A method of preparing enzalutamide

Abstract

The application belongs to the field of pharmaceutical chemical industry and particularly relates to a preparation method of enzalutamide. In the application, N-BOC-2-aminoisobutyramide is used as a starting material to form a ring with phenyl chlorothioformate to obtain 5,5-dimethyl-1-tert-butoxycarbonyl-2-thione imidazole-4-ketone, the obtained product is further subjected to nucleophilic substitution with 2-trifluoromethyl-4-bromobenzonitrile, is deprotected, and is subjected to nucleophilic substitution with 2-fluoro-4-bromobenzamide to obtain enzalutamide. The method uses N-BOC-2-aminoisobutyramide as a starting material, does not produce disubstituted impurities, has higher conversion rate, can obtain a product with high yield, and is more suitable for industrial amplification.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of pharmaceutical chemical industry, and particularly relates to a preparation method of enzalutamide. BACKGROUND

[0002] Enzalutamide (MDV3100) is a second-generation non-steroidal androgen receptor antagonist developed by Medivation in the United States and Astellas in Japan, and is approved for marketing by the US FDA and the European Medicines Agency in 2012 and 2013, respectively. Enzalutamide can block the androgen receptor signaling pathway of tumor cells and is mainly used for treating patients with advanced prostate cancer (CRPC). Enzalutamide has special efficacy for treating metastatic castration-resistant prostate cancer, and its structural formula is as follows:

[0003]

[0004] At present, the methods for synthesizing enzalutamide reported in the literature mainly include the following routes:

[0005] Method one: Chinese patent application CN101222922, WO2006124118, WO2013087004, WO201110320, WO2011029392, US20070254933 and the literature Journal of Medicinal Chemistry, 53(7), 2779-2796, 2010 report that 3-fluoro-4-methyl nitrobenzene is used as a raw material, and is subjected to oxidation by chromium trioxide / perylene acid, formamidation, nitro reduction to form an intermediate B, the intermediate B is condensed with cyanoacetone to form an intermediate C, and then the intermediate C is reacted with a compound A to obtain enzalutamide. The synthetic route is shown below:

[0006]

[0007] This route has the following disadvantages: the risk coefficient of perylene acid is relatively high, acetone cyanohydrin is a toxic product, and the cyclization reaction of the intermediate C and A requires microwave. Therefore, it is difficult to scale up this route in industry.

[0008] Method two: Chinese patent application CN103108549 and patent WO2011106570 report that 4-bromo-2-fluorobenzoic acid is used as a starting material, and the target product enzalutamide is obtained through five steps of synthesis of an intermediate A, formamidation, C-N coupling, methyl esterification and cyclization. The synthetic route is as follows:

[0009]

[0010] This route starting material is simple, low cost but using toxic and expensive reagent iodomethane, not conducive to industrial production.

[0011] Method three: Chinese patent application CN103108549 and patent WO2011106570 reported that 4-bromo-2-fluorobenzoic acid was used as starting material, formamidation, C-N coupling reaction, amide reaction to generate intermediate D, intermediate D and sulfur thiophosgene cyclization to generate enzalutamide, the route as follows:

[0012]

[0013] The disadvantages of this route: intermediate D and sulfur thiophosgene reaction yield is low, resulting in waste of raw materials and increase of production cost, this method is not suitable for industrial production.

[0014] Method four: Chinese patent application CN104844520 reported a kind of reaction with thiourea and isobutyric acid derivative as raw material, thiourea and isobutyric acid derivative react to obtain 5,5-dimethyl-2-thione imidazole-4-ketone;5-dimethyl-2-thione imidazole-4-ketone reacts with compound 4 under the action of base to obtain 5,5-dimethyl-3-(3-trifluoromethyl-4-fluorophenyl)-2-thione imidazole-4-ketone;5,5-dimethyl-3-(3-trifluoromethyl-4-fluorophenyl)-2-thione imidazole-4-ketone reacts with compound 6 under the action of base to obtain enzalutamide, the synthetic route as follows:

[0015]

[0016] The disadvantages of this reaction are that intermediate compound 3 has two reactive sites, and double-substituted impurities will be generated in the process of nucleophilic substitution with compound 4, so the yield of this part is only 65%, and the total yield is only 51%, which is not suitable for industrial production.

