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Method for synthesizing aromatase inhibitor

An aromatase and inhibitor technology, applied in the field of drug synthesis, can solve the problems of incomplete bromination reaction, unfavorable industrial production, low product content, etc., and achieve the effects of mild reaction conditions, good quality and high yield

Active Publication Date: 2015-03-04
JIANGSU QINGJIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This technological process mainly has the following problems: the bromination reaction cannot be carried out completely, and at the same time, some dibrominated by-products are produced, and there are major problems in the refining and purification of the product, usually with a purity of only about 75%, which also has a great impact on subsequent reactions; The content of the product obtained in the condensation reaction is low, and it is usually purified by column chromatography, which leads to cumbersome process and increased cost, which is not conducive to industrial production

Method used

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  • Method for synthesizing aromatase inhibitor
  • Method for synthesizing aromatase inhibitor
  • Method for synthesizing aromatase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] 1. Synthesis of intermediate A1: methyl 3,5-dibromomethylbenzoate:

[0027] Add 82g (0.5 mol) of methyl 3,5-dimethylbenzoate, AIBN (0.5g) and acetonitrile (500mL) into the reaction flask, add 180g (1.0mol) of NBS, stir and heat to reflux 75~80°C, Stir for 3 hours, the reaction is complete, concentrate under reduced pressure below 60°C, cool to room temperature, add 250mL of dichloromethane, wash with 50mL of 10% sodium sulfite solution, 50mL of 10% sodium carbonate solution, and 50mL of purified water, and dry over anhydrous sodium sulfate for 35 Concentrate at -40°C to obtain a yellow oil. Recrystallized with 300 mL of absolute ethanol to obtain 90 g of white solid crystals, yield 85.0%, mp 99-101 °C. 1H-NMR (CDCl 3 ) δ : 3.8 9(3H, s, OCH 3 ), 4 .25 (4H,s,CH 2 ), 7. 60(1H,t , J = 1.8 Hz,Ar-H), 8.02(2H,d , J =1 .8 Hz,Ar-H) .

[0028] 2. Synthesis of intermediate A2: methyl 3,5-dicyanomethylbenzoate:

[0029] Dissolve 80g (0.25mol) of methyl 3,5-dibromomethylbenzoa...

Embodiment 2

[0037] Synthesis of Anastrozole:

[0038] Add 48g (0.2mol) of intermediate 3,5-bis[(2,2-dimethyl)cyanomethyl]benzaldehyde and 13.0g (0.2mol) of 1,2,4-triazole to 200 mL of tetrahydrofuran Warm stirring for 2 hours, adding 42 g (0.2 mol) of sodium triacetate borohydride, stirring and heating to 45~55 ° C for 5 hours. After the reaction is complete, distill off THF under reduced pressure, pour the reaction solution into 200 mL of water, extract with ethyl acetate (200 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and distill off the solvent under reduced pressure to obtain a yellow oil The product was recrystallized from 200 mL of isopropanol to obtain 54 g of a white solid, with a yield of 90%.

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Abstract

The invention discloses a method for synthesizing an aromatase inhibitor anastrozole. A synthesis route comprises the steps: with 3, 5-dimethylbenzoate as a starting material, carrying out bromination, cyanation and methylation to obtain 3, 5-bis (2-cyano-2-yl) benzoate, reducing the intermediate to obtain 3,5-bis (2-cyano-2-yl) benzaldehyde, and carrying out a reductive amination reaction on the generated intermediate and 1.24-triazole to obtain anastrozole. The method has the advantages of easiness in operation, mild reaction conditions, high yield, high product purity and the like, and is suitable for industrial production of anastrozole.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing the drug compound aromatase inhibitor anastrozole. Background technique [0002] Anastrozole, chemical name: tetramethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-benzenediacetonitrile, chemical structure as follows: [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. Better curative effect and less toxicity and adverse reactions. [0005] As an important drug intermediate, the current synthetic method of anastrozole, the technical route generally adopted in industrial production is as follows: [0006] [0007] In the process of synthesizing anastrozole through halogenation and condensation of intermediate 5, the process is as follows: ...

Claims

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Application Information

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IPC IPC(8): C07D249/08
CPCC07D249/08
Inventor 隽海龙史红霞
Owner JIANGSU QINGJIANG PHARMA
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