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Preparation method of letrozole

A technology of letrozole and triazole, applied in the field of synthesis of highly selective third-generation aromatase inhibitors, can solve problems such as difficult large-scale industrial production, poor chemical selectivity, and harsh reaction conditions, and achieve The effect of low production cost, great application value and social and economic benefits, and simple route

Inactive Publication Date: 2016-07-27
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] The purpose of the present invention is to provide a new preparation method of letrozole, to overcome the harsh reaction conditions, complex operations, serious pollution, low yield, poor chemical selectivity and difficulty in large-scale industrialization in the prior art. production problem

Method used

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  • Preparation method of letrozole

Examples

Experimental program
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Effect test

Embodiment 1

[0049] Embodiment 1: Preparation of 4,4-dicyanodiphenylmethane (compound 3)

[0050]Add 36g (0.32mol) of potassium tert-butoxide into 120ml of tetrahydrofuran, add dropwise a solution of 23.4g (0.2mol) of tetrahydrofuran (40ml) of p-methylbenzonitrile at -10°C, stir for half an hour after the addition, and keep the temperature constant Change. Weigh 32.9g (0.24mol) of p-chlorobenzonitrile, dissolve it in 80ml tetrahydrofuran, slowly drop it into the above reaction solution, control the temperature and react at -5~0°C, and continue the reaction for 2h after dropping. After the reaction, add water and stir to precipitate a solid, suction filter, wash the filter cake with water, and dry to obtain 31.6 g of a light yellow product with a yield of 72%.

[0051] Melting point: 167-169℃, 1 HNMR (400MHz, CDCl 3 )δ7.62(d, 4H, J=8.2Hz), 7.29(d, 4H, J=8.2Hz), 4.11(s, 2H).

Embodiment 2

[0052] Embodiment 2: Preparation of 4,4-dicyanodiphenylmethane (compound 3)

[0053] Dissolve 23.4g (0.2mol) of p-toluonitrile in 40ml of tetrahydrofuran, and add n-butyllithium in tetrahydrofuran (128ml, 2.5M / L) dropwise under cooling at -60°C, and continue stirring after the addition is complete For half an hour, at this temperature, a tetrahydrofuran (80ml) solution of 32.9g (0.24mol) of p-chlorobenzonitrile was added dropwise, and the reaction temperature was controlled at -60 to -50°C, and the reaction was continued for 2h after dropping. Then it was slowly raised to room temperature, and after the reaction was completed, water was added to precipitate a solid, filtered with suction, washed with water, and dried to obtain 35.1 g of a light yellow product with a yield of 80%.

[0054] Melting point: 167-169℃, 1 HNMR (400MHz, CDCl 3 )δ7.62(d, 4H, J=8.2Hz), 7.29(d, 4H, J=8.2Hz), 4.11(s, 2H).

Embodiment 3

[0055] Embodiment 3: Preparation of 4,4-dicyanodiphenyl bromide (compound 4)

[0056] In the reaction flask, add 11.0g (0.050mol) 4,4'-dicyanodiphenylmethane (compound 3), 9.8g (0.056mol) NBS, 303mg benzoyl peroxide and 50ml dichloromethane, stir Reflux, react for 6 hours, cool to room temperature, add water and stir, separate the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and distill the filtrate to remove the solvent under reduced pressure to obtain 13.6 g of a yellow solid with a yield of 91.6%.

[0057] Melting point: 118-120°C. 1 HNMR (500MHz, CDCl 3 )δ7.68(d,4H,J=8.3Hz,7.55(d,4H,J=8.3Hz),6.25(s,1H).

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Abstract

The invention provides a preparation method of letrozole (6). The preparation method comprises the following steps: reacting a compound (1) with a compound (3) under the effect of an alkaline matter; performing a bromination reaction of the compound (3) to obtain a compound (4); condensing the compound (4) and 4-amino-1,2,4-triazole (5); and performing diazotization to remove the amino to obtain letrozole (6). According to the method provided by the invention, the route is simple; the cheap and easily available p-chlorobenzonitrile and p-tolunitrile are adopted as starting raw materials, and the target product letrozole is obtained through 3 steps of reactions in total; and the preparation method has the advantages of mild reaction conditions, simple and convenient operation, high yield, good chemical selectivity and low production cost, is suitable for industrial production and brings relatively great practical application value and social economic benefits.

Description

(1) Technical field [0001] The invention relates to a new method for preparing letrozole, which belongs to the technical field of synthesis of highly selective third-generation aromatase inhibitors. (2) Background technology [0002] The invention particularly relates to a synthesis process of a highly specific oral non-steroidal third-generation aromatase inhibitor letrozole. The structural formula of letrozole is as follows: [0003] [0004] Breast cancer is the most common malignancy in women worldwide. According to statistics from the International Agency for Research on Cancer (IARC) of the World Health Organization, in 2008, there were 1.38 million new cases of breast cancer in women worldwide, accounting for 22.9% of all female malignant tumors, and 460,000 women died of breast cancer, accounting for all female malignant tumors. 13.7% of cancer deaths accounted for 1.7% of all female deaths. According to statistics, there are 169,000 female breast cancer cases ...

Claims

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Application Information

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IPC IPC(8): C07D249/08
CPCC07D249/08
Inventor 张兴贤李鹏诚祁伟鹏周鑫煜周金金
Owner ZHEJIANG UNIV OF TECH
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