[0017] Through comparison, it can be found that the three routes inevitably use toxic cyanopropionitrile or iodomethane, which restricts the scale-up production of enzalutamide, so it is necessary to find a more environmentally friendly and better operation method. SUMMARY

[0018] The present application provides a kind of preparation method of high efficiency and stable enzalutamide, which uses N-BOC-2-amino isobutyramide as starting material, without double-substituted impurities, higher conversion rate, milder process conditions, more simple operation steps, lower cost, can obtain high yield product, more suitable for industrial scale-up.

[0019] The present application is realized by the following technical solutions:

[0020]

[0021] Compound II, i.e. N-Boc-2-aminoisobutyramide, is cyclized with phenyl chlorothioformate to obtain compound IV; compound IV and compound V are subjected to nucleophilic substitution to obtain compound VI; after deprotection of compound VI, it is substituted with compound VII to obtain enzalutamide.

[0022] Preferably, the following sections will describe the above steps in detail:

[0023] Preparation of compound IV

[0024] Compound II, compound III, i.e. phenyl chlorothioformate, and a base are added into organic solvent A at room temperature, and the reaction is stirred at a controlled temperature to obtain compound IV.

[0025] Preferably, the base is selected from one or a combination of 4-dimethylaminopyridine, sodium bicarbonate, sodium carbonate, triethylamine, diisopropylethylamine, and particularly preferably 4-dimethylaminopyridine.

[0026] Preferably, the molar ratio of compound II, phenyl chlorothioformate, and the base is 1:1.2-2.2:1.0-2.5, and particularly preferably 1:2.0:2.0.

[0027] Preferably, the organic solvent A is selected from one or a combination of N,N-dimethylformamide, n-hexane, n-heptane, acetonitrile, and tetrahydrofuran, and particularly preferably N,N-dimethylformamide.

[0028] Preferably, the reaction temperature is 40-65°C, and preferably 45-55°C.

[0029] In a preferred embodiment, the reaction needs to be post-treated, and the specific steps are as follows: 6 mol / L hydrochloric acid solution is added dropwise into the reaction system, and the product is stirred to crystallize, filtered, and dried to obtain compound IV.

[0030] Preparation of compound VI

[0031] Compound IV is added into organic solvent B, and a base is added in batches at low temperature. Compound V is dissolved in organic solvent B and slowly added into the reaction solution. After the addition is completed, the temperature is raised to room temperature, and the stirring is continued until the reaction is completed to obtain compound VI.

[0032] Preferably, the base is selected from one or a combination of sodium hydride, sodium hydroxide, sodium tert-butoxide, and sodium bis(trimethylsilyl)amide, and particularly preferably sodium hydride.

[0033] Preferably, the organic solvent B is selected from one or a combination of dichloromethane, chloroform, n-heptane, n-hexane, and 1,2-dichloroethane, and particularly preferably dichloromethane.

[0034] Preferably, the temperature of adding the base and compound V is -5-5℃.

[0035] Preferably, the molar ratio of compound IV, compound V, and base is 1:1.0-2.0:2.0-3.0, and particularly preferably 1:1.2:2.5.

[0036] In a preferred embodiment, the reaction needs to be post-treated, and the specific steps are as follows: the reaction solution is added to purified water, and the crude product is obtained by filtration, and the crude product is recrystallized by ethanol to obtain the target compound.

[0037] Preparation of compound I

[0038] Compound VI is added to dichloromethane, trifluoroacetic acid is added, and the reaction is stirred at room temperature. After monitoring the end of the reaction, the base is added in batches at low temperature, compound VII is dissolved in organic solvent C, and the reaction solution is slowly added. The reaction is completed at room temperature to obtain enzalutamide.

[0039] Preferably, the base is selected from one or a combination of sodium tert-butoxide, sodium hydride, sodium hydroxide, and sodium bis(trimethylsilyl)amide, and particularly preferably sodium tert-butoxide.

[0040] Preferably, the molar ratio of compound VI, trifluoroacetic acid, compound VII, and base is 1:2.0:1.2-2.2:2.5-3.5, and particularly preferably 1:2.0:2.0:3.0.

[0041] Preferably, the organic solvent C is selected from one or a combination of dichloromethane, chloroform, n-heptane, n-hexane, and 1,2-dichloroethane, and particularly preferably dichloromethane.

[0042] Preferably, the temperature of adding the base and compound VII is -5-5℃.

