Novel method for synthesizing 4,4',4''-trinitrile phenylmethane serving as letrozole-related substance

Abstract

The invention aims to obtain a large amount of high-purity 4,4',4''-trinitrile phenylmethane (I) serving as a letrozole-related substance. A high-purity target product is obtained by reacting 4-tolunitrile serving as a raw material with 4-fluorobenzonitrile in the presence of alkali and performing column chromatography and recrystallization.

Description

technical field

[0001] The invention relates to a method for synthesizing 4,4',4"-tricyanophenylmethane, a related substance of letrozole. Background technique

[0002] Letrozole, 4,4'-(1H-1,2,4-triazol-1-ylmethylene)bisbenzonitrile (IV), is a new generation of aromatase inhibitor, the chemical structure formula is as follows:

[0003]

[0004] IV

[0005] It is an artificially synthesized benzyltriazole derivative. It mainly reduces the level of estrogen by inhibiting aromatase, thereby eliminating the stimulating effect of estrogen on the growth of cancer cells. It is mainly used as a first-line treatment drug for postmenopausal women with advanced breast cancer.

[0006] U.S. Patent EP0236940 describes the synthetic method of letrozole, by 4-cyanobenzyl bromide (Ⅴ)

[0007]

[0008] Ⅴ

[0009] With 1H-1,2,4-triazole (Ⅵ)

[0010]

[0011] Ⅵ

[0012] The reaction affords 4-[1-(1,2,4-triazolyl)methyl]benzonitrile (VII),

[0013]

[0014] VII

[0015] Then ...

Examples

Embodiment 1

[0038] Add 22.4g of potassium tert-butoxide and 0.2L of dimethylformamide into a 1L three-necked flask, cool down to -10°C, stir for 10min, add 11.7g of 4-methylbenzonitrile dropwise at this temperature and dissolve in 150ml of N,N-dimethylformamide The solution of methyl formamide, control the dropping time over 30min, dropwise, keep stirring for 30min, add dropwise the solution of 25.0g 4-fluorobenzonitrile dissolved in 150mlN,N-dimethylformamide at this temperature, dropwise , Stirring at this temperature for 4h. After the reaction is complete, add 3N hydrochloric acid to extract it, adjust the pH to neutral, stir for 30 minutes, concentrate under reduced pressure until no liquid is evaporated to obtain a reddish-brown oil, add 500ml of water and 500ml of ethyl acetate to the concentrate, stir for 10min, and divide liquid, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a reddis...

Embodiment 2

[0040] Add 22.4g of potassium tert-butoxide and 0.2L of N,N-dimethylformamide into a 1L three-necked flask, cool down to -10°C, stir for 10min, add 11.7g of 4-methylbenzonitrile dropwise at this temperature and dissolve in 150ml of N,N -The solution of dimethylformamide, control the dropping time over 30min, after dropping, keep stirring for 30min, then add dropwise the solution of 25.0g of 4-fluorobenzonitrile dissolved in 150ml of N,N-dimethylformamide at this temperature , after dropping, the temperature was naturally raised and stirred overnight. After the reaction is complete, add 3N hydrochloric acid to extract it, adjust the pH to neutral, stir for 30 minutes, concentrate under reduced pressure until no liquid is evaporated to obtain a reddish-brown oil, add 500ml of water and 500ml of ethyl acetate to the concentrate, stir for 10min, and divide liquid, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under ...

Embodiment 3

[0042] Add 33.6g of potassium tert-butoxide and 0.2L of N,N-dimethylformamide into a 1L three-necked flask, cool down to -10°C, stir for 10min, and add dropwise a solution of 11.7g of 4-methylbenzonitrile dissolved in 150ml of DMF at this temperature , control the dropping time over 30min, after dropping, keep stirring for 30min, add dropwise 25.0g of 4-fluorobenzonitrile dissolved in 150ml of N,N-dimethylformamide solution at this temperature, after dropping, naturally heat up and stir overnight . After the reaction is complete, add 3N hydrochloric acid to extract it, adjust the pH to neutral, stir for 30 minutes, concentrate under reduced pressure until no liquid is evaporated to obtain a reddish-brown oil, add 500ml of water and 500ml of ethyl acetate to the concentrate, stir for 10min, and divide liquid, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a reddish-brown oily liqui...

