Production of 1-[3,5-2(2,2-dimethyl) ethylcyano] benzyl triazole

A technology of benzyltriazole and dimethyl, which is applied in the field of medicinal chemistry, can solve the problems of high price, long synthetic route, complex process, etc., and achieve the effect of simple and easy post-treatment method and mild reaction conditions

Active Publication Date: 2007-11-21
CHANGZHOU NO 4 PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the last step of this route, 1,2,4-triazole sodium in route I is replaced by 1,2,4-triazole sodium. The disadvantage is that the synthetic route is long and the process is complicated. The starting material 3,5-di Methyl toluate and reducing agent sodium borohydride are expensive and the reaction yield is low
Its shortcoming is that adopting this route to make the Anastrozole finished product purity is not high (relevant impurity>1%)

Method used

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  • Production of 1-[3,5-2(2,2-dimethyl) ethylcyano] benzyl triazole
  • Production of 1-[3,5-2(2,2-dimethyl) ethylcyano] benzyl triazole
  • Production of 1-[3,5-2(2,2-dimethyl) ethylcyano] benzyl triazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Add 30g of 3,5-bis[(2,2-dimethyl)cyanomethyl]toluene, 30.7g of N-bromosuccinimide, 1.6g of benzoyl peroxide and 300ml of carbon tetrachloride to the reaction In the bottle, reflux and stir for 2 hours, cool, filter, wash the filter residue twice with carbon tetrachloride, and evaporate the solvent to obtain 30.5 g of a light yellow solid, which is 3,5-bis[(2,2-dimethyl)cyanide Methyl]bromotoluene (III) was directly used in the next reaction without purification.

[0040] Add 7.2g of 1,2,4-triazole, 14.6g of anhydrous potassium carbonate, 5.9g of potassium hydroxide, 1.8g of tetrabutylammonium bromide, 200ml of dichloromethane and 30.5g of intermediate III into the reaction flask in sequence , kept stirring at 20°C, and detected by TLC (GF254 plate, petroleum ether-ethyl acetate, V:V=3:1), the reaction was complete in about 10 hours, the reaction solution was concentrated to dryness to obtain an oily substance, and 200ml of 1 N hydrochloric acid was added to dissolve the...

Embodiment 2

[0047]Add 30g of 3,5-bis[(2,2-dimethyl)cyanomethyl]toluene, 30.7g of N-bromosuccinimide, 1.6g of benzoyl peroxide and 300ml of chloroform into the reaction flask, Reflux and stir for 2 hours, cool and filter, wash the filter residue twice with chloroform, and evaporate the solvent to obtain 32 g of light yellow solid, which is 3,5-bis[(2,2-dimethyl)cyanomethyl]bromotoluene ( III), directly used in the next step reaction without purification.

[0048] Add 7.6g of 1,2,4-triazole, 15.3g of anhydrous potassium carbonate, 6.2g of potassium hydroxide, 1.9g of tetrabutylammonium iodide, 200ml of ethyl acetate and 32g of intermediate III into the reaction flask in sequence, Keep stirring at 40°C, TLC detection (GF254 plate, petroleum ether-ethyl acetate, V:V=3:1), the reaction is complete in about 6 hours, the reaction solution is concentrated to dryness to obtain an oily substance, add 200ml of 1N hydrochloric acid to dissolve the oily substance , filtered off the insolubles, added ...

Embodiment 3

[0055] Add 30g of 3,5-bis[(2,2-dimethyl)cyanomethyl]toluene, 30.7g of N-bromosuccinimide, 1.6g of benzoyl peroxide and 300ml of chloroform into the reaction flask, Reflux and stir for 2 hours, cool and filter, wash the filter residue twice with chloroform, and evaporate the solvent to obtain 31 g of light yellow solid, which is 3,5-bis[(2,2-dimethyl)cyanomethyl]bromotoluene ( III), directly used in the next step reaction without purification.

[0056] Add 7.4g of 1,2,4-triazole, 15.1g of anhydrous potassium carbonate, 6.1g of potassium hydroxide, 1.7g of tetrabutylammonium bromide, 200ml of dichloromethane and 31g of intermediate III to the reaction flask in sequence, 30 Keep stirring at ℃, TLC detection (GF254 plate, petroleum ether-ethyl acetate, V:V=3:1), the reaction is complete in about 7.5 hours, the reaction solution is concentrated to dryness to obtain an oily substance, add 200ml of 1N hydrochloric acid to dissolve the oily substance , filtered off the insolubles, ad...

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PUM

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Abstract

Production of 1-(3,5-2(2,2-dimethyl) methyl cyanide) benzyl pyrrodiazole is carried out by taking 3,5-2(2,2-dimethyl) ethyl-methyl) toluene (II) as raw material, synthesizing to obtain anatritra intermediate 3,5-2(2,2-dimethyl) ethyl-methyl) toluene bromide (III) and reacting with 1,2,4-triazanezole to obtain final product. It's simple and convenient, has less impurities and better product quality.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry. It specifically relates to a preparation method of 1-[3,5-bis(2,2-dimethyl)ethylcyano]benzyl triazole (anastrozole, I). Background technique [0002] 1-[3,5-bis(2,2-dimethyl)ethylcyano]benzyltriazole (anastrozole) (structural formula I, Anastrozole) is a selective non-steroidal aromatase inhibitor, At present, it is mainly used clinically for the treatment of advanced metastatic breast cancer in postmenopausal women. [0003] [0004] (EP: 0296749, USP: 4935437) reported synthetic routes have two: [0005] Synthetic route I is as follows: [0006] [0007] This route uses 3,5-dibromomethyltoluene as the starting material, and the intermediate 3,5-bis[(2,2-dimethyl)cyanomethyl is obtained through cyanation, methylation and bromination. ] bromotoluene (III), and then react with 1,2,4-triazole sodium to obtain the final product Anastrozole (I), although the method has few steps...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/08A61K31/4196A61P35/00
Inventor 王晓东潘璐屠永锐
Owner CHANGZHOU NO 4 PHARMA FACTORY
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