[0043] In a preferred embodiment, the reaction needs to be post-treated, and the specific steps are as follows: the reaction solution is added to purified water, and the crude product is obtained by filtration, and the crude product is recrystallized by isopropanol to obtain the target compound.

[0044] Compared with the prior art, the technical effects achieved by the present application are:

[0045] 1. N-BOC-2-aminoisobutyramide is used as a starting material to avoid the generation of double-substituted impurities in subsequent reactions, and the reaction selectivity is significantly improved.

[0046] 2. The present patent avoids the use of high-toxicity and high-price reagents such as cyanopropionitrile and iodomethane, which can effectively reduce costs; and also avoids the use of thionyl chloride, which is expensive, highly toxic, and has high environmental pressure, and conforms to the concept of green chemistry. DETAILED DESCRIPTION

[0047] The application will be further described by the following examples. It should be understood that the examples of the application are only used to illustrate the application, but not to limit the application. Therefore, any simple improvement on the method of the application is within the scope of the application.

[0048] The structure of the compound obtained by the application was confirmed:

[0049] Structure characterization of compound IV

[0050]

[0051] High resolution mass spectrum of compound I: ESI-HRMS: m / z = 245.01 [M+1] + 1 H-NMR, DMSO-d6) δ 1.54 (6H, s), 1.43 (9H, s). 13 C-NMR (DMSO) δ 182.3, 181.4, 158.3, 80.8, 72.5, 29.4 (3C), 25.3 (2C).

[0052] Structure characterization of compound VI

[0053]

[0054] ESI-HRMS: m / z = 414.12 [M+1] + 1 H-NMR, DMSO-d6) (δ ppm) 8.23 (1H, s), 7.85 (1H, d), 7.60 (1H, d), 1.79 (9H, s), 1.59 (6H, s); 13 C-NMR (DMSO) δ 181.5, 176.4, 154.9, 140.0, 135.3, 133.3, 120.5, 118.5, 117.4, 117.0, 105.6, 83.9, 72.7, 29.4 (3C), 23.3 (2C).

[0055] Structure characterization of compound I

[0056]

[0057] ESI-HRMS: m / z = 465.11 [M+1] + 1 ​​​H-NMR, DMSO-d6) 8.43 (1H, d), 8.41 (1H, d), 8.29 (1H, s), 8.09 (1H, d), 7.79 (1H, t), 7.41 (1H, d), 7.32 (1H, m), 2.80 (3H, d), 1.54 (6H, s); 13 C-NMR (DMSO) δ 173.2, 178.0, 170.8, 27.3, 160.0, 146.2, 140.1, 134.5, 133.2, 130.3, 123.4, 121, 9, 121.3, 119.0, 118.0, 117.2, 115.9, 78.5, 24.0 (2C).

[0058] Preparation of compound IV

[0059] Example 1

[0060] Into a reaction flask was added 4-dimethylaminopyridine (2.44 g, 20 mmol), N-BOC-2-aminoisobutyramide (2.02 g, 10 mmol), N,N-dimethylformamide (30 mL), and the temperature was raised to 50 °C. Phenylthiochloroformate (3.45 g, 20 mmol) was added, and the reaction was allowed to proceed for 5 h. To the reaction system was added dropwise 6 mol / L hydrochloric acid solution, and the product was crystallized by stirring. The product was filtered and dried to obtain compound IV, with a yield of 96.8% and an HPLC purity of 99.98%.

[0061] Example 2

[0062] Into a reaction flask was added 4-dimethylaminopyridine (1.22 g, 10 mmol), N-BOC-2-aminoisobutyramide (2.02 g, 10 mmol), n-hexane (30 mL), and the temperature was raised to 40 °C. Phenylthiochloroformate (3.45 g, 20 mmol) was added, and the reaction was allowed to proceed for 5 h. To the reaction system was added dropwise 6 mol / L hydrochloric acid solution, and the product was crystallized by stirring. The product was filtered and dried to obtain compound IV, with a yield of 92.2% and an HPLC purity of 99.62%.

[0063] Example 3

[0064] Into a reaction flask was added 4-dimethylaminopyridine (3.05 g, 25 mmol), N-BOC-2-aminoisobutyramide (2.02 g, 10 mmol), n-heptane (30 mL), and the temperature was raised to 65 °C. Phenylthiochloroformate (3.45 g, 20 mmol) was added, and the reaction was allowed to proceed for 5 h. To the reaction system was added dropwise 6 mol / L hydrochloric acid solution, and the product was crystallized by stirring. The product was filtered and dried to obtain compound IV, with a yield of 93.5% and an HPLC purity of 99.58%.

