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A kind of preparation method of bicalutamide sulfide intermediate

A technology of bicalutamide thioether and intermediates, which is applied in the field of preparation of bicalutamide thioether intermediates, can solve the problems of high cost, long production cycle, cumbersome operation, etc., and achieve simple operation, mild conditions, and reduce cost effect

Active Publication Date: 2021-11-16
常州新星联生物科技有限公司
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  • Abstract
  • Description
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Problems solved by technology

[0009] The object of the present invention is to provide a kind of preparation method of bicalutamide sulfide intermediate, specifically a kind of N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[4- The preparation method of fluorophenylthio]-2-hydroxyl-2-methylpropionamide, to overcome the existing method using highly dangerous sodium hydride, long production cycle, cumbersome operation, unsuitable solvent recovery, large pollution, more emissions, and no Disadvantages of environmental protection and high cost

Method used

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  • A kind of preparation method of bicalutamide sulfide intermediate

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Embodiment 1

[0023] Add 200ml of ethyl acetate into a 500ml three-necked bottle, place the three-necked bottle in a high-low temperature cooling and heating machine, cool the temperature of the reaction system to 0-5°C, add 1.0g of sodium methoxide into the three-necked bottle, and then drop Add 10.5 g of 4-fluorothiophenol, continue to stir at this temperature for 0.5 h after the addition, and then add N-[4-cyano-3-(trifluoromethyl)phenyl]-1,2- Epoxy-2-methylpropionamide 20g, after adding, the reaction system was warmed up to room temperature, TLC followed the reaction process, after reacting for 0.5h, the reaction was complete, washed 3 times with saturated brine, and the ethyl acetate was recovered by rotary evaporation under reduced pressure to If it cannot be evaporated, add 10ml of ethanol to dissolve, cool down at 0-5°C to fully crystallize, filter, and air-dry at 60°C to obtain N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[ 25 g of 4-fluorophenylthio]-2-hydroxy-2-methylpropionamide, yie...

Embodiment 2

[0025] Add 200ml of ethyl acetate into a 500ml three-necked bottle, place the three-necked bottle in a high-low temperature cooling and heating machine, cool the temperature of the reaction system to 0-5°C, add 0.25g of sodium methoxide into the three-necked bottle, and then drop Add 10.5 g of 4-fluorothiophenol, continue to stir at this temperature for 0.5 h after the addition, and then add N-[4-cyano-3-(trifluoromethyl)phenyl]-1,2- Epoxy-2-methyl propionamide 20g, after adding, the reaction system was warmed up to room temperature, TLC followed the reaction process, after 36 hours of reaction, the reaction was not complete, washed 3 times with saturated brine, and the ethyl acetate was recovered by rotary evaporation under reduced pressure. If it cannot be evaporated, add 10ml of ethanol to dissolve, cool down at 0-5°C to fully crystallize, filter, and air-dry at 60°C to obtain N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[ 4-fluorophenylthio]-2-hydroxy-2-methylpropionamide 12g, ...

Embodiment 3

[0027] Add 200ml of ethyl acetate into a 500ml three-necked bottle, place the three-necked bottle in a high-low temperature cooling and heating machine, cool the temperature of the reaction system to 0-5°C, add 4.4g of sodium methoxide into the three-necked bottle, and then drop Add 10.5 g of 4-fluorothiophenol, continue to stir at this temperature for 0.5 h after the addition, and then add N-[4-cyano-3-(trifluoromethyl)phenyl]-1,2- Epoxy-2-methylpropionamide 20g, after adding, the reaction system was warmed up to room temperature, TLC followed the reaction process, after reacting for 0.5h, the reaction was complete, washed 3 times with saturated brine, and the ethyl acetate was recovered by rotary evaporation under reduced pressure to If it cannot be evaporated, add 10ml of ethanol to dissolve, cool down at 0-5°C to fully crystallize, filter, and air-dry at 60°C to obtain N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[ 26 g of 4-fluorophenylthio]-2-hydroxy-2-methylpropionamide, yie...

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Abstract

The invention relates to a preparation method of a bicalutamide sulfide intermediate, and relates to the synthesis of chemical drugs, in particular to a kind of N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[ The preparation method of 4-fluorophenylthio]-2-hydroxy-2-methyl propionamide, the method is to take lower fatty acid ester as solvent, use the alkali metal salt of lower aliphatic alcohol as catalyst, 4-fluorophenyl sulfide Phenol and the alkali metal salt of lower aliphatic alcohol generate 4-fluorobenzenethiophenate, then add N-[4-cyano-3-(trifluoromethyl)phenyl]-1,2-epoxy-2- Methyl propionamide is reacted at room temperature, and the finished product is obtained through separation and purification. The preparation reaction conditions of the present invention are mild, and the use of high-risk sodium hydride and expensive tetrahydrofuran is avoided, and the reaction solvent can also be recovered and applied mechanically, thereby reducing costs and reducing emissions.

Description

technical field [0001] The invention relates to chemical synthesis of medicines, in particular to a preparation method of a bicalutamide sulfide intermediate. Background technique [0002] Bicalutamide (bicalutamide), the chemical name is (±)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2 -Hydroxy-2-methylpropionamide is a non-steroidal androgen antagonist developed by AstraZeneca in the United Kingdom. It was approved for marketing in the United Kingdom in 1995 and is mainly used for the treatment of prostate cancer. [0003] According to literature reports (Howard Tucker, US4636505A1; Howard Tucker et al., J Med Chem 1988, 31:954), the important starting material of bicalutamide N-[4-cyano-3-(trifluoromethyl)phenyl] -3-[4-Fluorophenylthio]-2-hydroxy-2-methylpropionamide (CAS No.: 90356-78-8) was synthesized using tetrahydrofuran as a solvent, firstly by 4-fluorothiophenol React with sodium hydride to generate sodium 4-fluorobenzenethiophenate, and t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C323/52C07C319/14C07C319/28C07C321/26C07C319/12
CPCC07C319/12C07C319/14C07C319/28C07C321/26C07C323/52
Inventor 曹勇施小风洪亮周晨
Owner 常州新星联生物科技有限公司
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