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Preparation method and intermediate product of mirtazapine

A technology for mirtazapine and products, applied in the field of preparation of mirtazapine, can solve the problems of unrecyclable sulfuric acid, large environmental pollution, difficult operation and the like, and achieves the effects of less pollution, easy product and simple operation

Inactive Publication Date: 2020-05-22
SHANGHAI SINE PHARMA LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These methods all use a large amount of sulfuric acid as a reaction solvent and catalyst, which is difficult to operate, and reagents such as sulfuric acid cannot be recycled in organic synthesis, and a large amount of acidic waste liquid has to be processed, which has the disadvantages of large environmental pollution.

Method used

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  • Preparation method and intermediate product of mirtazapine
  • Preparation method and intermediate product of mirtazapine
  • Preparation method and intermediate product of mirtazapine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] 60 g of 1-(3-hydroxymethylpyridin-2-yl)-2-phenyl-4-methylpiperazine (compound shown in formula I) was dissolved in acetone, and 15 mL of 12% hydrochloric acid aqueous solution was added to obtain A large amount of white precipitates were precipitated and dried in vacuo to obtain 50 g of 1-(3-hydroxymethylpyridin-2-yl)-2-phenyl-4-methylpiperazine hydrochloride.

[0035]Under nitrogen protection, 1-(3-hydroxymethylpyridin-2-yl)-2-phenyl-4-methylpiperazine hydrochloride (21.5g) was put into ethylene glycol dimethyl ether (150mL ), add 4 g of commercially available polystyrene sulfonic acid resin (Jiangsu Sekesaisi Co., Ltd. catalytic ion exchange resin (IONRESIN) success 292-1 type, control the temperature not to exceed 65 ° C, and then stir at 60-70 ° C for 7 h. Cool to 10°C, filter to obtain about 25g of solid mirtazapine intermediate product.Add the obtained solid to saturated aqueous sodium bicarbonate solution (250mL), stir at 10-20°C for 1 hour, filter, and wash the ...

Embodiment 2

[0038] Under nitrogen protection, 1-(3-hydroxymethylpyridin-2-yl)-2-phenyl-4-methylpiperazine (26.5g) was put into toluene (180mL) in batches, and 53g of sulfonic acid resin was added , Control the temperature not to exceed 65°C, then stir at 60-70°C for 7h. Cool to 10°C and filter to obtain 31 g of solid. The resulting solid was added to saturated aqueous sodium bicarbonate (280 mL), stirred at 10-20°C for 1 hour, filtered, the residual solid was washed with ethyl acetate (60 mL), and the filtered solution was extracted three times with ethyl acetate (120 mL). Separate the organic layer. The organic phases were combined, concentrated and dried under reduced pressure to obtain a solid; the obtained solid was dissolved in methanol (30 mL), and water (60 mL) was added dropwise to the solution at 50-60° C., cooled to 10-15° C. and stirred for 3 h after dropping. Filtrate and vacuum dry to obtain pure mirtazapine (16.1 g, purity 99.0%, HPLC detection conditions are the same as i...

Embodiment 3

[0040] Under nitrogen protection, 1-(3-hydroxymethylpyridin-2-yl)-2-phenyl-4-methylpiperazine hydrochloride (11.5g) was put into toluene (70mL) in batches, and 1.2 g commercially available perfluorosulfonic acid resin (Jiangyin Nanda Synthetic Chemical Co., Ltd. nafion-H type), control the temperature not to exceed 110°C, and then stir at 90-110°C for 5h. Cool to 10° C., and filter to obtain 14.5 g of solid (namely the intermediate product of mirtazapine). The resulting solid was added to saturated aqueous sodium bicarbonate (120 mL), stirred at 10-20°C for 1 hour, filtered, and the residual solid was washed with ethyl acetate (30 mL), and the filtered solution was extracted three times with ethyl acetate (60 mL). Separate the organic layer. The organic phases were combined, concentrated and dried under reduced pressure to obtain a solid; the obtained solid was dissolved in methanol (30 mL), and water (60 mL) was added dropwise to the solution at 50-60° C., cooled to 10-15° C...

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Abstract

The invention discloses a preparation method and an intermediate product of mirtazapine. The preparation method comprises the following steps: in an organic solvent, carrying out a cyclization reaction on a compound represented by a formula I and / or an inorganic acid salt thereof in the presence of a sulfonic acid resin, and separating to obtain a solid, ie., the mirtazapine intermediate product;and carrying out an ion exchange reaction on the mirtazapine intermediate product and an alkali to obtain mirtazapine. The preparation method has the advantages of simplicity and convenience in operation, easiness in product separation, small pollution, suitability for industrial production and the like.

Description

technical field [0001] The invention relates to a preparation method of mirtazapine and an intermediate product thereof. Background technique [0002] The structure of mirtazapine is shown below. The trade name is Remeron. It is a noradrenergic and specific 5-HT antidepressant developed by N.V.Organon in the Netherlands. It has a unique dual mechanism of action It has good clinical curative effect on various types of depression. [0003] [0004] There are three main methods for the synthesis of mirtazapine. WO2001042239 discloses the use of mandelic acid as the starting material to prepare the intermediate 2-phenyl-4-methanol through 7 steps of esterification, chlorination, aminolysis, amino protection, reduction, methylation and hydrogenation debenzylation. Basepiperazine, then condensed with 2-chloro-3-cyanopyridine, hydrolyzed and reduced to obtain 1-(3-hydroxymethylpyridin-2-yl)-2-phenyl-4-methylpiperazine. US6495685 discloses that phenyloxirane and N-methyl-2-eth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14
CPCC07D471/14
Inventor 徐军黄河孙宁云
Owner SHANGHAI SINE PHARMA LAB
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