[0065] Example 4

[0066] Into a reaction flask was added 4-dimethylaminopyridine (3.29 g, 27 mmol), N-BOC-2-aminoisobutyramide (2.02 g, 10 mmol), acetonitrile (30 mL), and the temperature was raised to 70 °C. Phenylthiochloroformate (4.13 g, 24 mmol) was added and the reaction was allowed to proceed for 5 h. To the reaction mixture was added 6 mol / L hydrochloric acid solution dropwise. The product was crystallized by stirring, filtered, and dried to give compound IV in a yield of 87.7% and a HPLC purity of 98.88%.

[0067] Example 5

[0068] Into a reaction flask was added sodium bicarbonate (1.68 g, 20 mmol), N-BOC-2-aminoisobutyramide (2.02 g, 10 mmol), tetrahydrofuran (30 mL), and the temperature was raised to 45 °C. Phenylthiochloroformate (2.06 g, 12 mmol) was added and the reaction was allowed to proceed for 5 h. To the reaction mixture was added 6 mol / L hydrochloric acid solution dropwise. The product was crystallized by stirring, filtered, and dried to give compound IV in a yield of 93.1% and a HPLC purity of 99.66%.

[0069] Example 6

[0070] Into a reaction flask was added sodium bicarbonate (1.68 g, 20 mmol), N-BOC-2-aminoisobutyramide (2.02 g, 10 mmol), tetrahydrofuran (30 mL), and the temperature was raised to 45 °C. Phenylthiochloroformate (2.06 g, 12 mmol) was added and the reaction was allowed to proceed for 5 h. To the reaction mixture was added 6 mol / L hydrochloric acid solution dropwise. The product was crystallized by stirring, filtered, and dried to give compound IV in a yield of 93.1% and a HPLC purity of 99.66%.

[0071] Example 7

[0072] Into a reaction flask was added sodium bicarbonate (1.68 g, 20 mmol), N-BOC-2-aminoisobutyramide (2.02 g, 10 mmol), tetrahydrofuran (30 mL), and the temperature was raised to 45 °C. Phenylthiochloroformate (2.06 g, 12 mmol) was added and the reaction was allowed to proceed for 5 h. To the reaction mixture was added 6 mol / L hydrochloric acid solution dropwise. The product was crystallized by stirring, filtered, and dried to give compound IV in a yield of 93.1% and a HPLC purity of 99.66%.

[0073] Example 8

[0074] Into a reaction flask, add diisopropylethylamine (3.11 g, 24 mmol), N-BOC-2- amino isobutyramide (2.02 g, 10 mmol), N,N-dimethylformamide (40 mL), warm to 70 °C, add phenyl chlorothioformate (4.13 g, 24 mmol), keep reaction for 5 h, add 5 mL of 6 mol / L hydrochloric acid solution dropwise to the reaction system, stir to crystallize, filter and dry to obtain compound IV, with a yield of 86.8% and an HPLC purity of 98.92%.

[0075] Preparation of compound VI

[0076] Example 9

[0077] Into a 100 mL three-necked flask, add 20 mL of dichloromethane, and then add compound IV (2.44 g, 10 mmol) and sodium hydride (0.60 g, 25 mmol) successively while stirring, and cool to 0-5 °C. After completion of the addition, continue to stir in the low-temperature bath for 30 min. Dissolve compound V (2.99 g, 12 mmol) in 12 mL of dichloromethane, and slowly add it dropwise to the reaction liquid while controlling the internal temperature at 0-5 °C. After completion of the addition, restore to room temperature, and continue to stir for 4 h. Monitor the completion of the reaction by TLC. Add the reaction liquid to 100 mL of water, filter to obtain the crude product, and recrystallize it from ethanol to obtain the target compound, with a yield of 96.8% and an HPLC purity of 99.90%.

