CN108329236A - A kind of preparation method of the miscellaneous Shandong amine intermediate of grace - 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, greater than 80%, and some reactions can be as high as 93%. Moreover, the post-treatment process of the present invention is simple, easy to operate, and suitable for industrialization. Moreover, the reaction conditions of the present invention are relatively mild, without 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 malignant tumor in men. In recent years, it has rapidly risen to a global tumor disease. In many European and American countries, the incidence of prostate cancer accounts for the first among male malignant tumors, and the mortality rate Take second place. About 220,800 men were diagnosed with prostate cancer in the United States in 2015, and about 20,710 of them died. It ranks first and second among all male tumors. In recent years, with the improvement of the early diagnosis level 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 the health of men in my country.

Enzalutamide is a new androgen inhibitor drug, a prostate cancer drug jointly developed by Astellas and Medivation, which 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, referring to the patent CN101460467B, and its synthetic route is as follows:

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

This synthesis method uses the Ullmann condensation reaction under the catalysis of cuprous chloride, the total yield is low, the waste water is much, and the pollution is large. Moreover, highly toxic methyl iodide is used for methylation, and the production cost is high. Difficult to industrial production.

Contents of the invention

4-((2-cyanopropan-2-yl)amino)-2-fluoro-N-methylbenzamide (compound 6) is an important intermediate for the preparation of enzalutamide, and the invention provides a kind of 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 clean process and easy operation.

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

(1) Propan-2-one and cyanide are reacted 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) by 2-amino-2-methylpropionitrile and 4-X-2-fluoro-N-methylbenzamide under the action of a catalyst, a substitution reaction occurs to generate 4-((2-cyanopropane-2- Base) amino) -2-fluoro-N-methylbenzamide;

Wherein X is F, Cl, Br or I.

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

In one 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 prepared with water, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone, ether, thiazol-2-amine, ethyl acetate, acetonitrile, benzene , toluene, N,N-dimethylformamide or dimethyl sulfoxide or a mixture of two or more solvents.

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

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

In one embodiment of the present invention, the step (2) is based on dichloromethane, chloroform, acetonitrile, ethyl acetate, butyl acetate, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone , ether, N,N-dimethylformamide or dimethyl sulfoxide, or a mixture of two or more solvents.

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

In one 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 prepared with dichloromethane, chloroform, acetonitrile, ethyl acetate, butyl acetate, methanol, ethanol, propanol, isopropanol, tetrahydrofuran, acetone , ether, N,N-dimethylformamide or dimethyl sulfoxide, or a mixture of two or more solvents.

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

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

Advantages and effects of the present invention:

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

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

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

specific implementation plan

The present invention is described in detail by the following examples, it is necessary to point out that the following examples are only used to further illustrate the present invention, and can not be interpreted as limiting the scope of the present invention, those skilled in the art according to the content of the above invention Some non-essential improvements and adjustments still belong to the protection scope of the present invention.

Embodiment 1: the preparation of compound 15

Ammonium chloride (9.6g, 0.18mol), propan-2-one (10.2g, 0.17mol), and ammonia (30% aqueous solution, 10mL) were added to 20mL 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 60 h to stop the reaction, extracted with dichloromethane (2*10 mL), and the combined organic layer was washed with saturated sodium chloride (5 mL) solution, then dried with anhydrous sodium sulfate, filtered, and the filtrate was After concentrating under reduced pressure, a white oil was obtained with a yield of 85-90%.

The preparation of embodiment 2 compound 10

Compound 9 (2.2g, 10mmol) was added to anhydrous ethylene glycol dimethyl ether (20mL), the solution was cooled to 0°C, and thionyl chloride (1.5g, 13mmol) was slowly added under stirring. The reaction was mild Exothermic, during the addition of thionyl chloride, the solution temperature does not exceed 5°C, after the addition is complete, react at 0°C for 1 hour, and then react the solution at 50°C for no less than 6 hours or TLC monitoring shows that the reaction is complete, and the solution temperature Cool down to 25°C, slowly add a solution of methylamine (0.9g, 30mmol) dissolved in ethylene glycol dimethyl ether (5mL) dropwise, and react the mixed solution at 35°C for 0.5h or stop the reaction after TLC monitoring shows that the reaction is complete , add saturated brine (15mL), extract with ethyl acetate (2*15mL), separate the layers, combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate, and dry to give a white solid with a yield of 88-93%.

