CN115703745A - Preparation method of enzalutamide - Google Patents

Abstract

The invention relates to a preparation method of enzalutamide, belonging to the technical field of medicine preparation. The method comprises the steps of taking N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine as a starting material, reacting at room temperature in the presence of an organic solvent and N, N-carbonyldiimidazole, reacting with an alcohol compound in the presence of alkali, and crystallizing, filtering, washing and drying to obtain a lipid compound; lipid compounds and 4-isothiocyanato-2- (trifluoromethyl) benzonitrile are mixed in an organic solvent, stirred and heated to react, and the enzalutamide is prepared after concentration, crystallization, filtration, washing and drying. The method can reduce the safety and occupational health risks and is beneficial to large-scale production; the consumption of the raw material 4-isothiocyanato-2- (trifluoromethyl) benzonitrile can also be reduced, thereby reducing the cost.

Description

A kind of preparation method of enzalutamide

technical field

The invention relates to a preparation method of enzalutamide, which belongs to the technical field of medicine preparation.

Background technique

Enzalutamide is a new non-steroidal androgen receptor antagonist for the treatment of prostate cancer, jointly developed by Astellas and Medivation, and its trade name is Xtandi. Enzalutamide was approved for marketing by the US Food and Drug Administration (FDA) on August 31, 2012, for the treatment of prostate cancer. The chemical formula of enzalutamide is 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thione-1- Imidazolidinyl]-2-fluoro-N-methylbenzamide, the molecular structure is as follows:

Currently, the reported preparation methods of enzalutamide mainly contain the following:

1) Patent WO2011106570 reports a preparation method of enzalutamide. The chemical reaction equation of described method is as follows:

Among them, 4-bromo-2-fluorobenzoic acid (compound 1 in the chemical reaction equation) is reacted with thionyl chloride (SOCl ₂ ) and methylamine (MeNH ₂ ) to prepare 4-bromo-2-fluoro-N- Methylbenzoic acid (compound 2 in the chemical reaction equation); 4-bromo-2-fluoro-N-methylbenzoic acid is prepared by reacting with 2-methylalanine under CuI catalysis to obtain N-[3-fluoro- 4-[(methylamino)carbonyl]phenyl]-2-methylalanine (compound 3 in the chemical reaction equation); N-[3-fluoro-4-[(methylamino)carbonyl]phenyl ]-2-methylalanine reacts with iodomethane (MeI) to prepare N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine methyl ester (chemical Compound 4) in the reaction equation; N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine methyl ester and 4-isothiocyanoyl-2-( Trifluoromethyl) benzonitrile (compound 5 in the chemical reaction equation), the molar ratio of the two is 2, and the reaction is prepared to obtain enzalutamide. The biggest problem of the method is that carcinogenic and neurotoxic chemical substance—methyl iodide is used in the synthesis process, which is not conducive to safe production.

2) Aiming at the deficiencies in patent WO2011106570, patent CN110396063 reports a preparation method of enzalutamide. The chemical reaction equation of described method is as follows:

Wherein, N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine (compound 3 in the chemical reaction equation) is used as starting material, and 2-bromoethyl Ethyl ether or p-methoxybenzyl chloride instead of methyl iodide carries out esterification and prepares compound 11 in the chemical reaction equation, and described compound 11 is 4-isothiocyanato-2-(trifluoromethyl) benzyl Nitrile (compound 5 in the chemical reaction equation) was reacted to obtain enzalutamide. In the method, 2-bromoethyl ethyl ether is extremely flammable (flash point 70 ° F), and p-methoxybenzyl chloride has a strong stimulating effect on human mucous membranes and respiratory tracts, causing certain safety and security risks in the enlarged production. Occupational health risk; the molar ratio of raw material 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (compound 5 in the chemical reaction equation) to compound 11 is 2.1～2.2, because the market price of compound 5 is relatively Expensive, resulting in higher production costs.

