An improved method for preparing apalutamide

Abstract

This invention relates to apalutamide, a method for preparing compound (1) or its salts or solvates: the invention also relates to the solid form of apalutamide, apalutamide solvates, and methods for preparing them. The invention further relates to the solid form of intermediates used in the methods for preparing compound (1).

Description

[0001] This invention relates to an improved method for preparing compound of formula (1), namely apalutamide:

[0002]

[0003] The present invention also relates to an intermediate in solid form used in the method for preparing compound (1). The present invention also relates to apalutamide in solid form, a solvates of apalutamide, and methods for preparing the same. Background of the Invention

[0005] Apalutamide, compound of formula (1),

[0006]

[0007] Chemically, 4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide is an androgen receptor antagonist that can be used to treat non-metastatic castration-resistant prostate cancer.

[0008] Apalutamide was first disclosed by the University of California in WO2007126765A2. This application also describes a method for preparing apalutamide. The disadvantages of the disclosed method are the use of a toxic reagent (sodium cyanide) and the use of microwave heating, which is unsuitable for large-scale production. Several other methods for preparing apalutamide are disclosed in the prior art. The methods described by Aragon Pharmaceuticals in WO2016100652 and WO2016100645 are relatively lengthy and use toxic reagents (phosgene, sodium cyanide). The method disclosed by the Sloan-Kettering Institute for Cancer Research in WO2008 / 119015A2 also uses toxic reagents (sulfophosgene, sodium cyanide) and also uses microwave radiation, which is unsuitable for large-scale production. The method disclosed in ScinoPharm WO2018136001A1 and Olon WO2019229625A1 has the disadvantage of using an excess of 5-isothiocyano-3-(trifluoromethyl)methylpyridinium nitrile, which is a reactive compound. This, along with the relatively high reaction temperature, results in a relatively low purity of the product, which requires purification by column chromatography.

[0009] Therefore, there is a need for an improved method for preparing apalutamide that has a relatively short reaction time, good yield and purity of intermediates and apalutamide, does not contain toxic reagents, and does not require column chromatography to purify the intermediates or apalutamide.

[0010] Apalutamide in solid form is disclosed, for example, in Aragon Pharmaceuticals WO2013184681A1 or Watson Laboratories WO2018112001A1 or Mylan WO2019135254A1 or WO2019242439A1 (Crystal Pharmaceutical).

[0011] There is still a need for apalutamide in a solid form with improved properties (such as crystallinity or stability). Invention Overview

[0013] This invention relates to a method for preparing a compound of formula (1) (i.e., apalutamide), or a salt thereof;

[0014] include:

[0015] a. Reacting compound (2) with compound (3) in the presence of a nonnucleophilic base to obtain compound (4), wherein the pK of the conjugate acid formed by the nonnucleophilic base is... a The value is higher than 25.

[0016]

[0017] R1 is selected from C1-C6 alkyl or substituted C1-C6 alkyl or aryl or substituted aryl.

[0018] R2 is selected from alkyl or substituted alkyl or aryl or substituted aryl or C(O)R3 or C(O)OR3.

[0019] R3 is selected from C1-C6 alkyl or substituted C1-C6 alkyl or aryl or substituted aryl;

[0020] b. Convert compound (4) into compound (1).

[0021] The present invention also relates to a method for separating compound (1) or its solvates into solid form. The present invention also relates to the solid form of intermediates used in the method for preparing compound (1).

[0022] The present invention also relates to the solid form of apalutamide 2-propanol solvate, form 7, characterized in that the XRPD pattern has 2θ values ​​of 4.6°, 7.1°, 13.8° and 16.0°2θ (±0.2°2θ).

[0023] The present invention further relates to the solid form of apalutamide 1-methoxy-2-propanol solvate, form 5, characterized in that the XRPD pattern has 2θ values ​​of 4.7°, 7.1° and 13.9°2θ (±0.2°2θ).

[0024] The present invention also relates to apalutamide in solid form, form 3, characterized in that:

[0025] a. XRPD patterns have 2θ values ​​of 4.7°, 7.1°, 13.3°, 13.8°, and 14.2°2θ (±0.2°2θ); and

[0026] b. Endothermic DSC diagram, with an initial temperature of approximately 111.9°C-115.9°C and a peak temperature of approximately 118.6°C-120.3°C.

[0027] The present invention also relates to the solid form of apalutamide methyl isobutyl ketone solvate, form 6, characterized in that the XRPD pattern has 2θ values ​​of 3.8°, 6.9°, 8.8°, 16.2° and 20.8°2θ (±0.2°2θ).

[0028] Brief description of the attached figures

[0029] Figure 1 XRPD diagram of methyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-5-yl)-2-fluorobenzoate in solid form prepared according to Example 3.

[0030] Figure 2 XRPD diagram of the solid form of 1-((3-fluoro-4-(methoxycarbonyl)phenyl)amino)cyclobutane-1-carboxylic acid prepared according to Example 1.

[0031] Figure 3 XRPD image of methyl 2-fluoro-4-((1-(methoxycarbonyl)cyclobutyl)amino)benzoate in solid form prepared according to Example 2.

[0032] Figure 4 XRPD diagram of apalutamide solid form 3 prepared according to Example 5 or Example 6.

[0033] Figure 5 DSC chromatogram of apalutamide solid form 3 prepared according to Example 5 or Example 6.

[0034] Figure 6 TGA chromatogram of apalutamide solid form 3 prepared according to Example 5 or Example 6.

[0035] Figure 7 XRPD diagram of apalutamide 1-methoxy-2-propanol solvate solid form 5 prepared according to Example 7.

[0036] Figure 8: DSC diagram of apalutamide 1-methoxy-2-propanol solvate solid form 5 prepared according to Example 7.

[0037] Figure 9 TGA chromatogram of apalutamide 1-methoxy-2-propanol solvate solid form 5 prepared according to Example 7.

[0038] Figure 10 XRPD image of apalutamide methyl isobutyl ketone solvate solid form 6 prepared according to Example 8.

[0039] Figure 11 DSC chromatogram of solid form 6 of apalutamide methyl isobutyl ketone solvate prepared according to Example 8.

[0040] Figure 12 TGA image of solid form 6 of apalutamide methyl isobutyl ketone solvate prepared according to Example 8.

[0041] Figure 13 XRPD diagram of apalutamide 2-propanol solvate solid form 7 prepared according to Example 9 or Example 10.

[0042] Figure 14 DSC chromatogram of apalutamide 2-propanol solvate solid form 7 prepared according to Example 9 or Example 10.

[0043] Figure 15 TGA chromatogram of apalutamide 2-propanol solvate solid form 7 prepared according to Example 9 or Example 10.

[0044] Figure 16 NMR spectrum of apalutamide 1-methoxy-2-propanol solvate solid form 5 prepared according to Example 7.

[0045] Figure 17 NMR spectrum of apalutamide 2-propanol solvate solid form 7 prepared according to Example 9 or Example 10.

[0046] Figure 18 XRPD diagram of the solid form (type A) of compound (2A) prepared according to Example 12. Invention Details

[0048] In the following text, “compound (number)” refers to the compound of formula (number).

