Synthesis method of apalutamide, intermediates thereof and synthesis method

Abstract

The present invention belongs to the field of pharmaceutical synthesis technology and discloses a synthesis method for apalutamide, its intermediates, and synthesis methods. This method addresses the problems of the prior art apalutamide synthesis process, which is complex, costly, unsuitable for industrialization, and environmentally unfriendly. In the present invention, a compound of formula VIII is converted into a compound of formula VII via a one-pot process. This compound of formula VII is then converted into a compound of formula IV, an intermediate of apalutamide, via a one-pot process. Compounds of formula IV and formula II are then cyclized to obtain compound I. The present invention is simple to operate, requires few steps, has low production costs, and offers high product yield and purity.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of apalutamide, an intermediate thereof and a synthesis method. Background Art

[0002] Apalutamide, whose chemical name 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 whose structure is shown in Formula I, is a second-generation androgen receptor antagonist developed by Johnson & Johnson for the treatment of non-metastatic castration-resistant prostate cancer (M0-CRPC). Apalutamide:

[0003]

[0004] Apalutamide is a derivative of diarylthiohydantoin, consisting of a pyridine ring, a benzene ring, a cyclobutane, and a thiohydantoin ring system. Its synthesis mainly revolves around the connection of arylamines and the construction of the thiohydantoin ring system, as shown below.

[0005]

[0006] There are two common synthetic routes for apalutamide: "[3+2] type" and "[4+1] type", as shown in the following table:

[0007]

[0008] Among them, there are two main "[3+2] type" synthetic routes: one is to prepare the compound of formula I by [3+2] cyclization of α-amino nitrile with thioisocyanate, such as the synthesis methods in 201180009819.9, 200780019654.7, 200780020099.X and "Improved Synthesis Process of Apalutamide" (China Journal of Pharmaceutical Industry, 2018, 49(4)). The details are as follows:

[0009]

[0010] This synthesis route uses the highly toxic sodium cyanide, and some synthesis methods use microwave methods, which increases the difficulty of factory scale-up production and is not suitable for industrial production.

[0011] The second [3+2] preparation route is to prepare the compound of formula I by [3+2] cyclization of α-carbamate and thioisocyanate, such as the synthesis methods used in 201610985993.1, 201711271655.2, and 201711474542.2, as follows:

[0012]

[0013] The yield of each step in this synthetic pathway is relatively low, the cost is high, the reaction process and post-processing process are relatively complicated, the optimization of the purification of the intermediates in each step is not carefully considered, and it is not suitable for industrial production. Therefore, it is necessary to further optimize the design of the reaction process and post-processing conditions of each step of the above [3+2] pathway to achieve the purpose of improving efficiency and yield and reducing costs to meet the needs of industrial production of this raw material.

[0014] The [4+1] preparation route of apalutamide is to prepare the compound of formula I by [4+1] cyclization of an α-aminoamide with a thiocarbonyl compound, for example, the synthesis method in 201580069602.5, specifically:

[0015]

[0016] This synthetic route requires the use of stoichiometric copper salts; and the final [4+1] cyclization step requires the use of relatively expensive thiocarbonyl compounds, which is costly.

[0017] Therefore, providing a method for synthesizing apalutamide with a simple process, fewer steps, easy operation and low production cost has become an urgent problem to be solved by those skilled in the art. Summary of the Invention

[0018] One of the objectives of the present invention is to provide a method for synthesizing apalutamide, which has a simple process, few steps, and is easy to operate. The reactions in each step are conventional reactions, the conditions are mild, and no other special equipment is required, which is suitable for industrial production.

[0019] A second object of the present invention is to provide an intermediate for synthesizing apalutamide.

[0020] The third object of the present invention is to provide a method for synthesizing the intermediate.

[0021] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0022] The intermediate for synthesizing apalutamide of the present invention has a structure as shown in Formula IV:

[0023]

[0024] ; wherein R is methyl or methoxy; preferably R is 4-methyl or 4-methoxy.

[0025] The present invention provides a method for synthesizing an apalutamide intermediate, using a compound of formula VIII as a starting material, undergoing an esterification-aminolysis reaction to produce a compound of formula VII, and then undergoing a coupling-carboxylic acid alkylation reaction to produce a compound of formula IV, wherein the reaction formula is:

[0026]

[0027] ; wherein X1 and X2 are both halogen, preferably, X1 and X2 are each independently selected from chlorine, bromine and iodine.

