CN102391178A - Method for controlling impurities of isoniazid - Google Patents
Method for controlling impurities of isoniazid Download PDFInfo
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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
The invention belongs to the pharmaceutical chemistry field, be specifically related to the control method of a kind of vazadrine impurity.
Background technology
The vazadrine (chemistry is by name: 4-pyridine formyl hydrazine, be called for short INH) and tubercule bacillus there is good anti-microbial effect, curative effect is better, and consumption is less, and toxicity is relatively low, is prone to accepted by patient, and the structural formula of vazadrine is following:
About the document of vazadrine synthetic route and few, two kinds of synthetic routes nothing more than, a kind of for Yi Yansuan and the direct condensation of Hydrazine Hydrate 80 make (Li Zhenghua. pharmaceutical chemistry [M]. Beijing: the People's Health Publisher, 1993:370.); A kind of in addition for being raw material with the 4-cyanopyridine; Be hydrolyzed to Isonicotinamide, make (Sycheva TP, Pavlova TN again with the Hydrazine Hydrate 80 condensation; Shehukina MN.Synthesis of isoniazid from 4-cyanopyridine [J] .Pharma Chem J, 1972:6:696-698.).Yet, also do not see bibliographical information for the control of vazadrine impurity.
Summary of the invention
The invention provides the control method of impurity in the building-up process of a kind of vazadrine, the following route of wherein said synthetic employing:
Hydrolysis reaction:
Condensation reaction:
This compound method belongs to prior art; Can be with reference to people such as Sycheva TP at " through the synthetic vazadrine of 4-cyanopyridine " (Pavlova TN; Shehukina MN.Synthesis of isoniazid from 4-cyanopyridine [J] .Pharma Chem J; 1972:6:696-698.) preparation method in the literary composition, but should existing method Control of Impurities not studied.The present invention is according to this synthetic route; Combine the requirement of the Pharmacopoeia of the People's Republic of China in 2010 simultaneously; Related substance should meet following requirement in the vazadrine that qualification makes: the content of impurity INH-A, INH-B, INH-C, INH-D, INH-E, INH-F, INH-G, INH-H, INH-I, INH-J all≤0.1%; Other single assorted content≤0.1%, the content of total impurities≤0.3%;
Wherein, the structural formula of described impurity is following:
This step reaction of condensation reaction of choosing synthetic vazadrine is as monitoring key point, through investigating the variation of the Impurity Distribution situation in bullion, highly finished product and the secondary refining article, thereby draws the actual purification effect of post-treating method.For the quality control index of raw material, reaction solution and midbody provides foundation.
Orientation of the present invention has been synthesized impurity INH-H, INH-J, and finishes the structure conclusive evidence, and other impurity obtains through buying the commercially available prod.Chromatographic condition (concrete) according to Pharmacopoeia of the People's Republic of China requirement in 2010 with reference to two ones 295 pages vazadrine of 2010 editions Chinese Pharmacopoeias assay item chromatographic condition; Test is according to prior art (Sycheva TP; Pavlova TN; Shehukina MN.Synthesis of isoniazid from 4-cyanopyridine [J] .Pharma Chem J, 1972:6:696-698.) the vazadrine bullion of preparation and the impurity data of highly finished product, as shown in the table:
Vazadrine Impurity Distribution data
| Project/content | Bullion | Highly finished product | The secondary refining article |
| INH-A | 0.12％ | Do not detect | Do not detect |
| INH-B | 0.02％ | Do not detect | Do not detect |
| INH-C | 0.05％ | Do not detect | Do not detect |
| INH-D | 0.08％ | Do not detect | Do not detect |
| INH-E | 2.5％ | 0.21％ | 0.03 |
| INH-F | 3.1％ | 0.25％ | 0.02 |
| INH-G | 0.10％ | 0.02％ | 0.01 |
| INH-H | Do not detect | Do not detect | Do not detect |
| INH-I | Do not detect | Do not detect | Do not detect |
| INH-J | 0.65％ | 0.18％ | 0.06 |
| INH | 93.38％ | 99.34％ | 99.88％ |
Can find out that from table impurity INH-J and INH-G removed through refining being difficult to, impurity INH-E and INH-F are not good through refining removal effect yet.
Impurity INH-E is for the intact Isonicotinamide midbody of condensation reaction unreacted, so will control the completeness that impurity INH-E must control condensation reaction.