[0078] Example 10

[0079] Into a 100 mL three-necked flask, add 20 mL of dichloromethane, and then add compound IV (2.44 g, 10 mmol) and sodium hydride (0.60 g, 25 mmol) successively while stirring, and cool to 0-5 °C. After completion of the addition, continue to stir in the low-temperature bath for 30 min. Dissolve compound V (2.99 g, 12 mmol) in 12 mL of dichloromethane, and slowly add it dropwise to the reaction liquid while controlling the internal temperature at 0-5 °C. After completion of the addition, restore to room temperature, and continue to stir for 4 h. Monitor the completion of the reaction by TLC. Add the reaction liquid to 100 mL of water, filter to obtain the crude product, and recrystallize it from ethanol to obtain the target compound, with a yield of 96.8% and an HPLC purity of 99.90%.

[0080] Example 11

[0081] Into a 100 mL three-necked flask, 20 mL of n-hexane was added, compound IV (2.44 g, 10 mmol) was added under stirring, cooled to 0-5 °C, sodium hydride (0.72 g, 30 mmol) was added in portions. After addition, low temperature continued to stir for 30 min. Compound V (2.99 g, 12 mmol) was dissolved in 12 mL of n-hexane, which was slowly added to the reaction solution, the internal temperature was controlled at 0-5 °C. After addition, the temperature was restored to room temperature, and stirring was continued for 4 h, TLC monitoring reaction completion. The reaction solution was added to 100 mL of water, and the crude product was obtained by filtration, and the target compound was obtained by recrystallization with ethanol, with a yield of 93.1% and an HPLC purity of 99.55%.

[0082] Example 12

[0083] Into a 100 mL three-necked flask, 20 mL of n-hexane was added, compound IV (2.44 g, 10 mmol) was added under stirring, cooled to 0-5 °C, sodium hydride (0.72 g, 30 mmol) was added in portions. After addition, low temperature continued to stir for 30 min. Compound V (2.99 g, 12 mmol) was dissolved in 12 mL of n-hexane, which was slowly added to the reaction solution, the internal temperature was controlled at 0-5 °C. After addition, the temperature was restored to room temperature, and stirring was continued for 4 h, TLC monitoring reaction completion. The reaction solution was added to 100 mL of water, and the crude product was obtained by filtration, and the target compound was obtained by recrystallization with ethanol, with a yield of 93.1% and an HPLC purity of 99.55%.

[0084] Example 13

[0085] Into a 100 mL three-necked flask, 20 mL of n-hexane was added, compound IV (2.44 g, 10 mmol) was added under stirring, cooled to 0-5 °C, sodium hydride (0.72 g, 30 mmol) was added in portions. After addition, low temperature continued to stir for 30 min. Compound V (2.99 g, 12 mmol) was dissolved in 12 mL of n-hexane, which was slowly added to the reaction solution, the internal temperature was controlled at 0-5 °C. After addition, the temperature was restored to room temperature, and stirring was continued for 4 h, TLC monitoring reaction completion. The reaction solution was added to 100 mL of water, and the crude product was obtained by filtration, and the target compound was obtained by recrystallization with ethanol, with a yield of 93.1% and an HPLC purity of 99.55%.

[0086] Example 14

[0087] Into a 100 mL flask, 20 mL of dichloromethane was added, under stirring, compound IV (2.44 g, 10 mmol) was added, cooled to 0-5 °C, and sodium tert-butoxide (2.40 g, 25 mmol) was added in portions. After the addition was completed, the low-temperature bath was continued to stir for 30 min. Compound V (4.98 g, 20 mmol) was dissolved in 12 mL of dichloromethane, and it was slowly added dropwise to the reaction solution, controlling the internal temperature to 0-5 °C. After the addition was completed, the temperature was returned to room temperature, and stirring was continued for 4 h, and the reaction completion was monitored by TLC. The reaction solution was added to 100 mL of water, and the crude product was obtained by filtration. Enzalutamide was obtained by recrystallization from ethanol, with a yield of 93.3% and an HPLC purity of 99.65%.

[0088] Example 15

[0089] Into a 100 mL flask, 20 mL of dichloromethane was added, under stirring, compound IV (2.44 g, 10 mmol) was added, cooled to 0-5 °C, and sodium tert-butoxide (2.40 g, 25 mmol) was added in portions. After the addition was completed, the low-temperature bath was continued to stir for 30 min. Compound V (4.98 g, 20 mmol) was dissolved in 12 mL of dichloromethane, and it was slowly added dropwise to the reaction solution, controlling the internal temperature to 0-5 °C. After the addition was completed, the temperature was returned to room temperature, and stirring was continued for 4 h, and the reaction completion was monitored by TLC. The reaction solution was added to 100 mL of water, and the crude product was obtained by filtration. Enzalutamide was obtained by recrystallization from ethanol, with a yield of 93.3% and an HPLC purity of 99.65%.

