A preparation method of enzalutamide and its intermediates

Abstract

The present invention provides a method for preparing enzalutamide and its intermediates. The method for preparing enzalutamide uses 3-trifluoromethyl-4-cyanoaniline and N,N-dimethyl(ethyl)thiocarbamoyl chloride as raw materials, and the 4-isothiocyanato-2-(trifluoromethyl)benzonitrile generated by the reaction is directly reacted with ENZ1 to generate the target product enzalutamide without separation and purification. The method for preparing enzalutamide and its intermediates provided by the present invention does not use highly toxic and foul-smelling thiophosgene and is low in cost. The method for preparing enzalutamide does not use 4-isothiocyanato-2-(trifluoromethyl)benzonitrile solid, is safe to operate, and is very suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of enzalutamide and an intermediate thereof. Background Art

[0002] Prostate cancer is one of the most common malignant tumors in men. In recent years, the incidence of prostate cancer in China has been on the rise, and most of the patients are already in the middle and late stages when they are discovered. Studies have shown that androgens play an important role in the occurrence and development of prostate cancer. At present, first-line endocrine therapy is the standard treatment for the initial treatment of advanced prostate cancer. Although this treatment method is effective for most patients in the initial stage, after a median treatment time of 14 to 30 months, almost all patients' lesions will gradually develop into castration-resistant prostate cancer (CRPC), with a median survival time of 1 to 2 years. Although docetaxel is approved for first-line chemotherapy of CRPC, the treatment method is single. At the same time, some patients cannot tolerate the toxicity of chemotherapy. Therefore, new effective and less toxic anti-tumor drugs are still needed for such patients.

[0003] Enzalutamide (4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thione-1-imidazolidinyl]-2-fluoro-N-methylbenzamide) was jointly developed by Medivation and Astellas. It was first approved for marketing by the US FDA on August 31, 2012, and then approved for marketing by the European EMA on June 21, 2013, and approved for marketing by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) on March 24, 2014. It is marketed by Astellas under the trade name Xtandi. Enzalutamide is an androgen receptor inhibitor that can reduce the proliferation of prostate cancer cells and induce their death. The drug is used to treat patients with metastatic castration-resistant prostate cancer who have previously received docetaxel therapy. Enzalutamide has the following structure:

[0004]

[0005] Prior art WO2011106570 reports a method for synthesizing enzalutamide, as shown in the following routes 1 and 2.

[0006]

[0007] Route 1

[0008]

[0009] Route 2

[0010] In addition, the prior art CN104803918A reports a method for synthesizing enzalutamide as shown in the following Scheme 3.

[0011]

[0012] Route 3

[0013] Both routes 1 and 3 require the separation of the 4-isothiocyanato-2-(trifluoromethyl)benzonitrile intermediate. Routes 1, 2 and 3 all use highly toxic and foul-smelling thiophosgene, and high production protection requirements are required. Both 4-isothiocyanato-2-(trifluoromethyl)benzonitrile and thiophosgene are genotoxic impurities (derived from the evaluation software specified in ICH regulations), and there are certain requirements for removal rate and analytical method development. When the inventors of the present application repeated the preparation method of route 1, employees were allergic when using thiophosgene to prepare 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. At the same time, it was found that 4-isothiocyanato-2-(trifluoromethyl)benzonitrile had poor stability, and high-temperature drying or long-term storage was very likely to produce self-coupled impurities, and its structure is as follows.

[0014]

[0015] In addition, the melting point of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile is only 40°C, which places high demands on production equipment and limits industrial production. Conventional drying equipment can easily melt the raw material, causing it to agglomerate, especially in the summer when the temperature is high. After agglomeration, the raw material adheres to the inner wall of the drying equipment and can only be taken out by manual crushing, which results in an extremely harsh working environment.

[0016] Therefore, although many prior arts have reported methods for preparing enzalutamide, they have basically not deviated from the scope of requiring the use of thiophosgene and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile solid, which places high demands on employee occupational health, genotoxicity risk control, etc.

[0017] In view of the problems existing in the prior art methods for preparing enzalutamide, such as the inconvenience of thiophosgene production, storage and use, the instability of the intermediate isothiocyanate, and the inconvenience of storage and transportation, the prior art CN117120436A discloses a one-pot method for synthesizing thiohydantoin derivatives as shown in the following route 4. In this method, compound A3, compound B3 and compound C2 are reacted in one pot to prepare enzalutamide. The specific reaction route is as follows:

[0018]

[0019] Route 4

[0020] The problems of this method are: (1) the yield is low, only 16.8%; (2) the thiolation reagent used is very expensive and is not suitable for industrial production.

