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Preparation of medicament intermediate 1-methyl-3-phenyl piperazine

A technology for phenylpiperazine and intermediates, which is applied in the field of preparation of pharmaceutical intermediates 1-methyl-3-phenylpiperazine, can solve the problems of low yield, achieve high reaction yield, simple post-treatment, The effect of easy operation

Active Publication Date: 2009-05-27
上海津力药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] The design idea of ​​this method can be used for reference, but the flammable and explosive NaH and ether are used, and the yield is too low, the two-step yield is only 58.1%

Method used

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  • Preparation of medicament intermediate 1-methyl-3-phenyl piperazine
  • Preparation of medicament intermediate 1-methyl-3-phenyl piperazine
  • Preparation of medicament intermediate 1-methyl-3-phenyl piperazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] A preparation method of a pharmaceutical intermediate MPP, the preparation method comprising the following steps:

[0076] (1) Preparation of compound II:

[0077] Step 1: Add 75 grams of styrene oxide (0.6 mol) and 150 ml of toluene into a 500 ml three-necked flask equipped with mechanical stirring and a condenser, heat to 80±5°C, and add 43 grams of N-methylethanolamine dropwise (0.57mol), dripped in about 1.5 hours, then incubated at the same temperature for about 2 hours, determined the end point of the reaction with TLC, and cooled to room temperature for use;

[0078] Step 2: Add 300ml of toluene and 170 grams of thionyl chloride (1.42mol) to another 1000ml three-necked flask, cool to 0-10°C with an ice-water bath, and slowly drop the reaction mixture obtained in the first step under stirring Add it into the 1000ml three-neck flask, and finish adding in about 2 hours. Control the temperature at 0-10°C. After the dropwise addition, slowly heat the system to room t...

Embodiment 2

[0085] A preparation method of a pharmaceutical intermediate MPP, the preparation method comprising the following steps:

[0086] (1) Preparation of compound II:

[0087] Step 1: Put 130kg of toluene into a 500-liter reactor, start stirring, add 80kg of styrene oxide, raise the temperature to 80-85°C, add 45.5kg of N-methylethanolamine dropwise, and finish dropping in about 80-90 minutes , heat preservation reaction, use TLC to spot the plate until the raw material reaction is complete, react for about 3 hours, cool to room temperature, and move to the high tank of the next step reaction;

[0088] The second step: put 86kg of toluene in a 1000 liter reaction kettle, slowly add 162kg of thionyl chloride (note the exotherm), cool the system down to 0-5°C, start adding the first step reaction solution dropwise, and keep the temperature at 0~10°C, drop it in about 3 hours, raise the temperature to room temperature (20±5°C) and stir for 30 minutes, then raise the temperature to 45...

Embodiment 3

[0097] A preparation method of a pharmaceutical intermediate MPP, the preparation method comprising the following steps:

[0098] (1) Preparation of compound II:

[0099] The first step: In a 500ml three-necked flask equipped with mechanical stirring and a condenser, add 71.25 grams of styrene oxide (0.57mol) and 150ml of toluene, heat to 40°C, and add dropwise 43 grams of N-methylethanolamine (0.57mol) mol), the dropwise addition was completed, and the reaction was then incubated at the same temperature for about 2 hours, and the end point of the reaction was determined by TLC, and the temperature was lowered to room temperature for use;

[0100] The second step: add 300ml of toluene and 136.5 grams of thionyl chloride (1.14mol) to another 1000ml three-necked flask, cool to 0-10°C with an ice-water bath, and slowly drop the reaction mixture obtained in the first step under stirring Add it into the 1000ml three-neck flask, control the temperature at 0-10°C, after the dropwise...

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Abstract

The invention relates to a method for preparing a medicine intermediate, namely 1-methyl-3-phenyl-piperazine. Epoxy phenylethane and N-methyl ethanolamine react for ring opening in a methylbenzene solution and further react with thionyl chloride to obtain N-(2- chloroethyl)-N-methyl-2-chloro-2-phenylethylamine hydrochloride, the hydrochloride reacts with toluene sulfonamide and sodium hydroxide in a DMF solution to obtain 1-methyl-4-p-toluenesufonyl-3-phenylpiperazine, the 1-methyl-4-p-toluenesufonyl-3-phenylpiperazine reacts with concentrated hydrochloric acid to remove sulfonyl, and a product is obtained through neutralization extraction and recrystallization. Compared with the prior art, the method for preparing the 1-methyl-3-phenyl-piperazine has the advantages of low cost of selected raw materials, cost conservation, few synthesis steps, convenient and safe operation, simple post-treatment, high reaction yield, high product purity, good quality, and suitability for industrialized application.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate, in particular to a preparation method of a pharmaceutical intermediate 1-methyl-3-phenylpiperazine. Background technique [0002] 1-methyl-3-phenylpiperazine (hereinafter referred to as MPP) is a key intermediate for the preparation of mirtazapine. Mirtazapine (mirtazapine) is an antidepressant drug (U.S.4062848). It is a selective serotonin reuptake inhibitor (SSRI). Clinical use in many countries of the world. [0003] So far, the methods for preparing MPP mainly contain the following: [0004] 1. Maeda, C.JP2001122863 reported that phenylglyoxal was used as a raw material, aminated and reduced to obtain 2-phenylpiperazine, and then methylated to obtain MPP. The synthetic route of this method is as follows: [0005] [0006] The raw materials used in this route are expensive, and the reaction yield is low, especially in the last step of methylation, there are several possible by-products, ...

Claims

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Application Information

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IPC IPC(8): C07D241/04
Inventor 潘朝阳胡惟孝武克孟跃杨忠愚戴龙华
Owner 上海津力药业股份有限公司
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