Preparation method of anastrozole

Abstract

The invention provides a preparation method of anastrozole. The preparation method comprises the following steps that 1, 5-bromomethyl-a,a,a',a'-tetramethyl-1,3-xylylene cyanide and 4-amino-1,2,4-triazole are taken as raw materials to react in an organic solvent, and crystallization is conducted to obtain an intermediate I, that is, a,a,a',a'-tetramethyl-5-[(4-amino-1,2,4-triazol)-methylene]-1,3-xylylene cyanide bromide; 2, the intermediate I is dissolved into a solvent, a little amount of water, acid and a metal catalyst are added, sodium azide is added in batches in a reflux state, immediate filtration is conducted after a complete reaction, a mother solution is concentrated until the volume of the solution is 0.25-0.75 times of the original volume of the mother solution, cooling crystallization is conducted, solids are filtered and subjected to PH regulation and extraction, and concentration is conducted to obtain a crude anastrozole product; 3, the crude anastrozole product is dissolved into an alcohol solvent, decoloring and cooling crystallization are conducted, and the fine anastrozole product is obtained. According to the preparation method, iso-anastrozole impurities influencing the medicinal efficacy are prevented from being generated from the source, no iso-anastrozole is detected out, the remaining single impurity content is less than 0.05%, and the remaining total impurity content is less than 0.2%.

Description

technical field [0001] The invention relates to the field of chemical pharmacy, in particular to a preparation method of anastrozole. Background technique [0002] The antineoplastic drug Anastrozle (Anastrozle), the chemical name is 1-[3,5-di(2,2-dimethyl)ethylcyano]benzyltriazole, which is a selective non- Steroidal aromatase inhibitors, which were first launched in the UK in 1995, have the following chemical structural formula: [0003] [0004] Anastrozole is a highly efficient and highly selective third-generation non-steroidal aromatase inhibitor, which is clinically used to treat advanced breast cancer in postmenopausal women who are ineffective in tamoxifen and other anti-estrogen therapy. Good curative effect and less toxicity and adverse reactions. [0005] The synthesis of anastrozole generally adopts the technical route in industrialized production at present as follows: [0006] [0007] Both the Chinese patent CN 103524439 and the European patent EP 17...

AI Technical Summary

Problems solved by technology

However, the preparation process of this route mainly has the following problems: the bromination reaction has many impurities and the yield is low; the content of the product obtained by the condensation reaction is low, and usually the yield after multiple recrystallizations reaches the standard is only 33.0% to 45.0%, resulting in cumbersome processes. The cost increases, which is very unfavorable for industrial production

[0008] As an impurity of anastrozole, anastrozole isomers are unsafe, and their content needs to be controlled and removed from the preparation process of anastrozole as much as possible. Recrystallization reduces the isomers to an acceptable level, as a result, the loss of the product is relatively large and the yield of the product is reduced

Images