[0049] This invention relates to a method for preparing apalutamide, i.e., compound (1) or a salt thereof.

[0050]

[0051] include:

[0052] a. Reacting compound (2) with compound (3) in the presence of a nonnucleophilic base to obtain compound (4), wherein the pK of the conjugate acid formed by the nonnucleophilic base is... a Value higher than 25;

[0053]

[0054] R1 is selected from C1-C6 alkyl or substituted C1-C6 alkyl or aryl or substituted aryl.

[0055] R2 is selected from alkyl or substituted alkyl or aryl or substituted aryl or C(O)R3 or C(O)OR3.

[0056] R3 is selected from C1-C6 alkyl or substituted C1-C6 alkyl or aryl or substituted aryl;

[0057] b. Convert compound (4) into compound (1).

[0058] R1 and R2 are preferably selected from C1-C6 alkyl or substituted C1-C6 alkyl, and more preferably both are CH3. The non-nucleophilic base (i.e., a sterically hindered organic base of poor nucleophile) used in step a may be selected from lithium bis(trimethylsilyl)amino or sodium bis(trimethylsilyl)amino or potassium bis(trimethylsilyl)amino or sodium hydride or potassium hydride or lithium diisopropylamino or lithium diethylamino or lithium dicyclohexylamino or lithium 2,2,6,6-tetramethylpiperidinium or Hauser base ((R)2NMgX, where R may be selected, for example, isopropyl or cyclohexyl or 2,2,6,6-tetramethylpiperidinyl, and X represents a halide) or turbo-Hauser base ((R)2NMgX–LiCl, where R may be selected, for example, isopropyl or cyclohexyl or 2,2,6,6-tetramethylpiperidinyl, and X represents a halide), preferably lithium bis(trimethylsilyl)amino or sodium bis(trimethylsilyl)amino or potassium bis(trimethylsilyl)amino. We have surprisingly discovered that when using nonnucleophilic bases, the pK of the conjugate acid formed by the nonnucleophilic base increases. a When the value is above 25, the reaction can proceed under mild conditions, and compound (3) can be used in very low excess. The high excess of compound (3) used in the reaction, along with the high reaction temperature, results in the formation of impurities in compound (4), which requires purification before converting compound (4) to compound (1) and is difficult to purify.

[0059] The molar ratio between compound (3) and compound (2) can be between 1:1.1 and 1:2, preferably between 1:1.1 and 1:1.3, and more preferably between 1:1.02 and 1:1.04. The molar ratio between the nonnucleophilic base and compound (2) can be between 1:0.8 and 1:2, preferably between 1:0.9 and 1:1.5. Reaction step a can be carried out in a suitable solvent. The solvent can be selected from dimethylformamide (DMF), tetrahydrofuran, or 2-methyltetrahydrofuran, or mixtures thereof, preferably tetrahydrofuran. Reaction step a can be carried out under a protective atmosphere, such as argon or nitrogen.

[0060] Compound (2) is mixed with the solvent or solvent mixture used. The mixture can then be cooled, for example to -10°C to 15°C, preferably to -10°C to 12°C. A nonnucleophilic base is added to the mixture. The nonnucleophilic base can be added in solution form in a suitable solvent, such as tetrahydrofuran used in the reaction, or it can be added in solid form. The nonnucleophilic base can be added in portions, for example in 2, 3, 4, 5, or 6 portions. If the nonnucleophilic base is used in solution form, it can be added dropwise. When adding the base, the temperature of the mixture is preferably maintained between 0°C and 15°C, preferably between 0°C and 5°C. After adding the base, the mixture can be stirred at a temperature of -10°C to 15°C, preferably between -10°C and 0°C, for 5 to 60 minutes. Then a solution of compound (3) is added to the mixture. Compound (3) can be dissolved, for example, in a solvent used in the reaction, such as tetrahydrofuran. The solution of compound (3) may be added in several parts, for example, in 2, 3, 4, 5, or 6 parts, preferably dropwise. When adding compound (3), the temperature of the mixture may preferably be maintained between -10°C and 15°C, more preferably between -10°C and 0°C, and the mixture may optionally be stirred at this temperature for 5 to 120 minutes, preferably 5 to 30 minutes. The reaction process may be monitored by suitable analytical techniques (e.g., by HPLC or GC).

[0061] After the reaction is complete, a water-immiscible organic solvent, such as diethyl ether or methyl tert-butyl ether, is added to the mixture. The addition of the immiscible solvent improves the treatment of the mixture in subsequent steps. The volume ratio between the solvent used in step a and the water-immiscible organic solvent can be between 1.5:1 and 2.5:1, preferably between 1.6:1 and 2:1. An acid, such as an aqueous solution of hydrochloric acid, is added to the mixture. The molar ratio between the acid and compound (2) can be between 1:2 and 1:5. The temperature of the mixture is kept below 20°C when the acid is added. Phase separation. The step of washing the organic phase with an aqueous solution of acid can be repeated, for example, 2 or 3 times. The organic phase can then be treated with activated carbon for 20 to 120 minutes. The weight ratio between compound (2) and activated carbon can be between 15:1 and 25:1. After treatment, the mixture is filtered. A water-immiscible solvent, such as an alcohol, such as ethanol or 1-propanol or 2-propanol or 2-butanol or isobutanol or 1-butanol, preferably 2-propanol, is added to the filtrate. The volume ratio between the added solvent and the solvent used in step a can be between 1:1 and 1:1.3. The mixture is concentrated to approximately half its original volume at an elevated temperature and cooled to a temperature between 20°C and 25°C to obtain a suspension. The suspension is stirred at a temperature between 20°C and 25°C for 30 to 180 minutes. The mixture is filtered and the resulting solid compound is dried (4).

[0062] Compound (4) can also be separated by the following method. After the reaction is complete, the reaction mixture is cooled to a temperature between -10°C and -5°C. An acid, such as HCl, is added to the mixture. The concentration of the acid can be between 0.04 g / ml and 0.15 g / ml. The molar ratio between the acid and compound (2) can be between 1.8:1 and 3:1, preferably between 2:1 and 2.5:1. The mixture is heated to a temperature between 25°C and 35°C and the phases are separated. The organic phase is washed with a 20% aqueous solution of NaCl (the volume ratio of NaCl solution to organic phase is approximately 3:1) and separated into layers. The organic layer is concentrated to half its original volume, and the solvent is converted to methanol by sequential addition and distillation of methanol. The mixture is then concentrated to half its original volume. Isopropanol is added to the mixture. The weight ratio between the added isopropanol and the methanol used for solvent switching can be between 1:2 and 1:3, preferably between 1:2.5 and 1:2.8. The mixture is heated to reflux and stirred at this temperature for 15–45 minutes. The mixture is cooled to a temperature between -10°C and 0°C and stirred at this temperature for 20–60 minutes to obtain a suspension. The suspension is filtered out, and the filter cake may optionally be washed with a suitable solvent, such as an aqueous methanol solution, and dried to provide compound (4).