[0021] In addition, for the synthesis method of the key intermediate 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, the prior art mainly discloses the following method:

[0022] Prior art CN104710367A discloses a method for synthesizing 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, as shown in the following route 1-a. The method uses 3-trifluoromethyl-4-cyanoaniline as a raw material, adds sodium hydride under nitrogen protection, adds carbon disulfide and refluxes for 20 hours, and then desulfurizes with an aqueous solution of lead nitrate and purifies by column chromatography to obtain the target product. Although the method uses carbon disulfide instead of thiophosgene to overcome the shortcomings of route 1, the subsequent process uses an aqueous solution of lead nitrate for desulfurization, generating a large amount of lead sulfide precipitation, which is very polluting to the environment, and the post-processing operation is cumbersome, and it is not suitable for industrial production, and the yield is low (about 65%).

[0023]

[0024] Route 1-a

[0025] Prior art CN104610111A discloses another 4-isothiocyanato-2-(trifluoromethyl)benzonitrile synthesis method, as shown in the following route 1-b. This route uses 2-trifluoromethyl-4-aminobenzonitrile as raw material, reacts with carbon disulfide under the action of an organic base (triethylenediamine) to generate 3-trifluoromethyl-4-cyanophenyl dithioformate, and then removes 1 molecule of H2S under the action of a desulfurization reagent (bis(trichloromethyl)carbonate) to obtain the target product, with a yield of 84%. Although the yield of the method is higher, the raw material carbon disulfide is a highly toxic substance, and post-processing purification adopts column chromatography, which is not suitable for industrial production.

[0026]

[0027] Route 1-b

[0028] Prior art CN107400073A discloses another 4-isothiocyanato-2-(trifluoromethyl)benzonitrile synthesis method, as shown in the following route 1-c. The method uses 3-trifluoromethyl-4-cyanoaniline as a starting material, reacts with thiochloroformic acid phenyl ester in an organic solvent to obtain an intermediate, and the intermediate is refluxed in toluene to remove a molecule of phenol to obtain the product 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, and the yield is 60% to 79%. Although the method is simple to operate and the yield is relatively high, the reagent thiochloroformic acid phenyl ester is relatively expensive, resulting in high production costs, and the target product obtained contains phenol residues, which are not easy to remove and have quality risks.

[0029]

[0030] Route 1-c

[0031] Prior art CN112876391 discloses another method for synthesizing 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, as shown in the following route 1-d. The method comprises the following steps: 1) Under anhydrous conditions, 3-trifluoromethyl-4-cyanobenzoic acid reacts with diphenylphosphoryl azide to generate 4-isocyanato-2-(trifluoromethyl)benzonitrile; 2) 4-isocyanato-2-(trifluoromethyl)benzonitrile reacts with Lawesson's reagent to generate 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. This method uses azide reagent and Lawesson's reagent, and there are problems such as many by-products, high cost, and environmental protection.

[0032]

[0033] Route 1-d

[0034] Prior art CN113717086A discloses another method for synthesizing 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, as shown in the following route 1-e. The method adds ammonium thiocyanate to ethyl acetate, drips benzoyl chloride, then drips an ethyl acetate solution of 3-trifluoromethyl-4-cyanoaniline, reacts to obtain N-((4-cyano-3-(trifluoromethyl)phenyl)carbamoyl)benzamide, then hydrolyzes in a 9-11% alkali metal hydroxide solution to obtain 1-(4-cyano-3-(trifluoromethyl)phenyl)thiourea, and finally stirs and heats in a deamination reagent to reflux to obtain 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. Although the method uses low reagent cost, the route is long, the operation steps are cumbersome, and the total yield is only 55%, and the three wastes generated are more, which is not conducive to industrial production.

[0035]

[0036] Route 1-e

[0037] Therefore, there is a need in the art for a method for preparing enzalutamide that does not use highly toxic thiophosgene and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile solid, has a low preparation cost for the intermediate 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, and is suitable for industrial large-scale production. Summary of the invention

[0038] In view of the defects of the preparation method of enzalutamide in the prior art, an object of the present invention is to provide a new preparation method of enzalutamide, which does not use highly toxic and smelly thiophosgene and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile solid, is safe to operate, and is suitable for industrial production.