3) Patent CN107690427 reports a preparation method of enzalutamide, the chemical reaction equation of the method is as follows:

Wherein, with N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine (compound 3 in the chemical reaction equation) as the starting material, first in 1-ethyl Under the action of 3(3-dimethylpropylamine)carbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBt), react with ethylamine (EtNH ₂ ) in solvent DMF to prepare amide compound 12 , Enzalutamide was prepared by reacting amide compound 12 with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile (compound 5 in the chemical reaction equation). In the method, highly toxic and volatile ethylamine raw materials need to be used, which is not conducive to large-scale production; the yield of enzalutamide is 47.3%, which is relatively low; the raw material 4-isothiocyanoyl-2 The molar ratio of -(trifluoromethyl)benzonitrile (compound 5 in the chemical reaction equation) to compound 12 is 2.2 to 5.4, relatively high, and the consumption is large, 4-isothiocyanoyl-2-(tri The market price of fluoromethyl)benzonitrile (compound 5) is relatively expensive, resulting in higher production costs.

Contents of the invention

In order to overcome the problems of safety and occupational health risks and high production costs in the preparation method of enzalutamide in the prior art, the object of the present invention is to provide a preparation method of enzalutamide, which can reduce safety and Occupational health risks are beneficial to scale up production; at the same time, the method can reduce the amount of raw material 4-isothiocyanoyl-2-(trifluoromethyl)benzonitrile, thereby reducing production costs.

In order to realize the object of the present invention, the following technical solutions are provided.

A preparation method of enzalutamide, the method steps are as follows:

(1) With N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine (compound 3 in the chemical reaction equation) as starting material, organic solvent, In the presence of N,N-carbonyldiimidazole (CDI), react at room temperature for 1h to 2h, and then react with alcohol compounds (ROH in the chemical reaction equation) at 20°C to 60°C for 4h to 10h in the presence of a base, After crystallization, filtration, washing and drying, a lipid compound (compound II in the chemical reaction equation) was obtained.

(2) Mix the lipid compound and 4-isothiocyanoyl-2-(trifluoromethyl)benzonitrile (compound 5 in the chemical reaction equation) in an organic solvent, and stir at 75°C to 95°C Heat the reaction for 10h-20h, concentrate and crystallize, filter, wash and dry to prepare enzalutamide (compound I in the chemical reaction equation).

The chemical equation of the method is as follows:

In step (1):

The organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile or tetrahydrofuran, preferably N,N-dimethylformamide or N,N-dimethylacetamide .

Preferably, the ratio of the volume of the organic solvent to the mass of the reaction raw material N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 2mL～10mL:1g, more preferably For 4mL: 1g.

Preferably, the molar ratio of N,N-carbonyldiimidazole (CDI) to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1-2:1 , more preferably 1.2:1.

The alcohol compound is 2,2,2-trifluoroethanol or 2,2-difluoroethanol.

Preferably, the molar ratio of the alcohol compound to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1 to 5:1, preferably 1.9: 1.

Preferably, the base is potassium carbonate, calcium carbonate, sodium carbonate, magnesium carbonate, N,N-diisopropylethylamine, N-methylmorpholine, triethylamine or pyridine, more preferably, the base is pyridine.

Preferably, the molar ratio of the base to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1-5:1, more preferably 2:1 .

The crystallization refers to the process of adding water to separate out lipid compound crystals after the reaction is finished.

Preferably, the volume ratio of water and organic solvent in the crystallization is 1-10:1, more preferably 3-5:1.

The water in the crystallization is preferably water with a purity equal to or higher than that of deionized water.

In step (2):

Preferably, the molar ratio of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile to lipid compound is 1.6-1.9:1, more preferably 1.6:1.

The organic solvent is a mixture of dimethyl sulfoxide and ethyl acetate, a mixture of dimethyl sulfoxide and isopropyl acetate, a mixture of N,N-dimethylformamide and ethyl acetate or N,N-dimethyl A mixture of methyl formamide and isopropyl acetate; preferably a mixture of dimethyl sulfoxide and isopropyl acetate; preferably the volume ratio of isopropyl acetate to dimethyl sulfoxide is 1 to 7:1.

