CN104016924B - A kind of " one kettle way " synthesizes grace and to mix the method for Shandong amine - Google Patents

Abstract

The invention provides a "one-pot method" method for synthesizing enzalutamide, which belongs to the field of pharmaceutical chemical synthesis. In this method, N-methyl-4-bromo-2-fluoro-benzamide and 2-methylalanine are firstly subjected to a copper-catalyzed Buchwald reaction, followed by the addition of halogenated alkanes to generate esters, and finally the addition of the key intermediate 4- Isothiocyanato-2-(trifluoromethyl)benzonitrile undergoes Bucherer-Bergs reaction to generate enzalutamide. The intermediate product reacts directly without separation, shortens the process cycle, is simple to operate, easy to separate and purify the final product, and has high product yield.

Description

A "one-pot" method for synthesizing enzalutamide

technical field

The invention relates to the field of pharmaceutical chemical synthesis, in particular to a method for preparing enzalutamide.

Background technique

Enzalutamide is a new drug for androgen inhibitors. It is a prostate cancer drug jointly developed by Astellas and Medivation. Its chemical name is 4-[3-[4-cyano-3-(trifluoromethyl Base) phenyl]-5,5-dimethyl-4-oxo-2-thione-1-imidazolidinyl]-2-fluoro-N-methylbenzamide, its structural formula is as follows:

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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:

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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:

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The method obtains the target product enzalutamide through four-step reactions, and the post-treatment process of this synthetic route is complicated and the operation is cumbersome.

Contents of the invention

The technical problem to be solved by the present invention is to provide a method for synthesizing enzalutamide with simple reaction process, easy operation, little environmental pollution and high economic benefit.

In order to solve the above-mentioned technical problems, the technical scheme adopted in the present invention is the "one-pot method" for synthesizing enzalutamide, which utilizes N-methyl-4-bromo-2-fluoro-benzamide and 2-methylalanine Acid is subjected to Buchwald reaction, then halogenated alkanes are added to react to generate ester, and finally the key intermediate 4-isothiocyanato-2-(trifluoromethyl)benzonitrile is added to generate Bucherer-Bergs reaction to generate enzalutamide. The reaction equation is:

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The specific operation steps are as follows:

A certain amount of N-methyl-4-bromo-2-fluoro-benzamide, 2-methylalanine, inorganic base and copper (I) catalyst were dissolved in dimethyl sulfoxide (DMSO), under nitrogen Under protection, heat to 120°C and stir the reaction, use LC-MS method to detect the reaction progress; then cool the reaction solution to 30~40°C, add alkylation reagent, the reaction time is 30~60min, use LC-MS method to detect the reaction progress ; Then add a certain amount of 4-isothiocyanato-2-(trifluoromethyl) benzonitrile in batches, react overnight at 80°C, and use LC-MS method to detect the reaction process; continue to add methanol, at 80°C After stirring for 45 minutes, cool the reaction solution to 20~30°C, add isopropyl acetate, water, and isopropanol to separate layers, extract the water layer with isopropyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate , add isopropanol, heat to 80°C to dissolve completely, cool to 0°C to precipitate a solid, filter, wash with isopropanol, and dry to obtain the product.

The addition amount of N-methyl-4-bromo-2-fluoro-benzamide is 1.0~1.2 equivalents of 2-methylalanine, the inorganic base is potassium carbonate, and the addition amount is 2-methylalanine 2.0 equivalents of copper (I) catalyst is ketone iodide, its addition is 0.05 equivalents of 2-methylalanine, and the alkylating agent is methyl iodide, ethyl iodide, iodopropane, iodobutane, benzyl Base iodide or methyl bromide, bromoethane, bromopropane, bromobutane, benzyl bromide, the addition of alkylating agent is 1.0 equivalents of 2-methylalanine.

The invention adopts a "one-pot method" to synthesize enzalutamide by improving the reaction process, the intermediate product does not need to be separated and reacted directly, shortens the process flow period, has simple operation process, simple separation and purification of the final product, and high product yield.

The above description is only an overview of the technical solutions of the present invention. In order to understand the technical means of the present invention more clearly and implement them according to the contents of the description, the preferred embodiments of the present invention will be described in detail below. The specific embodiment of the present invention is given in detail by the following examples.

detailed description

Embodiment one

Step 1): Preparation of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile

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Add 5.94L of water and 270mL of thiophosgene to a 20L three-necked flask, control the temperature at 20~30°C, add 457g of 4-amino-2-(trifluoromethyl)benzonitrile in batches under stirring conditions, and continue to Stir the reaction for 1 h, detect the complete reaction by TLC, extract with dichloromethane (1L×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, add petroleum ether for beating, pass through liquid nitrogen to crystallize, filter, and dry , Obtain product 500g, yield 89.3%.

¹ HNMR(400MHz,DMSO-d ₆ )δ7.95(dd,J=8.7and2.6Hz,1H),8.16(d,J=2.6Hz,1H),8.28(d,J=8.7Hz,1H); LC-MS: _m /z ₌ 229.1 ( _{C9H3F3N2S +} H ⁺ ).