[0039] The preparation method of enzalutamide provided by the present invention comprises the following steps:

[0040] (1) Compound 1 reacts with compound 2 to generate compound 3;

[0041] (2) removing the disubstituted amine group from compound 3 to generate compound 4. After the reaction is completed, adding an acid to the reaction solution to form a salt with the base in the reaction solution, which is then removed by filtration;

[0042] (3) adding compound 5 to the filtrate obtained in step (2) to react compound 4 with compound 5 to obtain enzalutamide,

[0043] The reaction formula is as follows:

[0044] , R1 and R2 are each independently selected from methyl and / or ethyl.

[0045] In another preferred embodiment, R1 and R2 are selected from methyl.

[0046] In another preferred embodiment, step (1) and step (2) are carried out in a one-pot process. In step (1), the reaction solution of step (2) is heated to remove the disubstituted amine group of compound 3 to generate compound 4.

[0047] In another preferred embodiment, the molar ratio of compound 1 to compound 2 is 1:1.0-2.0, more preferably 1:1.0-1.2.

[0048] In another preferred embodiment, the molar ratio of compound 1 to compound 5 is 1:0.5-1.0, more preferably 1:0.6-0.9.

[0049] In another preferred embodiment, in step (1), the reaction temperature of compound 1 and compound 2 is 0-50°C, more preferably 0-25°C.

[0050] In another preferred embodiment, the reaction temperature of step (2) is 80-130°C.

[0051] In another preferred embodiment, the reaction temperature of step (3) is 50-110°C.

[0052] In another preferred embodiment, in step (1), the acid is selected from sulfuric acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, glacial acetic acid, or a combination thereof, more preferably, sulfuric acid.

[0053] In another preferred embodiment, in step (1), the acid is selected from concentrated sulfuric acid.

[0054] In another preferred embodiment, in step (1), the molar ratio of compound 1 to acid is 1:0.1-0.4.

[0055] In another preferred embodiment, step (1), step (2) and step (3) are all carried out in an inert gas atmosphere, and more preferably, the inert gas is nitrogen.

[0056] In another preferred embodiment, the solvents used in the reactions of step (1), step (2) and step (3) are the same.

[0057] In another preferred embodiment, the solvent used in the reactions of step (1), step (2) and step (3) is selected from toluene, xylene, chlorobenzene, dimethyl sulfoxide (DMSO), isopropyl acetate, N-methylpyrrolidone (NMP), dimethyl sulfoxide or a mixture thereof, more preferably, chlorobenzene.

[0058] In another preferred embodiment, after adding the acid to the reaction solution in step (2), activated carbon or diatomaceous earth is added thereto, the mixture is stirred and filtered, and the obtained filtrate is used to react with compound 5.

[0059] Another aspect of the present invention provides a method for preparing compound 4, which has low raw material cost, high yield and is suitable for industrial production.

[0060] The preparation method of compound 4 provided by the present invention comprises the following steps:

[0061] (a) Compound 1 reacts with compound 2 to generate compound 3;

[0062] (b) Compound 3 is desulfurized to generate compound 4.

[0063] The reaction formula is as follows:

[0064] , wherein R1 and R2 are each independently selected from methyl and / or ethyl.

[0065] In another preferred embodiment, R1 and R2 are selected from methyl.

[0066] In another preferred embodiment, step (a) and step (b) are carried out in one pot, and in step (b), the reaction solution of step (a) is heated to remove the disubstituted amine group of compound 3 to generate compound 4.

[0067] In another preferred embodiment, the molar ratio of compound 1 to compound 2 is 1:1.0-2.0, more preferably 1:1.0-1.2.

[0068] In another preferred embodiment, the reaction temperature of step (a) is 0-50°C, and the reaction temperature of step (b) is 80-130°C.

[0069] In another preferred embodiment, the solvent used in the reactions of step (a) and step (b) is selected from toluene, xylene, chlorobenzene, dimethyl sulfoxide (DMSO), isopropyl acetate, N-methylpyrrolidone (NMP), dimethyl sulfoxide or a mixture thereof, more preferably, chlorobenzene.

[0070] In another preferred embodiment, both step (a) and step (b) are carried out in an inert gas atmosphere, more preferably, the inert gas is nitrogen.

[0071] In another preferred embodiment, activated carbon or diatomaceous earth is added to the reaction solution obtained in step (b), and then filtered. The obtained filtrate is concentrated to dryness, and the obtained residue is recrystallized to obtain a high-purity target compound.

