CN108329236B - A kind of preparation method of enzalutamide intermediate - Google Patents

Abstract

The invention discloses a preparation method of an enzalutamide intermediate, which belongs to the field of medicine and chemical industry. The reaction yield of each step of the present invention is very high, more than 80%, and some reactions can be as high as 93%. In addition, the post-treatment process of the invention is simple, easy to operate, and suitable for industrialization. In addition, the reaction conditions of the present invention are relatively mild, and there are no harsh reaction conditions of high temperature, high pressure and ultra-low temperature.

Description

A kind of preparation method of enzalutamide intermediate

technical field

The invention relates to a preparation method of an enzalutamide intermediate, which belongs to the field of medicine and chemical industry.

Background technique

Prostate cancer (PCa) is a common male malignant tumor. In recent years, it has rapidly become a global tumor disease. In many European and American countries, the incidence of prostate cancer ranks first among male malignant tumors, and the mortality rate occupy second place. About 220,800 men in the United States developed prostate cancer in 2015, and about 20,710 of them died. It ranks first and second among all male tumors, respectively. In recent years, with the improvement of the level of early diagnosis of prostate cancer, the incidence of prostate cancer in my country has been increasing year by year, and it will become a common malignant tumor affecting men's health in my country.

Enzalutamide is a new androgen inhibitor drug. It is a prostate cancer drug jointly developed by Astellas and Medivation. The drug was approved by the US FDA in 2012. According to statistics, the market sales of enzalutamide were US$580 million in 2013, US$1 billion in 2014, and US$2.2 billion in 2015. The chemical name is 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thione-1-imidazolidinyl] -2-Fluoro-N-methylbenzamide, its structural formula is as follows:

The compound enzalutamide was first researched and synthesized by the University of California, with reference to patent CN101460467B, and its synthetic route is as follows:

This synthetic method adopts iron powder as catalyst to prepare 4-amino-2-fluoro-N-methylbenzamide compound under acidic conditions, a large amount of waste water will be produced in this preparation process, and the product yield and purity are not high, It is not suitable for large-scale industrial production; in addition, the use of highly toxic chromium trioxide as an oxidant has a large toxic effect on the human body and the environment. Therefore, Medivation company has carried out improvement to its synthesis technique, with reference to patent document CN103108549A, the specific synthesis route is as follows:

The synthesis method uses the Ullmann condensation reaction catalyzed by cuprous chloride, and the total yield is low, the waste water is large, and the pollution is large. In addition, methylation is carried out by using highly toxic methyl iodide, and the production cost is high. Difficult to industrialize production.

SUMMARY OF THE INVENTION

4-((2-cyanopropan-2-yl)amino)-2-fluoro-N-methylbenzamide (compound 6) is an important intermediate for preparing enzalutamide, and the present invention provides a kind of this intermediate. The preparation method of the intermediate overcomes the problems of low synthesis yield, high production cost and environmental pollution in the preparation process of the intermediate in the prior art, and develops a production route with a clean process and easy operation.

The first object of the present invention is to provide a preparation method of enzalutamide intermediate 4-((2-cyanopropan-2-yl)amino)-2-fluoro-N-methylbenzamide, so The method includes the following steps:

(1) reacting propan-2-one and cyanide under weak base conditions to generate 2-amino-2-methylpropionitrile;

(2) 4-X-2-fluorobenzoic acid is converted into 4-X-2-fluoro-N-methylbenzamide under the action of a chlorinating agent;

(3) 4-((2-cyanopropane-2- base)amino)-2-fluoro-N-methylbenzamide;

wherein X is F, Cl, Br or I.

In an embodiment of the present invention, the weak base in the step (1) is ammonia water with different concentrations.

In an embodiment of the present invention, the concentration of the ammonia water is 18-33%.

In one embodiment of the present invention, the step (1) is water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone, ether, thiazol-2-amine, ethyl acetate, acetonitrile, benzene One or more of toluene, N,N-dimethylformamide or dimethyl sulfoxide are mixed as a solvent.