[0028] In some embodiments, both the esterification-amination reaction and the coupling-carboxylic acid alkylation reaction are carried out in a one-pot reaction.

[0029] In some embodiments, the compound of formula VIII is reacted with an acid or a reagent capable of hydrolyzing to an acid in an alcohol medium to form an ester, which is then hydrolyzed to form the compound of formula VII via a one-pot methylamine method;

[0030] The acid or the reagent capable of hydrolyzing into an acid is an organic acid, an inorganic acid or a mixture thereof; preferably concentrated sulfuric acid, POCl3, thionyl chloride; more preferably thionyl chloride;

[0031] The alcohol medium is selected from one or more of methanol, ethanol, propanol and benzyl alcohol.

[0032] In some embodiments, the compound of formula VIII is dissolved in an alcohol medium, and the acid is added under the protection of an inert gas; the inert gas is preferably nitrogen.

[0033] In some embodiments, the temperature of the esterification reaction is 35-55°C, preferably 40-50°C; the temperature of the aminolysis reaction is 15-35°C, preferably 20-30°C.

[0034] In some embodiments, the compound of formula VII and the compound of formula VI are subjected to a coupling reaction in the presence of a catalyst, an acid-binding agent, a ligand, and an aprotic polar solvent, and then reacted with the compound of formula V through a one-pot carboxylic acid alkylation reaction to produce the compound of formula IV;

[0035] The catalyst is a copper salt, preferably CuCl, CuBr or CuI;

[0036] The acid binding agent is sodium carbonate, potassium carbonate, cesium carbonate or potassium tert-butoxide;

[0037] The ligand is 2-acetylcyclohexanone or tetramethylethylenediamine;

[0038] The aprotic polar solvent is DMF or DMAc.

[0039] In some embodiments, after the coupling reaction is completed, the compound of formula V is added to the reaction system to carry out an alkylation reaction of the carboxylic acid.

[0040] In some embodiments, the coupling reaction is an Ullmann coupling reaction.

[0041] In the technical solution of the present invention, the coupling reaction is carried out at a high temperature of 80-150°C, preferably 115-130°C.

[0042] The coupling reaction is carried out under the protection of an inert gas, preferably nitrogen.

[0043] The alkylation reaction temperature of the carboxylic acid is 25-90°C, preferably 55-65°C.

[0044] In the technical solution of the present invention, the usage ratio of each material is: (eq refers to the molar equivalent ratio)

[0045] materials Equivalence ratio range Preferred equivalence ratio Compound of formula VII 1.0eq 1.0eq Compound of formula VI 1.0eq~2.0eq 1.1~1.5eq catalyst 0.01eq~0.5eq 0.05eq

[0046] The present invention provides a method for synthesizing apalutamide, wherein a compound of formula IV and a compound of formula II are cyclized to obtain apalutamide, a compound of formula I; the reaction formula is:

[0047]

[0048] Wherein, R is methyl or methoxy; preferably, R is 4-methyl or 4-methoxy.

[0049] Specifically, the compound of formula IV and the compound of formula II are subjected to [3+2] cyclization under the combined action of a low-polarity solvent and a polar aprotic solvent to obtain the compound of formula I;

[0050] Preferably, the low polarity solvent is selected from acetonitrile and toluene;

[0051] Preferably, the polar aprotic solvent is selected from DMF, DMAc and DMSO.

[0052] In some embodiments, the ratio of the materials used in the synthesis of apalutamide is: (eq refers to molar equivalent ratio)

[0053] materials Equivalence ratio range Preferred equivalence ratio Compounds of formula IV 1.0eq 1.0eq Compound of formula II 2.0eq~3.0eq 2.5eq

[0054] In some embodiments, the compound of formula II is prepared from the compound of formula III in the presence of thiophosgene:

[0055]

[0056] In some embodiments, the preparation method of the compound of formula II provided herein optionally comprises a post-treatment step, wherein the post-treatment step is specifically as follows: after the reaction is completed, most of the solvent is evaporated, a low-polarity solvent and an adsorbent are added to the residue, and the mixture is stirred and filtered to remove impurities;

[0057] Preferably, the low-polarity solvent is selected from petroleum ether, n-hexane and n-heptane; and the adsorbent is selected from aluminum oxide, activated carbon and column chromatography silica gel.