[0072] The present invention also provides a method for preparing enzalutamide, comprising the following steps:

[0073] (1) Compound 1 reacts with compound 2 to generate compound 3;

[0074] (2) Compound 3 removes the disubstituted amine group to generate compound 4;

[0075] (3) reacting compound 4 with compound 5 to obtain enzalutamide,

[0076] The reaction formula is as follows:

[0077] , wherein R1 and R2 are each independently selected from methyl and / or ethyl. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the self-coupled impurity of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile;

[0079] Figure 2 is the H NMR spectrum of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile;

[0080] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of enzalutamide prepared in Example 4;

[0081] Figure 4 is the nuclear magnetic resonance fluorine spectrum of enzalutamide prepared in Example 4;

[0082] Figure 5 is the mass spectrum of enzalutamide prepared in Example 6. DETAILED DESCRIPTION

[0083] The inventors of the present application found in the process of preparing enzalutamide that commercially available 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (Compound 4) or homemade 4-isothiocyanato-2-(trifluoromethyl)benzonitrile usually has an obvious impurity after being left to stand, which is a self-coupled impurity of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, and the structure is as follows:

[0084]

[0085] There may be two reasons for the generation of this impurity. One is that the raw material (3-trifluoromethyl-4-cyanoaniline, compound 1) reacts with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile to form it. The other is that 4-isothiocyanato-2-(trifluoromethyl)benzonitrile condenses itself under high temperature and long-term storage to form this impurity (the main source). In order to better study the reaction mechanism of this impurity, we directed the synthesis of this impurity. 3-trifluoromethyl-4-cyanoaniline and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile were added to DMSO in a ratio of 1:1, the temperature was raised to 80°C, and the reaction was carried out for 12 hours to obtain the target impurity product. After adding water to the reaction solution, solids were precipitated and filtered. The obtained filter cake was slurried with a small amount of toluene to obtain the impurity compound with higher purity.

[0086] The H NMR spectrum data of the impurity compound are shown in Table 1 below. The NMR spectrometer used is: Bruker DMX-500, and the solvent is: DMSO-d6.

[0087] Table 1

[0088]

[0089] The mass spectrum data of the impurity compound are as follows:

[0090] Using electrospray ionization (ESI) and negative ion detection, [MH] - 413 peak, [2M-H] - 827 peaks.

[0091] The raw materials themselves are prone to produce impurities, which requires additional purification steps for production, resulting in increased production costs. Therefore, the inventors of the present application tried to reduce the storage time of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile as much as possible, and it is best to prepare it on the spot for the next reaction.

[0092] In addition, according to ICH regulations, the Sarah and Derek software detected that 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (Compound 4) itself has genotoxic toxicity, which is the cause of the operator's allergy. See Table 2 below for details.

[0093] Table 2

[0094]

[0095] As can be seen from Table 2 (ICH M7 Class 3 impurities), 4-isothiocyanato-2-(trifluoromethyl)benzonitrile has certain genotoxic toxicity. In the prior art, 4-isothiocyanato-2-(trifluoromethyl)benzonitrile solid is generally used for the next step of reaction, which inevitably involves its separation and purification. The preparation personnel need to be exposed to the environment where 4-isothiocyanato-2-(trifluoromethyl)benzonitrile solid exists, and the operation safety is poor.

[0096] Therefore, due to the instability and genotoxicity of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, and the low melting point causing inconvenient operation, it is very necessary to develop a preparation method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile that does not require separation and purification (i.e., does not require solid form) during the preparation of enzalutamide, which not only makes the preparation of enzalutamide convenient but also safe. Based on this technical problem, the inventors of the present application have conducted in-depth research on the preparation method of enzalutamide.

[0097] In addition, during the process of researching and developing the preparation method of enzalutamide, the inventors of the present application found that the preparation of the key intermediate 4-isothiocyanato-2-(trifluoromethyl)benzonitrile also has problems such as high raw material cost and unsafe operation, and then studied and developed the preparation method of the intermediate.

[0098] In the process of studying and finding that the reaction of compound 1 and compound 2 can obtain the target compound with a high yield, the inventors of the present application have studied a large number of similar compounds and found that compound 2-1 is currently the most suitable for the industrial preparation process of enzalutamide, which not only has a high yield but also low cost. For example, the inventors of the present application experimented with the following reaction. According to the method of Example 4 below, a reaction solution of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile was prepared. After treating the reaction solution, compound 5 was added thereto to react for the preparation of enzalutamide. The reaction raw materials used and the reaction results are shown in Table 1 below.

[0099] Table 1

[0100]

[0101]

[0102] Note: In Table 1, the molar ratio of compound 1 to compound 2-1, compound 2-2, compound 2-3, compound 2-4 and compound 2-5 is 1:1.1.