The concentrated crystallization means that after the reaction is finished, the organic solvent is removed under reduced pressure, isopropanol is added and heated to 75°C to 90°C, and then the temperature is lowered to crystallize; the ratio of the volume of the isopropanol to the weight of the lipid compound is 3mL ~10mL:1g, preferably 6mL~7mL:1g.

Beneficial effect

1. The present invention provides a method for preparing enzalutamide. In the preparation process, highly toxic chemical raw materials such as methyl iodide and ethanolamine, extremely flammable raw material 2-bromoethyl ethyl ether and other raw materials that are not conducive to large-scale production are not used. , but use 2,2,2-trifluoroethanol and 2,2-difluoroethanol with relatively low toxicity and relatively high safety, which reduces safety and occupational health risks and is conducive to scale-up production.

2. The present invention provides a method for preparing enzalutamide. The method uses cheap and easy-to-obtain N,N-carbonyldiimidazole as a condensation agent to easily and conveniently prepare a new lipid compound, which can efficiently prepare Enzalutamide; its advantage is that during the reaction of lipid compounds with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, the by-product 2,2,2-trifluoroethanol or 2,2 -Difluoroethanol has weaker nucleophilicity, which can effectively reduce the side reaction with 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, and ultimately reduce the need for expensive raw material 4- The amount of isothiocyanato-2-(trifluoromethyl)benzonitrile used. After calculation, to produce 1kg enzalutamide, the required 4-isothiocyanoyl-2-(trifluoromethyl)benzonitrile of the prior art is 1.19kg～2.28kg, and the present invention is 0.98kg; meanwhile, in In the process of producing 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, it is necessary to use the highly toxic substance thiophosgene to reduce the concentration of 4-isothiocyanato-2-(trifluoromethyl)benzene The use amount of formonitrile can further reduce safety and environmental protection pressure, and is conducive to large-scale production.

Detailed ways

The present invention will be described in detail below in conjunction with specific examples, but not as a limitation to the patent of the present invention.

In order to enable a detailed understanding of the technical features and contents of the present invention, preferred embodiments of the present invention will be described in more detail below. Although preferred embodiments of the present invention have been described in the examples, it should be understood that the invention can be embodied in various forms and should not be limited by the embodiments set forth herein.

Example 1

Take the raw material N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine (compound 3 in the chemical reaction equation) 10.0g (39.3mmol), N,N- Put 8.0g (49.3mmol) of carbonyldiimidazole (CDI) and 40mL of N,N-dimethylformamide in the reaction flask, stir at room temperature for 1.5h, then add 6.4g (80.9mmol) of pyridine and 2,2,2-trifluoro Ethanol 7.5g (74.9mmol), reacted at 25°C for 10h, poured 160mL of deionized water into the reaction solution, precipitated crystals, filtered, washed with deionized water 3 times, 20mL each time, dried in vacuum at 60°C to obtain 12.2g of the product , the yield was 92%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result proved that the structure of the product was shown as compound II-a in the chemical reaction equation, and it was a lipid compound. The specific test results are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.69–7.62 (m, 1H), 7.46 (t, J = 8.9Hz, 1H), 6.88 (s, 1H), 6.31 (dd, J = 8.7, 2.3 Hz, 1H), 6.14(dd, J=14.5, 2.3Hz, 1H), 4.81(q, J=9.0Hz, 2H), 2.73(d, J=4.5Hz, 3H), 1.52(s, 6H); HRMS (ESI) Calcd for C14H16F4N2O5Na[M+Na] ⁺ 359.0989, found: 359.0986.

Example 2

Take the raw material N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine (compound 3 in the chemical reaction equation) 10.0g (39.3mmol), N,N- Put 12.7g (78.3mmol) of carbonyldiimidazole (CDI) and 40mL of N,N-dimethylformamide in the reaction flask, stir at room temperature for 1.5h, then add 15.5g (196.0mmol) of pyridine and 2,2,2-trifluoro Ethanol 19.6g (195.9mmol), reacted at 25°C for 10h, poured 160mL of deionized water into the reaction liquid, precipitated crystals, filtered, washed with deionized water 3 times, 20mL each time, and dried in vacuum at 60°C to obtain 11.9g of the product , the yield was 90%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result was the same as in Example 1, which proved that the product structure was shown as compound II-a in the chemical reaction equation, and it was a lipid compound.