[0058] The English abbreviations of the compounds or groups described in the present invention are:

[0059] DMF: N,N-dimethylformamide

[0060] DMSO: dimethyl sulfoxide

[0061] DMAc: N,N-dimethylacetamide

[0062] Compared with the prior art, the present invention has the following beneficial effects:

[0063] The present invention is scientifically designed and simple to operate. The one-pot process reduces costs and steps. In the present invention, the preparation of the compound of formula VII from the compound of formula VIII and the preparation of the compound of formula IV from the compound of formula VII are both one-pot operations, simplifying the process steps, shortening the production cycle, and reducing production energy consumption, thereby achieving greater economics and making the operation more suitable for industrial production.

[0064] In the present invention, in the process of preparing the compound of formula VII from the compound of formula VIII, the materials used are cheap and readily available, the reaction selectivity is good, the by-products are few, and the post-treatment is simple, and the target product can be obtained by crystallization and filtration. Compared with the method of directly using carboxylic acid to prepare amide via acyl chloride, the reaction steps are reduced, the extraction and concentration operations in the conventional preparation method via acyl chloride are avoided, and the process operation is simpler.

[0065] In the present invention, in the reaction of preparing the compound of formula IV using the compound of formula VII as the raw material through the "one-pot process", it is only necessary to control the temperature in stages; and the final product can be precipitated from the reaction system by crystallization, and the product can be obtained after recrystallization. The process is simple and the yield and purity are high.

[0066] In the present invention, the R group is a methyl or methoxy group, and the benzyl group is modified and optimized to achieve significant advantages. The introduction of a methyl or methoxy group to the benzyl group enhances the activity of the benzyl group, significantly increasing the yield of the compound of Formula IV and the yield of the compound of Formula I. Furthermore, experiments in the present invention show that, taking compound IV-A as an example, the introduction of a methyl or methoxy group facilitates precipitation from the aqueous phase compared to when R=H, resulting in better crystallization and solidification, and facilitating the separation and purification of the intermediate.

[0067] In the reaction of preparing the compound of formula II using the compound of formula III as the raw material, the target compound of formula II is a low-polarity, high-boiling-point compound, which is difficult to refine and purify. Existing methods are limited to column chromatography separation and high-temperature vacuum distillation, which are extremely difficult to purify and costly. The present invention unexpectedly discovered that most of the impurities involved in the reaction are highly polar impurities. Therefore, the present invention achieves the purpose of purification by adding a small amount of adsorbent to a low-polarity solvent and filtering it through hot beating, which greatly saves industrial production costs and avoids the disadvantages of traditional column chromatography analysis that is not suitable for industrial production and requires a lot of solvents and manpower; high-temperature vacuum distillation has poor safety and high production energy consumption.

[0068] The one-pot process of the present invention allows multiple reaction steps to be performed in a single pot. The coordinated execution of these steps requires coordination of the reaction environment for each step. Through ingenious design and meticulous exploration of the reaction process, the present invention successfully maintains the low-cost advantage of the one-pot process while ensuring product yield and quality purity. DETAILED DESCRIPTION

[0069] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be purchased commercially.

[0070] instrument:

[0071] The structures of the compounds were determined by nuclear magnetic resonance (1HNMR) or mass spectrometry (MS).

[0072] Nuclear magnetic resonance spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (instrument model: BRUKER AVANCE 400 NMR); the solvent was DMSO-d6, and the temperature was 22°C;

[0073] LC-MS detection was performed using an Agilent 6120B Ms liquid chromatograph-single quadrupole, positive ion mode, ESI ionization source, and a scan range of 50 m / z to 3000 m / z;

[0074] The purity of the intermediate compounds in each step was determined by high performance liquid chromatography (HPLC-UV), the detector was an ultraviolet (UV) detector, and the chromatographic column was Boston Uni C18.

[0075] The abbreviations of the reagents involved in the examples have the following Chinese meanings:

[0076]

[0077]

[0078] The features and performance of the present invention are further described in detail below with reference to the embodiments.