[0063] Compound (4) can be further purified by crystallization from a solvent selected from 1-propanol, 2-propanol, 2-butanol, isobutanol, or 1-butanol, preferably 2-propanol. Compound (4) is mixed with a solvent. The concentration of compound (4) in the solvent can be between 0.06 g / ml and 0.2 g / ml, preferably between 0.08 g / ml and 0.15 g / ml. The mixture can be heated, preferably to the reflux temperature of the solvent used, to dissolve compound (4). The mixture is then cooled to a temperature between 50°C and 80°C and stirred at this temperature for 1 to 10 hours. The mixture is then cooled to a temperature between 20°C and 25°C and stirred at this temperature for 2 to 15 hours. The resulting solid compound (4) is then filtered and optionally dried.

[0064] When R1 is CH3, compound (4) corresponds to the following formula:

[0065]

[0066] The obtained solid forms can be characterized by XRPD patterns with 2θ values ​​of 4.8°, 7.1°, and 15.9°2θ (±0.2°2θ). Solid forms can also be characterized by XRPD patterns with 2θ values ​​of 4.8°, 7.1°, 10.9°, 14.4°, and 15.9°2θ (±0.2°2θ). Solid forms can be further characterized by the XRPD patterns described in the table below:

[0067]

[0068] The solid form can also be obtained through Figure 1 The XRPD pattern shown is used to characterize it.

[0069] Compound (4) can be converted into compound (1), namely apalutamide, for example by a method comprising reacting compound (4) with methylamine or a salt thereof. This reaction can be carried out in a suitable solvent, such as tetrahydrofuran (THF) or 2-methyltetrahydrofuran (2-MeTHF). Methylamine or a salt thereof can be used in the form of an aqueous solution, for example, a 10%, 20%, 30%, 40%, or 50% solution. The concentration of compound (4) in the solvent can be between 0.3 g / ml and 1 g / ml, preferably between 0.3 g / ml and 0.5 g / ml. The molar ratio between compound (4) and methylamine or a salt thereof can be between 1:20 and 1:30, preferably between 1:23 and 1:27.

[0070] Compound (4) is mixed with a solvent, and the mixture is slowly added to methylamine or a solution thereof at a temperature of -10°C to 10°C, i.e., over 5, 10, 20, 30, 40, 50, or 60 minutes or dropwise. The mixture is stirred at the same temperature for 2 to 5 hours. The reaction process can be monitored by suitable analytical techniques (e.g., by HPLC or GC). After the reaction is complete, a solution of acid in alcohol is added to the mixture, for example, a solution of 6M HCl in isopropanol or a solution of acetic acid in water. The concentration of acetic acid in water can be from 1 g / ml to 2 g / ml, preferably from 1.1 g / ml to 1.5 g / ml. The molar ratio between the acid (preferably HCl or acetic acid) and the compound of formula (4) can be from 20:1 to 30:1, preferably from 23:1 to 27:1. In the case of using HCl during the addition, a suspension is formed. The suspension can be stirred for 10 to 60 minutes and filtered. The obtained solid can optionally be dried to provide compound (1).

[0071] When using acetic acid, the acid is added slowly, for example over a period of 15 to 40 minutes. During the addition, the temperature of the mixture is maintained between 0°C and 20°C. After the acid is added, the mixture is heated to a temperature of 25°C to 30°C. The phases are separated, and an aqueous solution of a carbonate, such as sodium carbonate or potassium carbonate, is added to the organic phase. The phases are separated again, and an aqueous solution of a carbonate, such as sodium carbonate or potassium carbonate, is added to the organic phase. An aqueous solution of acetic acid is added to the organic phase. The concentration of acetic acid can be 1 to 3% (wt / wt). The weight ratio between the added acetic acid and compound (4) can be between 1.9:1 and 2.5:1, preferably between 1.9:1 and 2.2:1. The mixture is heated to 55°C to 65°C, and 2-propanol is added. The weight ratio between 2-propanol and the added acetic acid can be between 1:2 and 1:3, preferably between 1:2.2 and 1:2.8. The phases are separated again, and 2-propanol is added to the organic phase. The weight ratio between the added 2-propanol and the 2-propanol added in the previous step can be between 6.5:1 and 7:5:1. The mixture is heated to reflux and stirred at this temperature for 10 to 45 minutes. The mixture is cooled to a temperature of -10°C to 0°C over 2 to 4 hours. At this temperature, the mixture is stirred for 20 to 60 minutes, the solids are filtered off, optionally washed with cold 2-propanol, and dried to obtain apalutamide, compound (1), preferably in solid form 7.

[0072] Compound (2) can be prepared by a method comprising reacting compound (5) with an acid and an alcohol R2OH, wherein R2 can be selected from alkyl or substituted alkyl or aryl or substituted aryl or C(O)R3 or C(O)OR3, and R3 can be selected from C1-C6 alkyl or substituted C1-C6 alkyl or aryl or substituted aryl:

[0073]

[0074] R1 is selected from C1-C6 alkyl or substituted C1-C6 alkyl or aryl or substituted aryl, preferably CH3.

[0075] The acid may be selected from, for example, sulfuric acid or toluenesulfonic acid. The alcohol may be selected from methanol or ethanol or propanol or 2-propanol or butanol, preferably methanol. The compound (5) is mixed with the alcohol. The concentration of compound (5) in the alcohol may be between 0.1 g / ml and 0.3 g / ml, preferably between 0.12 g / ml and 0.25 g / ml. The acid is slowly added to the mixture, for example in 2, 3, 4, 5 or 6 parts, preferably dropwise. The mixture is then heated to 50°C to the reflux temperature of the solvent used, and stirred at this temperature for 2 to 10 hours, preferably 3 to 6 hours. The reaction process can be monitored by suitable analytical techniques (e.g., by HPLC or GC). After the reaction is complete, the mixture is cooled to 15°C to 30°C, preferably 20°C to 35°C, more preferably 30°C to 35°C. An aqueous solution of alkali is slowly added to the mixture, preferably over a period of 10 to 120 minutes. As a base, hydroxides such as sodium hydroxide or potassium hydroxide, carbonates such as sodium carbonate or potassium carbonate, bicarbonates such as sodium bicarbonate or potassium bicarbonate, or organic bases such as trimethylamine, triethylamine, or diisopropylethylamine can be used. Triethylamine or sodium carbonate is preferred. When a hydroxide such as sodium hydroxide or potassium hydroxide, a carbonate such as sodium carbonate or potassium carbonate, or a bicarbonate such as sodium bicarbonate or potassium sodium bicarbonate is used as the base, the molar ratio between acid and base can be between 0.5:1 and 1:1, preferably 1:1. When using an organic base, preferably triethylamine, the concentration of the base in water can be between 0.4 g / ml and 0.8 g / ml, and the molar ratio between acid and base can be between 1:3 and 1:5, preferably between 1:3 and 1:4.

[0076] Optionally, the mixture can be cooled to a temperature between -10°C and 0°C. The mixture is stirred for 30 to 180 minutes. The resulting suspension is filtered out and the resulting compound can be dried (2).

