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Method for preparing anastrozole

A technology of anastrozole and condensation, applied in the field of pharmaceutical synthesis, can solve the problems of inability to complete the bromination reaction, unfavorable industrialized production, low product content, etc., and achieves the effects of mild reaction conditions, improved conversion rate, and high yield

Active Publication Date: 2014-02-05
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 from the condensation reaction is low, and it is usually purified by column chromatography, which leads to cumbersome process and increased cost, which is very unfavorable for industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] 1: Synthesis of intermediate 3,5-bis[(2,2-dimethyl)cyanomethyl]-bromomethylbenzene:

[0016] a, a, a', a', 50g (0.22mol) of 5-pentamethyl-1,3-diacetonitrile benzene, 500mL of acetonitrile, and 1.0g of AIBN were added to the reaction flask, and 205g (0.25mol) of NBS was added ), stirred and heated to reflux 75-80°C, stirred for 3 hours, the reaction was complete, concentrated under reduced pressure below 60°C, cooled to room temperature, added 250 mL of dichloromethane, followed by 50 mL of 10% sodium sulfite solution, 10% sodium carbonate solution Wash with 50 mL, 50 mL of 10% sodium chloride solution, and 50 mL of water, dry over anhydrous sodium sulfate, concentrate at 35-40°C, add 30 mL of isopropanol and 490 mL of n-hexane, heat to 50-55°C, keep warm for 30 minutes, slowly Cool slowly to 25-30°C, stir for 1 h, filter, and wash with 25 mL of n-hexane to obtain 57 g of off-white solid crystals, with a yield of 85.0% and a purity of 92%.

[0017] 2: Synthesis of Anast...

Embodiment 2

[0027] 1: Synthesis of intermediate 3,5-bis[(2,2-dimethyl)cyanomethyl]-bromomethylbenzene:

[0028] a, a, a', a', 50g (0.22mol) of 5-pentamethyl-1,3-diacetonitrile benzene, 500mL of carbon tetrachloride, and 1.0g of AIBN were added to the reaction flask, and 205g of NBS was added (0.25 mol), stirred and heated to reflux 75-80°C, stirred for 4 hours, the reaction was complete, concentrated under reduced pressure below 60°C, cooled to room temperature, added 250 mL of dichloromethane, followed by 50 mL of 10% sodium sulfite solution, 10% Wash with 50 mL of sodium carbonate solution, 50 mL of 10% sodium chloride solution, and 50 mL of water, dry over anhydrous sodium sulfate, concentrate at 35-40°C, add 30 mL of isopropanol and 490 mL of n-hexane, heat to 50-55°C, and keep warm After 30 minutes, slowly cool to 25-30°C, stir for 1 hour, filter, and wash with 25 mL of n-hexane to obtain 60 g of off-white solid crystals, with a yield of 89.5% and a purity of 93%.

[0029] 2: Synthe...

Embodiment 3

[0032] 1: Synthesis of intermediate 3,5-bis[(2,2-dimethyl)cyanomethyl]-bromomethylbenzene:

[0033] a, a, a', a', 50g (0.22mol) of 5-pentamethyl-1,3-diacetonitrile benzene, 500mL of acetonitrile, and 2.0g of benzoyl peroxide were added to the reaction flask, and NBS was added 205g (0.25 mol), stirred and heated to reflux 75-80°C, stirred for 3 hours, the reaction was complete, concentrated under reduced pressure below 60°C, cooled to room temperature, added 250 mL of dichloromethane, followed by 50 mL of 10% sodium sulfite solution, 10 Wash with 50 mL of % sodium carbonate solution, 50 mL of 10% sodium chloride solution, and 50 mL of water, dry over anhydrous sodium sulfate, concentrate at 35-40°C, add 30 mL of isopropanol and 490 mL of n-hexane, heat to 50-55°C, Keep warm for 30 minutes, slowly cool to 25-30°C, stir for 1 hour, filter, and wash with 25 mL of n-hexane to obtain 57 g of off-white solid crystals, with a yield of 85.0% and a purity of 78%.

[0034] 2: Synthesis ...

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Abstract

The invention discloses a method for preparing anastrozole. The anastrozole is prepared by using a,a,a',a',5-pentamethyl-1,3-diacetonitrile benzene as a starting material, bromizing under the action of a brominating agent NBS to generate a midbody 3,5-bi[(2,2-dimethyl)cyan methyl]-benzyl bromide, and catalyzing and condensing the midbody with 1,2,4-triazole in water and organic solvent by phase transfer to prepare anastrozole. The method has the advantages of simplicity in operation, mild reaction condition, high yield and high purity of products, 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 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. Good curative effect and less toxicity and adverse reactions. [0005] As an important drug intermediate, the technical route commonly used in the synthesis of anastrozole in industrialized production is as follows: [0006] [0007] In the process of synthesizing anastrozole through halogenation and condensation of intermediate 5, the process is as follows: dissolve intermediate 5 in carbon te...

Claims

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Application Information

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