), 8.75 (d, 1H), 8.47 (d, 1H), 7.84 (t, 1H), 7.48 (t, 1H), 7.38 (m, 1H), 2.81 (d, 3H), 2.65 (t, 2H), 2.48 (m, 2H), 1.98 (m, 1H), 1.59 (m, 1H).

[0059] Purification of Apatamide

[0060] At room temperature, 5 g of apalutamide crude product and 15 mL (3V) of ethyl acetate were added to a reaction flask, and the temperature was raised to 70 °C to 80 °C and stirred until clear. 30 mL (6V) of n-heptane was added dropwise. After the addition was complete, the temperature was lowered to 20 °C to 30 °C and stirred for 1 h to 2 h. Then, it was filtered and dried to obtain 4.60 g of a white solid. As shown in Figure 10 the yield was 92%.

[0061] The synthesis route provided by the embodiment of the present invention is short, with high yield and low cost. All operations in the process route are conventional operations, without high-temperature deep cooling and other special production equipment, and the materials and reagents used in this route are easily purchased and inexpensive on the market.

[0062] Finally, it should be noted that those skilled in the art should understand that the present invention is not limited by the above-mentioned embodiments. The above-mentioned embodiments and the description in the specification only illustrate the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements will fall within the scope of the present invention claimed. The scope of the present invention claimed is defined by the appended claims and their equivalents.

Claims

1. A preparation method of apalutamide, characterized in that, it comprises the following steps: 4-Bromo-2-fluorobenzoic acid (SM1) reacts with thionyl chloride and methylamine to generate N-methyl-4-bromo-2-fluorobenzamide. The N-methyl-4-bromo-2-fluorobenzamide reacts with 1-aminocyclobutane-1-carboxylic acid hydrochloride to generate intermediate 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane carboxylic acid. 5-Amino-3-(trifluoromethyl)cyanopyridine reacts with phenyl chloroformate to generate intermediate phenyl (6-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamate. The 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane carboxylic acid reacts with the phenyl (6-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamate to generate crude apalutamide. The crude product is purified to obtain the finished product of apalutamide; wherein, the structural formula of 5-amino-3-(trifluoromethyl)cyanopyridine is as follows:

2. The preparation method according to claim 1, characterized in that, the N-methyl-4-bromo-2-fluorobenzamide is prepared by the following steps: Add 4-bromo-2-fluorobenzoic acid and methanol to the reaction system, cool down to below 20 °C, dropwise add thionyl chloride. After the addition is completed, heat up to reflux and stir, then cool down to 30 °C and dropwise add aqueous methylamine solution. After the addition is completed, stir at 30-40 °C for 2 h, then cool down to 20-30 °C, dropwise add water. After the addition is completed, stir for 2 h, filter, and dry to obtain the N-methyl-4-bromo-2-fluorobenzamide.

3. The preparation method according to claim 1, characterized in that, the 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane carboxylic acid is prepared by the following steps: Add N-methyl-4-bromo-2-fluorobenzamide, 1-aminocyclobutane-1-carboxylic acid hydrochloride, potassium carbonate, N,N-dimethylacetamide and water to the reaction system, displace with inert gas for 3 times, add copper(I) chloride and 2-acetylcyclohexanone. After the addition is completed, heat up to 110 °C and react for 16 h. Separate out the aqueous phase, dropwise add hydrochloric acid to the aqueous phase to adjust the pH value to 1-2, filter, and dry to obtain the 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane carboxylic acid.

4. The preparation method according to claim 1, characterized in that, the crude apalutamide is prepared by the following steps: Add the 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutanecarboxylic acid and phenyl(6-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamate to the reaction system, then add N,N-dimethylacetamide and triethylamine, heat up to 70 - 80 °C and stir for 2 h, cool down to 10 - 20 °C, add dimethylaminopyridine and isopropyl acetate, dropwise add phenyl chlorothionoformate and triethylamine. After addition, heat up to 50 °C - 60 °C and react for 2 h. After the reaction is completed, cool down to 0 °C - 10 °C, dropwise add 4 mol / L hydrochloric acid to adjust the pH to 1 - 2, wash the organic phase with water twice, concentrate the organic phase to half of the solvent, heat up to 50 °C - 60 °C and dropwise add n-heptane. After addition, cool down to 20 °C - 30 °C and stir for 1 h, filter, drain, add isopropanol and water to the filter cake, heat up to 50 °C - 60 °C and dropwise add n-heptane. After addition, cool down to 20 °C - 30 °C and stir for 1 h, filter, and dry to obtain the crude apalutamide.

5. The preparation method according to claim 1, characterized in that, the purification method of the apalutamide finished product comprises the following steps: Add the crude apalutamide and ethyl acetate to the reaction system, heat up to 70 - 80 °C and stir until clear, dropwise add n-heptane. After addition, cool down to 20 - 30 °C and stir for 1 - 2 h, filter, and dry to obtain the apalutamide finished product.

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