Synthesis method of anticancer drug darolutamide

Abstract

This scheme belongs to the field of organic synthesis technology, discloses the synthesis method of anticancer medicine darolutamide, and the synthesis method designs a new synthesis route: using formula (S1) compound as starting material, first converted into formula (1ab) or formula (1ac) compound, and then converted into formula (TM-1) compound; the obtained formula (TM-1) compound reacts with formula (1ad) or formula (1ae) compound converted from formula (S5) compound to synthesize formula (TM-2) compound, and then converted into formula (TM-3 compound); the obtained formula (TM-3) compound reacts with formula (S6) compound to synthesize formula (TM-4) compound, and then converted into formula (TM-5) darolutamide. The synthesis process does not need to use expensive palladium catalysts or ligands, so there is no problem of heavy metal residues or heavy metal toxicity in the drug product caused by palladium catalysts in the pharmaceutical process, and there is no need to remove trace metal residues from the target product; the raw materials used are cheap and easy to obtain, the reaction system is green and environmentally friendly, simple to handle, high yield, and good purity.

Description

Technical Field

[0001] This solution belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing the anticancer drug darolutamide. Background Art

[0002] Pyrazole nitrogen-containing heterocyclic compounds are widely found in natural products, pharmaceuticals, and related bioactive molecules, and have long been a hot topic in organic synthesis research. For example, the commercially available pyrazole anticancer drug darolutamide (generic name: Darolutamide; trade name: Nubeqa) contains a pyrazole structure. This prescription drug is used to treat patients with non-metastatic castration-resistant prostate cancer, a very common malignancy of the male reproductive system. Therefore, research into the synthesis of this pyrazole anticancer drug is of paramount importance.

[0003] Previous synthesis processes used a transition metal palladium-catalyzed coupling reaction as a key step (see WO 2016 / 162604A1; US ​​10189789 B2; WO 2011 / 051540 A1; WO 2012 / 143599 A1; CN 111116476 A). However, the synthesis methods still have limitations, such as: (1) the palladium catalysts used are usually very expensive and sensitive to air or moisture, and the operation must be carried out strictly; (2) the palladium catalysts are toxic to heavy metals, and removing trace metal residues from the target product is very challenging in the pharmaceutical industry. Therefore, it is of great significance to develop new green synthesis conditions for the preparation of the pyrazole anticancer drug darolutamide and to develop new environmentally friendly and cost-effective solutions. Summary of the Invention

[0004] This proposal aims to overcome at least one defect (shortcoming) in the prior art and provide a new method for synthesizing the anticancer drug darolutamide, avoiding the use of heavy metal catalysts.

[0005] In order to solve the above technical problems, the synthesis method of darolutamide of formula (TM-5) adopted in this scheme is: using the compound of formula (S1) as the starting material, it is first converted into a compound of formula (1ab) or formula (1ac), and then converted into a compound of formula (TM-1); the obtained compound of formula (TM-1) is reacted with a compound of formula (1ad) or formula (1ae) converted from a compound of formula (S5) to synthesize a compound of formula (TM-2), and then converted into a compound of formula (TM-3); the obtained compound of formula (TM-3) is reacted with a compound of formula (S6) to synthesize a compound of formula (TM-4), and then converted into darolutamide of formula (TM-5).

[0006] Its synthetic route is:

[0007]

[0008] The above-mentioned synthesis method comprises the following steps:

[0009] S1. Preparation of compound of formula (TM-1)

[0010] This step converts the compound of formula (S1) into the compound of formula (1ab) or (1ac), and then converts the compound of formula (1ab) or (1ac) into the compound of formula (TM-1). Specifically, it includes:

[0011] S11. Synthesizing 4-formyl-2-chlorobenzonitrile by reacting the compound of formula (S1) with formylpiperidine. Specifically comprising:

[0012] S111. Under degassing conditions at 0±2°C, isopropylmagnesium chloride was slowly added dropwise to the system of the compound of formula (S1) and anhydrous tetrahydrofuran (THF). After the addition was complete, the reaction was continued with stirring for a period of time;

[0013] S112. Formylpiperidine is slowly added dropwise to the reaction solution obtained in step S111. After the addition is complete, the reaction is stirred until the reaction is complete;

[0014] S113. Quench the mixture obtained in step S112, extract, dry the organic layer, concentrate under reduced pressure, purify, and dry.

[0015] Wherein, the addition amount of isopropylmagnesium chloride is 1.4±0.2 times of the molar amount of the compound of formula (S1), and the addition amount of formylpiperidine is 1.5±0.2 times of the molar amount of the compound of formula (S1). The addition time in step S111 is 30±5 minutes, and the reaction time is 3±0.5 hours. The addition time in step S112 is 30±5 minutes, and the reaction end point is monitored by thin layer chromatography (TLC). In step S113, the mixture is quenched with an ice-saturated NH4Cl aqueous solution, extracted with ethyl acetate (EtOAc), and the organic layer is dried over anhydrous Na2SO4. The crude product obtained by concentration under reduced pressure is separated and purified by chromatographic column chromatography with a mobile phase of petroleum ether / ethyl acetate system, and the purified pure product is dried under vacuum.

[0016] S12. The compound of formula (1ab) is synthesized by reacting 4-formyl-2-chlorobenzonitrile with (triphenylphosphine)acetaldehyde, or the compound of formula (1ac) is synthesized by reacting 4-formyl-2-chlorobenzonitrile with dimethyl (1-diazoethyl)phosphonate.

[0017] The method of synthesizing the compound of formula (1ab) by reacting 4-formyl-2-chlorobenzonitrile with (triphenylphosphine) acetaldehyde specifically includes:

[0018] S1211. 4-formyl-2-chlorobenzonitrile, (triphenylphosphine) acetaldehyde and anhydrous tetrahydrofuran (THF) were reacted under degassed conditions at room temperature until the reaction was complete;

[0019] S1212. Filter the mixture obtained in step S1211, concentrate under reduced pressure, purify, and dry.

[0020] The amount of (triphenylphosphine)acetaldehyde added is 2.2±0.2 times the molar amount of 4-formyl-2-chlorobenzonitrile. The reaction endpoint in step S1211 is monitored by thin layer chromatography (TLC). In step S1212, the crude product obtained by concentration under reduced pressure is separated and purified using a column chromatography system with a mobile phase of petroleum ether / ethyl acetate, and the purified product is dried under vacuum.