Example 3

Take the raw material N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine (compound 3 in the chemical reaction equation) 10.0g (39.3mmol), N,N- Put 8.0g (49.3mmol) of carbonyldiimidazole (CDI) and 40mL of N,N-dimethylformamide in the reaction flask, stir at room temperature for 1.5h, then add 6.4g (80.9mmol) of pyridine and 2,2,2-trifluoro Ethanol 7.5g (74.9mmol), heated to 60°C for 4 hours, poured 160mL deionized water into the reaction solution, precipitated crystals, filtered, washed 3 times with deionized water, 20mL each time, vacuum dried at 60°C to obtain the product 12.7g, yield 96%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result was the same as in Example 1, which proved that the product structure was shown as compound II-a in the chemical reaction equation, and it was a lipid compound.

Example 4

Take the raw material N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine (compound 3 in the chemical reaction equation) 10.0g (39.3mmol), N,N- Put 8.0g (49.3mmol) of carbonyldiimidazole (CDI) and 40mL of N,N-dimethylformamide in the reaction flask, stir at room temperature for 1.5h, then add 6.4g (80.9mmol) of pyridine and 2,2,2-trifluoro 7.5g (74.9mmol) of ethanol, heated to 60°C for 4 hours, poured 120mL deionized water into the reaction liquid, precipitated crystals, filtered, washed 3 times with deionized water, 20mL each time, dried in vacuum at 60°C to obtain the product 11.5 g, yield 87%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result was the same as in Example 1, which proved that the product structure was shown as compound II-a in the chemical reaction equation, and it was a lipid compound.

Example 5

Take the raw material N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine (compound 3 in the chemical reaction equation) 10.0g (39.3mmol), N,N- Put 8.0g (49.3mmol) of carbonyldiimidazole (CDI) and 40mL of N,N-dimethylformamide in the reaction flask, stir at room temperature for 1.5h, then add 6.4g (80.9mmol) of pyridine and 2,2,2-trifluoro Ethanol 7.5g (74.9mmol), heated to 60°C for 4 hours, poured 200mL deionized water into the reaction solution, precipitated crystals, filtered, washed with deionized water 3 times, 20mL each time, vacuum dried at 60°C to obtain the product 12.8 g, yield 97%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result was the same as in Example 1, which proved that the product structure was shown as compound II-a in the chemical reaction equation, and it was a lipid compound.

Example 6

Take the raw material N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine (compound 3 in the chemical reaction equation) 10.0g (39.3mmol), N,N- Put 8.0g (49.3mmol) of carbonyldiimidazole (CDI) and 40mL of N,N-dimethylformamide in the reaction flask, stir at room temperature for 1.5h, then add 6.4g (80.9mmol) of pyridine and 6.2 g (75.6mmol), heated to 60°C for 4h, poured 160mL of deionized water into the reaction liquid, precipitated crystals, filtered, washed with deionized water 3 times, 20mL each time, and dried in vacuum at 60°C to obtain 11.8g of the product , the yield was 94%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result proved that the structure of the product was shown as compound II-b in the chemical reaction equation, and it was a lipid compound. The specific test results are as follows:

¹ H NMR (400MHz, Chloroform-d) δ7.90(t, J=9.0Hz, 1H), 6.57(d, J=12.0 Hz, 1H), 6.36(dd, J=8.7, 2.4Hz, 1H), 6.16(dd, J=14.9, 2.4Hz, 1H), 5.84(tt, J=54.9, 3.9Hz, 1H), 4.55(s, 1H), 4.31(td, J=13.6, 4.0Hz, 2H), 2.98 (dd,J=4.8,1.2 Hz,3H),1.62(s,6H).HRMS(ESI) Calcd for C14H17F3N2O5Na[M+Na] ⁺ 341.1083,found:341.1081.