[0079] Example 1

[0080] This example discloses a one-pot method for synthesizing the compound of formula VII-A, N-methyl-4-bromo-2-fluorobenzamide, specifically:

[0081]

[0082] 4-Bromo-2-fluorobenzoic acid (60 g, 0.27 mol), a compound of formula VIII-A, was dissolved in methanol (180 mL) under nitrogen atmosphere. 19.5 g of thionyl chloride was added dropwise. After the addition was complete, the temperature was raised to 45±5°C. After the reaction of the raw materials was complete, the temperature was slowly lowered to 25±5°C. 100 g of a 25-30 wt% aqueous methylamine solution was slowly added dropwise. After the addition was complete, the temperature was maintained at 25±5°C. The reaction was continued for 2 hours, and then 1000 ml of purified water was slowly added dropwise. After the addition was complete, stirring was continued for 2 hours. Filtering and collecting the filter cake yielded 62.5 g of the intermediate N-methyl-4-bromo-2-fluorobenzamide (compound of formula VII-A), with a yield of 98%. HPLC analysis showed a purity of 99.92% and a maximum impurity content of 0.04%.

[0083] Compound of formula VII-A: LC-MS: m / z=231.9[M+1] + 、233.9[M+3] +

[0084] 1 H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 7.64-7.52 (m, 2H), 7.46 (d, J=8.3Hz, 1H), 2.80 (d, J=4.8Hz, 3H).

[0085] Example 2

[0086] This example discloses a one-pot method for synthesizing the compound of formula IV-A, 4-methoxybenzyl-1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutanoate, specifically:

[0087]

[0088] 60 g of the compound of formula VII-A (1.0 eq), 1.1 eq of the compound of formula VI-A (I) - aminocyclobutanecarboxylic acid (32 g), 3 eq of K2CO3 (107 g), 0.05 eq of CuCl (1.2 g), and 0.05 eq of tetramethylethylenediamine (1.5 g) were added to 360 ml of DMF under nitrogen atmosphere. The mixture was reacted at 115-130°C for 4-6 hours, then cooled to 60±5°C. 1.1 eq of the compound of formula V-A, 4-methoxybenzyl chloride (40 g) was added dropwise. After reacting for 1 hour, the mixture was cooled to room temperature, and 90 ml of concentrated aqueous ammonia was added dropwise, followed by 300 ml of purified water. The mixture was stirred for 1 hour. Filtered to obtain a filter cake. The filter cake and 300 ml of ethyl acetate were heated to 75±5°C to dissolve the mixture, stirred for 15 min, and 100 ml of petroleum ether was added dropwise at a temperature above 70°C. After the addition was complete, the temperature was naturally cooled to room temperature. The mixture was stirred for 0.5 h and filtered to obtain 83 g of compound 4A with a yield of 87%. The purity was 99.00% and the maximum impurity content was 0.24% as determined by HPLC.

[0089] Compound of formula IV-A: LC-MS: m / z=387.2[M+1] +

[0090] 1 H NMR (400MHz, DMSO-d6) δ7.68(t,J=5.3Hz,1H),7.59(t,J=8.7Hz,1H),7.32(s,1H),7.20(d,J=8.3Hz,2H),6.88(d,J=8.3Hz,2H),6.32(d,J=8 .2Hz,1H),6.10(d,J=14.2Hz,1H),5.11(s,2H),3.76(s,3H),2.84(d,J=4.6Hz,3H),2.76–2.62(m,2H),2.32–2.18(m,2H),2.11–1.91(m,2H).

[0091] Experimental Example 3

[0092] This embodiment discloses a method for synthesizing a compound of formula II from a compound of formula III, specifically:

[0093]

[0094] The compound of formula III, 5-amino-3-trifluoromethyl-2-cyanopyridine (100 g, 1.0 eq), was dissolved in 0.5 L of acetone, and 1.2 eq of thiophosgene (74 g) was added dropwise. After reacting at room temperature for 1 to 3 hours, most of the solvent was removed by distillation under reduced pressure. The residue was added with 1.0 L of n-hexane and 50 g of neutral alumina, heated to 40±5° C. and stirred for 1 hour. After filtration and concentration, 105 g of the compound of formula II was obtained as an off-white solid, 5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine, with a yield of 86%. The purity was 99.10% as determined by HPLC, and the maximum impurity content was 0.68%.

[0095] Compound of formula II

[0096] 1 H NMR (400MHz, DMSO-d6) δ9.04 (d, J = 2.2 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H).