[0077] When both R1 and R2 are CH3, compound (2) corresponds to the following formula:

[0078]

[0079] The obtained solid forms can be characterized by XRPD plots with 2θ values ​​of 10.2°, 14.5°, and 17.4°2θ (±0.2°2θ). Solid forms can also be characterized by XRPD patterns with 2θ values ​​of 10.2°, 14.5°, 15.2°, 17.4°, and 19.0°2θ (±0.2°2θ). Solid forms can be further characterized by the XRPD patterns described in the table below:

[0080]

[0081] The solid form can also be obtained through Figure 3 The XRPD pattern shown is used to characterize it.

[0082] Compound (5) can be prepared by reacting compound (6) and compound (7) or their salts under a protective gas atmosphere, wherein the protective gas optionally flows over the reaction mixture:

[0083]

[0084] R1 is selected from C1-C6 alkyl or substituted C1-C6 alkyl or aryl or substituted aryl, preferably CH3.

[0085] Compounds (6) and (7) are commercially available.

[0086] The reaction can be carried out in a suitable solvent, such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), or dimethylacetamide (DMAC), with DMSO or DMAC being preferred. Compound (7) can be used in the form of a salt, such as an HCl salt. The molar ratio between compound (6) and compound (7) can be between 1:1.3 and 1:2, preferably between 1:1.4 and 1:1.6. The concentration of compound (6) in the solvent can be between 0.1 g / ml and 0.4 g / ml, preferably between 0.25 g / ml and 0.35 g / ml. The concentration of compound (7) in the solvent can be between 0.1 g / ml and 0.35 g / ml, preferably between 0.25 g / ml and 0.31 g / ml. The reaction is carried out in the presence of a base such as a hydroxide such as sodium hydroxide or potassium hydroxide, or a carbonate such as sodium carbonate or potassium carbonate, or sodium bicarbonate such as sodium bicarbonate or potassium sodium bicarbonate. Potassium carbonate is preferred. The reaction is carried out in the presence of a catalyst such as CuCl or CuBr or Cu acetate, preferably CuCl. The molar ratio between the base and compound (6) can be between 2:1 and 5:1, preferably between 2.5:1 and 3.5:1. The molar ratio between the catalyst and compound (6) can be between 0.15:1 and 0.4:1, preferably between 0.2:1 and 0.3:1. The reaction is carried out under a protective gas, such as nitrogen or argon. We have unexpectedly found that the reaction time can be significantly shortened when the protective gas flows over the reaction mixture (compared to when the protective gas remains over the mixture). The protective atmosphere optionally flows over the reaction mixture, i.e., it enters the space above the reaction mixture at a defined rate at a first position and exits the space above the reaction mixture at another position. The rate can be between 1 and 100 liters per minute (L / min), preferably between 10 and 100 L / min, more preferably between 30 and 60 L / min. Compounds (6) and (7) are mixed with a base and a catalyst in a solvent. The resulting mixture is stirred for 2 to 6 hours under a protective gas stream at a temperature from 80°C to the reflux temperature of the solvent used. The reaction process can be monitored by suitable analytical techniques (e.g., by HPLC or GC). After the reaction is complete, the mixture is cooled to a temperature between -20°C and 10°C. Water or an aqueous solution of an acid is added to the mixture. The acid can be selected from, for example, HCl, phosphoric acid, or formic acid, with HCl being preferred. The concentration of the acid in the water can be between 0.1 g / ml and 0.5 g / ml, preferably between 0.15 g / ml and 0.25 g / ml. The volume ratio between water and the solvent used in the reaction can be between 1.8:1 and 3:1. The volume ratio between the aqueous solution of the acid and the solvent used in the reaction can be between 1.5:1 and 3:1, preferably between 1:1.5 and 1:2. The aqueous solution of the acid or water is added slowly, for example over 5, 10, 20, 30, or 40 minutes.During the addition process, the temperature of the mixture should be maintained below 22°C. Set the temperature of the mixture to 10°C to 25°C and adjust the pH of the mixture to 2.4–2.6 using, for example, hydrochloric acid (HCl). Stir the mixture for 20 to 60 minutes to obtain a suspension. Filter the obtained suspension and wash the filtered solids with an aqueous solution of acid (e.g., with 0.01M HCl solution) and optionally dry them.

[0087] The obtained solid can be purified, for example, by a method comprising dissolving the solid in a mixture of acetate and alcohol and washing the mixture with an aqueous solution of acid. The concentration of the solid in the mixture can be between 0.05 g / ml and 0.3 g / ml, preferably between 0.09 g / ml and 0.15 g / ml. The acetate can be selected, for example, methyl acetate or ethyl acetate or propyl acetate or butyl acetate or mixtures thereof. The alcohol can be selected, for example, methanol or ethanol or propanol or 2-propanol or isopropanol or butanol or tert-butanol or mixtures thereof. The volume ratio between the acetate and alcohol can be between 8:1 and 12:1. The volume ratio between the mixture of acetate and alcohol and the aqueous solution of acid can be between 1:1 and 2:1, preferably between 1.3:1 and 1.7:1. Phase separation. The organic phase can be distilled off to obtain the solid compound (5), or the compound (5) can be separated by using the following steps. The obtained organic phase is mixed with a solvent, preferably toluene. The volume ratio between the solvent and the acetate / alcohol mixture can be between 1:1 and 1:1.5. Optionally, the resulting mixture may be heated to a temperature of 50°C to 80°C to obtain a solution. In the case of a two-phase system, the phases are separated. The organic phase is concentrated to 35-45% of its original volume. The mixture is cooled to a temperature of 20°C to 25°C and stirred at this temperature for 3 to 15 hours to obtain a suspension. The solid compound (5) is filtered off and optionally dried.

[0088] When R1 is CH3, compound (5) corresponds to the following formula:

[0089]

[0090] The resulting solid forms can be characterized by XRPD plots with 2θ values ​​of 5.2°, 10.4°, and 17.3°2θ (±0.2°2θ). The solid forms can also be characterized by XRPD patterns with 2θ values ​​of 5.2°, 10.4°, 17.1°, 17.3°, and 21.5°2θ (±0.2°2θ). The solid forms can be further characterized by the XRPD patterns described in the table below:

[0091]

[0092] The solid form can also be obtained through Figure 2 The XRPD pattern shown is used to characterize it.

[0093] The present invention also relates to the solid form of apalutamide 2-propanol solvate, form 7, characterized by an XRPD pattern having 2θ values ​​of 4.6°, 7.1°, 13.8°, and 16.0°2θ (±0.2°2θ). Form 7 can be further characterized by an XRPD pattern having 2θ values ​​of 4.6°, 7.1°, 10.7°, 13.8°, 16.0°, 18.5°, and 20.1°2θ (±0.2°2θ). Form 7 can be further characterized by the XRPD 2θ values ​​(±0.2°2θ) as shown in the table below:

[0094]

[0095]

[0096] Form 7 can also be achieved through Figure 13 The XRPD pattern shown or Figure 14 The DSC chart shown or Figure 15 The TGA diagram shown or Figure 17 The NMR spectrum shown is used to characterize it.