Example 7

Get the compound II-a 4.0g (11.9mmol) that above-mentioned embodiment makes, 4-isothiocyanoyl-2-(trifluoromethyl) benzonitrile (compound 5 in chemical reaction equation) 5.1g (22.3 mmol), 6 mL of isopropyl acetate and 3 mL of dimethyl sulfoxide were mixed, heated to 85 ° C, stirred and heated for 14 h; concentrated under reduced pressure to remove most of the organic solvent, then added 25 mL of isopropanol, stirred at 85 ° C for 2 h, and then cooled to Crystallize at 5°C, filter, wash the filter cake three times with 10 mL of isopropanol, and dry in vacuum at 60°C for 8 hours to obtain 4.6 g of white solid product with a yield of 83%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result proved that the structure of the product was shown as compound I in the chemical reaction equation, which was enzalutamide. The specific test results are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.46(br, 1H), 8.42-8.40(d, J=8.0Hz, 1H), 8.29(s, 1H), 8.10-8.08(d, J=8.0 Hz,1H),7.81-7.76(t,J=8.0Hz,1H),7.46-7.42 (dd,J=8.4Hz,J=1.6Hz,1H),7.35-7.31(dd,J=8.4Hz,J =1.6Hz, 1H), 2.81-2.78 (d, J=8.0Hz, 1H), 1.54(s, 6H).

Example 8

Get the compound II-a 4.0g (11.9mmol) that above-mentioned embodiment makes, 4-isothiocyanoyl-2-(trifluoromethyl) benzonitrile (compound 5 in chemical reaction equation) 4.4g (19.3mmol ), isopropyl acetate (IPAc) 6mL and dimethyl sulfoxide (DMSO) 3mL were mixed, heated to 85°C, stirred and heated for 14h; concentrated under reduced pressure to remove most of the solvent, then added 25mL of isopropanol, stirred at 85°C for 2h , then cooled to 5°C for crystallization, filtered, and the filter cake was washed three times with 10 mL of isopropanol, and vacuum-dried at 60°C for 8 hours to obtain 4.5 g of a white solid product with a yield of 82%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result was the same as in Example 7, which proved that the product structure was enzalutamide as shown in compound I in the chemical reaction equation.

Example 9

Get the compound II-a 4.0g (11.9mmol) that above-mentioned embodiment makes, 4-isothiocyanoyl-2-(trifluoromethyl) benzonitrile (compound 5 in chemical reaction equation) 4.4g (19.3mmol ), ethyl acetate (EA) 6mL and dimethyl sulfoxide (DMSO) 3mL were mixed, heated to 75°C, stirred and heated for 14h; concentrated under reduced pressure to remove most of the solvent, then added 25mL of isopropanol, stirred at 85°C for 2h, Then cooled to 5° C. to crystallize, filtered, and the filter cake was washed three times with 10 mL of isopropanol, and vacuum-dried at 60° C. for 8 hours to obtain 3.9 g of a white solid product with a yield of 71%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result was the same as in Example 7, which proved that the product structure was enzalutamide as shown in compound I in the chemical reaction equation.

Example 10

Get the compound II-a 4.0g (11.9mmol) that above-mentioned embodiment makes, 4-isothiocyanoyl-2-(trifluoromethyl) benzonitrile (compound 5 in chemical reaction equation) 4.4g (19.3mmol ), ethyl acetate (EA) 6mL and N,N-dimethylformamide (DMF) 3mL were mixed, heated to 75°C, stirred and heated for 14h; concentrated under reduced pressure to remove most of the solvent, and then added 25mL of isopropanol, Stir at 85°C for 2 hours, then cool to 5°C to crystallize, filter, wash the filter cake three times with 10 mL of isopropanol, and dry in vacuum at 60°C for 8 hours to obtain 2.8 g of white solid product with a yield of 51%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result was the same as in Example 7, which proved that the product structure was enzalutamide as shown in compound I in the chemical reaction equation.

