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A kind of preparation method of Anastrozole impurity

A technology for sodium triazole and compound is applied in the field of preparation of anastrozole impurities, and achieves the effects of simple operation, high product purity and short synthesis route

Active Publication Date: 2021-09-14
CHONGQING HUAPONT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] At present, there is no relevant report to publish 2,3-bis(3-(1-cyano-1-methylethyl)-5-(1H-1,2,4-triazole-1-methyl)phenyl )-2-methylpropionitrile preparation method, in order to better control the quality of anastrozole product, guarantee the drug safety of anastrozole, need to do method verification to the impurity of anastrozole south, therefore, it is necessary to In-depth research on the synthesis process of this impurity

Method used

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  • A kind of preparation method of Anastrozole impurity
  • A kind of preparation method of Anastrozole impurity
  • A kind of preparation method of Anastrozole impurity

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Embodiment 1

[0050] Step 1: Preparation of 2-[3-(1-cyanoethyl)-5-methylphenyl]-2-methylpropionitrile (formula III)

[0051] to N 2 Add 26.0g of 5-methyl-1,3-benzenediacetonitrile and 260ml of DMF into the protected reaction flask, stir, then add 65.0g of methyl iodide, and cool down to 0-5°C in an ice-water bath. Add 14.6 g of sodium hydride in batches under temperature control at 0-5°C, and keep warm at 0-5°C for 0.5h after addition. Pour the reaction solution into 800ml of water, extract once with 400ml of dichloromethane, and extract once more with 200ml, combine the organic phases, wash with drinking water 400ml×3 times, evaporate the organic phases to dryness under reduced pressure, and purify through the column, eluent: n-Hexane / ethyl acetate=15 / 1, the purer eluent was collected and evaporated to dryness under reduced pressure to obtain 10.0 g of off-white solid with a yield of 31.0%.

[0052] Step 2: Preparation of 2,3-bis(3-(1-cyano-1-methylethyl)-5-methylphenyl)-2-methylpropioni...

Embodiment 2

[0061] Step 1: Preparation of 2-[3-(1-cyanoethyl)-5-methylphenyl]-2-methylpropionitrile (formula III)

[0062] to N 2 Add 26.0g of 5-methyl-1,3-benzenediacetonitrile and 260ml of DMF into the protected reaction flask, stir, then add 57.8g of dimethyl sulfate, and cool down to 0-5°C in an ice-water bath. Add 14.6 g of sodium hydride in batches under temperature control at 0-5°C, and keep warm at 0-5°C for 0.5h after addition. Pour the reaction solution into 800ml of water, extract once with 400ml of dichloromethane, and extract once more with 200ml, combine the organic phases, wash with drinking water 400ml×3 times, evaporate the organic phases to dryness under reduced pressure, and purify through the column, eluent: n-Hexane / ethyl acetate=15 / 1, the purer eluent was collected and evaporated to dryness under reduced pressure to obtain 9.7 g of off-white solid with a yield of 30.0%.

[0063] Step 2: Preparation of 2,3-bis(3-(1-cyano-1-methylethyl)-5-methylphenyl)-2-methylpropio...

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Abstract

The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of an anastrozole impurity. The present invention uses 5-methyl-1,3-benzenediacetonitrile as a raw material to obtain the anastrozole impurity through methylation reaction, substitution reaction, N-halogenated succinimide radical reaction and nucleophilic substitution reaction: 2,3‑bis(3‑(1‑cyano‑1‑methylethyl)‑5‑(1H‑1,2,4‑triazole‑1‑methyl)phenyl)‑2‑methyl Propionitrile, the present invention announces the preparation method of this impurity for the first time, has the characteristics such as short synthetic route, simple and convenient operation, the obtained product is high in purity, and is convenient for reference substance research. The preparation method is of great significance for the impurity research of anastrozole, and it can be used for qualitative and quantitative analysis of impurities in the production of anastrozole, thereby improving the quality standard of anastrozole, thereby providing important guiding significance for safe drug use.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of an anastrozole impurity. Background technique [0002] Anastrozole, the structural formula is as follows: [0003] [0004] Anastrozole is an effective selective non-steroidal aromatase inhibitor, which is mainly used for the first-line treatment of advanced breast cancer in postmenopausal women, and also for the treatment of breast cancer that cannot be controlled by tamoxifen and other anti-estrogen therapy. Advanced breast cancer in postmenopausal women, it works by significantly reducing the concentration of estradiol in serum, and the reduction of estrogen level can reduce tumor volume or delay tumor growth. [0005] The European Pharmacopoeia reports an impurity of anastrozole, 2,3-bis(3-(1-cyano-1-methylethyl)-5-(1H-1,2,4-triazole-1 -methyl) phenyl)-2-methylpropionitrile, structural formula such as formula I: [0006] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D249/08
CPCC07D249/08
Inventor 邓青均王显慧
Owner CHONGQING HUAPONT PHARMA