[0097] Form 7 can be prepared by methods including the following:

[0098] a. Dissolve apalutamide in 2-propanol;

[0099] b. Separate solid form.

[0100] The concentration of apalutamide in 2-propanol can be between 0.04 g / ml and 0.06 g / ml. Apalutamide can optionally be dissolved at a temperature of 60°C to 75°C. The mixture of apalutamide and 2-propanol can be stirred (optionally heated to 60°C-75°C) for 30 to 120 minutes to dissolve apalutamide. The mixture is then cooled to a temperature of 15°C to 25°C and stirred at this temperature for 5 to 15 hours. The solids are filtered off and optionally dried, for example, in air for 2 to 10 hours, to provide the apalutamide 2-propanol solvate, form 7.

[0101] Form 7 can also be prepared by methods including the following:

[0102] a. A slurry (a mixture of solid apalutamide and 2-propanol) is prepared by mixing apalutamide with 2-propanol;

[0103] b. Separate solid form.

[0104] The concentration of apalutamide in 2-propanol can be between 0.04 g / ml and 0.06 g / ml. Preferably, apalutamide is mixed with 2-propanol at a temperature of 15°C to 25°C. The mixture is stirred for 10 to 20 hours. The solid is filtered off and optionally dried, for example, in air for 2 to 10 hours, to provide the apalutamide 2-propanol solvate, form 7.

[0105] Form 7 can also be prepared by methods including the following:

[0106] a. Dissolve compound (1) in a mixture of 2-propanol and methanol, wherein the weight ratio of 2-propanol to methanol may be between 1:0.4 and 1:0.8;

[0107] b. Optionally, cool the mixture;

[0108] c. Separate the form of compound (1) 7.

[0109] The concentration of compound (1) in a mixture of 2-propanol and methanol can be between 0.06 g / ml and 0.1 g / ml, preferably between 0.075 g / ml and 0.085 g / ml. Compound (1) can be dissolved at elevated temperatures, preferably at the reflux temperature of the solvent mixture. After dissolution, the mixture is optionally cooled, preferably to -10°C to 45°C, more preferably to -10°C to 25°C. In the most preferred embodiment of the invention, the mixture is cooled to a temperature between -10°C and 0°C. The mixture is preferably cooled over a period of 1 to 5 hours. The mixture is then stirred at this temperature for 20 to 45 minutes. The solid is filtered off, optionally washed with cold 2-propanol and dried to give compound (1) in solid form 7.

[0110] This invention further relates to the solid form of apalutamide 1-methoxy-2-propanol solvate, form 5, characterized by an XRPD pattern having 2θ values ​​of 4.7°, 7.1°, and 13.9°2θ (±0.2°2θ). Form 5 can be further characterized by an XRPD pattern having 2θ values ​​of 4.7°, 7.1°, 9.3°, 10.7°, 13.9°, and 16.0°2θ (±0.2°2θ). Form 5 can be further characterized by the XRPD 2θ values ​​(±0.2°2θ) as shown in the table below:

[0111] Angle (2θ) strength(%) Angle (2θ) strength(%) Angle (2θ) strength(%) 4.7 90.7 20.4 7.0 27.5 3.9 7.1 26.9 21.2 8.8 27.9 4.5 9.3 22.6 21.8 11.1 28.3 8.1 10.7 19.5 22.5 11.6 29.7 4.0 13.9 100.0 22.8 6.0 29.9 6.5 14.9 7.8 23.2 3.9 30.1 4.5 16.0 21.5 23.8 9.7 30.7 5.3 16.6 10.3 24.2 12.0 31.9 3.6 18.4 21.5 24.4 14.9 32.5 4.5 18.5 21.7 24.8 10.1 34.2 4.7 19.2 4.0 26.1 14.6 34.7 3.4 19.9 15.3 26.8 5.0

[0112] Form 5 can also be achieved through Figure 7 The XRPD pattern shown in Figure 8 or the DSC diagram shown in Figure 8 or Figure 9 The TGA diagram shown or Figure 16 The NMR spectrum shown is used to characterize it.

[0113] Solid form 5 can be prepared by methods including the following:

[0114] 1. Contact amorphous apalutamide with 1-methoxy-2-propanol;

[0115] 2. Separate solid forms.

[0116] The concentration of apalutamide in 1-methoxy-2-propanol can be between 0.08 g / ml and 0.15 g / ml. The mixture is stirred at 20°C to 30°C for 2 to 6 hours. The solids are filtered off and optionally dried to provide apalutamide 1-methoxy-2-propanol solvate, form 5.

[0117] The present invention also relates to apalutamide in solid form, form 3, characterized in that:

[0118] a. XRPD patterns have 2θ values ​​of 4.7°, 7.1°, 13.3°, 13.8°, and 14.2°2θ (±0.2°2θ); and

[0119] b. Endothermic DSC diagram, with an initial temperature of approximately 111.9°C-115.9°C and a peak temperature of approximately 118.6°C-120.3°C.

[0120] The features of form 3 also include:

[0121] a. XRPD patterns have 2θ values ​​of 4.7°, 7.1°, 9.4°, 10.8°, 13.3°, 13.8°, 14.2°, and 16.2°2θ (±0.2°2θ); and

[0122] b. The DSC plot has a first peak and a second peak. The first peak is endothermic, with an initial temperature of approximately 71.2°C-87.5°C and a peak temperature of approximately 78.7°C-90.5°C. The second peak has an initial temperature of approximately 111.9°C-115.9°C and a peak temperature of approximately 118.6°C-120.3°C.

[0123] Form 3 can be further characterized by the XRPD 2θ values ​​(±0.2°2θ) in the table below:

[0124] Angle (2θ) strength(%) Angle (2θ) strength(%) Angle (2θ) strength(%) 4.7 100.0 16.7 19.7 24.7 10.6 7.1 34.1 17.1 14.3 25.0 11.4 9.4 4.8 18.3 20.6 26.1 12.6 10.8 7.9 20.2 16.8 26.8 8.2 11.6 3.8 20.5 6.8 27.9 6.0 13.3 13.6 21.4 14.5 30.1 7.2 13.8 17.4 21.9 7.3 30.4 6.7 14.2 26.3 22.5 10.0 31.4 4.2 15.1 6.5 23.4 5.5 32.8 4.9 16.2 19.0 24.3 8.8

[0125] Form 3 can also be achieved through Figure 4 The XRPD diagram shown or Figure 5 The DSC chart shown or Figure 6 The TGA diagram shown is used to characterize it.

[0126] Form 3 can be prepared by methods including the following:

[0127] a. Mixing amorphous apalutamide with water to prepare a slurry (a mixture of solid apalutamide and water);

[0128] b. Separate solid form.

[0129] The concentration of apalutamide in water can be between 0.08 g / ml and 0.15 g / ml. The mixture is stirred at 15°C to 30°C for 1 to 5 hours. The solids are filtered off and optionally dried to provide solid form 3.

[0130] Solid form 3 can also be obtained by exposing apalutamide crystal form 7 or crystal form 5 to a temperature of 40°C to 60°C and a humidity of 75% to 90% relative humidity for 30 to 40 days.