[0021] The method for synthesizing the compound of formula (1ac) by reacting 4-formyl-2-chlorobenzonitrile with dimethyl (1-diazoethyl)phosphonate specifically includes:

[0022] S1221. Dimethyl (1-diazoethyl)phosphonate (Ohira-Bestmann reagent) was slowly added dropwise to a system of 4-formyl-2-chlorobenzonitrile, K2CO3, and anhydrous methanol (MeOH). After the addition was complete, the reaction was stirred at room temperature until the reaction was complete.

[0023] S1222. Filter the mixture obtained in step S1221, concentrate under reduced pressure, purify, and dry.

[0024] The amount of K2CO3 added is 2.0±0.2 times the molar amount of 4-formyl-2-chlorobenzonitrile, and the amount of dimethyl (1-diazoethyl)phosphonate (Ohira-Bestmann reagent) added is 1.3±0.1 times the molar amount of 4-formyl-2-chlorobenzonitrile. The addition time in step S1221 is 10±2 minutes, and the reaction endpoint is monitored by thin-layer chromatography (TLC). The crude product obtained by vacuum concentration in step S1222 is separated and purified using a column chromatography system with a mobile phase of petroleum ether / ethyl acetate, and the purified product is dried under vacuum.

[0025] S13. The compound of formula (TM-1) is synthesized by reacting the compound of formula (1ab) with p-toluenesulfonylhydrazide, or the compound of formula (1ac) is synthesized by reacting with trimethylsilylated diazomethane.

[0026] The synthesis of the compound of formula (TM-1) by reacting the compound of formula (1ab) with p-toluenesulfonylhydrazide specifically includes:

[0027] S1311. The compound of formula (1ab), p-toluenesulfonyl hydrazide and anhydrous acetonitrile (MeCN) were stirred under degassed conditions at room temperature until the reaction was complete;

[0028] S1312. NaOH was added to the mixture obtained in step S1311, and then the reaction was stirred at 85±5°C until the reaction was completed;

[0029] S1313. The mixture obtained in step S1312 is concentrated under reduced pressure, purified, and dried.

[0030] The amount of p-toluenesulfonyl hydrazide added is 1.1±0.5 times the molar amount of the compound of formula (1ab), and the amount of NaOH added is 1.2±0.5 times the molar amount of the compound of formula (1ab). The reaction endpoints of steps S1311 and S1312 are monitored by thin layer chromatography. The crude product obtained by reduced pressure concentration in step S1313 is separated and purified by column chromatography using a mobile phase of petroleum ether / ethyl acetate, and the purified product is dried under vacuum.

[0031] The synthesis of the compound of formula (TM-1) by reacting the compound of formula (1ac) with trimethylsilylated diazomethane specifically includes:

[0032] S1321. Under degassing conditions, trimethylsilylated diazomethane was slowly added dropwise to the system of the compound of formula (1ac) and anhydrous tetrahydrofuran (THF). After the addition was complete, the reaction was continued at 100±5°C until the reaction was complete;

[0033] S1322. The mixture obtained in step S1321 is concentrated under reduced pressure, purified, and dried.

[0034] The amount of trimethylsilylated diazomethane added is 1.5±0.2 times the molar amount of the compound of formula (lac). The addition time in step S1321 is 5±1 minutes, and the reaction endpoint is monitored by thin layer chromatography (TLC). In step S1322, the crude product obtained by concentration under reduced pressure is purified by washing with petroleum ether, and the purified product is dried under vacuum.

[0035] S2. Preparation of compound of formula (TM-2)

[0036] In this step, the compound of formula (TM-1) is reacted with a derivative of the compound of formula (S5), formula (1ad) or formula (1ae), to synthesize the compound of formula (TM-2).

[0037] The synthesis of the compound of formula (TM-2) by reacting the compound of formula (TM-1) with a derivative of the compound of formula (S5) (1ad) specifically includes:

[0038] S211. The compound of formula (S5), triphenylphosphine (PPh3), carbon tetrabromide (CBr4) and anhydrous dichloromethane (DCM) are stirred at 0±2°C for a period of time, and then stirred at room temperature until the reaction is complete;

[0039] S212. The mixture obtained in step S211 is filtered, concentrated under reduced pressure, purified, and dried to obtain a compound of formula (1ad);

[0040] S213. The compound of formula (TM-1), the compound of formula (1ad) obtained in step S212, Cs2CO3 and anhydrous N,N-dimethylformamide (DMF) were reacted under degassing and stirring at 65±5°C until the reaction was completed;

[0041] S214. Quench the mixture obtained in step S213, extract, dry the organic layer, concentrate under reduced pressure, purify, and dry.

[0042] Wherein, the amount of triphenylphosphine (PPh3) added is 1.1±0.05 times the molar amount of the compound of formula (S5), the amount of carbon tetrabromide (CBr4) added is 1.1±0.05 times the molar amount of the compound of formula (S5), the amount of the compound of formula (1ad) added is 1.4±0.1 times the molar amount of the compound of formula (TM-1), and the amount of Cs2CO3 added is 2.0±0.2 times the molar amount of the compound of formula (TM-1). The reaction time at 0±2°C in step S211 is 30±5 minutes, and the end point of the reaction at room temperature is monitored by thin layer chromatography (TLC). The crude product obtained by reduced pressure concentration in step S212 is separated and purified by column chromatography with a mobile phase of petroleum ether / ethyl acetate system, and the purified pure product is dried under vacuum. The reaction end point of step S213 is monitored by thin layer chromatography (TLC). In step S214, the mixture is quenched with water, extracted with ethyl acetate (EtOAc), the organic layer is dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product is washed and purified with petroleum ether, and the purified pure product is dried under vacuum.

[0043] The synthesis of the compound of formula (TM-2) by reacting the compound of formula (TM-1) with a derivative of the compound of formula (S5) (1ae) specifically includes:

[0044] S221. To a system of the compound of formula (S5), 4-dimethylaminopyridine (DMAP), p-toluenesulfonyl chloride, and anhydrous dichloromethane (DCM), triethylamine (NEt3) was slowly added dropwise at 0±2°C. After the addition was complete, the reaction was stirred at 0±2°C for a period of time, and then stirred at room temperature until the reaction was complete.

