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

[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 yellow liquid with a yield of 85%.

[0058] (2) Preparation of potassium 2-cyano-2-methylpropionate from ethyl 2-cyano-2-methylpropionate

[0059] Potassium hydroxide (1.91g, 34mmol) and 50mL of ethanol were added to a 150mL round bottom flask equipped with a magnet, and ethyl 2-cyano-2-methylpropionate (4.80mL) was added to another 100mL round bottom flask. g, 34mmol) and 30mL ethanol. Add the ethanol solution of ethyl 2-cyano-2-methylpropionate dropwise to the ethanol solution of potassium hydroxide under stirring, and continue to stir for 2 hours after the dropwise addition. After the reaction was completed, the ethanol was 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 97%.

[0060] (3) Preparation of 2,2'-(5-methyl-1,3-phenylene)bis(2-methylpropionitrile)

[0061] In an oven-dried 50 mL Schlenk bottle equipped with a magnet, add dipolyallylpalladium chloride (0.0044g, 0.012mmol), XantPhos (0.0208g, 0.036mmol), 3,5-dibromo Toluene (3.00 g, 12 mmol) and potassium 2-cyano-2-methylpropionate (4.35 g, 28.8 mmol). The cover is coated with a vacuum grease grinding plug, connected to the Schrank vacuum line, the air in the container is drained and filled with nitrogen, repeat 3 times, and 12 mL of mesitylene is added under the reverse flow of nitrogen. After the addition, cover with a stopper, put it into a 140°C oil pan after clamping, and stir for 20 hours. After the reaction was completed, it was directly separated by chromatographic column to obtain white crystals with a yield of 88%.

[0062] The resulting product was subjected to nuclear magnetic resonance, figure 1 2,2'-(5-methyl-1,3-phenylene) bis(2-methylpropionitrile) hydrogen nuclear magnetic resonance spectrum, figure 2 It is the carbon nuclear magnetic resonance spectrum of 2,2'-(5-methyl-1,3-phenylene)bis(2-methylpropionitrile).

[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 round bottom flask. Add the ethanol solution of ethyl cyanoacetate dropwise to the ethanol solution of sodium hydroxide under stirring, and continue stirring for 2 hours after the addition is complete. After the reaction was completed, ethanol was removed with a vacuum rotary evaporator, filtered, and washed three times with a small amount of ether to obtain a white solid with a yield of 96%.

[0069] (2) Preparation of 2,2'-(5-methyl-1,3-phenylene)bisacetonitrile from sodium cyanoacetate

[0070] In an oven-dried 50 mL Schlenk bottle equipped with a magnet, add di-allyl palladium chloride (0.0059 g, 0.016 mmol), S-Phos (0.0197 g, 0.048 mmol), 3,5- Dichlorotoluene (2.58 g, 16 mmol) and sodium cyanoacetate (4.11 g, 38.4 mmol). The lid is coated with a vacuum grease grinding plug, connected to the Schrank vacuum line, the air in the container is drained and filled with nitrogen, repeat 3 times, and 16 mL of mesitylene is added under the backflow of nitrogen. After the addition, cover with a stopper, put it into a 140°C oil pan after clamping, and stir for 20 hours. After the reaction was completed, it was directly separated by chromatographic column to obtain white crystals with a yield of 84%.

[0071] (3) Preparation of 2,2'-(5-methyl-1,3-phenylene)bis(2-methylpropionitrile)

[0072] Add 2,2'-(5-methyl-1,3-phenylene)bisacetonitrile (2.04g, 12mmol), NaH (1.27g, 52.8mmol) and 50mL DMF. After stirring in an ice-water bath for 10 minutes, iodomethane (7.49 g, 52.8 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 white crystals with a yield of 90%.

[0073] Wherein starting material 3,5-dihalogenated toluene (X=Cl, Br) can be synthesized through four steps by traditional method:

[0074]

[0075] The method for synthesizing the anastrozole intermediate 2,2'-(5-methyl-1,3-phenylene)bis(2-methylpropionitrile) provided by the present invention has been described in detail above. In this paper, specific examples are used to illustrate the principle and implementation of the present invention, and the descriptions of the above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be pointed out that for those skilled in the art, without departing from the principle of the present invention, some improvements and modifications can also be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.