[0090] Preparation of Compound I

[0091] Example 16

[0092] Into a 100 mL flask, 20 mL of dichloromethane was added, under stirring, compound IV (2.44 g, 10 mmol) was added, cooled to 0-5 °C, and sodium tert-butoxide (2.40 g, 25 mmol) was added in portions. After the addition was completed, the low-temperature bath was continued to stir for 30 min. Compound V (4.98 g, 20 mmol) was dissolved in 12 mL of dichloromethane, and it was slowly added dropwise to the reaction solution, controlling the internal temperature to 0-5 °C. After the addition was completed, the temperature was returned to room temperature, and stirring was continued for 4 h, and the reaction completion was monitored by TLC. The reaction solution was added to 100 mL of water, and the crude product was obtained by filtration. Enzalutamide was obtained by recrystallization from ethanol, with a yield of 93.3% and an HPLC purity of 99.65%.

[0093] Example 17

[0094] Into a reaction flask, 30 mL of chloroform was added, and then compound VI (4.13 g, 10 mmol), trifluoroacetic acid (2.28 g, 20 mmol) were added under stirring. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was cooled to -5-0 °C, and then sodium tert-butoxide (2.40 g, 25 mmol) was added in portions. After the addition was completed, the solution was stirred at low temperature for 30 min. Compound VII (4.62 g, 20 mmol) was dissolved in chloroform and then slowly added to the reaction solution at -5-0 °C. After the addition was completed, the solution was stirred at room temperature for 5 h. The reaction was completed as monitored by TLC. The reaction solution was added to 50 mL of water, and then the crude product was obtained by filtration. After drying, enzalutamide was recrystallized from isopropanol (50 mL) to obtain a yield of 93.9% and a purity of 99.60% by HPLC.

[0095] Example 18

[0096] Into a reaction flask, 30 mL of chloroform was added, and then compound VI (4.13 g, 10 mmol), trifluoroacetic acid (2.28 g, 20 mmol) were added under stirring. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was cooled to -5-0 °C, and then sodium tert-butoxide (2.40 g, 25 mmol) was added in portions. After the addition was completed, the solution was stirred at low temperature for 30 min. Compound VII (4.62 g, 20 mmol) was dissolved in chloroform and then slowly added to the reaction solution at -5-0 °C. After the addition was completed, the solution was stirred at room temperature for 5 h. The reaction was completed as monitored by TLC. The reaction solution was added to 50 mL of water, and then the crude product was obtained by filtration. After drying, enzalutamide was recrystallized from isopropanol (50 mL) to obtain a yield of 93.9% and a purity of 99.60% by HPLC.

[0097] Example 19

[0098] Into a reaction flask, 30 mL of chloroform was added, and then compound VI (4.13 g, 10 mmol), trifluoroacetic acid (2.28 g, 20 mmol) were added under stirring. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was cooled to -5-0 °C, and then sodium tert-butoxide (2.40 g, 25 mmol) was added in portions. After the addition was completed, the solution was stirred at low temperature for 30 min. Compound VII (4.62 g, 20 mmol) was dissolved in chloroform and then slowly added to the reaction solution at -5-0 °C. After the addition was completed, the solution was stirred at room temperature for 5 h. The reaction was completed as monitored by TLC. The reaction solution was added to 50 mL of water, and then the crude product was obtained by filtration. After drying, enzalutamide was recrystallized from isopropanol (50 mL) to obtain a yield of 93.9% and a purity of 99.60% by HPLC.

[0099] Example 20

[0100] Into a reaction flask was placed 30 mL of 1,2-dichloroethane, and then compound VI (4.13 g, 10 mmol) and trifluoroacetic acid (2.28 g, 20 mmol) were added under stirring. The reaction was stirred at room temperature for 2 h, and then the reaction solution was cooled to 5-10 °C. Sodium tert-butoxide (3.56 g, 37 mmol) was added in portions. After the addition was completed, the solution was stirred at low temperature for 30 min, and then compound VII (4.62 g, 20 mmol) was dissolved in 1,2-dichloroethane and slowly added dropwise into the reaction solution. After the addition was completed, the solution was allowed to return to room temperature and stirred for 5 h. The reaction was monitored by TLC. The reaction solution was added to 50 mL of water, and the crude product was obtained by filtration. After drying, enzalutamide was recrystallized from isopropanol (50 mL) to give a yield of 89.3% and an HPLC purity of 98.85%.