[0045] S222. The mixture obtained in step S221 is quenched, extracted, the organic layer is dried, concentrated under reduced pressure, purified, and dried to obtain a compound of formula (1ae);

[0046] S223. The compound of formula (TM-1), the compound of formula (1ae) obtained in step S222, Cs2CO3 and anhydrous N,N-dimethylformamide (DMF) were reacted under degassing and stirring at 55±5°C until the reaction was completed;

[0047] S224. Quench the mixture obtained in step S223, extract, dry the organic layer, concentrate under reduced pressure, purify, and dry.

[0048] Among them, the amount of 4-dimethylaminopyridine (DMAP) added is 1.0±0.05 times the molar amount of the compound of formula (S5), the amount of p-toluenesulfonyl chloride added is 1.1±0.05 times the molar amount of the compound of formula (S5), the amount of triethylamine (NEt3) added is 1.2±0.05 times the molar amount of the compound of formula (S5), the amount of the compound of formula (1ae) added is 1.4±0.1 times the molar amount of the compound of formula (TM-1), and the amount of Cs2CO3 added is 2.0±0.2 times the molar amount of the compound of formula (TM-1). The dropwise addition time in step S221 is 5±1 minutes, the reaction time at 0±2°C is 60±5 minutes, and the endpoint of the reaction at room temperature is monitored by thin layer chromatography (TLC). In step S222, the mixture is quenched with water, extracted with dichloromethane (DCM), and the organic layer is dried over anhydrous Na2SO4. The crude product obtained by concentration under reduced pressure is separated and purified by column chromatography using a mobile phase of petroleum ether / ethyl acetate system, and the purified product is dried under vacuum. The reaction endpoint of step S223 is monitored by thin layer chromatography (TLC). In step S224, the mixture is quenched with water, extracted with ethyl acetate (EtOAc), and the organic layer is dried over anhydrous Na2SO4. The crude product obtained by concentration under reduced pressure is washed and purified with petroleum ether, and the purified product is dried under vacuum.

[0049] S3. Preparation of compound of formula (TM-3)

[0050] This step converts the compound of formula (TM-2) into the compound of formula (TM-3), and there are two specific schemes:

[0051] The first option includes:

[0052] S311. At 0±2°C, a dichloromethane trifluoroacetic acid solution (DCM / TFA) was slowly added dropwise to the compound of formula (TM-2). After the addition was complete, the reaction was stirred until the reaction was complete.

[0053] S312. Quench the mixture obtained in step S311, extract, dry the organic layer, concentrate under reduced pressure, purify, and dry.

[0054] In step S311, the addition time is 5±1 minutes, and the reaction endpoint is monitored by thin layer chromatography (TLC). In step S312, the mixture is quenched with 10% Na2CO3 solution, extracted with dichloromethane (DCM), and the organic layer is dried over anhydrous Na2SO4. The crude product obtained by concentration under reduced pressure is washed with petroleum ether and purified, and the purified product is dried under vacuum.

[0055] The second option includes:

[0056] S321. Under a nitrogen atmosphere, HCl was slowly added dropwise to the system of the compound of formula (TM-2) and ethanol (EtOH). After the addition was complete, the reaction was continued at 65 ± 5 ° C until the reaction was completed;

[0057] S322. Quench the mixture obtained in step S321, extract, dry the organic layer, concentrate under reduced pressure, purify, and dry.

[0058] The amount of HCl added is 2.0±0.2 times the molar amount of the compound of formula (TM-2). The addition time in step S321 is 5±1 minutes, and the reaction endpoint is monitored by thin layer chromatography (TLC). In step S322, the mixture is quenched with a saturated Na2CO3 solution, extracted with dichloromethane (DCM), and the organic layer is dried over anhydrous Na2SO4. The crude product obtained by concentration under reduced pressure is washed and purified with petroleum ether, and the purified product is dried under vacuum.

[0059] S4. Preparation of compound of formula (TM-4)

[0060] This step is to synthesize the compound of formula (TM-4) by reacting the compound of formula (TM-3) with the compound of formula (S6), which specifically includes:

[0061] S41. Under degassing conditions at 0±2°C, triethylamine (NEt3) was slowly added dropwise to a system of the compound of formula (TM-3), the compound of formula (S6), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 1-hydroxybenzotriazole (HOBt) and anhydrous N,N-dimethylformamide (DMF). After the addition was complete, the reaction was stirred at 0±2°C for a period of time, and then stirred at room temperature until the reaction was complete.

[0062] S42. The mixture obtained in step S41 is quenched, extracted, the organic layer is dried, concentrated under reduced pressure, purified, and dried.

[0063] Wherein, the addition amount of the compound of formula (S6) is 1.3±0.1 times the molar amount of the compound of formula (TM-3), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) is 1.3±0.1 times the molar amount of the compound of formula (TM-3), and 1-hydroxybenzotriazole (HOBt) is 1.3±0.1 times the molar amount of the compound of formula (TM-3). In step S41, the addition time is 5±1 minutes, the reaction time at 0±2°C is 60±5 minutes, and the end point of the reaction at room temperature is monitored by thin layer chromatography (TLC). In step S42, the mixture is quenched with water, extracted with ethyl acetate (EtOAc), and the organic layer is dried over anhydrous Na2SO4. The crude product obtained by concentration under reduced pressure is washed and purified with petroleum ether / ethyl acetate, and the purified pure product is dried under vacuum.

[0064] S5. Preparation of compound of formula (TM-5)

[0065] This step involves reducing the compound of formula (TM-4) to darolutamide of formula (TM-5) in sodium borohydride, specifically comprising:

[0066] S51. NaBH4 was slowly added dropwise to the system of the compound of formula (TM-4) and anhydrous ethanol (EtOH) at 0±2°C. After the addition was complete, the reaction was stirred until the reaction was complete;

[0067] S52. The mixture obtained in step S51 is quenched, extracted, the organic layer is dried, concentrated under reduced pressure, purified, and dried.

[0068] The amount of NaBH4 added is 2.0±0.2 times the molar amount of the compound of formula (TM-4). The addition time in step S51 is 5±1 minutes, and the reaction endpoint is monitored by thin layer chromatography (TLC). In step S52, the mixture is quenched with ice water, extracted with dichloromethane (DCM), and the organic layer is dried over anhydrous Na2SO4. The crude product obtained by concentration under reduced pressure is washed and purified with petroleum ether, and the purified product is dried under vacuum.

