A "one-pot" method for synthesizing enzalutamide

A certain amount of enzalutamide technology, applied in the field of pharmaceutical chemical synthesis, can solve the problems of complicated treatment process and cumbersome operation, and achieve the effect of simple separation and purification, simple operation process and shortened process cycle

Active Publication Date: 2016-04-13
SHANGHAI DINGYA PHARM CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The method obtains the target product enzalutamide through a four-step reaction, and the post-treatment process of this synthetic route is complicated and the operation is cumbersome

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Step 1): Preparation of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile

[0019] .

[0020] 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%.

[0021] 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 (C 9 h 3 f 3 N 2 S+H + ).

[0022] Step 2): Preparation of N-methyl-4-bromo-2-fluoro-benzamide

[0023] .

[0024] At room temperature, 200g of 2-fluoro-4-bromobenzoic acid was dissolved in 1400mL of ethyl acetate, and then und...

Embodiment 2

[0030] Step 1), step 2) are the same as embodiment one.

[0031] Step 3): Preparation of Enzalutamide

[0032] .

[0033] 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 precipit...

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PUM

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Abstract

The invention provides a one-pot method for synthetizing enzalutamide and belongs to the field of medicinal chemical synthesis. The method comprises the following steps: firstly, carrying out copper-catalyzed Buchwald reaction on N-methyl-4-bromo-2-fluoro-benzamide and 2-methyl alanine, adding halogenated hydrocarbon, reacting to generate ester, finally adding a key intermediate 4-isothiocyano-2-(trifluoromethyl) cyanophenyl and carrying out bucherer-Bergs reaction to generate the enzalutamide. The method is simple in operation and high in product yield and has the advantages that the intermediate products are not needed to be separated and directly reacted, so that the process flow cycle is shortened; the final product is easy to separate and purify.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a method for preparing enzalutamide. Background technique [0002] 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: [0003] . [0004] 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: [0005] . [0006] 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 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/86
CPCC07D233/86
Inventor 阮诗文严海艳夏洪飞徐丽萍
Owner SHANGHAI DINGYA PHARM CHEM CO LTD
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