In an embodiment of the present invention, the reaction temperature of the step (1) is 0° C. or normal temperature.

In an embodiment of the present invention, in the step (2), the chlorinating agent is oxalyl chloride, sulfonyl chloride or chloroform.

In one embodiment of the present invention, the step (2) is dichloromethane, trichloromethane, acetonitrile, ethyl acetate, butyl acetate, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone , diethyl ether, N,N-dimethylformamide or dimethyl sulfoxide in one or more mixed as solvent.

In one embodiment of the present invention, in the step (3), the catalyst is cesium carbonate, potassium carbonate, calcium carbonate, sodium carbonate, magnesium carbonate, barium carbonate, triethylamine, potassium bicarbonate, sodium bicarbonate or carbonic acid calcium hydrogen.

In an embodiment of the present invention, the catalyst in the step (3) is preferably cesium carbonate.

In one embodiment of the present invention, the step (3) is dichloromethane, trichloromethane, acetonitrile, ethyl acetate, butyl acetate, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone , diethyl ether, N,N-dimethylformamide or dimethyl sulfoxide in one or more mixed as solvent.

In one embodiment of the present invention, the reaction equation of the method is:

The second object of the present invention is to provide the application of the method in the preparation of a medicament for prostate cancer.

Advantages and effects of the present invention:

The yield of each step is very high, more than 80%, and some reactions can be as high as 93%.

The post-processing process is simple, easy to operate, and suitable for industrialization.

The reaction conditions are relatively mild, and there are no harsh reaction conditions of high temperature, high pressure and ultra-low temperature.

specific implementation

The present invention will be specifically described by the following examples. It is necessary to point out that the following examples are only used to further illustrate the present invention, and should not be construed as limiting the protection scope of the present invention. Some non-essential improvements and adjustments made still belong to the protection scope of the present invention.

Example 1: Preparation of Compound 15

Ammonium chloride (9.6 g, 0.18 mol), propan-2-one (10.2 g, 0.17 mol), and ammonia (30% aqueous solution, 10 mL) were added to 20 mL of pure water, and cyanide was added under stirring at 0°C Sodium chloride (8.6 g, 0.17 mol). The mixed solution was stirred at room temperature for 60h to stop the reaction, extracted with dichloromethane (2*10mL), the combined organic layers were washed with saturated sodium chloride (5mL) solution, then dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced under reduced pressure. Concentration under reduced pressure gave a white oil in 85-90% yield.

Example 2 Preparation of Compound 10

Compound 9 (2.2g, 10mmol) was added to anhydrous ethylene glycol dimethyl ether (20mL), the solution was cooled to 0°C, thionyl chloride (1.5g, 13mmol) was slowly added under stirring, the reaction was mild Exothermic, during the addition of thionyl chloride, the temperature of the solution should not exceed 5 °C. After the addition of thionyl chloride, the solution should be reacted at 0 °C for 1 hour, and then the solution should be reacted at 50 °C for no less than 6 hours or TLC monitoring showed that the reaction was complete. When the temperature dropped to 25°C, the methylamine (0.9g, 30mmol) solution dissolved in ethylene glycol dimethyl ether (5mL) was slowly added dropwise to it, and the mixed solution was reacted at 35°C for 0.5h or the reaction was stopped after TLC monitoring showed that the reaction was complete. , added saturated brine (15mL), extracted with ethyl acetate (2*15mL), layered, combined the organic layers, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain a white solid with a yield of 88-93%.

Example 3 Preparation of Compound 10

To a stirred solution of compound 9 (1.5 g, 6.84 mmol) in DCM (15 mL) was added oxalyl chloride (3.45 g, 27.39 mmol) dropwise at 0 °C. After the addition was complete, 2-3 drops of DMF were added at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dry THF (20 mL). To this solution was added methylamine (50 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was azeotroped with toluene to give the product in 80-85% yield.