[0069] This scheme redesigns the route for synthesizing darolutamide (TM-5) from 4-bromo-2-chlorobenzonitrile (S1). The synthesis process does not require the use of expensive palladium catalysts or ligands, thereby eliminating the problems of heavy metal residues or heavy metal toxicity in the drug product caused by palladium catalysts in the pharmaceutical process, and there is no need to remove trace metal residues from the target product. The raw materials used are bulk, inexpensive, and readily available, the reaction system is environmentally friendly, and the production of difficult-to-purify byproducts is avoided. The operation steps and post-processing process are simple, and the overall yield is high and the purity is good.

[0070] Compared with the existing technology, this solution has the following beneficial effects:

[0071] (1) This synthetic route does not require the use of expensive palladium as a catalyst or expensive ligands in any step of the reaction, so there is no problem of heavy metal residues or heavy metal toxicity in the drug product caused by palladium catalysts in the pharmaceutical process;

[0072] (2) The chemical conversion or route designed in this scheme does not involve the problem of expensive industrial heavy metal waste disposal;

[0073] (3) The chemical reaction designed in this scheme uses readily available and inexpensive raw materials; the developed reaction system is green and environmentally friendly; the operation steps and post-processing process are simple, the overall yield of the route is high, and the product purity is good. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figure 1 This is the synthetic route of this scheme.

[0075] Figure 2 The NMR of compound 1aa 1 H NMR spectrum.

[0076] Figure 3 The NMR of compound 1aa 13 C NMR spectrum.

[0077] Figure 4 This is the NMR of compound 1ab 1 H NMR spectrum.

[0078] Figure 5 This is the NMR of compound 1ab 13 C NMR spectrum.

[0079] Figure 6 This is the NMR of compound 1ac 1 H NMR spectrum.

[0080] Figure 7 This is the NMR of compound 1ac 13 C NMR spectrum.

[0081] Figure 8 The NMR of compound 1ad 1 H NMR spectrum.

[0082] Figure 9 The NMR of compound 1ad 13 C NMR spectrum.

[0083] Figure 10 The NMR of compound 1ae 1 H NMR spectrum.

[0084] Figure 11 The NMR of compound 1ae 13C NMR spectrum.

[0085] Figure 12 The NMR of compound TM-1 1 H NMR spectrum.

[0086] Figure 13 The NMR of compound TM-1 13 C NMR spectrum.

[0087] Figure 14 The NMR of compound TM-2 1 H NMR spectrum.

[0088] Figure 15 The NMR of compound TM-2 13 C NMR spectrum.

[0089] Figure 16 The NMR of compound TM-3 1 H NMR spectrum.

[0090] Figure 17 The NMR of compound TM-3 13 C NMR spectrum.

[0091] Figure 18 The NMR of compound TM-4 1 H NMR spectrum.

[0092] Figure 19 The NMR of compound TM-4 13 C NMR spectrum.

[0093] Figure 20 This is the NMR of compound TM-5 1 H NMR spectrum.

[0094] Figure 21 This is the NMR of compound TM-5 13 C NMR spectrum. DETAILED DESCRIPTION

[0095] This protocol uses the inexpensive commercial reagent 4-bromo-2-chlorobenzonitrile S1, which undergoes a series of transformations to obtain aldehyde 1ab or alkyne 1ac compounds. Then, the aldehyde 1ab or alkyne 1ac compounds are converted to pyrazole compound TM-1. Pyrazole compound TM-1 undergoes a substitution reaction with a derivative of amino alcohol compound S5 and is subsequently converted to pyrazole compound TM-3. Compound TM-3 is condensed with commercial pyrazole carboxylic acid reagent S6 to obtain compound TM-4. Finally, the carbonyl group of TM-4 is reduced to an alcohol under the reducing conditions of sodium borohydride to obtain the target compound TM-5 (Darolutamide).

[0096]

[0097] In order to allow those skilled in the art to better understand this solution, the following is a detailed description of this solution in conjunction with specific examples. The process methods used in the examples are all conventional methods unless otherwise specified; the materials used are all commercially available unless otherwise specified.

[0098] 1. Synthesis of pyrazole compound TM-1

[0099] Option 1

[0100]

[0101] Step 1: In an air atmosphere, a 250 mL round-bottom flask equipped with a magnetic separator was charged with 4-bromo-2-chlorobenzonitrile (S1, 40 mmol, 8660 mg) and anhydrous THF (100 mL). The reaction flask was then degassed three times with nitrogen. The mixture was placed in an ice bath at 0°C. Isopropylmagnesium chloride (2 M in THF, 1.4 equiv., 56 mmol, 28 mL) was slowly added dropwise over approximately 30 minutes. After the addition was complete, the reaction was stirred in an ice bath at 0°C for 3 hours. Formylpiperidine (1.5 equiv., 60 mmol, 6.7 mL) was added dropwise to the reaction mixture in an ice bath at 0°C over approximately 30 minutes. After the addition was complete, the reaction was stirred in an ice bath at 0°C for 3 hours (monitored by TLC). After the reaction was complete, the mixture was quenched with an ice-cold saturated aqueous NH4Cl solution (200 mL) and extracted with EtOAc (150 mL × 3). The organic layer was dried over anhydrous Na2SO4. The resulting solution was concentrated under reduced pressure to obtain a dark brown solid crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 5:1, R f =0.30). The pure product was dried under vacuum to obtain compound 1aa (pale yellow solid, 40 mmol scale, 4.8 g, yield 72%).

[0102] Use H 1 -NMR (Bruker FT-NMR) and C 13 The structure of the compound 1aa obtained above was confirmed by Bruker FT-NMR. Figures 2-3 As shown:

[0103] 1 H NMR (400MHz, CDCl3): δ10.05 (s, 1H), 8.02-8.01 (m, 1H), 7.88 (d, J = 1.0Hz, 2H);

[0104] 13 C{1 H}NMR(100MHz, CDCl3):189.24,139.72,138.16,134.79,130.29,127.64,118.28,115.02.