[0103] During the reaction of the present invention, if the disappearance of the raw material is detected by commonly used means in the art (eg, thin layer chromatography or liquid chromatography), it can be determined that the key raw material has been completely converted and the reaction is complete.

[0104] In the description of the present invention, "after the reaction is completed" means that one of the raw materials is completely converted and its disappearance is detected by conventional means.

[0105] In some specific embodiments of the present invention, the method for preparing enzalutamide of the present invention comprises the following steps:

[0106] (1) Compound 1 reacts with compound 2-1 to generate compound 3;

[0107] (2) removing the diamine group from compound 3 to generate compound 4. After the reaction is completed, adding an acid to the reaction solution to form a salt with the base in the reaction solution, which is then removed by filtration;

[0108] (3) adding compound 5 to the filtrate obtained in step (2) to react compound 4 with compound 5 to obtain enzalutamide,

[0109] The reaction formula is as follows:

[0110]

[0111] In step (1), compound 1 and compound 2-1 are reacted in an inert gas atmosphere. Compound 2 is added dropwise to a solution containing compound 1 at -5 to 5°C, and the reaction is continued at this temperature for 1 to 3 hours. The ice bath is then removed and the temperature is raised to room temperature, and the reaction is continued for 1 to 3 hours until compound 1 is completely converted and the reaction is completed.

[0112] In step (2), the reaction solution of step (1) is directly heated to 80-130° C. to remove the dimethylamine group of the generated compound 3-1 to generate compound 4. After the compound 3-1 is completely converted, an acid is added to the reaction solution, and a small amount of diatomaceous earth or activated carbon is added. The acid neutralizes the alkali in the reaction solution to form a salt, which is removed by filtration. The filtrate obtained is directly used for the next reaction.

[0113] In step (3), compound 5 is added to the filtrate obtained in step (2), and the reaction solution is heated to 50-110° C. to react compound 4 with compound 5 to obtain enzalutamide. After compound 5 is completely converted, alcohol (for quenching unreacted compound 4) is added to the reaction solution, and the reaction is carried out at 40-80° C. for 0.5-2 h. The reaction solution is washed with an acidic aqueous solution, an alkaline aqueous solution and neutral water in sequence, and the obtained organic phase is concentrated. The obtained residue is recrystallized twice to obtain high-purity enzalutamide.

[0114] In some specific embodiments of the present invention, the preparation method of compound 4 provided by the present invention comprises the following steps:

[0115] (a) Compound 1 reacts with compound 2-1 to generate compound 3-1;

[0116] (b) heating the reaction solution of step (1) to remove the dimethylamino group of compound 3-1 to generate compound 4.

[0117] The reaction formula is as follows:

[0118]

[0119] In step (a), compound 1 and compound 2-1 are reacted in an inert gas atmosphere. Compound 2 is added dropwise to a solution containing compound 1 at -5 to 5°C, and the reaction is continued at this temperature for 1 to 3 hours. The ice bath is then removed and the temperature is raised to room temperature, and the reaction is continued for 1 to 3 hours until compound 1 is completely converted and the reaction is completed.

[0120] In step (b), the reaction solution of step (a) is directly heated to 80-130° C. to remove the dimethylamino group of the generated compound 3-1 to generate compound 4. After the compound 3-1 is completely converted, activated carbon or diatomaceous earth is added to the reaction solution, filtered, and the obtained filtrate is concentrated to dryness. The obtained residue is recrystallized using a solvent to obtain high-purity 4-isothiocyanato-2-(trifluoromethyl)benzonitrile.

[0121] The 4-isothiocyanato-2-(trifluoromethyl)benzonitrile obtained in the present invention can be reacted with compound 5 according to the method disclosed in the prior art (for example, WO2011106570) to obtain enzalutamide.

[0122] Compared with the prior art, the preparation method of enzalutamide and its intermediates of the present invention has the following beneficial effects:

[0123] 1. The preparation of the intermediate 4-isothiocyanato-2-(trifluoromethyl)benzonitrile does not use highly toxic and smelly thiophosgene, and has low raw material cost and high yield, which is very suitable for industrial production.

[0124] 2. The highly toxic and foul-smelling thiophosgene is not used in the preparation process of enzalutamide. In some embodiments, step (1) and step (2) are carried out in one pot, and the intermediate product obtained in step (2) does not need to be separated and purified. After the amine in the reaction solution is neutralized with acid, it can be directly used in the reaction of step (3) after filtering, avoiding the operator from being exposed to the genotoxic intermediate 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. There is no self-coupling impurity of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, which is very suitable for industrial large-scale production.