[0097] Example 4

[0098] This embodiment discloses a method for synthesizing the compound of formula I, 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide, from the compound of formula IV-A and the compound of formula II, specifically:

[0099]

[0100] Under nitrogen, 74 g of the compound of Formula IV-A, 8 ml of DMF, and 1000 ml of acetonitrile were added to a reaction flask. The temperature was raised to 80 ± 5°C. A solution of 108 g of the compound of Formula II in 150 ml of acetonitrile was slowly added dropwise in eight evenly divided portions (one drop per hour). After the addition was complete, the mixture was stirred for 24 hours. The reaction solution was concentrated to dryness, and isopropanol (800 ml) was added. The temperature was raised to 85 ± 5°C, stirred for 2 hours, then slowly cooled to 0 ± 5°C and stirred for 12 hours. The mixture was filtered, and the filter cake was rinsed twice with 150 ml of isopropanol to obtain a crude compound of Formula I. Crystallization was repeated using isopropanol once more. The above procedure yielded 84 g of the refined compound of Formula I, with a yield of 88%. HPLC analysis revealed a purity of 99.92%, with a maximum impurity content of 0.08%.

[0101] Compound of formula I: LC-MS: m / z=478.1[M+1] +

[0102] 1H NMR (400MHz, DMSO-d6) δ9.23(d,J=2.0Hz,1H),8.77(d,J=2.0Hz,1H),8.54–8.39(m,1H),7.92(t,J=8.0Hz,1H),7.50(dd,J=10.5,1.8H z,1H),7.43(dd,J=8.1,1.8Hz,1H),2.89(d,J=4.6Hz,3H),2.78–2.66(m,2H),2.64–2.49(m,2H),2.11–1.98(m,1H),1.72–1.55(m,1H).

[0103] The embodiments described above are some, but not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but rather merely represents selected embodiments of the present invention. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are also within the scope of protection of the present invention.

Claims

1. An intermediate for synthesizing apalutamide, the structure of which is shown in Formula IV: in, R is methyl or methoxy.

2. The intermediate according to claim 1, characterized in that R is 4-methyl or 4-methoxy.

3. The method for synthesizing the intermediate according to claim 1 or 2, characterized in that: The compound of formula VIII is used as the starting material, and an esterification-amination reaction is performed to generate a compound of formula VII. The compound of formula VII is then subjected to a coupling-carboxylic acid alkylation reaction to generate a compound of formula IV. The reaction formula is: Wherein, X1 and X2 are both halogen.

4. The method for synthesizing the intermediate according to claim 3, characterized in that: X1 and X2 are each independently selected from chlorine, bromine and iodine.

5. The method for synthesizing the intermediate according to claim 3, wherein: The compound of formula VIII is reacted with an acid or a reagent capable of hydrolyzing to an acid in an alcohol medium to form an ester, and then hydrolyzed with methylamine in one pot to form the compound of formula VII; The acid or the reagent capable of hydrolyzing into an acid is an organic acid, an inorganic acid or a mixture thereof; The alcohol medium is selected from one or more of methanol, ethanol, propanol and benzyl alcohol.

6. The method for synthesizing the intermediate according to claim 4, wherein: The compound of formula VIII is reacted with an acid or a reagent capable of hydrolyzing to an acid in an alcohol medium to form an ester, and then hydrolyzed with methylamine in one pot to form the compound of formula VII; The acid or the reagent capable of hydrolyzing into an acid is an organic acid, an inorganic acid or a mixture thereof; The alcohol medium is selected from one or more of methanol, ethanol, propanol and benzyl alcohol.

7. The method for synthesizing the intermediate according to claim 5 or 6, characterized in that: The acid or the reagent capable of being hydrolyzed into an acid is concentrated sulfuric acid, POCl3 or thionyl chloride.

8. The method for synthesizing the intermediate according to claim 7, wherein: The acid or the reagent capable of hydrolyzing into an acid is thionyl chloride.

9. The method for synthesizing the intermediate according to claim 3, wherein: The compound of formula VII and the compound of formula VI undergo a coupling reaction in the presence of a catalyst, an acid-binding agent, a ligand, and an aprotic polar solvent, and then undergo a one-pot alkylation reaction with the compound of formula V using carboxylic acid to produce the compound of formula IV; The catalyst is a copper salt; The acid binding agent is sodium carbonate, potassium carbonate, cesium carbonate or potassium tert-butoxide; The ligand is 2-acetylcyclohexanone or tetramethylethylenediamine; The aprotic polar solvent is DMF or DMAc.