[0105] Step 2: In an air atmosphere, a 100 mL round-bottom flask equipped with a magnetic separator was charged with the raw material 1aa (6.0 mmol, 994 mg), a phosphine reagent (S2, 2.2 equiv., 13.2 mmol, 4.0 g) and anhydrous THF (40 mL). The reaction flask was then degassed three times with nitrogen and the mixture was stirred at room temperature for 15 h (monitored by TLC). After the reaction was completed, the solution was filtered and concentrated under reduced pressure to obtain a dark brown solid crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 3:1, R f =0.35). The pure product was dried under vacuum to obtain compound 1ab (light yellow solid, 6.0 mmol scale, 0.8 g, yield 70%).

[0106] Use H 1 -NMR (Bruker FT-NMR) and C 13 The structure of the compound 1ab obtained above was confirmed by Bruker FT-NMR. Figures 4-5 As shown:

[0107] 1 H NMR(400MHz,CDCl3):(E / Z>20 / 1,detected by 1 H NMR) δ9.76(d,J=7.4Hz,1H),7.75(d,J=8.2Hz,1H),7.70(d,J=1.4Hz,1H),7.55( dd,J=8.2Hz,1.4Hz,1H),7.42(d,J=16.0Hz,1H),6.77(dd,J=16.0Hz,7.4Hz,1H);

[0108] 13 C{ 1 H}NMR(100MHz, CDCl3):192.51,147.84,139.53,137.72,134.46,132.01,129.24,126.48,115.41,114.84.

[0109] Step 3: In an air atmosphere, a 100 mL round-bottom flask equipped with a magnetic separator was charged with starting material 1ab (1.0 equiv., 4 mmol, 766 mg), p-methylbenzenesulfonylhydrazide (1.1 equiv., 4.4 mmol, 820 mg), and anhydrous MeCN (20 mL). The reaction flask was then degassed three times with nitrogen, and the mixture was stirred at room temperature for 4 h (monitored by TLC). After complete consumption of starting material 1ab, NaOH (1.2 equiv., 4.8 mmol, 192 mg) was added, and the mixture was stirred at 85°C for 12 h (monitored by TLC). The resulting solution was concentrated under reduced pressure to obtain a crude solid product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 2:1, Rf = 0.20). The pure product was dried under vacuum to obtain pyrazole compound TM-1 (pale yellow solid, 4.0 mmol scale, 530.0 mg, 65% yield).

[0110] Option 2:

[0111]

[0112] Step 1: In an air atmosphere, a 100 mL round-bottom flask equipped with a magnetic separator was charged with raw material 1aa (1.0 equiv., 10 mmol, 1656 mg), K2CO3 (2.0 equiv., 20 mmol, 2730 mg), and anhydrous MeOH (50 mL). Then, Ohira-Bestmann reagent (S3, 1.3 equiv., 13.0 mmol, 2.0 mL) was slowly added dropwise over approximately 10 minutes. After the addition was complete, the mixture was stirred at room temperature for 15 hours (monitored by TLC). After the reaction was complete, the solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 15:1, R f =0.45). The pure product was dried under vacuum to give compound 1ac (pale yellow solid, 10 mmol scale, 730.0 mg, 45% yield).

[0113] Use H 1 -NMR (Bruker FT-NMR) and C 13 The structure of the compound 1ac obtained above was confirmed by Bruker FT-NMR. Figures 6-7 As shown:

[0114] 1 H NMR (400MHz, CDCl3): δ7.64-7.61 (m, 2H), 7.46 (dd, J = 8.0Hz, 1.6Hz, 1H), 3.36 (s, 1H);

[0115] 13 C{ 1 H}NMR(100MHz, CDCl3)::136.82,133.69,133.16,130.59,,128.22,115.53,113.30,82.81,80.64.

[0116] Step 2: In an air atmosphere, a 250 mL round-bottom flask equipped with a magnetic separator was charged with 1ac (1.0 equiv., 10 mmol, 1.62 g) and anhydrous THF (60 mL). The reaction flask was then degassed three times with nitrogen, followed by the slow addition of the diazo reagent (S4, 2M solution in hexanes, safeseal; 1.5 equiv., 15 mmol, 7.5 mL) over approximately 5 minutes. After the addition was complete, the mixture was reacted at 100°C for 16 hours (monitored by TLC). The resulting solution was concentrated under reduced pressure to obtain a crude solid product. The crude solid product was washed with petroleum ether (150 mL) to obtain the pure product. The product was then dried under vacuum to afford the pyrazole compound TM-1 (pale yellow solid, 10 mmol scale, 1.9 g, 93% yield).

[0117] Use H 1 -NMR (Bruker FT-NMR) and C 13 -NMR (Bruker FT-NMR) was used to confirm the structure of the compound TM-1 obtained in Scheme 1 and Scheme 2. The results are as follows Figures 12-13 As shown:

[0118] 1 H NMR (400MHz, DMSO-d6): δ13.29(br,s,1H),8.15(s,1H),7.99(s,2H),7.89(s,1H),7.00(s,1H);

[0119] 13 C{ 1 H}NMR(100MHz,DMSO-d6):147.42,140.11,135.93,135.06,130.82,125.79,124.18,116.34,109.87,103.66.

[0120] 2. Synthesis of pyrazole compound TM-2

[0121] Option 1:

[0122]

[0123] Step 1: In a nitrogen atmosphere, in a 100 mL round-bottom flask equipped with a magnetic bar, at 0°C, the amino alcohol starting material (S5, 1.0 equiv., 5 mmol, 876 mg), PPh3 (1.1 equiv., 5.5 mmol, 1442 mg), CBr4 (1.1 equiv., 5.5 mmol, 1824 mg) and anhydrous DCM (30 mL) were added. The reaction was then stirred for 0.5 h in an ice bath at 0°C. Finally, the reaction was stirred for 12 h at room temperature (monitored by TLC). After the reaction was completed, the reaction solution was filtered and the resulting solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 15:1, R f =0.50). The pure product was dried under vacuum to give 1ad (white solid, 5.0 mmol scale, 476.0 mg, 40% yield).

[0124] Use H 1 -NMR (Bruker FT-NMR) and C 13 The structure of the compound 1ad obtained above was confirmed by Bruker FT-NMR. Figures 8-9 As shown:

[0125] 1 H NMR (400MHz, CDCl3): δ4.67(br,s,1H),3.93(br,s,1H),3.53(m,1H),3.46-3.43(m,1H),1.44(s,9H),1.23(d,J=6.6Hz,3H);

[0126] 13 C{ 1 H}NMR(100MHz, CDCl3):154.87,79.69,46.16,39.71,28.33,19.26.