[0125] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually carried out under normal conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts. The reagents or raw materials used in the following examples are generally commercially available, or can be prepared according to the methods disclosed in the prior art, unless otherwise stated.

[0126] The instrument used for purity detection in the following examples is Agilent 6400 LC-MS / MS, and the nuclear magnetic resonance spectrometer used is Bruker DMX-500.

[0127] Example 1

[0128] Preparation of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (Compound 4)

[0129] At room temperature, mix 1.35 kg (10.9 mol, 1.09 equiv) of N,N-dimethylthiocarbamoyl chloride with 5 L of chlorobenzene, stir to dissolve, and protect with nitrogen throughout the process for standby use.

[0130] At room temperature, 1.86 kg (10.0 mol, 1.0 equiv) of the raw material 3-trifluoromethyl-4-cyanoaniline was put into a 20 L glass bottle, 6.0 L of chlorobenzene was added, stirred, nitrogen was filled to isolate the air, and the chlorobenzene solution of N, N-dimethylthiocarbamoyl chloride was slowly added dropwise at 0 ° C. After the addition was completed, the reaction was continued for 2 h, the ice bath was removed and the temperature was raised to room temperature for 2 h, and the temperature was further raised to 100 ° C for 2 h, and the temperature was lowered to room temperature, and a small amount of diatomaceous earth was added and stirred for 15 min, and the filter residue was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure (the temperature should not exceed 80 ° C), 1 L of n-heptane was added and evaporated twice, and after evaporation to dryness, 3 L of n-heptane was added and the temperature was raised to 70 ° C for dissolution, and the temperature was lowered to -10 ° C for crystallization for 2 h, and the filter cake was dried to obtain 1.64 kg of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. HPLC purity was 99.7%, and the molar yield was 71.7%. MS: m / z = 227 [MH] - The product was confirmed to be 4-isothiocyanato-2-(trifluoromethyl)benzonitrile by NMR detection.

[0131] H NMR spectrum Figure 2 .

[0132] Example 2

[0133] Preparation of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (Compound 4)

[0134] At room temperature, mix 129 g (1.04 mol, 1.04 equiv) of N,N-dimethylthiocarbamoyl chloride with 500 mL of toluene, stir to dissolve, and protect with nitrogen throughout the process for standby use.

[0135] At room temperature, 186 g (1.0 mol, 1.0 equiv) of the raw material 3-trifluoromethyl-4-cyanoaniline was put into a 2L glass bottle, 500 L of toluene was added, stirred, nitrogen was filled to isolate the air, and a toluene solution of N,N-dimethylthiocarbamoyl chloride was slowly added dropwise. After the addition was completed, the temperature was raised to 50°C for reaction for 2 h, and then the temperature was raised to 80°C for reaction for 1 h, and then the temperature was lowered to room temperature. A small amount of diatomaceous earth was added and stirred for 15 min, and the residue was removed by filtration. The filtrate was concentrated to dryness under reduced pressure, and 200 mL of cyclohexane was added and evaporated twice. After evaporation, 200 mL of cyclohexane was added and the temperature was raised to 70°C for dissolution, and the temperature was lowered to 0-5°C for crystallization for 2 h, and the filter cake was dried to obtain 149 g of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. HPLC purity 99.5%, molar yield 65.0%. MS: m / z=227[MH] - .

[0136] Example 3

[0137] Preparation of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (Compound 4)

[0138] At room temperature, mix 159.2 g (1.05 mol, 1.05 equiv) of N,N-diethylthiocarbamoyl chloride with 500 mL of toluene, stir to dissolve, and protect with nitrogen throughout the process for standby use. At room temperature, 186 g (1.0 mol, 1.0 equiv) of the raw material 3-trifluoromethyl-4-cyanoaniline was put into a 2L glass bottle, 500 L of toluene was added, stirred, nitrogen was filled to isolate the air, and a toluene solution of N, N-diethylthiocarbamoyl chloride was slowly added dropwise. After the addition was completed, the temperature was raised to 50°C for reaction for 2 h, and then the temperature was raised to 90°C for reaction for 1 h, and then the temperature was lowered to room temperature. A small amount of diatomaceous earth was added and stirred for 15 min, and the residue was removed by filtration. The filtrate was concentrated to dryness under reduced pressure, 200 mL of cyclohexane was added and evaporated twice, and after evaporation to dryness, 200 mL of cyclohexane was added and the temperature was raised to 70°C for dissolution, and the temperature was lowered to 0-5°C for crystallization for 2 h, and the filter cake was dried to obtain 147.8 g of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. HPLC purity was 99.1%, and the molar yield was 64.2%. MS: m / z=227[MH] - .