Example 11

Get the compound II-a 4.0g (11.9mmol) that above-mentioned embodiment makes, 4-isothiocyanoyl-2-(trifluoromethyl) benzonitrile (compound 5 in chemical reaction equation) 4.4g (19.3mmol ), isopropyl acetate (IPAc) 6mL and dimethyl sulfoxide (DMSO) 1mL were mixed, heated to 85°C, stirred and heated for 14h; concentrated under reduced pressure to remove most of the solvent, then added 25mL of isopropanol, stirred at 85°C for 2h , then cooled to 5°C for crystallization, filtered, and the filter cake was washed three times with 10 mL of isopropanol, and vacuum-dried at 60°C for 8 hours to obtain 3.2 g of a white solid product with a yield of 58%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result was the same as in Example 7, which proved that the product structure was enzalutamide as shown in compound I in the chemical reaction equation.

Example 12

Get lipid compound (compound II-b in the chemical reaction equation) 3.8g (11.9mmol), 4-isothiocyanato-2-(trifluoromethyl) benzonitrile (chemical In the reaction equation, compound 5) 5.0g (21.9mmol), isopropyl acetate (IPAc) 6mL and dimethylsulfoxide (DMSO) 3mL were mixed, heated to 85°C, stirred and heated for 14h; concentrated under reduced pressure to remove most of the solvent, Then add 25 mL of isopropanol, stir at 85°C for 2 hours, then cool to 5°C to crystallize, filter, wash the filter cake with 10 mL of isopropanol three times, and dry in vacuum at 60°C for 8 hours to obtain 4.5 g of white solid product , the yield was 82%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result was the same as in Example 7, which proved that the product structure was enzalutamide as shown in compound I in the chemical reaction equation.

Example 13

Get lipid compound (compound II-b in the chemical reaction equation) 3.8g (11.9mmol), 4-isothiocyanoyl-2-(trifluoromethyl) benzonitrile (chemical reaction equation) obtained in embodiment 6 Compound 5) 4.4g (19.3mmol), isopropyl acetate (IPAc) 6mL and dimethyl sulfoxide (DMSO) 3mL were mixed, heated to 85°C, stirred and heated for 14h; concentrated under reduced pressure to remove most of the solvent, and then Add 25mL of isopropanol, stir at 85°C for 2h, then cool to 5°C to crystallize, filter, wash the filter cake with isopropanol 3 times, the amount of each wash is 10mL, and dry in vacuum at 60°C for 8h to obtain a white solid product 4.4 g, yield 79%.

The chemical reaction equation of described method is as follows:

The product was detected by proton nuclear magnetic spectrum, and the detection result was the same as in Example 7, which proved that the product structure was enzalutamide as shown in compound I in the chemical reaction equation.

Having described various embodiments of the present invention, the foregoing description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and alterations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.

Claims (10)