[0127] Step 2: In an air atmosphere, a 50 mL round-bottom flask equipped with a magnetic separator was charged with starting material TM-1 (1.0 equiv., 1.0 mmol, 204 mg), 1ad (1.4 equiv., 1.4 mmol, 333 mg), Cs2CO3 (2.0 equiv., 2.0 mmol, 652 mg), and anhydrous DMF (8 mL). The reaction flask was then degassed three times with nitrogen, and the mixture was stirred at 65°C for 20 h (monitored by TLC). After completion of the reaction, the mixture was quenched with water (20 mL) and extracted with EtOAc (15 mL x 3). The organic layer was dried over anhydrous Na2SO4. The resulting solution was concentrated under reduced pressure to obtain a dark yellow crude solid. The crude solid was washed with petroleum ether (50 mL) to obtain the pure product. After drying under vacuum, the pyrazole compound TM-2 was obtained (pale yellow solid, 1.0 mmol scale, 260.5 mg, 72% yield).

[0128] Option 2:

[0129]

[0130] Step 1: In an air atmosphere, in a 250 mL round-bottom flask equipped with a magnetic bar, the amino alcohol starting material (S5, 1.0 equiv., 20 mmol, 3505 mg), DMAP (0.1 equiv., 2.0 mmol, 244 mg), p-toluenesulfonyl chloride (1.1 equiv., 22 mmol, 4195 mg), and anhydrous DCM (60 mL) were added at 0°C. NEt3 (1.2 equiv., 24 mmol, 3.4 mL) was slowly added dropwise over approximately 5 minutes. The reaction was then stirred in an ice bath at 0°C for 1 hour. Finally, the reaction was stirred at room temperature for 15 hours (monitored by TLC). After completion of the reaction, the mixture was quenched with water (150 mL) and extracted with DCM (150 mL × 3). The organic layer was dried over anhydrous Na2SO4. The resulting solution was concentrated under reduced pressure to obtain a solid crude product. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 5:1, R f =0.35). The pure product was dried under vacuum to obtain compound 1ae (white solid, 20 mmol scale, 5.6 g, yield 85%).

[0131] Use H 1 -NMR (Bruker FT-NMR) and C 13 The structure of the compound 1ae obtained above was confirmed by Bruker FT-NMR. Figures 10-11 As shown:

[0132] 1H NMR (400MHz, CDCl3): δ7..79-7.77(m,2H),7.35-7.33(m,2H),4.60-4.59(m,1H),4. 03-4.01(m,1H),3.94-3.88(m,2H),2.44(s,3H),1.39(s,9H),1.14(d,J=6.8Hz,3H);

[0133] 13 C{ 1 H}NMR(100MHz, CDCl3):154.83,144.95,132.48,129.90,127.90,79.64,72.52,45.20,28.25,21.63,17.15.

[0134] Step 2: In an air atmosphere, a 250 mL round-bottom flask equipped with a magnetic separator was charged with starting materials TM-1 (1.0 equiv., 10 mmol, 2.04 g), 1ae (1.4 equiv., 14.0 mmol, 4.6 g), Cs2CO3 (2.0 equiv., 20 mmol, 6.5 g), and anhydrous DMF (60 mL). The reaction flask was then degassed three times with nitrogen, and the mixture was stirred at 55°C for 20 h (monitored by TLC). After completion of the reaction, the mixture was quenched with water (300 mL) and extracted with EtOAc (150 mL x 3). The organic layer was dried over anhydrous Na2SO4. The resulting solution was concentrated under reduced pressure to obtain a dark yellow crude solid. The crude solid was washed with petroleum ether (200 mL) to obtain the pure product. The product was then dried under vacuum to afford the pyrazole compound TM-2 (pale yellow solid, 10 mmol scale, 2.8 g, 78% yield).

[0135] Use H 1 -NMR (Bruker FT-NMR) and C 13 -NMR (Bruker FT-NMR) was used to confirm the structure of the compound TM-2 obtained in Scheme 1 and Scheme 2. The results are as follows Figures 14-15 As shown:

[0136] 1 H NMR (400MHz, CDCl3): δ7.96(s,1H),7.77-7.75(m,1H),7.67-7.65(m,1H),7.45(d,J=2.0Hz,1H),6.61(d,J=2.0Hz,1H),4.80(br,s 1H),4.30-4.22(m,2H),4.11-4.03(m,1H),1.42(s,9H),1.16(d,J=6.8Hz,3H);

[0137] 13 C{ 1 H}NMR (100MHz, CDCl3):155.11,148.55,139.34,137.19,134.15,132.31,1 26.54,123.87,116.31,111.44,103.89,79.73,56.72,47.00,28.35,18.18.

[0138] 3. Pyrazole compound TM-3

[0139] Option 1:

[0140]

[0141] In a 100 mL round-bottom flask equipped with a magnetic stirrer, at 0°C, a solution of TM-2 (1.0 equiv., 2.0 mmol, 720 mg) was slowly added dropwise with DCM / TFA (10 mL, V / V = 2 / 1) over approximately 5 minutes. The reaction was then stirred in an ice bath at 0°C for 3 h (monitored by TLC). After completion, the mixture was quenched with 10% Na2CO3 solution (100 mL) and extracted with DCM (50 mL x 3). The organic layer was dried over anhydrous Na2SO4. The resulting solution was concentrated under reduced pressure to obtain a crude solid. The crude solid was washed with petroleum ether (50 mL) to obtain the pure product. The product was then dried under vacuum to afford the pyrazole compound TM-3 (pale yellow solid, 2.0 mmol scale, 485.0 mg, 93% yield).

[0142] Option 2:

[0143]

[0144] Under nitrogen, in a 100 mL round-bottom flask equipped with a magnetic bar, 2N HCl (2.0 equiv. in EtOH, 5 mL) was slowly added dropwise to a solution of TM-2 (1.0 equiv., 5.0 mmol, 1.8 g) in EtOH (25 mL) over approximately 5 minutes. The reaction was then continued at 65°C for 12 hours (monitored by TLC). After completion, the mixture was quenched with saturated NaCO solution (50 mL) and extracted with DCM (100 mL x 3). The organic layer was dried over anhydrous NaSO. The resulting solution was concentrated under reduced pressure to obtain a crude solid. The crude solid was washed with petroleum ether (150 mL) to obtain the pure product. The product was then dried under vacuum to afford the pyrazole compound TM-3 (pale yellow solid, 5.0 mmol scale, 1185.0 mg, 91% yield).