[0139] Example 4

[0140] Preparation of Enzalutamide

[0141] At room temperature, 1.30 kg (10.5 mol, 1.05 equiv) of N,N-dimethylthiocarbamoyl chloride was mixed with 5 L of chlorobenzene, stirred to dissolve, and nitrogen was used for protection. At room temperature, 1.86 kg (10.0 mol, 1.0 equiv) of the raw material 3-trifluoromethyl-4-cyanoaniline was put into a 20 L glass kettle, 6.0 L of chlorobenzene was added, stirred, nitrogen was filled to isolate the air, and the chlorobenzene solution of N,N-dimethylthiocarbamoyl chloride was slowly added dropwise at 0 ° C. After the addition was completed, the reaction was continued for 2 h, the ice bath was removed and the temperature was raised to room temperature for 2 h, and the temperature was continued to rise to 100 ° C for 2 h, and the temperature was cooled to room temperature, and 150 ml of concentrated sulfuric acid was slowly added, and a small amount of diatomaceous earth was added and stirred for 15 min. The residue was removed by filtration, and compound 5 1.88 kg (7.0 mol, 0.7 equiv) was added to the filtrate, and 2 L DMSO, strictly protect with nitrogen, heat to 80℃ for 4h, cool to 40℃, add 100ml methanol, heat to 60℃ for 1h, the reaction is finished, the reaction solution is stirred and washed with 4.0L 2.0N dilute hydrochloric acid, 4.0L 2.0N sodium hydroxide solution and 4.0L drinking water for 30 minutes, concentrated to dryness under reduced pressure, add 3L isopropanol to the residue and heat to reflux, cool to 5-10℃ for crystallization for 2h, filter, continue to add 3L isopropanol to the wet product and heat to reflux, cool to -5-0℃, dry to obtain 2.37kg of enzalutamide. HPLC purity 99.8%, molar yield 72.8% based on compound 5. HPLC and NMR detection (NMR hydrogen spectrum and NMR fluorine spectrum are shown in Figure 2). Figure 3 and Figure 4 ), confirmed to be enzalutamide. ESI-MS (m / z): 465.1 [M+H] + .

[0142] 1H NMR(500MHz,DMSO-d6)δ1.53(s,6H),2.79(d,3H),7.41-7.31(m,1H),7.43-7 .42(d,1H),7.76(s,1H),8.06(s,1H),8.28-8.27(d,1H),8.39-8.38(d,1H),

[0143] 8.42-8.41(d,1H).

[0144] 13C NMR(500MHz,DMSO-d6)δ183.17,177.82,166.51,162.85,141.41,141.02,139.36,137.04,134.5 6,133.97,131.13,129.21,128.30,126.22,121.20,118.09,111.84,69.69,29.37,26.06,26.05.

[0145] Example 5

[0146] Preparation of Enzalutamide

[0147] At room temperature, 13.6 g (0.11 mol, 1.1 equiv) of N,N-dimethylthiocarbamoyl chloride was mixed with 50 ml of toluene, stirred to dissolve, and nitrogen was used for standby. At room temperature, 18.6 g (0.1 mol, 1.0 equiv) of the raw material 3-trifluoromethyl-4-cyanoaniline was placed in a 500 mL glass bottle, 50 ml of toluene was added, stirred, nitrogen was filled to isolate the air, and the toluene solution of N,N-dimethylthiocarbamoyl chloride was slowly added dropwise at 0°C. After the addition was completed, the ice bath was removed and the temperature was raised to 40°C for reaction for 2 h, and the temperature was continued to rise to reflux for reaction for 2 h, and the temperature was lowered to room temperature, and 2 ml of concentrated sulfuric acid was slowly added, and a small amount of diatomaceous earth was added and stirred for 15 min, and the residue was removed by filtration, and compound 521.4 g (0.08 mol, 0.8 equiv) was added to the filtrate. , add 20mlNMP, do strict nitrogen protection, heat to 100℃ for reaction for 2h, cool to 40℃, add 10ml methanol, heat to 60℃ for reaction for 1h, the reaction is over, the reaction solution is stirred and washed with 40ml 2.0N dilute hydrochloric acid, 40ml 2.0N sodium hydroxide solution and 40ml drinking water for 30 minutes, and concentrated to dryness under reduced pressure. Add 30ml isopropanol to the residue and heat to reflux, cool to 5-10℃ for crystallization for 2h, filter, continue to add 30ml isopropanol to the wet product and heat to reflux, cool to -5-0℃, and dry to obtain 25.5g of enzalutamide. HPLC purity is 99.7%, and the molar yield is 68.4% based on compound 5.