[0131] Form 3 was tested for 6 months at high humidity (75% RH / 40°C) or for 1 month at 90% RH / 55°C. The XRPD pattern remained unchanged after testing. Therefore, Form 3 is very stable under these conditions. When Form A (disclosed in WO2013184681A1) of the prior art was tested under the same conditions, the crystal structure changed during the test.

[0132] The present invention also relates to a solid form of apalutamide methyl isobutyl ketone solvate, form 6, characterized in that the XRPD pattern has 2θ values ​​of 3.8°, 6.9°, 8.8°, 16.2°, and 20.8°2θ (±0.2°2θ). Form 6 can be further characterized by an XRPD pattern having 2θ values ​​of 3.8°, 6.9°, 7.7°, 8.8°, 15.4°, 16.2°, and 20.8°2θ (±0.2°2θ).

[0133] Form 6 can be further characterized by the XRPD 2θ values ​​(±0.2°2θ) as shown in the table below:

[0134]

[0135]

[0136] Form 6 can also be achieved through Figure 10 The XRPD diagram shown or Figure 11 The DSC chart shown or Figure 12 The TGA diagram shown is used to characterize it.

[0137] Form 6 can be prepared by methods including the following:

[0138] 1. Contact amorphous apalutamide with methyl isobutyl ketone;

[0139] 2. Separate solid forms.

[0140] The concentration of apalutamide in methyl isobutyl ketone can be between 0.14 mg / g and 0.18 mg / g. The mixture is heated to a temperature of 55°C to 70°C and stirred at this temperature for 120 minutes. The mixture is then cooled to a temperature of 20°C to 30°C and stirred at this temperature for 5 to 12 hours. The solids are filtered off and optionally dried to provide solid form 6.

[0141] The present invention will be further illustrated by the following examples. Example

[0142] Example 1: Preparation of compound (R1:CH3) of formula (5), 1-((3-fluoro-4-(methoxycarbonyl)phenyl)amino)cyclobutane Alkyl-1-carboxylic acid

[0143]

[0144] Mix 20 g of methyl 4-bromo-2-fluorobenzoate with 19.51 g of 1-amino-cyclobutane-1-carboxylate, 35.6 g of potassium carbonate, 2.124 g of copper chloride (I), and 120 ml of dimethylformamide (DMF). Stir the mixture under a strong argon flow (10 L / min) and heat it to 100–110 °C. Stir the mixture for 4 hours.

[0145] Then, cool the mixture to 20–25°C, then to 0–5°C. Add 240 ml of water to the mixture within 2 minutes. Cool the mixture to 10–15°C. Add concentrated (35%) HCl aqueous solution to adjust the pH to 2.5. Collect the solid formed by filtration, wash with 50 ml of 0.01 M HCl aqueous solution and vacuum dry for 20 minutes. Dissolve the obtained solid in a mixture containing 250 ml of ethyl acetate and 25 ml of methanol. Wash the mixture with 200 ml of 0.01 M HCl aqueous solution. Separate the phases. Add 250 ml of toluene to the organic phase. Heat the mixture to 60°C. A two-phase system appears. Separate the phases and concentrate the organic phase (60°C, 300 -> 200 mbar) to a volume of 200 g to obtain a suspension.

[0146] The hot suspension was cooled to 20-25°C and stirred overnight. The solid was filtered, washed with 50 ml of toluene, and dried (stripped at 45°C, 100 Torr, N2 for 4 hours). 17.1 g (74% of theoretical yield) of 1-((3-fluoro-4-(methoxycarbonyl-)phenyl)amino)cyclobutane-1-carboxylic acid with a purity of 99.67% (HPLC IN, 277 nm) was obtained.

[0147] The XRPD of the obtained solid corresponds to Figure 2 The XRPD diagram shown is shown below.

[0148] Example 2: Preparation of compound (R1:CH3, R2:CH3), 2-fluoro-4-((1-(methoxycarbonyl)cyclobutyl) Methyl aminobenzoate

[0149]

[0150] 10.4 g of 1-((3-fluoro-4-(methoxycarbonyl)phenyl)amino)cyclobutane-1-carboxylic acid was suspended in 66 mL of methanol. 2.161 mL of concentrated sulfuric acid (96%) was added dropwise.

[0151] The mixture was then heated to reflux and stirred for 4 hours. The mixture was cooled to 20–25°C. A solution of 4.12 g sodium carbonate in 66 ml of water was slowly added over 10 minutes to maintain a gentle CO2 release. The mixture was then stirred at 20–25°C for 1 hour. The resulting solid was collected by filtration, washed with 30 ml of water, and dried (45°C, 100 Torr, N2 stripping, 16 hours). 10.6 g (96% of theoretical yield) of methyl 2-fluoro-4-((1-(methoxycarbonyl)cyclobutyl)amino)benzoate was obtained with a purity of 99.26% (HPLC in, 277 nm).

[0152] The obtained solid XRPD pattern corresponds to Figure 3 The XRPD diagram shown.

[0153] Example 3: Preparation of compound (R1:CH3) of formula (4), 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8- methyl oxo-6-thio-5,7-diazaspiro[3.4]oct-5-yl)-2-fluorobenzoate

[0154]

[0155] Mix 10 g of methyl 2-fluoro-4-((1-(methoxycarbonyl)cyclobutyl)amino)benzoate with 50 ml of tetrahydrofuran (THF). Cool the mixture to 8-12°C. Add 26.1 ml of bis(trimethylsilyl)aminolithium (LiHMDS) (1.5 M THF solution) dropwise. Maintain the temperature at 8-12°C. Stir the mixture at 8-12°C for 5 minutes, then add 8.96 g of 5-isothiocyano-3-(trifluoromethyl)pyridinium nitrile solution in 15 ml of THF, while maintaining the temperature at 8-12°C. After addition, cool the mixture to 0-5°C and stir for 30 minutes. Dilute the mixture with 50 ml of methyl tert-butyl ether. Cool it again to 0-5°C and add 50 ml of 1 M HCl aqueous solution, keeping the temperature below 20°C.

[0156] Separate the phases and wash the organic phase twice with 50 ml of 1M HCl aqueous solution. Add 500 mg of activated charcoal to the organic phase. Stir the mixture for 30 minutes. Filter the mixture and mix the filtrate with 100 ml of 2-propanol. Concentrate the mixture (70°C, 400 mbar) to 80 g. Cool the mixture to room temperature with stirring (700 rpm) to obtain a suspension. Stir the mixture at 20–25°C for 1 hour. The solid was collected by filtration, washed twice with 15 ml of cold (<10 °C) 2-propanol, dried by suction for 20 minutes, and then dried (20-25 °C, 100 Torr, N2 stripping, over the weekend; then 80 °C, 100 Torr, nitrogen stripping) to obtain 13.85 g of methyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-5-yl)-2-fluorobenzoate (81% of theoretical yield) with a purity of 99.21% (HPLC in, 275 nm).