[0145] Use H 1 -NMR (Bruker FT-NMR) and C 13 -NMR (Bruker FT-NMR) was used to confirm the structure of the compound TM-3 obtained by the above two schemes. The results are as follows Figures 16-17 As shown:

[0146] 1 H NMR (400MHz, CDCl3): δ7.95(d,J=1.4Hz,1H),,7.75(dd,J=8.1Hz,1.4Hz,1H),7.66(d,J=8.1Hz,1H),7.50(d,J=2.3Hz,1H),6.60(d,J= 2.3Hz,1H),4.16(dd,J=13.6Hz,4.4Hz,1H),3.93(dd,J=13.6Hz,8.2Hz,1H),3.54-3.46(m,1H),1.78(br,s,2H),1.15(d,J=6.4Hz,3H);

[0147] 13 C{ 1 H}NMR(100MHz, CDCl3)::148.62,139.26,137.11,134.11,132.13,126.43,123.81,116.31,111.28,103.70,60.51,47.30,20.80.

[0148] 4. Synthesis of pyrazole compound TM-4

[0149]

[0150] In an air atmosphere, a 250 mL round-bottom flask equipped with a magnetic separator was charged with TM-3 (1.0 equiv., 5.0 mmol, 1.3 g), a commercial pyrazole carboxylic acid reagent (S6, 1.3 equiv., 6.5 mmol, 1.0 g), EDCI (1.3 equiv., 6.5 mmol, 1250 mg), HOBt (1.3 equiv., 6.5 mmol, 880 mg), and anhydrous DMF (50 mL). The reaction flask was then degassed three times with nitrogen. NEt (2.0 equiv., 10 mmol, 1.4 mL) was slowly added dropwise over approximately 5 minutes at 0°C in an ice bath. The mixture was stirred at 0°C for 1 hour. Finally, the reaction was stirred at room temperature for 15 hours (monitored by TLC). After completion of the reaction, the mixture was quenched with water (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was dried over anhydrous Na2SO4. The resulting solution was concentrated under reduced pressure to yield a crude solid product. The crude solid product was washed with petroleum ether / ethyl acetate (200 mL, V / V = 10 / 1) to obtain the pure product and dried under vacuum to obtain pyrazole compound TM-4 (white solid, 5.0 mmol scale, 1.65 g, 83% yield).

[0151] Use H 1 -NMR (Bruker FT-NMR) and C 13 The structure of the compound TM-4 obtained above was confirmed by Bruker FT-NMR. Figures 18-19 As shown:

[0152] 1 H NMR (400MHz, DMSO-d6): δ14.18(br,s,1H),8.51(d,J=7..8Hz,1H),8.01(s,1H),7.97-7.92(m,2H),7.81(d,J=2. 2Hz,1H),7.31(s,1H),6.92(d,J=2.2Hz,1H),4.47-4.34(m,1H),4.30(m,2H),2.49(s,3H),1.15(d,J=6.2Hz,3H);

[0153] 13 C{ 1 H}NMR (100MHz, DMSO-d6):147.78,140.01,136.32,135.46,133.60,126.04,124.49,116.71,110.33,104.73,56.14,45.74,27.01,18.25.

[0154] 5. Synthesis of target compound TM-5 (Darolutamide)

[0155]

[0156] In a 150 mL round-bottom flask equipped with a magnetic stirrer, NaBH₄ (2.0 equiv., 8.0 mmol, 304 mg) was slowly added to a solution of TM-4 (1.0 equiv., 4.0 mmol, 1588 mg) in anhydrous EtOH (40 mL) at 0°C in an air atmosphere over approximately 5 minutes. The reaction was then stirred at 0°C in an ice bath for 12 hours (monitored by TLC). After completion, the mixture was quenched with ice water (200 mL) and extracted with DCM (100 mL x 3). The organic layer was dried over anhydrous Na₂SO₄. The resulting solution was concentrated under reduced pressure to obtain a crude solid. The crude solid was washed with petroleum ether (100 mL) to obtain the pure product. The product was then dried under vacuum to afford the target compound TM-5 (pale yellow solid, 4.0 mmol scale, 1195 mg, 75% yield).

[0157] Use H 1 -NMR (Bruker FT-NMR) and C 13 The structure of the compound TM-5 obtained above was confirmed by Bruker FT-NMR. Figures 20-21 As shown:

[0158] 1 H NMR (400MHz, DMSO-d6): δ13.10(br,s,1H),8.26-8.24(m,1H),8.09(s,1H),8.02-8.00(m,2H),7.81(d,J=2.2Hz,1H),6.95(d,J=2.2Hz,1H),6.39( br,s,1H),5.48-5.47(m,1H),4.78(m,1H),4.47-4.40(m,1H),4.38-4.33 (m,1H),4.29-4.24(m,1H),1.37(d,J=6.2Hz,3H),1.10(d,J=6.2Hz,3H);

[0159] 13 C{ 1H}NMR(100MHz,DMSO-d6):161.41,149.61,147.37,146.39,139.62,135.96,135.11,133. 25,125.74,124.15,116.35,109.93,104.26,101.77,60.97,55.72,44.71,23.80,18.06.

[0160] Obviously, the above embodiments of this solution are merely examples for the purpose of clarifying this solution and are not intended to limit the implementation of this solution. Those skilled in the art will be able to make other variations or modifications based on the above description. It is not necessary and impossible to enumerate all implementation methods here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of this solution shall be included within the scope of protection of the claims of this solution.

