Preparation method of isoniazid

A technology of isoniazid and isoniazid, applied in the direction of organic chemistry, can solve the problems of easy generation of impurities, high reaction temperature, high energy consumption, etc., and achieve the effects of reducing waste discharge, reducing costs, and simple operation

Active Publication Date: 2015-11-25
浙江新赛科药业有限公司
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Problems solved by technology

[0004] There are not many documents about the synthetic route of isoniazid, and there are no more than two synthetic routes, one is obtained by direct condensation of isonicotinic acid and hydrazine hydrate (Li Zhenghua. Medicinal Chemistry [M]. Beijing: People's Health Publishing House, 1993 : 370.), the shortcoming of this method is that reaction temperature is higher, energy consumption is higher, and isonicotinic acid has residual; Another kind is to be raw material with 4-cyanopyridine, hydrolyzes to isonicotinamide, then with hydrazine hydrate It is prepared by condensation (SychevaTP, PavlovaTN, ShehukinaMN.Synthesisofisoniazidfrom4-cyanopyridine[J].PharmaChemJ, 1972:6:696-698.), the disadvantage of this method is that the hydrolysis of 4-cyanopyridine is not easy to control, and it is easy to produce the by-product different smoke Acid, and easy to produce impurities J

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  • Preparation method of isoniazid
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  • Preparation method of isoniazid

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Embodiment 1

[0059] The preparation of embodiment 1 isoniazid

[0060] Add 200g (1.62mol) of isonicotinic acid, 1200g of ethanol, and 16.4g (0.162mol) of triethylamine into a 2000ml three-necked flask, stir and cool down to 0°C to 5°C, slowly add 212g (1.78mol) of thionyl chloride dropwise, After the dropwise addition, keep the temperature at 0°C to 5°C for 2 hours, then raise the temperature to 20°C to 25°C and keep the temperature for 20 hours. After the reaction is completed, concentrate under reduced pressure to obtain an oil, add 119g (2.43mol) of hydrazine hydrate, and heat up to 70 ℃~75℃, keep warm for 10 hours, add diluent (350g of water), raise the temperature properly, and dissolve to get the aqueous solution of crude isoniazid, add 10g of activated carbon, keep warm at 70℃~75℃ for half an hour, filter, the filtrate is natural Cool for 6 hours, then slowly cool to 0°C, filter, and dry to obtain the finished product of isoniazid, with a purity of 99.94%, a single impurity less tha...

Embodiment 2

[0062] The preparation of embodiment 2 isoniazid

[0063] Add 200g (1.62mol) of isonicotinic acid, 1600g of ethanol, and 16.4g (0.162mol) of triethylamine into a 3000ml three-necked flask, stir and cool down to 5°C to 10°C, slowly add 250g (2.1mol) of thionyl chloride dropwise, After the dropwise addition, keep the temperature at 5°C to 10°C for 2 hours, then raise the temperature to 20°C to 25°C and keep it for 20 hours. After the reaction is completed, concentrate under reduced pressure to obtain an oil, add 143g (2.92mol) of hydrazine hydrate, and heat up to 73 ℃~76℃, keep warm for 10 hours, add diluent (350g of water), raise the temperature properly, and dissolve to get the aqueous solution of crude isoniazid, add 10g of activated carbon, keep warm at 70℃~75℃ for half an hour, filter, the filtrate is natural Cool for 6 hours, then slowly cool to 0°C, filter, and dry to obtain the finished product of isoniazid, with a purity of 99.95%, a single impurity of less than 0.10%, ...

Embodiment 3

[0064] The preparation of embodiment 3 isoniazid

[0065] Add 200g (1.62mol) of isonicotinic acid, 2000g of ethanol, and 16.4g (0.162mol) of triethylamine into a 3000ml three-necked flask, stir and cool down to 5°C-10°C, slowly add 289g (2.43mol) of thionyl chloride dropwise, After the dropwise addition, keep the temperature at 5°C to 10°C for 2 hours, then raise the temperature to 25°C to 30°C and keep it for 20 hours. After the reaction is completed, concentrate under reduced pressure to obtain an oil, add 158g (3.2mol) of hydrazine hydrate, and heat up to 75°C. ℃~80℃, keep warm for 10 hours, add diluent (350g of water), raise the temperature properly, and dissolve to get the aqueous solution of crude isoniazid, add 10g of activated carbon, keep warm at 70℃~75℃ for half an hour, filter, the filtrate is natural Cool for 6 hours, then slowly cool to 0°C, filter, and dry to obtain the finished product of isoniazid, with a purity of 99.93%, a single impurity of less than 0.10%, ...

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Abstract

The invention discloses a preparation method of isoniazid. The method comprises the following steps: 1) performing esterification reaction to isonicotinic acid, alcohol and acylating reagent to obtain isonicotinic acid ester; 2) performing condensation reaction to isonicotinic acid ester and hydrazine hydrate and performing post-treatment to reaction liquid to obtain isoniazid finished products. The isoniazid is prepared firstly through esterification of isonicotinic acid and alcohol and then condensation of the obtained ester and hydrazine hydrate. The method can well control the content of impurities in the target product isoniazid, high-purity isoniazid can be obtained, the purity is above 99.9 percent and the content of individual impurity is smaller than 0.10 percent. The method is simple to operate, is easy to control and is applicable to industrial operation. In addition, by using recovered isonicotinic acid to prepare isoniazid, the cyclic utilization of resources can be realized, the waste emission is reduced, the cost is reduced and the method is very suitable for industrial production.

Description

technical field [0001] The invention relates to the field of isoniazid medicinal chemistry, in particular to a preparation method of isoniazid. Background technique [0002] Isoniazid (chemical name: 4-pyridinyl hydrazide, INH for short) has good antibacterial effect on Mycobacterium tuberculosis, good curative effect, small dosage, relatively low toxicity, and is easily accepted by patients. The structural formula is as follows: [0003] [0004] There are not many documents about the synthetic route of isoniazid, and there are no more than two synthetic routes, one is obtained by direct condensation of isonicotinic acid and hydrazine hydrate (Li Zhenghua. Medicinal Chemistry [M]. Beijing: People's Health Publishing House, 1993 : 370.), the shortcoming of this method is that reaction temperature is higher, energy consumption is higher, and isonicotinic acid has residual; Another kind is to be raw material with 4-cyanopyridine, hydrolyzes to isonicotinamide, then with hy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/86C07D213/803C07D213/79
CPCC07D213/79C07D213/803C07D213/86
Inventor 杨和军李洪武郭拥政蒋栋吕士华朱铁军李远张喜
Owner 浙江新赛科药业有限公司
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