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Method for preparing antidepressant mirtazapine

A technology of mirtazapine and antidepressant, which is applied in the field of preparation of antidepressant drug mirtazapine, and can solve the problems of increasing synthesis steps and the like

Inactive Publication Date: 2015-02-18
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

From intermediate D through intermediate E to re-synthesize mirtazapine, although the yield rises to 80% from 70% during direct synthesis, this route increases the synthesis steps, and also uses the difficult-to-operate reductant aluminum tetrahydrogen lithium

Method used

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  • Method for preparing antidepressant mirtazapine
  • Method for preparing antidepressant mirtazapine
  • Method for preparing antidepressant mirtazapine

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Example 1: 1,3,4,14b-tetrahydro-2-methylpyrazine[2,1-a]pyrido[2,3-c][2]benzazepine-10(2H) - Preparation of ketones

[0022] Under a nitrogen atmosphere, 1-(3-carboxy-2-pyridyl)-2-phenyl-4-methylpiperazine (5.0 g, 16.8 mmol), dichloromethane (40 mL) were added to a 100 mL three-necked flask, N,N-Dimethylformamide (1mL) was stirred, and then the system was cooled to about 0°C with an ice-water bath, and thionyl chloride (4.0g, 33.6mmol) was added dropwise into the reaction system liquid, and in 15min finished adding. After removing the ice-water bath and reacting at room temperature for 70 minutes, the system liquid was cooled to about 0°C, and anhydrous aluminum trichloride (12.1 g, 90.6 mmol) was added in batches, and after the addition was completed, the temperature was naturally raised to room temperature for reaction, and TLC It was detected that the reaction of raw materials was complete. Pour the reaction solution into ice water (200 mL), add 10% NaOH aqueous so...

Embodiment 2

[0024] Embodiment 2: the preparation of mirtazapine

[0025] Under a nitrogen atmosphere, add D (419.0 mg, 1.5 mmol), diethylene glycol (8 mL), and dimethyl sulfoxide (1 mL) into a 25 mL three-necked flask and stir. Then add solid potassium hydroxide (210.4mg, 3.8mmol), then weigh 80% hydrazine hydrate (375.5mg, 6.0mmol) with a syringe and add it dropwise to the reaction system. After the temperature is stable, heat the system to 120-125°C for 1 hour, then distill off the water and excess hydrazine hydrate in the system under reduced pressure. After cooling, pour the system solution into water (25 mL) and stir for 20 min, extract three times with ethyl acetate (50 mL), combine the organic phases, wash once with water, and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness to obtain 378.1 mg of a brown-yellow solid. After purification by column chromatography (ethyl acetate:petroleum ether:triethylamine=10:40:0.05), 351.1 mg of a whit...

Embodiment 3

[0027] Embodiment 3: the preparation of mirtazapine

[0028] Under nitrogen atmosphere, add D (2.8g, 10.0mmol) and diethylene glycol (25mL) into a 50mL three-necked flask and stir. Then add potassium hydroxide solid (1.4g, 25.0mmol), then weigh 80% hydrazine hydrate (2.5g, 40.0mmol) in the dropping funnel, add dropwise in the reaction system, the reaction exotherm is obvious, after adding Raise the temperature by 8°C in total. After the temperature stabilizes, heat the system to 120-125°C and react for 1 hour. Then evaporate the water and excess hydrazine hydrate in the system under reduced pressure. After steaming, continue to heat up to 170°C for reaction. The response is complete. After cooling, the system solution was poured into water (50 mL) and stirred for 20 min, extracted three times with ethyl acetate (120 mL), the organic phases were combined, washed once with water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to drynes...

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Abstract

The invention discloses a method for preparing mirtazapine by using a ketone intermediate D to directly obtain the mirtazapine. The method comprises the following steps: carrying out a Friedel-Craft reaction on a carboxylic acid intermediate A under catalysis of an acylation reagent and Lewis acid to obtain ketone intermediate D, processing the ketone intermediate D to obtain a coarse product after the reaction, and implementing next reaction without further purification; through a Wolff-Kishner-Huangminglong reaction, reducing the ketone intermediate D into a target product, namely mirtazapine, post-processing the product and extracting coarse product from an aqueous phase, and recrystallizing through a mixed solvent of two or more components to obtain a high-purity product. The method disclosed by the invention is simple and convenient, safe and high in yield.

Description

technical field [0001] The present invention relates to the improvement of the preparation method of the compound, in particular to the improvement of the preparation method of the antidepressant mirtazapine. Background technique [0002] Mirtazapine, chemical name 1,2,3,4,10,14b-hexahydro-2-methylpyrazine[2,1-α]pyrido[2,3-c][2] Benzoazepine, a noradrenergic and specific serotonergic receptor blocker developed by Organon in the Netherlands. It has no blocking effect on M choline receptors and dopamine receptors, almost no adverse reactions of choline and dopamine, and has obvious therapeutic effect on severe depression patients, with small adverse reactions and good tolerance. The drug was first launched in the Netherlands by Organon in 1994, and entered the Chinese market in 2001. [0003] According to literature reports, there are multiple synthetic routes for mirtazapine, and these methods have disadvantages such as long steps, complex reaction system, difficult control...

Claims

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Application Information

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IPC IPC(8): C07D471/14
CPCC07D471/14
Inventor 徐浩刘艳陈海霞吕英慧刘鹏飞
Owner NANJING UNIV OF TECH
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