1. a preparation method of enzalutamide, characterized in that: the method steps are as follows: (1) Starting from N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine, in the presence of organic solvent and N,N-carbonyldiimidazole reaction at room temperature for 1h to 2h, then in the presence of alkali, react with alcohol compounds at 20°C to 60°C for 4h to 10h, and then obtain lipid compounds through crystallization, filtration, washing and drying; (2) Mix the lipid compound and 4-isothiocyanoyl-2-(trifluoromethyl)benzonitrile in an organic solvent, stir and heat the reaction at 75°C to 95°C for 10h to 20h, and concentrate and crystallize , filtering, washing and drying to prepare enzalutamide; In step (1): The organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile or tetrahydrofuran; The alcohol compound is 2,2,2-trifluoroethanol or 2,2-difluoroethanol; In step (2): The organic solvent is a mixture of dimethyl sulfoxide and ethyl acetate, a mixture of dimethyl sulfoxide and isopropyl acetate, a mixture of N,N-dimethylformamide and ethyl acetate or N,N-dimethyl A mixture of methyl formamide and isopropyl acetate. 2. the preparation method of a kind of enzalutamide according to claim 1, is characterized in that: In step (1): The organic solvent is N,N-dimethylformamide or N,N-dimethylacetamide; The base is potassium carbonate, calcium carbonate, sodium carbonate, magnesium carbonate, N,N-diisopropylethylamine, N-methylmorpholine, triethylamine or pyridine; The water in the crystallization is water whose purity is above that of deionized water; In step (2): The organic solvent is a mixture of dimethyl sulfoxide and isopropyl acetate. 3. the preparation method of a kind of enzalutamide according to claim 2, is characterized in that: In step (1): the base is pyridine. 4. the preparation method of a kind of enzalutamide according to claim 1, is characterized in that: In step (1): The ratio of the volume of the organic solvent to the mass of the reaction raw material N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 2mL～10mL:1g; The molar ratio of N,N-carbonyldiimidazole to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1～2:1; The molar ratio of the alcohol compound to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1-5:1; The molar ratio of the base to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1 to 5:1; The volume ratio of water and organic solvent in crystallization is 1～10:1; In step (2): The molar ratio of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile to lipid compound is 1.6～1.9:1; The volume ratio of isopropyl acetate to dimethyl sulfoxide is 1-7:1. 5. the preparation method of a kind of enzalutamide according to claim 4, is characterized in that: In step (1): The ratio of the volume of the organic solvent to the mass of the reaction raw material N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 4mL:1g; The molar ratio of N,N-carbonyldiimidazole to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1.2:1; The molar ratio of the alcohol compound to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1.9:1; The molar ratio of the base to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 2:1; The volume ratio of water and organic solvent in the crystallization is 3-5:1; In step (2): The molar ratio of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile to lipid compound was 1.6:1. 6. the preparation method of a kind of enzalutamide according to claim 1, is characterized in that: In step (1): The organic solvent is N,N-dimethylformamide or N,N-dimethylacetamide; The base is potassium carbonate, calcium carbonate, sodium carbonate, magnesium carbonate, N,N-diisopropylethylamine, N-methylmorpholine, triethylamine or pyridine; The water in the crystallization is water whose purity is above that of deionized water; The ratio of the volume of the organic solvent to the mass of the reaction raw material N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 2mL～10mL:1g; The molar ratio of N,N-carbonyldiimidazole to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1～2:1; The molar ratio of the alcohol compound to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1-5:1; The molar ratio of the base to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1 to 5:1; The volume ratio of water and organic solvent in crystallization is 1～10:1; In step (2): Described organic solvent is the mixture of dimethyl sulfoxide and isopropyl acetate; The molar ratio of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile to lipid compound is 1.6～1.9:1; The volume ratio of isopropyl acetate to dimethyl sulfoxide is 1-7:1. 7. the preparation method of a kind of enzalutamide according to claim 1, is characterized in that: In step (1): The organic solvent is N,N-dimethylformamide or N,N-dimethylacetamide; The base is potassium carbonate, calcium carbonate, sodium carbonate, magnesium carbonate, N,N-diisopropylethylamine, N-methylmorpholine, triethylamine or pyridine; The water in the crystallization is water whose purity is above that of deionized water; The ratio of the volume of the organic solvent to the mass of the reaction raw material N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 4mL:1g; The molar ratio of N,N-carbonyldiimidazole to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1.2:1; The molar ratio of the alcohol compound to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 1.9:1; The molar ratio of the base to N-[3-fluoro-4-[(methylamino)carbonyl]phenyl]-2-methylalanine is 2:1; The volume ratio of water and organic solvent in the crystallization is 3-5:1; In step (2): Described organic solvent is the mixture of dimethyl sulfoxide and isopropyl acetate; The molar ratio of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile and lipid compound is 1.6:1; The volume ratio of isopropyl acetate to dimethyl sulfoxide is 1-7:1. 8. the preparation method of a kind of enzalutamide according to claim 7, is characterized in that: In step (1): the base is pyridine. 9. according to the preparation method of a kind of enzalutamide described in any one of claims 1～8, it is characterized in that: in step (2): said concentrated crystal refers to that after the reaction ends, the organic solvent is depressurized Remove, add isopropanol and heat up to 75°C-90°C, and then crystallize by cooling down; the ratio of the volume of isopropanol to the mass of lipid compound is 3mL-10mL:1g. 10. A method for preparing enzalutamide according to claim 9, characterized in that: in step (2): the ratio of the volume of isopropanol to the mass of lipid compounds is 6mL-7mL:1g.