[0101] Example 21

[0102] Into a reaction flask was placed 30 mL of 1,2-dichloroethane, and then compound VI (4.13 g, 10 mmol) and trifluoroacetic acid (2.28 g, 20 mmol) were added under stirring. The reaction was stirred at room temperature for 2 h, and then the reaction solution was cooled to 5-10 °C. Sodium tert-butoxide (3.56 g, 37 mmol) was added in portions. After the addition was completed, the solution was stirred at low temperature for 30 min, and then compound VII (4.62 g, 20 mmol) was dissolved in 1,2-dichloroethane and slowly added dropwise into the reaction solution. After the addition was completed, the solution was allowed to return to room temperature and stirred for 5 h. The reaction was monitored by TLC. The reaction solution was added to 50 mL of water, and the crude product was obtained by filtration. After drying, enzalutamide was recrystallized from isopropanol (50 mL) to give a yield of 89.3% and an HPLC purity of 98.85%.

[0103] Example 22

[0104] Into a reaction flask was placed 30 mL of 1,2-dichloroethane, and then compound VI (4.13 g, 10 mmol) and trifluoroacetic acid (2.28 g, 20 mmol) were added under stirring. The reaction was stirred at room temperature for 2 h, and then the reaction solution was cooled to 5-10 °C. Sodium tert-butoxide (3.56 g, 37 mmol) was added in portions. After the addition was completed, the solution was stirred at low temperature for 30 min, and then compound VII (4.62 g, 20 mmol) was dissolved in 1,2-dichloroethane and slowly added dropwise into the reaction solution. After the addition was completed, the solution was allowed to return to room temperature and stirred for 5 h. The reaction was monitored by TLC. The reaction solution was added to 50 mL of water, and the crude product was obtained by filtration. After drying, enzalutamide was recrystallized from isopropanol (50 mL) to give a yield of 89.3% and an HPLC purity of 98.85%.

[0105] Example 23

[0106] Into a 250 ml three necked flask, 150 ml DMF was added, under stirring, 13.6 g of 2-methyl-2-chloro-propionic acid methyl ester, 7.6 g of thiourea and 10.1 g of triethylamine were added. The reaction mixture was heated to 80-90 °C and stirred for 7 h. The reaction was monitored by TLC. The reaction mixture was cooled to room temperature and added to 600 ml of water. The solid was stirred for 30 min and filtered. The filter cake was washed with water for 2 times. The filter cake was dried under vacuum at 50-55 °C till constant weight. The product was recrystallized from ethanol to get 5,5-dimethyl-2-thioxoimidazol-4-one in 85.5 % yield.

[0107] Example 24

[0108] Into a 250 ml three necked flask, 150 ml DMF was added, under stirring, 13.6 g of 2-methyl-2-chloro-propionic acid methyl ester, 7.6 g of thiourea and 10.1 g of triethylamine were added. The reaction mixture was heated to 80-90 °C and stirred for 7 h. The reaction was monitored by TLC. The reaction mixture was cooled to room temperature and added to 600 ml of water. The solid was stirred for 30 min and filtered. The filter cake was washed with water for 2 times. The filter cake was dried under vacuum at 50-55 °C till constant weight. The product was recrystallized from ethanol to get 5,5-dimethyl-2-thioxoimidazol-4-one in 85.5 % yield.

[0109] Comparative Example

[0110] Into a 250 ml three necked flask, 150 ml DMF was added, under stirring, 13.6 g of 2-methyl-2-chloro-propionic acid methyl ester, 7.6 g of thiourea and 10.1 g of triethylamine were added. The reaction mixture was heated to 80-90 °C and stirred for 7 h. The reaction was monitored by TLC. The reaction mixture was cooled to room temperature and added to 600 ml of water. The solid was stirred for 30 min and filtered. The filter cake was washed with water for 2 times. The filter cake was dried under vacuum at 50-55 °C till constant weight. The product was recrystallized from ethanol to get 5,5-dimethyl-2-thioxoimidazol-4-one in 85.5 % yield.