The preparation of embodiment 3 compound 10

To a stirred solution of compound 9 (1.5 g, 6.84 mmol) in DCM (15 mL) was added dropwise oxalyl chloride (3.45 g, 27.39 mmol) 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 anhydrous 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.

The preparation of embodiment 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) K ₂ CO ₃ (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 H ₂ O (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 obtain the product in 83-87% yield.

The preparation of embodiment 5 compound 6

Compound 10 (0.69g, 3mmol) was dissolved in anhydrous DMF (60mL), cesium carbonate (2.44g, 6.45mmol) was added to the solution and the solution was warmed up to 80°C, dissolved in DMF (5mL) Compound 15 was added thereto, reacted at 80°C for 6h to stop the reaction, cooled to room temperature, added pure water (30mL) and stirred for 0.5h, then extracted with ethyl acetate (3*30mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product in 85-90% yield. ¹ H NMR (400MHz, CDCl ₃ ) δ7.76(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=14.7,2.2Hz,1H),6.43(br,1H),2.83(s,3H),1.72(s,6H); ¹³ C NMR(101MHz,CDCl ₃ )δ164.21,161.43,149.32,132.18 , 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. Any person familiar with this technology can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore The scope of protection of the present invention should be defined by the claims.

Claims (10)

1. a kind of preparation method of enzalutamide intermediate 4-((2-cyanopropan-2-yl) amino)-2-fluoro-N-methylbenzamide, it is characterized in that, described method comprises Follow the steps below: (1) Propan-2-one and cyanide are reacted 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) by 2-amino-2-methylpropionitrile and 4-X-2-fluoro-N-methylbenzamide under the action of a catalyst, a substitution reaction occurs to generate 4-((2-cyanopropane-2- Base) amino) -2-fluoro-N-methylbenzamide; Wherein X is F, Cl, Br or I. 2. method according to claim 1, is characterized in that, in described step (1), weak base is ammoniacal liquor. 3. The method according to claim 2, characterized in that the concentration of the ammonia water is 18-33%. 4. method according to claim 1, is characterized in that, described step (1) is with water, methanol, ethanol, propanol, Virahol, tetrahydrofuran, acetone, ether, thiazol-2-amine, ethyl acetate One or more mixtures of esters, acetonitrile, benzene, toluene, N,N-dimethylformamide or dimethyl sulfoxide are used as solvents. 5. The method according to claim 1, characterized in that, the reaction temperature of the step (1) is 0° C. or normal temperature. 6. The method according to claim 1, characterized in that, in the step (2), the chlorinating agent is oxalyl chloride, sulfonyl chloride or dichloride. 7. method according to claim 1, is characterized in that, described step (2) is with dichloromethane, chloroform, acetonitrile, ethyl acetate, butyl acetate, methyl alcohol, ethanol, propanol, isopropyl alcohol One or two or more of alcohol, tetrahydrofuran, acetone, ether, N,N-dimethylformamide or dimethyl sulfoxide are used as solvents. 8. method according to claim 1, is characterized in that, in described step (3), catalyzer is cesium carbonate, salt of wormwood, calcium carbonate, sodium carbonate, magnesium carbonate, barium carbonate, triethylamine, potassium bicarbonate, Sodium bicarbonate or calcium bicarbonate. 9. method according to claim 1, is characterized in that, described step (3) is with dichloromethane, chloroform, acetonitrile, ethyl acetate, butyl acetate, methyl alcohol, ethanol, propanol, isopropyl alcohol One or two or more of alcohol, tetrahydrofuran, acetone, ether, N,N-dimethylformamide or dimethyl sulfoxide are used as solvents. 10. The application of the method according to claim 1 in the preparation of a medicament for prostate cancer.