Preparation method of posaconazole intermediate 1-(4-aminophenyl)-4-(4-hydroxylphenyl)piperazine

Abstract

The invention discloses a preparation method of a posaconazole intermediate, namely 1-(4-aminophenyl)-4-(4-hydroxylphenyl)piperazine, belonging to the field of medicinal chemistry. The preparation method comprises the following steps: S1, with chlorobromobenzene and anhydrous piperazine as raw materials, generating 1,4-bis(4-chlorophenyl)piperazine under certain conditions; S2, performing single-side methylation on the product generated in the step S1 to obtain 1-(4-methoxyphenyl)-4-(4-chlorophenyl)piperazine; S3, performing ammoniation on the product in the step S2 to obtain 1-(4-methoxyphenyl)-4-(4-aminophenyl)piperazine; and S4, demethylating the product obtained in the step S3, and carrying out crystallizing and purifying to obtain the 1-(4-aminophenyl)-4-(4-hydroxylphenyl)piperazine.The raw materials used in the preparation method are very cheap; reaction conditions are relatively simple; the method is easy to implement; yield is high; and the cost of a final product can be obviously reduced.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of a posaconazole intermediate 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine. Background technique [0002] Posaconazole is a derivative of itraconazole, a second-generation triazole antifungal drug that was listed on the US FDA in 2006, and is widely used in patients with an increased risk of infection due to severe immunodeficiency. Posaconazole (chemical name: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-tri Azol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3 -base]-1,2,4-triazol-3-one), the structural formula is: [0003] [0004] 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine is one of the important intermediates for the synthesis of posaconazole API, molecular formula C 16 h 19 N 3 O, molecular weight 269.34, structural formula is [0005] According to the records of patent U...

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Problems solved by technology

[0009] The purpose of the present invention is to: the price of raw materials and catalyst palladium carbon in the existing preparation method above are expensive, catalytic hydrogenation requires a closed space, strict requirements for equipment, difficult reaction operation, safety risks, and high-pressure hydrogenation is easy to produce By-products increase the difficulty of purification. The invention provides a method for preparing a novel posaconazole intermediate 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine

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