[0157] The obtained solid material was refluxed and dissolved in 140 ml of 2-propanol with stirring. The mixture was cooled to 75 °C and stirred at this temperature for 2 hours. The mixture was cooled to 20-20 °C and stirred overnight. The solid was collected by filtration (glass frit, S3), washed twice with 15 ml of cold (<10 °C) 2-propanol, and dried (80 °C, 100 Torr, N2 stripping, 2 hours). 13.70 g (80% of theoretical yield) of methyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-5-yl)-2-fluorobenzoate (purity 99.62% (HPLC, 275 nm)).

[0158] The obtained solid XRPD pattern corresponds to Figure 1 The XRPD diagram shown.

[0159] Example 4: Preparation of apalutamide, compound of formula (1)

[0160]

[0161] Over 10 minutes, a mixture of 3 g of methyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-5-yl)-2-fluorobenzoate in 5 ml of tetrahydrofuran was added to 14.47 ml of pre-cooled (0–4 °C) aqueous methylamine solution (40% solution) while maintaining the temperature of the reaction mixture at 0–2 °C. The resulting solution was stirred at 0 °C for another 2 hours. The reaction was quenched with a solution of 26 ml of 6 M HCl in isopropanol, and precipitation occurred. The solid formed was collected by filtration, washed with 10 ml of water, dried by air suction, and then dried in a vacuum desiccator (80 °C, 100 Torr, N2 stripping, 16 h). 2.62 g of apalutamide (86% of theoretical yield) was obtained with a purity of 98.15% (HPLC, 1N, 275 nm).

[0162] Example 5: Preparation of apalutamide in solid form, form 3

[0163] Mix 1 g of amorphous apalutamide with 10 ml of water. Stir the suspension at 20–25 °C for 1 hour and filter. Vacuum dry the solid at 60 °C for 18 hours to provide apalutamide form 3 in quantitative (almost 100%) yield.

[0164] The obtained solid XRPD pattern corresponds to Figure 4 The XRPD plot is shown. The DSC plot of the obtained solid corresponds to... Figure 5 The DSC plot is shown. The TGA plot of the obtained solid corresponds to... Figure 6 The TGA pattern shown.

[0165] Example 6: Preparation of apalutamide in solid form, form 3

[0166] APM form 7 was exposed to 40°C and 75% relative humidity (or 55°C / 90% relative humidity) for 1 month to provide apalutamide in solid form 3. The resulting solid XRPD pattern corresponds to Figure 4 The XRPD pattern shown. The DSC pattern of the resulting solid corresponds to... Figure 5 The DSC pattern shown. The TGA pattern of the obtained solid corresponds to... Figure 6 The TGA pattern shown.

[0167] Example 7: Preparation of apalutamide 1-methoxy-2-propanol solvate in solid form, form 5

[0168] 1 g of amorphous apalutamide was mixed with 8 ml of 1-methoxy-2-propanol. The reaction mixture was stirred at 25–27 °C for 3 hours. The suspension was filtered, the filter cake was washed with 1 ml of 1-methoxy-2-propanol, and dried in a vacuum desiccator (25 °C, 130 mbar, N2 stripping, 2 hours) to provide 0.71 g of apalutamide 1-methoxy-2-propanol solvate in solid form. The XRPD plot of the obtained solid corresponds to... Figure 7 The XRPD pattern shown is given. The DSC pattern of the resulting solid corresponds to the DSC pattern shown in Figure 8. The TGA pattern of the resulting solid corresponds to... Figure 9 The TGA pattern shown.

[0169] Example 8: Preparation of solid form, form 6, of apalutamide methyl isobutyl ketone solvate.

[0170] 50 mg of amorphous apalutamide was mixed with 305 mg of methyl isobutyl ketone. The mixture was heated to 60 °C, cooled to 25–27 °C, and stirred at 25–27 °C for 10 hours. The suspension was filtered, and the filter cake was dried in a vacuum desiccator (25 °C, 130 mbar, N2 stripping, 2 hours) to provide 63 mg of apalutamide methyl isobutyl ketone solvate in solid form. The XRPD plot of the obtained solid corresponds to... Figure 10 The XRPD pattern shown. The DSC pattern of the resulting solid corresponds to... Figure 11 The DSC pattern shown. The resulting TGA pattern of the solid corresponds to... Figure 12 The TGA pattern shown.

[0171] Example 9: Preparation of solid form, form 7, of apalutamide 2-propanol solvate.

[0172] 0.30 g apalutamide was mixed with 6 ml 2-propanol (2-PrOH). The mixture was heated to 70 °C and stirred at this temperature for 0.5 h. The mixture was then cooled to ambient temperature (20-25 °C) and stirred at this temperature for 12 h. The suspension was filtered, the filter cake was washed with 2 ml 2-PrOH, and air-dried for 3 h to give 0.34 g apalutamide 2-propanol solvate solid form 7. The XRPD plot of the obtained solid corresponds to... Figure 13 The XRPD pattern shown. The DSC pattern of the resulting solid corresponds to... Figure 14 The DSC pattern shown. The resulting TGA pattern of the solid corresponds to... Figure 15 The TGA pattern shown.

[0173] Example 10: Preparation of solid form, form 7, of apalutamide 2-propanol solvate.

[0174] 0.30 g of amorphous apalutamide was mixed with 6 ml of 2-propanol (2-PrOH). The mixture was stirred at ambient temperature (20-25 °C) for 12 hours. The suspension was filtered, the filter cake was washed with 2 ml of 2-PrOH, and air-dried for 3 hours to provide 0.32 g of apalutamide in 2-propanol solvate solid form. The XRPD plot of the obtained solid corresponds to... Figure 13 The XRPD pattern shown. The DSC pattern of the resulting solid corresponds to... Figure 14 The DSC pattern shown. The resulting TGA pattern of the solid corresponds to... Figure 15 The TGA pattern shown.

[0175] Example 11: Compound of formula (5) (R1:CH3), 1-((3-fluoro-4-(methoxycarbonyl)phenyl)amino)cyclobutane- Preparation of 1-formic acid:

[0176]

[0177] 12 kg of dimethyl sulfoxide (DMSO) was mixed with 3.28 kg of 1-aminocyclobutane-1-carboxylate. The mixture was heated at 40-45 °C until completely dissolved, then cooled to 30 °C. Then, 5.77 kg of potassium carbonate was slowly added (over 20 minutes), and the mixture was stirred at the same temperature for 15 minutes. 382 g of copper(I) chloride, 3.6 kg of methyl 4-bromo-2-fluorobenzoate, and 1.9 kg of DMSO were added. The mixture was then heated to 100 °C and stirred for 2.5 hours. After the reaction was complete, the mixture was cooled to 8 °C, and then a mixture of 6.19 kg of concentrated hydrochloric acid (36%) and 12.2 kg of water was slowly added (over 90 minutes) while maintaining the temperature below 22 °C. After the addition, the mixture was stirred at 15-25 °C for 30 minutes and then filtered. The filter cake was washed with 4 x 7.2 kg of water and dried at 45 °C for 6 hours to obtain 3.61 kg of the title product with a purity of 97.8% (HPLC IN).

