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

A technology of aminophenyl and posaconazole, which is applied in organic chemistry and other fields, can solve problems such as strict equipment requirements, safety risks, and difficult reaction operations, and achieve the effects of reduced product costs, high yields, and low prices

Active Publication Date: 2020-07-03
四川澄华生物科技有限公司
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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 rea

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

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[0030] In order to make the object, technical solution and advantages of the present invention clearer, the present invention is further described in detail. It should be understood that the specific embodiments described here are only used to explain the present invention, and are not intended to limit the present invention, that is, the described embodiments are only some of the embodiments of the present invention, but not all of the embodiments.

[0031] A preparation method of posaconazole intermediate 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine, comprising the following steps:

[0032] S1: Preparation of 1,4-bis(4-chlorophenyl)piperazine M1:

[0033] Take 100ml of dimethyl sulfoxide, add 10g of anhydrous piperazine, 46.67g of p-chlorobromobenzene, 48g of potassium carbonate; stir and heat to 175-185°C, keep warm for reaction; start TLC monitoring after 4h (methanol: dichloromethane = 1 ; 4, ninhydrin color), sampling once every 1-1.5h, until the anhydrous piperazine...

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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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Application Information

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IPC IPC(8): C07D295/135
CPCC07D295/135Y02A50/30
Inventor 黄松邓治荣张翔向世明彭捷田昌力
Owner 四川澄华生物科技有限公司
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