10. The method for synthesizing the intermediate according to any one of claims 4 to 6 or 8, characterized in that: The compound of formula VII and the compound of formula VI undergo a coupling reaction in the presence of a catalyst, an acid-binding agent, a ligand, and an aprotic polar solvent, and then undergo a one-pot alkylation reaction with the compound of formula V using carboxylic acid to produce the compound of formula IV; The catalyst is a copper salt; The acid binding agent is sodium carbonate, potassium carbonate, cesium carbonate or potassium tert-butoxide; The ligand is 2-acetylcyclohexanone or tetramethylethylenediamine; The aprotic polar solvent is DMF or DMAc.

11. The method for synthesizing the intermediate according to claim 7, characterized in that: The compound of formula VII and the compound of formula VI undergo a coupling reaction in the presence of a catalyst, an acid-binding agent, a ligand, and an aprotic polar solvent, and then undergo a one-pot alkylation reaction with the compound of formula V using carboxylic acid to produce the compound of formula IV; The catalyst is a copper salt; The acid binding agent is sodium carbonate, potassium carbonate, cesium carbonate or potassium tert-butoxide; The ligand is 2-acetylcyclohexanone or tetramethylethylenediamine; The aprotic polar solvent is DMF or DMAc.

12. The method for synthesizing the intermediate according to claim 9 or 11, characterized in that: The catalyst is CuCl, CuBr or CuI.

13. The method for synthesizing the intermediate according to claim 10, characterized in that: The catalyst is CuCl, CuBr or CuI.

14. The method for synthesizing the intermediate according to claim 9 or 11, characterized in that: The coupling reaction is carried out at a high temperature of 80-150°C; The alkylation reaction temperature of the carboxylic acid is 25-90°C.

15. The method for synthesizing the intermediate according to claim 14, characterized in that: The coupling reaction is carried out at a high temperature of 115-130°C; The alkylation reaction temperature of the carboxylic acid is 55-65°C.

16. The method for synthesizing the intermediate according to claim 9 or 11, characterized in that: The molar equivalent ratio of the compound of formula VII, the compound of formula VI and the catalyst is 1.0:1.0-2.0:0.01-0.

5.

17. The method for synthesizing the intermediate according to claim 16, characterized in that: The molar equivalent ratio of the compound of formula VII, the compound of formula VI and the catalyst is 1.0:1.1 to 1.5:0.

05.

18. A method for synthesizing apalutamide, characterized in that: The compound of formula IV and the compound of formula II are cyclized to obtain the compound of formula I, and the reaction formula is: Wherein, R is methyl or methoxy.

19. The method for synthesizing apalutamide according to claim 18, characterized in that: R is 4-methyl or 4-methoxy.

20. The method for synthesizing apalutamide according to claim 18 or 19, characterized in that: The compound of formula IV and the compound of formula II undergo [3+2] cyclization under the combined action of a low-polarity solvent and a polar aprotic solvent to obtain the compound of formula I.

21. The method for synthesizing apalutamide according to claim 20, characterized in that: The low polarity solvent is selected from acetonitrile and toluene.

22. The method for synthesizing apalutamide according to claim 20, characterized in that: The polar aprotic solvent is selected from DMF, DMA and DMSO.

23. The method for synthesizing apalutamide according to claim 18 or 19, characterized in that: The molar equivalent ratio of the compound of formula IV to the compound of formula II is 1.0:2.0-3.

0.

24. The method for synthesizing apalutamide according to claim 23, characterized in that: The molar equivalent ratio of the compound of formula IV to the compound of formula II is 1.0:2.

5.

25. The method for synthesizing apalutamide according to claim 20, characterized in that: The compound of formula II is prepared from the compound of formula III in the presence of thiophosgene:

26. The synthesis method according to claim 25, characterized in that The step of preparing the compound of formula II from the compound of formula III in the presence of thiophosgene optionally comprises a post-treatment step, wherein the post-treatment step comprises adding a low-polarity solvent and an adsorbent, stirring and filtering to remove impurities.

27. The synthesis method according to claim 26, characterized in that The low-polarity solvent is selected from petroleum ether, n-hexane and n-heptane; and the adsorbent is selected from aluminum oxide, activated carbon and column chromatography silica gel.

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