[0148] ESI-MS (m / z): 465.1 [M+H] + .

[0149] Example 6

[0150] Preparation of Enzalutamide

[0151] At room temperature, 16.7 g (0.11 mol, 1.1 equiv) of N, N-diethylthiocarbamoyl chloride was mixed with 50 ml of toluene, stirred to dissolve, and nitrogen was used for protection. At room temperature, 18.6 g (0.1 mol, 1.0 equiv) of the raw material 3-trifluoromethyl-4-cyanoaniline was put into a 500 mL glass bottle, 50 ml of toluene was added, stirred, nitrogen was filled to isolate the air, and the toluene solution of N, N-dimethylthiocarbamoyl chloride was slowly added dropwise at 0°C. After the addition was completed, the ice bath was removed and the temperature was raised to 42°C for reaction for 2 hours, and the temperature was continued to be raised to reflux for reaction for 2 hours, and the temperature was lowered to room temperature, and 2 ml of concentrated sulfuric acid was slowly added, and a small amount of diatomaceous earth was added and stirred for 15 minutes, and the residue was removed by filtration, and compound 521.4 g (0.08 mol, 0.8 equiv) was added to the filtrate, and 20 ml NMP, do a strict nitrogen protection, heat to 100 ℃ for 2h, cool to 40 ℃, add 10ml of methanol, heat to 60 ℃ for 1h, the reaction is over, the reaction solution is stirred and washed with 40ml of 2.0N dilute hydrochloric acid, 40ml of 2.0N sodium hydroxide solution and 40ml of drinking water for 30 minutes, and concentrated to dryness under reduced pressure. Add 30ml of isopropanol to the residue and heat to reflux, cool to 5-10 ℃ for crystallization for 2h, filter, continue to add 30ml of isopropanol to the wet product and heat to reflux, cool to -5-0 ℃, and dry to obtain 26.0g of enzalutamide. HPLC purity 99.6%, molar yield 69.7% based on compound 5. The mass spectrum of the obtained enzalutamide is shown in Figure 5 .

[0152] ESI-MS (m / z): 465.1 [M+H] + .

[0153] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing enzalutamide, characterized in that: The preparation method comprises the following steps: (1) Compound 1 reacts with compound 2 to generate compound 3; (2) removing the disubstituted amine group from compound 3 to generate compound 4. After the reaction is completed, adding an acid to the reaction solution to form a salt with the base in the reaction solution, which is then removed by filtration; (3) adding compound 5 to the filtrate obtained in step (2) to react compound 4 with compound 5 to obtain enzalutamide, Step (1) and step (2) are carried out in a one-pot process. In step (2), the reaction solution of step (1) is heated to remove the disubstituted amine group of compound 3 to generate compound 4. In step (2), the acid is selected from sulfuric acid, phosphoric acid, benzenesulfonic acid, methanesulfonic acid, glacial acetic acid, or a combination thereof, The reaction formula is as follows: Wherein, R1 and R2 are each independently selected from methyl and / or ethyl, The reaction solvent used in steps (1), (2) and (3) is chlorobenzene, The molar ratio of compound 1 to compound 2 is 1:1.0-2.0, The molar ratio of compound 1 to compound 5 is 1:0.5-1.0, In step (1), the reaction temperature of compound 1 and compound 2 is 0 to 50°C. The reaction temperature of step (2) is 80 to 130° C., and The reaction temperature of step (3) is 50-110°C.

2. The method for preparing enzalutamide according to claim 1, characterized in that: R1 and R2 are selected from base.

3. The method for preparing enzalutamide according to claim 1, characterized in that: The molar ratio of compound 1 to compound 2 is 1:1.0-1.

2.

4. The method for preparing enzalutamide according to claim 1, characterized in that: The molar ratio of compound 1 to compound 5 is 1:0.6-0.

9.

5. The method for preparing enzalutamide according to claim 1, characterized in that: In step (1), the reaction temperature of compound 1 and compound 2 is 0 to 25°C.

6. The method for preparing enzalutamide according to claim 1, characterized in that: In step (2), the acid is selected from sulfuric acid.

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