Claims

1. A method for synthesizing darolutamide of formula (TM-5), characterized in that: The synthetic route is: The synthesis method comprises: S1. Converting the compound of formula (S-1) into a compound of formula (1ab) or (1ac), and then converting the compound of formula (1ab) or (1ac) into a compound of formula (TM-1); S2. The compound of formula (TM-2) is synthesized by reacting the compound of formula (TM-1) with a derivative of the compound of formula (S-5) (1ad) or (1ae); S3. The compound of formula (TM-2) is converted into the compound of formula (TM-3); S4. The compound of formula (TM-4) is synthesized by reacting the compound of formula (TM-3) with the compound of formula (S-6); S5. The compound of formula (TM-4) is reduced in sodium borohydride to darolutamide of formula (TM-5); Step S1 comprises: S11. reacting a compound of formula (S-1) with formylpiperidine to synthesize 4-formyl-2-chlorobenzonitrile; S12. reacting 4-formyl-2-chlorobenzonitrile with (triphenylphosphine)acetaldehyde to synthesize a compound of formula (1ab), or reacting 4-formyl-2-chlorobenzonitrile with dimethyl (1-diazoethyl)phosphonate to synthesize a compound of formula (1ac); S13. reacting the compound of formula (1ab) with p-methylbenzenesulfonylhydrazide to synthesize a compound of formula (TM-1), or reacting the compound of formula (1ac) with trimethylsilylated diazomethane to synthesize a compound of formula (TM-1); Step S2 comprises: S211. reacting a compound of formula (S-5), triphenylphosphine, carbon tetrabromide, and anhydrous dichloromethane with stirring at 0±2°C for a period of time, and then stirring at room temperature until the reaction is complete; S212. filtering the mixture obtained in step S211, concentrating under reduced pressure, purifying, and drying to obtain a compound of formula (1ad); S213. reacting a compound of formula (TM-1), the compound of formula (1ad) obtained in step S212, Cs2CO3, and anhydrous N,N-dimethylformamide with stirring at 65±5°C while degassing, until the reaction is complete; S214. quenching the mixture obtained in step S213, extracting, drying the organic layer, concentrating under reduced pressure, purifying, and drying; or step S2 comprises: S221. At 0±2°C, triethylamine is slowly added dropwise to a system of the compound of formula (S-5), 4-dimethylaminopyridine, p-toluenesulfonyl chloride and anhydrous dichloromethane. After the addition is completed, the reaction is continued to stir at 0±2°C for a period of time, and then the reaction is stirred at room temperature until the reaction is completed; S222. The mixture obtained in step S221 is quenched, extracted, the organic layer is dried, concentrated under reduced pressure, purified, and dried to obtain the compound of formula (1ae); S223. The compound of formula (TM-1), the compound of formula (1ae) obtained in step S222, Cs2CO3 and anhydrous N,N-dimethylformamide are reacted under degassing and stirring at 55±5°C until the reaction is completed; S224. The mixture obtained in step S223 is quenched, extracted, the organic layer is dried, concentrated under reduced pressure, purified, and dried.

2. The method for synthesizing darolutamide of formula (TM-5) according to claim 1, characterized in that: Step S11 includes: S111. Under degassed conditions at 0±2°C, slowly add isopropylmagnesium chloride dropwise to a system of the compound of formula (S-1) and anhydrous tetrahydrofuran. After the addition is complete, continue stirring the reaction for a period of time. S112 to the reaction solution obtained in step S111 was slowly added dropwise formyl piperidine, after the addition was complete, the reaction was continued with stirring until the reaction was complete; S113. The mixture obtained in step S112 is quenched, extracted, the organic layer is dried, concentrated under reduced pressure, purified, and dried.

3. The method for synthesizing darolutamide of formula (TM-5) according to claim 1, characterized in that: Step S12 The method comprises: S1211 reacting 4-formyl-2-chlorobenzonitrile, (triphenylphosphine) acetaldehyde, and anhydrous tetrahydrofuran under degassed conditions at room temperature until the reaction is complete; S1212 filtering the mixture obtained in step S1211, concentrating under reduced pressure, purifying, and drying; Alternatively, the method may include: S1221. slowly adding dimethyl (1-diazoethyl)phosphonate dropwise to a system of 4-formyl-2-chlorobenzonitrile, K2CO3, and anhydrous methanol, and continuing to stir the reaction at room temperature until the reaction is complete; S1222. filtering the mixture obtained in step S1221, concentrating under reduced pressure, purifying, and drying.

4. The method for synthesizing darolutamide of formula (TM-5) according to claim 1, characterized in that: Step S13 The method comprises: S1311. reacting a compound of formula (1ab), p-toluenesulfonyl hydrazide, and anhydrous acetonitrile under degassing conditions and stirring at room temperature until the reaction is complete; S1312. adding NaOH to the mixture obtained in step S1311, and stirring the mixture at 85±5°C until the reaction is complete; S1313. concentrating the mixture obtained in step S1312 under reduced pressure, purifying, and drying; Or the method includes: S1321. Under degassing conditions, slowly dropwise adding trimethylsilylated diazomethane to a system of the compound of formula (1ac) and anhydrous tetrahydrofuran, and continuing the reaction at 100±5°C until the reaction is complete; S1322. Concentrating the mixture obtained in step S1321 under reduced pressure, purifying, and drying.

5. The method for synthesizing darolutamide of formula (TM-5) according to claim 1, characterized in that: Step S3 The method comprises: S311. slowly adding a solution of dichloromethane in trifluoroacetic acid to the compound of formula (TM-2) at 0±2°C, and continuing to stir the reaction until the reaction is complete; S312. quenching the mixture obtained in step S311, extracting the mixture, drying the organic layer, concentrating under reduced pressure, purifying, and drying the mixture; Or the method includes: S321. Under a nitrogen atmosphere, slowly dropwise adding HCl to a system of the compound of formula (TM-2) and ethanol. After the dropwise addition is completed, the reaction is continued at 65±5°C until the reaction is complete; S322. The mixture obtained in step S321 is quenched, extracted, and the organic layer is dried, concentrated under reduced pressure, purified, and dried.

6. The method for synthesizing darolutamide of formula (TM-5) according to claim 1, characterized in that: Step S4 includes: S41. Slowly add triethylamine dropwise to a system of the compound of formula (TM-3), the compound of formula (S-6), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenzotriazole, and anhydrous N,N-dimethylformamide under degassing conditions at 0±2°C. After the addition is complete, continue stirring at 0±2°C for a period of time, and then stir at room temperature until the reaction is complete. S42. The mixture obtained in step S41 is quenched, extracted, and the organic layer is dried, concentrated under reduced pressure, purified, and dried.

7. The method for synthesizing darolutamide of formula (TM-5) according to claim 1, characterized in that: Step S5 includes: S51. Slowly add NaBH4 dropwise to the mixture of the compound of formula (TM-4) and anhydrous ethanol at 0±2°C. Continue stirring the mixture until the reaction is complete. S52. The mixture obtained in step S51 is quenched, extracted, and the organic layer is dried, concentrated under reduced pressure, purified, and dried.

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