Preparation of 3,5-di(2-cyano-isopropyl)-toluene

Abstract

The invention relates to a novel synthesis process of pharmaceutical intermediate 3, 5-bi(2-cyanoindole-isopropyl)-toluene, belonging to the chemical synthesis technology field. The invention uses 5-methyl-1, 3-dimethyl phthalate as the material, synthesizes anastrozole intermediate 3, 5-bi(2-cyanoindole-isopropyl)-toluene by esterification, reduction, brominating, cyaniding and methylation reaction. The reduction method using borohydrides is performed in aether solvent, the method can completely avoid using high-toxicity solvent such as CCl4 or the like; in the methylation reaction, expensive iodomethane is replaced by p-toluenesulfonic acid methyl; the purity of product 3, 5-bi(2-cyanoindole-isopropyl)-toluene (2) is high.

Description

technical field [0001] The invention relates to a new synthesis process of 3,5-bis(2-cyano-isopropyl)-toluene, a drug intermediate, and belongs to the technical field of chemical synthesis. Background technique [0002] Anastrozole (anastrozole, 1) is a selective non-steroidal aromatase inhibitor developed by Zeneca, UK, for the treatment of postmenopausal women with advanced metastatic breast cancer. [0003] [0004] In several reported synthetic methods of anastrozole, 3,5-bis(2-cyano-isopropyl)-toluene (2) is an important synthetic intermediate. The common method is to obtain compound 3 after bromination of 3,5-bis(2-cyano-isopropyl)-toluene (2) by NBS, and then react with 1,2,4-triazole under alkaline conditions reaction, after purification, anastrozole was obtained (Scheme 1). Thus, the yield, purity and cost of the intermediate 3,5-bis(2-cyano-isopropyl)-toluene (2) have an important impact on the yield, purity and cost of the final produc...

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Problems solved by technology

[0008] The main problem of this technique is: (1) the productive rate and the purity from m-trimethylbenzene (4) to compound 5 are relatively low; (2) bromination reaction needs to use carbon tetrachloride as solvent, because tetrachloride Carbon is very toxic and should be avoided in the drug production process; (3) The methylation reaction from compound 6 to compound 2 requires the use of expensive methyl iodide

Bull.Soc.Chim. (1883, volume 40, page 110) also reported that compound 3,5-dimethylol-toluene (8) can be treated with fuming hydrogen bromide to obtain compound 5, so this reaction is also difficult to industrialize (Scheme 3)

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