A kind of preparation method of posaconazole intermediate

Abstract

The invention discloses a method for preparing a posaconazole intermediate represented by formula I. The method takes p-bromonitrobenzene and anhydrous piperazine as raw materials and undergoes condensation reaction, reduction reaction, monoacylation reaction and cyclization. The target product is prepared by reaction and diazotization hydrolysis reaction. Compared with the prior art synthesis method using 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine as the starting material, the preparation method provided by the invention has easy-to-obtain raw materials, high reaction efficiency, and the reaction The conditions are mild, the yield of the target product is high, and the method has the advantages of simplicity, high efficiency and low cost.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a posaconazole intermediate 2-((2S, 3S)-2-(benzyloxy)-3-pentyl)-4-(4-(4-(4 - Preparation method of hydroxyphenyl)piperazin-1 yl)phenyl)-2,4-dihydro-1,2,4-triazol-3(4H)-one. Background technique [0002] Posaconazole is an antifungal drug developed by Schering-Plough for infections caused by Candida, Aspergillus and other pathogenic fungi. Its intravenous injection was approved by the FDA in March 2014. Due to its good curative effect and low toxicity, posaconazole has a wide range of clinical applications, so the development and research on its synthesis process are also increasing year by year. Compound 2-((2S, 3S)-2-(benzyloxy)-3-pentyl)-4-(4-(4-(4-hydroxyphenyl)piperazin-1 yl) as shown in formula I )phenyl)-2,4-dihydro-1,2,4-triazole-3(4H)-one is an important intermediate in the synthesis of posaconazole. [0003] [0004] At present, the methods disclosed in patents W...

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Problems solved by technology

[0008] The above-mentioned disclosed prior art all needs to prepare the posaconazole intermediate shown in formula I by compound 1-(4-aminophenyl)-4-(4-hydroxyphenyl) piperazine, but compound 1- The synthesis conditions of (4-aminophenyl)-4-(4-hydroxyphenyl)piperazine are harsh, as shown in the synthetic method disclosed in patent CN101824009A and CN111362886A, all need 3-step reaction or 4-step reaction synthesis to obtain 1-( 4-aminophenyl)-4-(4-hydroxyphenyl)piperazine, and requires strong acid such as hydrobromic acid or boron trichloride for demethylation, which has the disadvantages of severe reaction conditions, many reaction steps, and low yield

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