[0178] Example 12: Preparation of compound (R1:CH3, R2:CH3), 2-fluoro-4-((1-(methoxycarbonyl)cyclobutyl) Methyl aminobenzoate

[0179]

[0180] 7 kg of 1-((3-fluoro-4-(methoxycarbonyl)phenyl)amino)cyclobutane-1-carboxylic acid (7.0 kg) was mixed with 22.1 kg of methanol. The mixture was heated to 40 °C, and then 2.83 kg of concentrated sulfuric acid (96%) was added. The mixture was heated to 65 °C and stirred for 3 hours. The mixture was cooled to 35 °C, and then 5.9 kg of triethylamine and 10.5 kg of water were added. The mixture was cooled to -2 °C, stirred for 20 minutes, and filtered. The filter cake was washed with 2 x 8.8 kg of 50% methanol aqueous solution and dried at room temperature for 5 hours to give 6.91 kg of the title product with a purity of 99.8% (HPLC IN).

[0181] The obtained XRPD map of the solid corresponds to Figure 18 The XRPD pattern shown.

[0182] Example 13: Preparation of compound (R1:CH3), 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)- Methyl 8-oxo-6-thio-5,7-diazaspiro[3.4]oct-5-yl)-2-fluorobenzoate

[0183]

[0184] 5 kg of methyl 2-fluoro-4-((1-(methoxycarbonyl)cyclobutyl)amino)benzoate was dissolved in 14 kg of tetrahydrofuran (THF). The mixture was cooled to -5°C, and then 13.92 kg of bis(trimethylsilyl)aminolithium (LiHMDS) (20% THF solution) was added. The temperature was maintained below 5°C during the addition. After the addition was complete, the mixture was stirred for 15 minutes and cooled to -9°C. Then, a solution of 4.24 kg of 5-isothiocyano-3-(trifluoromethyl)pyridinium nitrile in 5.5 kg of tetrahydrofuran was slowly added (over 20 minutes) while maintaining the temperature below 0°C. After the addition was complete, the mixture was cooled to -9°C. A mixture of 3.6 kg of concentrated hydrochloric acid (36%) and 16.8 kg of water was added to the mixture. The mixture was then heated to 30°C, and the bottom aqueous phase was separated. The organic phase was then washed with 15 kg of 20% sodium chloride aqueous solution. The organic extract was concentrated under vacuum to approximately 15 L, then switched to methanol by sequentially adding and distilling 31.7 kg of methanol, ultimately concentrating the mixture to approximately 35 L. 11.8 kg of isopropanol was added, the mixture was heated under reflux for 20 minutes, then cooled to -5°C, stirred for 30 minutes, and filtered. The filter cake was washed with 2 x 13 kg of 60% methanol aqueous solution and dried at 45°C for 6 hours to give 7 kg of the title product, with a purity of 99.6% (HPLC IN).

[0185] Example 14: Preparation of apalutamide, compound of formula (1)

[0186]

[0187] 20.3 kg of methylamine (40% aqueous solution) was cooled to 3 °C. Over 5 minutes, 5 kg of a solution of methyl 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-5-yl)-2-fluorobenzoate in 12.7 kg of 2-methyltetrahydrofuran (2Me THF) was slowly added. The mixture was then stirred at 4–5 °C for 4.5 hours.

[0188] A solution of 15.4 kg glacial acetic acid in 13.4 kg water was slowly added (over 90 minutes) while maintaining the temperature of the mixture below 20°C. After addition, the mixture was heated to 30°C, and the bottom aqueous phase was separated. The organic phase was mixed with 20 kg of 20% K₂CO₃ aqueous solution and stirred at 30°C for 1 minute, then the bottom aqueous phase was separated. Under the same conditions, the remaining organic phase was washed again with 20 kg of 6% K₂CO₃ aqueous solution. 10 kg of 2% acetic acid aqueous solution was added to the organic phase, and the reactor contents were heated to 60°C. 3.9 kg of 2-propanol was added, and the bottom aqueous phase was separated. The organic phase was mixed with another 27.5 kg of 2-propanol, the mixture was heated to reflux, stirred for 15 minutes, and then cooled to -5°C over a linear temperature ramp over 3 hours. The mixture was then stirred for 30 minutes, filtered, and the filter cake was washed with 2 x 7.8 kg of cold 2-propanol. The obtained crystalline solid was dried at 45 °C for 6 hours to obtain 4.6 kg of crude apalutamide form 7 (HPLC purity 99.86%). The XRPD plot of the obtained solid corresponds to... Figure 1 The XRPD pattern shown. The DSC pattern of the resulting solid corresponds to... Figure 2 The DSC pattern shown. The resulting TGA pattern of the solid corresponds to... Figure 3 The TGA pattern shown.

[0189] Example 15: Preparation of apalutamide, in solid form of compound (1)

[0190] 4.6 kg apalutamide was mixed with 28.3 kg 2-propanol and 15.3 kg methanol. The mixture was heated and stirred under reflux for 10 minutes until the apalutamide was completely dissolved. The solution was then cooled to -8 °C over a linear temperature ramp over 3 hours. The mixture was stirred for 30 minutes, filtered, and the filter cake was washed with 2 x 7.3 kg 2-propanol. The resulting crystalline solid was dried at 45 °C for 6 hours to give 4.2 kg of the final apalutamide form 7 (HPLC purity 99.90%). The XRPD plot of the obtained solid corresponds to... Figure 13 The XRPD pattern shown. The DSC pattern of the resulting solid corresponds to... Figure 14 The DSC pattern shown. The resulting TGA pattern of the solid corresponds to... Figure 15 The TGA pattern shown.

Claims

1. A method for preparing compound (1) or a salt thereof, ， include a. Reacting compound (2) with compound (3) in the presence of a nonnucleophilic base to obtain compound (4), wherein the nonnucleophilic base is selected from bis(trimethylsilyl)aminolithium, bis(trimethylsilyl)aminosodium, or bis(trimethylsilyl)aminopotassium. R1 is selected from C1-C6 alkyl groups. R2 is selected from C1-C6 alkyl groups; b. Compound (4) is converted into compound (1) by reacting compound (4) with methylamine or its salt.

2. The method of claim 1, wherein R1 and R2 are CH3.

3. The method of claim 1, wherein reaction step a is carried out in dimethylformamide, tetrahydrofuran, or 2-methyltetrahydrofuran.

4. The method according to claim 1, wherein compound (2) is prepared by a method comprising reacting compound (5) with an acid and an alcohol R2OH, wherein R2 is selected from C1-C6 alkyl groups. 。 5. The method according to claim 4, wherein the alcohol R2OH is methanol.

6. The method according to claim 4, wherein compound (5) is prepared by reacting compound (6) and compound (7) or a salt thereof under a protective gas, wherein the protective gas flows above the reaction mixture: ， R1 is selected from C1-C6 alkyl groups.

7. The method according to claim 6, wherein the protective gas is argon or nitrogen.

8. The method of claim 6, wherein the protective gas flows over the reaction mixture at a rate of 1 to 100 liters per minute.

9. The solid form of compound (2A) is form A. Its features It has the XRPD pattern shown in Figure 3.

10. Use of the solid form of compound (2A) of claim 9 in the preparation of compound (1) or its salt. 。

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