[0111] Into a 250 ml three-necked flask, 100 ml DMF was added, 5,5-dimethyl-2-thioxoimidazol-4-one 13.1 g was added under stirring, cooled to 0-5 °C in ice water bath, 6 g sodium hydride was added in portions. After addition, the ice water bath was continued to stir for 30 min. 22.75 g 2-trifluoromethyl-4-bromobenzonitrile was dissolved in 60 ml DMF, which was slowly added to the reaction liquid, the internal temperature was controlled at 0-5 °C. After addition, it was restored to room temperature, continued to stir for 4 h, TLC monitoring reaction completion. The reaction liquid was added to 500 ml water, filtered to get the crude product. After drying, column chromatography purification to get 5,5-dimethyl-3-(3-trifluoromethyl-4-fluorophenyl)-2-thioxoimidazol-4-one, yield 60.2%.

[0112] Into a 250 ml three-necked flask, 100 ml DMF was added, 5,5-dimethyl-3-(3-trifluoromethyl-4-fluorophenyl)-2-thioxoimidazol-4-one 18.5 g was added under stirring, cooled to 0-5 °C in ice water bath, 3.9 g sodium hydride was added in portions. After addition, the ice water bath was continued to stir for 30 min. 13.68 g 2-fluoro-4-bromobenzamide was dissolved in 30 ml DMF, which was slowly added to the reaction liquid, the internal temperature was controlled at 0-5 °C. After addition, it was restored to room temperature, continued to stir for 5 h, TLC monitoring reaction completion. The reaction liquid was added to 500 ml water, filtered to get the crude product. After drying, column chromatography purification to get enzalutamide, yield 81.2%.

Claims

1. A process for the preparation of enzalutamide, characterized in that, The preparation method comprises the following steps: 1) at room temperature, compound II, compound III and a base are added into an organic solvent A, and the reaction is stirred to obtain compound IV; 2) compound IV is added into an organic solvent B, a base is added in batches at low temperature, compound V is dissolved in the organic solvent B and slowly added into the reaction solution, the temperature is increased to room temperature, and the reaction is stirred until it is completed to obtain compound VI; 3) compound VI is added into dichloromethane, trifluoroacetic acid is added, the reaction is stirred at room temperature, a base is added in batches at low temperature after the reaction is monitored to be completed, compound VII is dissolved in an organic solvent C and slowly added into the reaction solution, the temperature is increased to room temperature, and the reaction is stirred until it is completed to obtain enzalutamide; The synthesis route is as follows: 。 2. The production method according to claim 1, characterized by, In step 1), the base is selected from one of 4-dimethylaminopyridine, sodium bicarbonate, sodium carbonate, triethylamine and diisopropylethylamine.

3. The preparation method according to claim 1, characterized in that, In step 1), the molar ratio of compound II, compound III and the base is 1:1.2-2.2:1.0-2.

5.

4. The method of claim 1, wherein, In step 1), the organic solvent A is selected from one of N,N-dimethylformamide, n-hexane, n-heptane, acetonitrile and tetrahydrofuran or a combination thereof; and the reaction temperature is 40-65 DEG C.

5. The preparation method according to claim 1, characterized in that, In steps 2) and 3), the base is selected from one of sodium hydride, sodium hydroxide, sodium tert-butoxide and sodium bis(trimethylsilyl)amide.

6. The method of claim 1, wherein, In step 2), the molar ratio of compound IV, compound V and the base is 1:1.0-2.0:2.0-3.

0.

7. The preparation method according to claim 1, characterized in that, In step 2), the organic solvent B is selected from one of dichloromethane, trichloromethane, n-heptane, n-hexane and 1,2-dichloroethane or a combination thereof; and the temperature for adding the base and compound V is -5-5 DEG C.

8. The method of claim 1, wherein, In step 3), the molar ratio of compound VI, trifluoroacetic acid, compound VII and the base is 1:2.0:1.2-2.2:2.5-3.

5.

9. The method of claim 1, wherein, In step 3), the organic solvent C is selected from one of dichloromethane, trichloromethane, n-heptane, n-hexane and 1,2-dichloroethane or a combination thereof.

10. The method of claim 1, wherein, In step 3), the temperature for adding the base and compound VII is -5-5 DEG C.

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