Preparation of Example 4 Compound 6

Compound 10 (0.53 g, 2.29 mmol), compound 15 (0.30 g, 3.54 mmol), CuI (87 mg, 0.458 mmol) K2CO3 (0.79 _g , 5.72 mmol) were mixed in DMF ( ₅ mL). _H2O (0.5 mL) and TEA (11 mg, 0.1 mmol) were added, followed by 2-acetylcyclohexanone (60 mg, 0.43 mmol). The reaction mixture was heated to 95-100°C for 4 hours. The reaction mixture was diluted with _H2O (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product in 83-87% yield.

Example 5 Preparation of Compound 6

Compound 10 (0.69 g, 3 mmol) was dissolved in anhydrous DMF (60 mL), cesium carbonate (2.44 g, 6.45 mmol) was added to the solution and the solution was warmed to 80 °C. Compound 15 was added, and the reaction was stopped at 80° C. for 6 h. The reaction was cooled to room temperature, pure water (30 mL) was added, and the mixture was stirred for 0.5 h, and then extracted with ethyl acetate (3*30 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product in 85-90% yield. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.76 (t, J=8.7Hz, 1H), 7.08 (d, J=10.3Hz, 1H), 6.70 (dd, J=8.7, 2.3Hz, 1H), 6.59 (dd, J=14.7, 2.2 Hz, 1H), 6.43 (br, 1H), 2.83 (s, 3H), 1.72 (s, 6H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 164.21, 161.43, 149.32, 132.18 , 121.43, 110.82, 110.76, 100.75, 47.62, 27.52, 25.87; MS(ESI): calcd for C ₁₂ H ₁₄ FN ₃ O[M+H] ⁺ 236.1194, found 236.1190.

Although the present invention has been disclosed above with preferred embodiments, it is not intended to limit the present invention. Anyone who is familiar with this technology can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, The protection scope of the present invention should be defined by the claims.

Claims (9)

1. A process for preparing enzalutamide intermediate 4- ((2-cyanopropan-2-yl) amino) -2-fluoro-N-methylbenzamide comprising the steps of:

(1) reacting the propan-2-one with cyanide under the condition of weak base to generate 2-amino-2-methyl propionitrile;

(2) 4-X-2-fluorobenzoic acid is converted into 4-X-2-fluoro-N-methylbenzamide under the action of a chlorinating agent;

(3) 2-amino-2-methylpropanenitrile and 4-X-2-fluoro-N-methylbenzamide are subjected to substitution reaction under the action of a catalyst to generate 4- ((2-cyanopropane-2-yl) amino) -2-fluoro-N-methylbenzamide;

wherein X is F, Cl, Br or I;

the catalyst in the step (3) is cesium carbonate.

2. The method according to claim 1, wherein the weak base in step (1) is ammonia.

3. The method of claim 2, wherein the concentration of the aqueous ammonia is 18% to 33%.

4. The method according to claim 1, wherein the solvent in step (1) is one or more selected from water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone, diethyl ether, thiazol-2-amine, ethyl acetate, acetonitrile, benzene, toluene, N-dimethylformamide and dimethylsulfoxide.

5. The method according to claim 1, wherein the reaction temperature of step (1) is 0 ℃ or normal temperature.

6. The method according to claim 1, wherein the chlorinating agent in the step (2) is oxalyl chloride, sulfuryl chloride or thionyl chloride.

7. The method according to claim 1, wherein the solvent in step (2) is one or more selected from dichloromethane, chloroform, acetonitrile, ethyl acetate, butyl acetate, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone, diethyl ether, N-dimethylformamide, and dimethylsulfoxide.

8. The method according to claim 1, wherein the solvent in step (3) is one or more selected from dichloromethane, chloroform, acetonitrile, ethyl acetate, butyl acetate, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone, diethyl ether, N-dimethylformamide, and dimethylsulfoxide.

9. Use of the method of claim 1 for the preparation of a medicament for treating prostate cancer.