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Synthetic method of mirtazapine

A synthesis method and technology of mirtazapine, applied in the field of medicine, can solve the problems of serious agglomeration, difficulty in dissolving, affecting the effect and progress of the reaction, etc., and achieve the effects of high product yield, elimination of agglomeration and low cost.

Inactive Publication Date: 2014-01-15
SHANDONG LUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] During the preparation of mirtazapine, during the mixing process of 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenylpiperazine and concentrated sulfuric acid, it is easy to agglomerate into blocks, resulting in It is difficult to dissolve. If a small amount of solvent such as ethanol is not added, the agglomeration will be more serious, which will prevent the homogeneous progress of the reaction and affect the effect and progress of the reaction. The occurrence of agglomeration also makes it unsuitable for large-scale industrial production.

Method used

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  • Synthetic method of mirtazapine
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  • Synthetic method of mirtazapine

Examples

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Embodiment 1

[0029] Preparation of 1,2,3,4,10,14b-hexahydro-2-methylpyrazinyl-[2,1-a]pyrido[2,3-C]azepine (namely mirtazapine) :

[0030] Add 30ml of THF to a 250ml three-neck flask, slowly add 24ml of concentrated sulfuric acid, add mechanical stirring and a thermometer, and cool down to 5-10°C in an ice-water bath. Under stirring, start to add 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenylpiperazine solid in batches, a total of 15g, after the addition is complete, stir at room temperature for 10min until homogeneous, then add 13.5ml Concentrated sulfuric acid began to heat up to 50 ° C for 6 hours. After the reaction is complete, add 150ml of ice water, add concentrated ammonia water dropwise under the ice water bath to adjust the pH to 2, add 1g of activated carbon and stir for decolorization for 1 hour, filter with suction, adjust the pH of the filtrate to 9 with concentrated ammonia water, extract twice with 150ml of dichloromethane, and combine The organic phase was backwashed with...

Embodiment 2

[0032] Preparation of 1,2,3,4,10,14b-hexahydro-2-methylpyrazinyl-[2,1-a]pyrido[2,3-C]azepine (namely mirtazapine) :

[0033] Add 60ml of THF to a 250ml three-necked flask, slowly add 24ml of concentrated sulfuric acid, add mechanical stirring and a thermometer, and cool down to 5-10°C in an ice-water bath. Under stirring, start to add 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenylpiperazine solid in batches, a total of 15g, after the addition is complete, stir at room temperature for 10min until homogeneous, then add 13.5ml Concentrated sulfuric acid began to heat up to 50 ° C for 6 hours. After the reaction is complete, add 150ml of ice water, add concentrated ammonia water dropwise under the ice water bath to adjust the pH to 2, add 1g of activated carbon and stir for decolorization for 1 hour, filter with suction, adjust the pH of the filtrate to 9 with concentrated ammonia water, extract twice with 150ml of dichloromethane, and combine The organic phase was backwashed wi...

Embodiment 3

[0035] Preparation of 1,2,3,4,10,14b-hexahydro-2-methylpyrazinyl-[2,1-a]pyrido[2,3-C]azepine (namely mirtazapine) :

[0036] Add 15ml of THF to a 250ml three-neck flask, slowly add 24ml of concentrated sulfuric acid, add mechanical stirring and a thermometer, and cool down to 5-10°C in an ice-water bath. Under stirring, start to add 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenylpiperazine solid in batches, a total of 15g, after the addition is complete, stir at room temperature for 10min until homogeneous, then add 13.5ml Concentrated sulfuric acid began to heat up to 50 ° C for 6 hours. After the reaction is complete, add 150ml of ice water, add concentrated ammonia water dropwise under the ice water bath to adjust the pH to 2, add 1g of activated carbon and stir for decolorization for 1 hour, filter with suction, adjust the pH of the filtrate to 9 with concentrated ammonia water, extract twice with 150ml of dichloromethane, and combine The organic phase was backwashed with...

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Abstract

The invention relates to a synthetic method of mirtazapine. The synthetic method is characterized by comprising the following steps: 1), slowing adding 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenylpiperazine in a mixed solution of concentrated sulfuric acid and tetrahydrofuran, after adding, supplementing just enough concentrated sulfuric acid; 2), when material adding is finished, taking reaction at the temperature of 0-80 DEG C for 0-1 day to obtain mirtazapine. Compared to the prior art, the synthetic method of mirtazapine has the following beneficial effects: the proper quantity of tetrahydrofuran is added in the reaction system as a cosolvent to eliminate agglomeration of 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenylpiperazine in concentrated sulfuric acid, and the reaction can be carried out mildly and homogeneously, so that the material feeding speed is relatively improved, the agglomeration phenomenon can be reduced or avoided, and the method will not generate side reaction; in the meantime, the yield of the product is high, the cost is low, and the synthetic method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to an antidepressant drug 1,2,3,4,10,14b-hexahydro-2-methylpyrazinyl-[2,1-a]pyrido[2 , 3-C] Azepine is an improved synthetic method of mirtazapine. technical background [0002] Mirtazapine (English name is mirtazapine, compound I) is an effective antidepressant drug (US4062848), which is a selective serotonin reuptake inhibitor. Marketed in the Netherlands, it was approved by the US FDA in 1996 and has been widely used clinically in many countries around the world. [0003] [0004] There are several methods for preparing mirtazapine reported in the literature. U.S. Patent No. 4,062,848 reports that the cyano intermediate A is hydrolyzed under strong alkaline conditions to generate a carboxyl intermediate B, and the carboxyl intermediate B is further reduced to a hydroxyl intermediate C. Finally, mirtazapine D was obtained by cyclization. As follows: [0005] [0006] Patent JP200...

Claims

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Application Information

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IPC IPC(8): C07D471/14
CPCC07D471/14
Inventor 苏小勇许卫东
Owner SHANDONG LUYAO PHARMA