Method for synthesizing anastrozole intermediate-2,2'-(5-methyl-1,3-phenylene)-bis-(2-methyl propionitrile)

A technology of anastrozole and methylpropionitrile, applied in the field of compound synthesis, can solve the problems of difficult synthesis of starting materials and low yield of intermediates, and achieve the effect of easy synthesis, high yield, and cheap and easy-to-obtain raw materials

Active Publication Date: 2011-02-16
UNIV OF SCI & TECH OF CHINA
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0012] The use of highly toxic cyanide is inevitable in both methods, and the synthesis of starting materials is di

Method used

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  • Method for synthesizing anastrozole intermediate-2,2'-(5-methyl-1,3-phenylene)-bis-(2-methyl propionitrile)
  • Method for synthesizing anastrozole intermediate-2,2'-(5-methyl-1,3-phenylene)-bis-(2-methyl propionitrile)
  • Method for synthesizing anastrozole intermediate-2,2'-(5-methyl-1,3-phenylene)-bis-(2-methyl propionitrile)

Examples

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Example Embodiment

[0055] Example 1:

[0056] (1) Preparation of ethyl 2-cyano-2-methylpropionate

[0057] Add ethyl cyanoacetate (4.52g, 40mmol), DBU (22.07g, 88mmol) and 50mL DMF to a 150ml round bottom flask equipped with a magnet. After stirring in an ice-water bath for 10 minutes, iodomethane (12.49 g, 88 mmol) was slowly added dropwise. After the dropwise addition, the round-bottomed flask was covered with a lid, the ice-water bath was removed, and the reaction was stirred at room temperature for 2 h. After the reaction, the solution in the round bottom flask was transferred to a 250mL separatory funnel, 80mL of ethyl acetate was added, the organic phase was extracted twice with 80mL of water, and once with 80mL of saturated saline. After the extraction, the organic phase was dried with anhydrous magnesium sulfate for 20 minutes, filtered, and the solvent ethyl acetate was removed by a vacuum rotary evaporator, and then separated by a simple chromatographic column to obtain a light yello...

Example Embodiment

[0063] Example 2:

[0064] (1) Preparation of sodium cyanoacetate

[0065] method 1:

[0066] Sodium hydroxide (1.60 g, 40 mmol) and 50 mL of ethanol were added to a 150 mL round bottom flask equipped with a magnet, and cyanoacetic acid (3.40, 40 mmol) and 30 mL of ethanol were added to another 100 mL round bottom flask. Add the ethanol solution of cyanoacetic acid dropwise to the ethanol solution of sodium hydroxide under stirring, and continue stirring for 20 minutes after the dropwise addition is completed. After the reaction was completed, ethanol and a small amount of water produced were removed by a vacuum rotary evaporator, filtered, and washed three times with a small amount of ether to obtain a white solid with a yield of 98%.

[0067] Method 2:

[0068] Sodium hydroxide (1.60 g, 40 mmol) and 50 mL of ethanol were added to a 150 mL round bottom flask equipped with a magnet, and ethyl cyanoacetate (4.52 g, 40 mmol) and 30 mL of ethanol were added to another 100 mL ...

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Abstract

The invention provides a method for synthesizing an anastrozole intermediate-2,2'-(5-methyl-1,3-phenylene)-bis-(2-methyl propionitrile), which comprises the following steps: dissolving a cyanoacetate derivative and 3,5-dihalogenated toluene in a solvent, carrying out decarboxylation cyanomethylation reaction under the action of a palladium catalyst and an organic phosphorus ligand, obtaining a target product, or obtaining 2,2'-(5-methyl-1,3-phenylene)-bis-(acetonitrile), and further being reacted with halogenated methane or methane which is ready to be halogenated in the presence of a strong base hydride, and generating the target product. The method for synthesizing the intermediate can avoid the use of highly toxic cyanide, and has the advantages of cheap price and easy obtainment of raw materials, easy synthesis, no side reactions and high yield.

Description

technical field [0001] The invention relates to the field of compound synthesis, in particular to a method for synthesizing an anticancer drug anastrozole intermediate 2,2'-(5-methyl-1,3-phenylene)bis(2-methylpropionitrile) . Background technique [0002] The chemical name of Anastrozole is: 2,2'-[5-(1H-1,2,4-triazol-1-yl-methyl)-1,3-phenylene]bis(2 -methylpropionitrile) or a,a,a',a'-tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-diethylcyanobenzene . Its chemical formula is: [0003] [0004] The chemical formula of its synthetic intermediate 2,2'-(5-methyl-1,3-phenylene)bis(2-methylpropionitrile) is: [0005] [0006] Anastrozole is a potent and selective non-steroidal aromatase inhibitor developed by AstraZeneca (AstraZeneca). It is suitable for advanced breast cancer in postmenopausal women who cannot be controlled by tamoxifen and other anti-estrogen therapy, and has high medicinal value. The drug was launched in the UK in September 1995, and the US FDA has...

Claims

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Application Information

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IPC IPC(8): C07C255/33C07C253/30
Inventor 尚睿黄铮傅尧郭庆祥刘磊
Owner UNIV OF SCI & TECH OF CHINA
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