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Method for synthesizing mirtazapine

A synthetic method and compound technology, applied in the direction of organic chemistry, can solve the problems of many by-products, expensive raw materials, harsh conditions, etc., and achieve the effects of easy control, simple operation, and cost reduction

Active Publication Date: 2016-03-02
BEIJING MEDISAN TECH +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method has harsh conditions, many by-products, and relatively expensive raw materials

Method used

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  • Method for synthesizing mirtazapine
  • Method for synthesizing mirtazapine
  • Method for synthesizing mirtazapine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Preparation of 2-chloronicotinamide (Compound B)

[0038] Add 400ml of concentrated sulfuric acid and 2-chloronicotinonitrile (138g, 1mol) to a 1000ml three-necked flask. After it is completely dissolved, heat to 90°C and stir for 2 hours. Pour the above reaction solution into a mixture of 1000ml ammonia and 1kg ice After stirring for 1 hour, a solid crude product was obtained after filtration. The crude product was added to 1000 ml of ethyl acetate, stirred for 1 hour, and separated by filtration to obtain a white solid. The white solid was further dried by blowing at 50° C. to obtain 153 g of intermediate 2-chloronicotinamide as a white solid with a yield of 98%. 1HNMR (300M, DMSO) δ 8.46 (dd, 1H), 8.06 (s, 1H), 7.91 (dd, 1H), 7.77 (S, 1H) 7.48 (dd, 1H); 13CNMR (75M, DMSO) δ 167. 11, 150.20, 146.48, 138.00, 133.53, 123.18

Embodiment 2

[0039] Example 2: Preparation of 2-(4-methyl-2-phenyl-1-piperazinyl)nicotinamide (Compound D)

[0040] Add 600ml of N,N-dimethylformamide, 2-chloronicotinamide (153g, 0.98mol), 1-methyl-3phenylpiperazine (172g, 0.98mol), potassium fluoride to a 1000ml three-necked flask (114g, 1.96mol), heated to 140°C, stirred for 16 hours, added the crude product to 1000ml of ice water, stirred for 1 hour, filtered and separated to obtain a white solid. The white solid was further dried by blowing at 50°C to obtain 261 g of 2-(4-methyl-2phenyl-1-piperazinyl)nicotinamide, a white solid, with a yield of 90%. 1HNMR (300M, DMSO) δ 8.40 (dd, 1H), 7.88 (dd, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.49-7.36 (m, 2H), 7.32-7.28 (m , 3H), 6.86(dd, 1H), 4.73-4.64(m, 2H), 3.19-3.10(m, 1H), 3.05-2.98(m, 3H), 2.52-2.41(m, 2H), 2.29(s , 3H); 13CNMR (75M, DMSO) δ 168.11, 162.50, 146.60, 140.00, 137.30, 129.01, 128.50, 127.93, 122.82, 121.30, 54.93, 52.36, 54.68, 53.62, 45.90

Embodiment 3

[0041] Example 3: Preparation of 2-(4-methyl-2phenyl-1-piperazinyl)nicotinic acid (Compound E)

[0042] Add 600ml of 95% ethanol, 2-(4-methyl-2phenyl-1-piperazinyl)nicotinamide (148g, 0.5mol), potassium hydroxide (280g, 5mol) to a 1000ml three-necked flask, and heat to increase Bring to 110℃, stir and reflux for 26 hours, add 2L of water, remove the solvent under reduced pressure, add dropwise 6N hydrochloric acid to pH 7-8, extract three times with dichloromethane (2L×3), and dry the organic phase with 1kg anhydrous sodium sulfate , A white solid was obtained. The white solid was further dried by blowing at 50°C to obtain 134 g of 2-(4-methyl-2phenyl-1-piperazinyl)nicotinic acid, a white solid, with a yield of 90%. 1HNMR (300M, CDCl3) δ 8.50 (dd, 1H), 8.31 (dd, 1H), 7.26-7.22 (m, 2H), 7.18-7.06 (m, 4H), 4.80 (dd, 1H), 3.44 (td , 1H), 3.17-3.06 (m, 3H), 2.63-2.53 (m, 2H), 2.43 (s, 3H); 13CNMR (75M, CDCl3) δ 165.31, 159.86, 152.22, 140.29, 136.97, 128.29, 128.02 , 122.60, 121.2...

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Abstract

The invention discloses a method for synthesizing mirtazapine. According to the method, 2-halogenated nicotinonitrile is used as an initial compound, and 2-chloronicotinamide, 2-(4-methyl-2phenyl-1-piperazinyl)nicotinamide, 2-(4-methyl-2phenyl-1-piperazinyl)nicotinic acid, 1-(3-hydroxymethylpyridyl-2-)-4-methyl-2-phenylpiperazine and other intermediate products are sequentially synthesized to prepare the mirtazapine. Against the defects in a current mirtazapine synthesizing method, the process is improved, a new synthesizing route is designed, and a preparation method which is economical and is easy for practical operation is provided to mirtazapine synthesis. The method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing antipsychotic mirtapine (English name Mirtapine), which belongs to the technical field of chemical synthesis. Background technique [0002] Mirtazapine is the generic name drug of Remeron (mirtazapine) of Oujia Agricultural Company. Mirtazapine is the world's first antidepressant with dual inhibitory effects on the secondary uptake of norepinephrine and serotonin. Remeron was approved by the US FDA in 1996 and has been clinically used in more than 70 countries [0003] It is reported in US4062848 that a nitrile-based intermediate is hydrolyzed under alkaline conditions, then reduced with lithium aluminum hydride to prepare the intermediate mirtazapine, and finally the ring-closing reaction is completed to obtain the final product mirtazapine. The method uses a relatively expensive reducing agent, lithium aluminum hydride, and the post-treatment is cumbersome and costly. [0004] [0005] JP2001 / 1...

Claims

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Application Information

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IPC IPC(8): C07D471/14
CPCC07D471/14
Inventor 刘津爱李元珍宁瑞博王明新
Owner BEIJING MEDISAN TECH
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