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Preparation method of isoniazid

A technology of isoniazid and isoniazid, applied in the direction of organic chemistry, etc., can solve the problems of incomplete reaction of isoniazid, viscous system, low purity of isoniazid, etc., and shorten the reaction time and reaction conditions of hydrazine condensate hydrolysis. Mild, high-efficiency effects

Pending Publication Date: 2020-05-12
沈阳双鼎制药有限公司
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Problems solved by technology

[0005] The first is obtained by the direct condensation of isonicotinic acid and hydrazine hydrate ("National Compilation of Raw Materials Processes" 1980,194-195.), the disadvantage of this method is that the reaction temperature is high, the energy consumption is large, and the isonicotinic acid Incomplete reaction, resulting in low purity of isoniazid
[0006] The second is to use 4-cyanopyridine as a raw material, hydrolyzed to isonicotinamide, and then condensed with hydrazine hydrate (SychevaTP, Pavlova TN, Shehukina MN. Synthesis of isoniazid from 4-cyanopyridine. PharmaChem J, 1972: 6: 696-698.), the disadvantage of this method is: the hydrolysis of 4-cyanopyridine is not easy to control, and it is easy to produce by-product isonicotinic acid and 4-amino-3,5-bis(4-pyridine)-1,2,4 - Triazole, etc., resulting in low purity of isoniazid
In the condensation reaction, the crude isonicotinic acid ethyl ester produced by the esterification reaction is directly hydrolyzed with hydrazine hydrate, and no solvent is added, the system is viscous, and the stirring effect is poor, resulting in prolonged reaction time and low production efficiency

Method used

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  • Preparation method of isoniazid
  • Preparation method of isoniazid
  • Preparation method of isoniazid

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preparation example Construction

[0034] This embodiment provides a method for preparing isoniazid, which mainly includes the following steps:

[0035] 1) Using isonicotinic acid, alcohol and an acylating agent as raw materials for esterification to obtain isonicotinate;

[0036] 2) drop isonicotinate into an alcohol solution of hydrogen chloride in an ether reagent, and react to obtain isonicotinate hydrochloride;

[0037] 3) After freeing isoniazid ester hydrochloride, carry out hydrazinolysis reaction with hydrazine hydrate to obtain crude isoniazid;

[0038] 4) After refining the crude product of isoniazid, the finished product is obtained.

[0039] This embodiment provides a new synthetic route for isoniazid, in view of the existence of insufficiently reacted isonicotinic acid, isonicotinamide introduced from isonicotinic acid raw materials and potential 2 - picolinic acid impurity, and both isonicotinic acid and 2-pyridinecarboxylic acid can transfer reaction, cause the purity of the isoniazid that mak...

Embodiment 1

[0055] The preparation of embodiment 1 ethyl isonicotinate hydrochloride

[0056] Add 200g (1.62mol) of isonicotinic acid, 1600ml of dichloromethane, and 10ml of N,N-dimethylformamide into a 3000ml four-necked bottle to obtain a white suspension. Slowly add 620g (4.86mol) of oxalyl chloride dropwise. After the dropwise addition is completed, stir at a temperature of 10-50°C for 4 hours, then add 150.4g (3.24mol) of absolute ethanol dropwise, and stir for 30 minutes after the dropwise addition. The aqueous sodium carbonate solution prepared in advance (220g sodium carbonate dissolved in 800ml water) was adjusted to pH=7-8, separated, and the lower organic phase was washed with 600g 15% sodium chloride aqueous solution. Concentrate the organic phase under reduced pressure at 45°C until there is no obvious fraction, add 400ml of methyl tert-butyl ether, concentrate under reduced pressure at 50°C until there is no obvious fraction, add 3200ml of methyl tert-butyl ether to the conc...

Embodiment 2

[0057] The preparation of embodiment 2 isoniazid crude products

[0058] Add 250 g (1.33 mol) of isonicotinic acid ethyl ester hydrochloride prepared in Example 1 into a 2000 ml three-necked bottle, 250 ml of purified water, stir to dissolve, and add dropwise the sodium carbonate aqueous solution prepared in advance (42.5 g sodium carbonate dissolved in 500 ml water) to pH=7~8, then add 250ml of dichloromethane, separate the layers, collect the lower organic phase, add 300ml of purified water, drop in 116.5g (1.87mol) of 80% hydrazine hydrate, heat up to 60~100°C, and Separation of dichloromethane and other low-boiling fractions while heating up, heat at 60-100°C for 0.5-4 hours, after the reaction is complete, cool down to 0-5°C, keep warm for 1 hour, filter with suction, rinse with 250ml of absolute ethanol to get a white solid powder, Air-dried at 50°C for 3 hours to obtain 148.9 g of crude isoniazid, with a yield of 81.6% and a purity of 99.92%.

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Abstract

The invention discloses a preparation method of isoniazide, comprising the following steps: carrying out an esterification reaction among isonicotinic acid, alcohol and an acylation reagent to generate isonicotinate, carrying out a reaction between isonicotinate and an ether reagent in an alcoholic solution of hydrogen chloride to generate isonicotinate hydrochloride, condensing with hydrazine hydrate to generate an isoniazide crude product, and refining to obtain the finished product. According to the method, by adding the step of reacting isonicotinate to generate isonicotinate hydrochloride, on one hand, the subsequent condensation hydrazinolysis reaction time can be greatly shortened and preparation efficiency is improved; on the other hand, isonicotinic acid which is not fully reacted, isonicotinamide introduced by an isonicotinic acid raw material and potential 2-picolinic acid impurities can be removed, the purity of the finally obtained isoniazide is as high as 99.99%, and thesingle impurity content is smaller than 0.10%. The preparation method is mild in reaction condition, easy to operate, good in product quality, high in yield, high in preparation speed and suitable forindustrial production.

Description

technical field [0001] The disclosure of the invention relates to the technical field of drug synthesis, 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 chemical structural formula is as follows: [0003] [0004] At present, there are mainly three synthetic routes of isoniazid, which are as follows: [0005] The first is obtained by the direct condensation of isonicotinic acid and hydrazine hydrate ("National Compilation of Raw Materials Processes" 1980,194-195.), the disadvantage of this method is that the reaction temperature is high, the energy consumption is large, and the isonicotinic acid Incomplete reaction results in low purity of isoniazid. [0006] The second is to use 4-cyanopyridine as a raw material,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/86
CPCC07D213/86
Inventor 马占芝涂爽马佳妮蔡巍
Owner 沈阳双鼎制药有限公司
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