Preparation process of sertaconazole nitrate as antifungal medicine

Abstract

The present invention discloses the preparation process of sertaconazole nitrate as antifungal medicine. The medicine is prepared through refluxing 1-(2, 4-dichlorophenyl)-2-(1-imidazolyl) ethyl alcohol in the mixture solution of alcohol and organic solvent in alkaline condition, the subsequent reaction with 3-bromomethyl-7-chlorobenzol [b] thiophene, and reaction with nitric acid to form salt. Compared with other preparation process, the present invention has the advantages of mild reaction condition, easy product decolorizing, simple operation, lowered cost and being suitable for large scale production.

Description

【Technical field】 [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of antifungal drug sertaconazole nitrate. 【Background technique】 [0002] Topical antifungal drug Sertaconazole Nitrate (Sertaconazole Nitrate), molecular formula: C 20 h 15 C 13 N 2 S·HNO 3 , developed by the Spanish company Ferrer, was launched in Spain for the first time in 1992, and is now on the market in China, the United States, Germany, Argentina, Peru and other countries. It has the characteristics of high curative effect, low recurrence rate and low toxicity. In the prior art, the following patents relate to the preparation method of sertaconazole nitrate, such as EP151477, ES529608, ED535656, JP60 / 181186, US5135943, etc., the above-mentioned patent technology is relevant, and its synthetic route adopts 1-(2, 4-dichlorobenzene)-2-(1-imidazole)ethanol and 3-bromomethyl-7-chlorobenzo[b]thiophene as raw materials, under the protection ...

AI Technical Summary

Problems solved by technology

The disadvantages of this synthesis method are:

[0003] The reaction needs to be completed under the protection of an inert gas; the sodium hydride used is a flammable and explosive chemical, which is dangerous and unsafe to use, so the reaction must be operated under anhydrous and anaerobic conditions; the hexamethylphosphoric triamide used It is a toxic solvent, carcinogenic, expensive, and difficult to recover; firstly, sertaconazole is prepared, and it needs to be separated and purified with a silica gel column, and then reacted with nitric acid to prepare sertaconazole nitrate, which is cumbersome and difficult to operate, and is not suitable for large-scale production

[0004] In addition, Chinese patent ZL01127506.5 relates to a new preparation method of sertaconazole nitrate, which uses 1-(2,4-dichlorobenzene)-2-(1-imidazole)ethanol and 3-bromomethyl-7- Chlorobenzo[b]thiophene is used as raw material, toluene, water are used as solvent, tetrabutylammonium chloride is used as catalyst, phase transfer catalytic reaction is carried out under the participation of sodium hydroxide, and the salt is directly formed without separation of sertaconazole The preparation of sertaconazole nitrate by reaction does not require anhydrous and anaerobic operation, which is greatly improved compared with foreign literature methods, but there are also shortcomings: the phase transfer catalytic reaction needs higher price tetrabutylammonium chloride to do Catalyst, because the reaction needs to be carried out at a relatively high temperature (80°C), the resulting product is reddish-brown, difficult to decolorize, and difficult to purify, with large losses, cumbersome operation, and increased synthesis costs

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