Method for controlling impurities of isoniazid

A technology of isoniazid and impurities, applied in the field of control of isoniazid impurities, to achieve the effect of easy control and simple operation

Inactive Publication Date: 2012-03-28
浙江新赛科药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the control of isoniazid impurities has not been reported in the literature

Method used

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  • Method for controlling impurities of isoniazid
  • Method for controlling impurities of isoniazid
  • Method for controlling impurities of isoniazid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The preparation of embodiment 1 isoniazid

[0037] Add 120g MnO to the 2000ml three-necked bottle 2 , then hot-melted 600g (5.76mol) 4-cyanopyridine (HPLC chromatographic purity is 99.8%, wherein the content of impurity INH-C is 0.07%, the content of impurity INH-D is 0.06%, the content of impurity INH-B The content is 0.07%) and 360g of water are added, the temperature is raised to 95 ℃ for 3 hours, and after 3 hours, 600g of water is added and filtered. The filtrate was concentrated under reduced pressure, and when about 720g of water was reclaimed, the concentration was stopped (in the concentrate that was recorded by HPLC, the content of INH-A was 0.30%, and the content of INH-F was 1.20%), nitrogen protection, 894g (17.88 mol) hydrazine hydrate was added, the temperature was raised, and the time was started at 90°C. After 2.5 hours of heat preservation at 90°C, the diluent (450g of water) was added, the temperature was raised appropriately, and dissolved to obtain...

Embodiment 2

[0038] The refining of embodiment 2 isoniazid

[0039] Add the aqueous solution of the crude isoniazid product prepared in Example 1 to a 2000ml three-necked flask, add 5g of activated carbon, heat to 75°C, keep warm for half an hour, filter, and the filtrate is naturally cooled for 4 hours, then cooled to 0°C, filtered, The refined product is obtained once, and the refined product is recrystallized once by the same method, and dried to obtain the finished product of isoniazid.

[0040] Adopt the purity of the isoniazid finished product of HPLC method test gained, the content of relevant impurity, the result is as follows:

[0041] The purity of the finished product of isoniazid is 99.91%; the impurity INH-A is not detected, the impurity INH-B is not detected, the impurity INH-C is not detected, the impurity INH-D is not detected, and the content of the impurity INH-E is 0.02 %, the content of INH-F is 0.01%, the content of INH-G is 0.02%, the impurity INH-H is not detected, ...

Embodiment 3

[0042] Example 3 Preparation of INH-J

[0043] Add 13g (0.1mol) of isonicotinic acid into a 250ml flask, weigh 80g (1.6mol) of hydrazine hydrate, and gradually raise the temperature to 140°C for 24 hours. Finally a yellow oily liquid was obtained. After the product was cooled and solidified, it was recrystallized with acetone to obtain 4 g of the product.

[0044] Confirmation of product structure:

[0045]

[0046] NMR data:

[0047] Hydrogen spectrum ( 1 H-NMR) and attribution

[0048] Numbering

δ, ppm

proton

1，4，5，6

8.075-8.086

4

2，3，7，8

8.803

4

9

6.540

2

[0049] Infrared spectral data:

[0050]3299.10cm -1 : v N-H

[0051] 3173.13em -1 : v N-H

[0052] 1600.53cm -1 : v C = N

[0053] Mass spectrometry data: the quasi-molecular ion peak in the spectrogram is [M-H] + The mass number of the sample is m / z237, and the relative molecular mass of the sample is 238, which is co...

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PUM

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Abstract

The invention discloses a method for controlling impurities of isoniazid, which comprises the following steps of: controlling the chromatographic purity of a 4-cyanopyridine material to be greater than or equal to 99.8%, wherein the content of an INH-C(Isonicotinyl Hydrazine-C) impurity is less than or equal to 0.1%, the content of an INH-D(Isonicotinyl Hydrazine-D) impurity is less than or equal to 0.1%, and the content of an INH-B(Isonicotinyl Hydrazine-B) impurity is less than or equal to 0.1%; in a hydrolytic reaction step, controlling the reaction temperature to be 95-105 DEG C and the reaction time to be 1.5-3 hours; in a condensation reaction step, controlling the reaction temperature to be 90-97 DEG C and the reaction time to be 1.5-2.5 hours; controlling the molar ratio of the 4-cyanopyridine to hydrazine hydrate to be 1:(2-4); and obtaining isoniazid with high purity and low impurity. The method disclosed by the invention is simple in operation, easy to control and suitable for industrialized operation.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for controlling isoniazid impurities. 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 other is prepared from 4-cyanopyridine as raw material, hydrolyzed to isonicotinamide, and then condensed with hydrazine hydrate (Sycheva TP, Pavlova TN, Shehukina MN.Synthesis of isoniazid from 4-cyanopyridine[J ]. Ph...

Claims

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Application Information

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IPC IPC(8): C07D213/86
Inventor 郭拥政吕士华杨和军张铁斌徐虎
Owner 浙江新赛科药业有限公司
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