Step 2): Preparation of N-methyl-4-bromo-2-fluoro-benzamide

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At room temperature, 200g of 2-fluoro-4-bromobenzoic acid was dissolved in 1400mL of ethyl acetate, and then under nitrogen protection, 1g of N,N-dimethylformamide and 150g of thionyl chloride were successively added to the mixture, and waited After the addition of the raw materials, reflux for 4 hours, concentrate and dry to obtain 230 g of the crude product of 4-bromo-2-fluorobenzoyl chloride, add 1000 mL of ethyl acetate to dissolve, and slowly add the solution dropwise to a mixture of 800 mL of methylamine and ethyl acetate solution (volume ratio: 1:1), the temperature was controlled at 30~35°C, and the stirring reaction was continued for 15 minutes. After the reaction was detected by TLC, 400 mL of saturated saline was added for layering, and 500 mL of ethyl acetate was added to the water layer for layering. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated, and dried to obtain 195 g of a white solid with a yield of 92%.

¹ HNMR(400MHz,DMSO-d ₆ ):δ2.83(s,3H),7.33–7.48(m,2H),7.78–7.84(m,1H),8.46(s,1H); LC-MS:m /z=232.1 (C ₈ H ₇ BrFNO+H ⁺ ).

Step 3): the preparation of enzalutamide

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278.4 g of N-methyl-4-bromo-2-fluoro-benzamide, 103 g of 2-methylalanine, 276 g of potassium carbonate, and 9.5 g of cuprous iodide were dissolved in 2.3 L of dimethylsulfoxide (DMSO), Heated to 120°C and stirred for 16 hours under the protection of nitrogen, then cooled the reaction solution to 30~40°C, added 218g of benzyl iodide, and added 342g of 4-isothiocyanato-2-(trifluoromethyl) in batches after 60 minutes of reaction Benzonitrile, react overnight at 80°C, detect the reaction progress by LC-MS method; continue to add 100mL methanol, stir at 80°C for 45min, cool the reaction solution to 20~30°C, add 4L isopropyl acetate, 2L water , 1L isopropanol layered, the aqueous layer was extracted with isopropyl acetate, the organic phase was combined, dried with anhydrous sodium sulfate, filtered, concentrated, added 1L isopropanol, heated to 80°C to dissolve completely, cooled to 0°C to precipitate The solid was filtered, washed with isopropanol, and dried to obtain 309 g of the product, with a yield of 66.6%.

Embodiment two

Step 1), step 2) are the same as embodiment one.

Step 3): Preparation of Enzalutamide

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Dissolve 232g N-methyl-4-bromo-2-fluoro-benzamide, 103g 2-methylalanine, 276g potassium carbonate and 9.5g cuprous iodide in 2.3L dimethyl sulfoxide (DMSO), in Under nitrogen protection, heat to 120°C and stir for 14 hours, then cool the reaction solution to 30~40°C, add 142g of methyl iodide, and add 342g of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile in batches after 40 minutes of reaction , react overnight at 80°C, and detect the reaction progress by LC-MS method; continue to add 100mL methanol, stir at 80°C for 45min, then cool the reaction solution to 20~30°C, add 4L isopropyl acetate, 2L water, 1L Separate layers of isopropanol, extract the aqueous layer with isopropyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, add 1L of isopropanol, heat to 80°C to dissolve completely, cool to 0°C to precipitate a solid, Filter, wash with isopropanol, and dry to obtain 262 g of the product, with a yield of 56.5%.

Experimental data of enzalutamide: ¹ H-NMR (400MHz, DMSO-d ₆ ): δ1.58(s,6H),2.82(s,3H),7.33–7.48(m,2H)7.78–7.84(m , 1H), 8.08–8.12 (m, 1H), 8.30–8.49 (m, 3H); LC-MS: m/z=465.1 (C ₂₁ H ₁₆ F ₄ N ₄ O ₂ S+H ⁺ ).

Claims (5)

1. A "one pot method" method for synthesizing enzalutamide, characterized in that: a certain amount of N-methyl-4-bromo-2-fluoro-benzamide, 2-methylalanine, Inorganic base and copper(I) catalyst were dissolved in dimethyl sulfoxide (DMSO), heated to 120°C under nitrogen protection and stirred for reaction, and the reaction progress was detected by LC-MS method; then the reaction liquid was cooled to 30~40°C, Add an alkylating agent, the reaction time is 30~60min; then add a certain amount of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile in batches, react at 80°C overnight, and wait until the reaction is complete, Continue to add methanol, stir at 80°C for 45min, then cool the reaction solution to 20~30°C, add isopropyl acetate, water, and isopropanol to separate layers, extract the water layer with isopropyl acetate, combine the organic phases, and use Dry over sodium sulfate, filter, concentrate, add isopropanol, heat to 80°C to dissolve completely, cool to 0°C to precipitate a solid, filter, wash with isopropanol, and dry to obtain the product. 2. The "one pot method" method for synthesizing enzalutamide according to claim 1, characterized in that: the addition of N-methyl-4-bromo-2-fluoro-benzamide is 2-methyl 1.0~1.2 equivalents of alanine. 3. The method for "one-pot" synthesis of enzalutamide according to claim 1, characterized in that: the inorganic base is potassium carbonate, and its add-on is 2.0 equivalents of 2-methylalanine. 4. The method for "one-pot" synthesis of enzalutamide according to claim 1, characterized in that: the copper (I) catalyst is ketone iodide, and its addition is 0.05% of that of 2-methylalanine. equivalent. 5. The "one-pot method" method for synthesizing enzalutamide according to claim 1, wherein the alkylating agent is methyl iodide, ethyl iodide, propane iodide, butane iodide, benzyl iodide or methyl bromide , bromoethane, bromopropane, bromobutane, benzyl bromide, the addition of alkylating agent is 1.0 equivalents of 2-methylalanine.