technical field

[0001] The invention relates to a method for synthesizing 4,4',4"-tricyanophenylmethane, a related substance of letrozole. Background technique

[0002] Letrozole, 4,4'-(1H-1,2,4-triazol-1-ylmethylene)bisbenzonitrile (IV), is a new generation of aromatase inhibitor, the chemical structure formula is as follows:

[0003]

[0004] IV

[0005] It is an artificially synthesized benzyltriazole derivative. It mainly reduces the level of estrogen by inhibiting aromatase, thereby eliminating the stimulating effect of estrogen on the growth of cancer cells. It is mainly used as a first-line treatment drug for postmenopausal women with advanced breast cancer.

[0006] U.S. Patent EP0236940 describes the synthetic method of letrozole, by 4-cyanobenzyl bromide (Ⅴ)

[0007]

[0008] Ⅴ

[0009] With 1H-1,2,4-triazole (Ⅵ)

[0010]

[0011] Ⅵ

[0012] The reaction affords 4-[1-(1,2,4-triazolyl)methyl]benzonitrile (VII),

[0013]

[0014] VII

[0015] Then ...

Examples

Embodiment 1

[0038] Add 22.4g of potassium tert-butoxide and 0.2L of dimethylformamide into a 1L three-necked flask, cool down to -10°C, stir for 10min, add 11.7g of 4-methylbenzonitrile dropwise at this temperature and dissolve in 150ml of N,N-dimethylformamide The solution of methyl formamide, control the dropping time over 30min, dropwise, keep stirring for 30min, add dropwise the solution of 25.0g 4-fluorobenzonitrile dissolved in 150mlN,N-dimethylformamide at this temperature, dropwise , Stirring at this temperature for 4h. After the reaction is complete, add 3N hydrochloric acid to extract it, adjust the pH to neutral, stir for 30 minutes, concentrate under reduced pressure until no liquid is evaporated to obtain a reddish-brown oil, add 500ml of water and 500ml of ethyl acetate to the concentrate, stir for 10min, and divide liquid, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a reddis...

Embodiment 2

[0040] Add 22.4g of potassium tert-butoxide and 0.2L of N,N-dimethylformamide into a 1L three-necked flask, cool down to -10°C, stir for 10min, add 11.7g of 4-methylbenzonitrile dropwise at this temperature and dissolve in 150ml of N,N -The solution of dimethylformamide, control the dropping time over 30min, after dropping, keep stirring for 30min, then add dropwise the solution of 25.0g of 4-fluorobenzonitrile dissolved in 150ml of N,N-dimethylformamide at this temperature , after dropping, the temperature was naturally raised and stirred overnight. After the reaction is complete, add 3N hydrochloric acid to extract it, adjust the pH to neutral, stir for 30 minutes, concentrate under reduced pressure until no liquid is evaporated to obtain a reddish-brown oil, add 500ml of water and 500ml of ethyl acetate to the concentrate, stir for 10min, and divide liquid, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under ...

Embodiment 3

[0042] Add 33.6g of potassium tert-butoxide and 0.2L of N,N-dimethylformamide into a 1L three-necked flask, cool down to -10°C, stir for 10min, and add dropwise a solution of 11.7g of 4-methylbenzonitrile dissolved in 150ml of DMF at this temperature , control the dropping time over 30min, after dropping, keep stirring for 30min, add dropwise 25.0g of 4-fluorobenzonitrile dissolved in 150ml of N,N-dimethylformamide solution at this temperature, after dropping, naturally heat up and stir overnight . After the reaction is complete, add 3N hydrochloric acid to extract it, adjust the pH to neutral, stir for 30 minutes, concentrate under reduced pressure until no liquid is evaporated to obtain a reddish-brown oil, add 500ml of water and 500ml of ethyl acetate to the concentrate, stir for 10min, and divide liquid, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a reddish-brown oily liqui...

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