Two portions are divided in the source of impurity INH-F; Excessive hydrolysis in hydrolysis reaction is produced a part by the 4-cyanopyridine; Hydrolysis is produced another part by the condensation reaction Isonicotinamide; So control impurity INH-F, the temperature and time and the catalyst consumption of necessary control hydrolysis reaction, the temperature and time of control condensation reaction.
Impurity INH-G derives from the 3-cyanopyridine hydrolysis of bringing in the starting raw material 4-cyanopyridine and produces, so will control impurity INH-G, must control the content of 3-cyanopyridine in the starting raw material.
Impurity INH-J derives from following generation of situation that Yi Yansuan in the condensation reaction (INH-F) is higher in temperature with Hydrazine Hydrate 80, the time is long, so will control impurity INH-J, must control the temperature and time of condensation reaction.
Through above argumentation, can confirm that the 4-cyanopyridine is the critical materials that influences the vazadrine quality product, hydrolysis and condensation are the committed steps that influences the vazadrine quality product.Therefore, the present invention's quality product that will guarantee the vazadrine through quality and hydrolysis, the condensation reaction of control 4-cyanopyridine.Concrete, chromatographic purity>=99.8% of 4-cyanopyridine raw material, the content of impurity INH-C≤0.1% wherein, the content of impurity INH-D≤0.1%, the content of impurity INH-B≤0.1%; In the hydrolysis reaction step, control reaction temperature is 95 ℃-105 ℃, and the reaction times is 1.5 hours-3 hours; In the step of condensation, control reaction temperature is 90 ℃-97 ℃, and the reaction times is 1.5 hours-2.5 hours; The mol ratio of control 4-cyanopyridine and Hydrazine Hydrate 80 is: 1: 2-4.
In order to reach better effect, preferably:
In the hydrolysis reaction step, the content of INH-A is less than 0.5% in the product of hydrolysis reaction, and the content of INH-F is less than 2.5%.
In the step of condensation, the content of INH-E further is preferably less than 2% less than 3% in the product of condensation reaction, and the content of INH-F is less than 3.5%, and the content of INH-J is less than 0.7%.
Control 4-cyanopyridine and catalyzer MnO
2Mass ratio be 5-7: 1.
The data of content of the present invention, purity are the per-cent of the peak area that calculates of peak area normalization method commonly used in the chromatographic computation.
The measuring method of purity of the present invention, its related substances is existing routine techniques, and like the HPLC method, chromatographic condition is following:
Moving phase: 0.02mol/L disodium phosphate soln (phosphoric acid is transferred pH=6): methyl alcohol (85: 15, volume ratio);
Chromatographic column: (L1) 250 * 4.6mm;
Detect wavelength: 262nm;
Flow velocity: 1.0ml/min;
Column temperature: 25 ℃;
Sample size: 10 μ l.
Compared with prior art, the present invention has following advantage:
The inventive method can well controlled target product vazadrine in the content of impurity, obtain highly purified vazadrine, and this method is simple to operate, be easy to control, be suitable for the industriallization operation.
Embodiment
Following examples are in order the present invention to be further specified, should it not to be regarded as limitation of the present invention.
The preparation of embodiment 1 vazadrine
In the 2000ml there-necked flask, add 120g MnO
2(the HPLC chromatographic purity is 99.8% to again that thermosol is good 600g (5.76mol) 4-cyanopyridine; Wherein the content of impurity INH-C is 0.07%, and the content of impurity INH-D is 0.06%, and the content of impurity INH-B is 0.07%) and the adding of 360g water; Be warming up to 95 ℃ of insulations and add water 600g after 3 hours, filter.Filtrating is carried out concentrating under reduced pressure, when reclaiming out about 720g water, stops to concentrate that (HPLC records in the enriched material, and the content of INH-A is 0.30%; The content of INH-F is 1.20%), the inflated with nitrogen protection adds 894g (17.88mol) Hydrazine Hydrate 80, heats up; 90 ℃ begin to clock, and 90 ℃ of insulations added diluent (water 450g) after 2.5 hours; Suitably heat up, dissolving, (HPLC records wherein, and the content of INH-E is 1.01% to get the vazadrine aqueous solution of crude; The content of INH-F is 2.11%, and the content of INH-J is 0.40%), vazadrine bullion yield 95%.
Making with extra care of embodiment 2 vazadrine
In the 2000ml there-necked flask, add the vazadrine aqueous solution of crude that embodiment 1 makes, add gac 5g, be heated to 75 ℃; After insulation half a hour, filter the first naturally cooling 4 hours of filtrating; Be chilled to 0 ℃ again, filter, get highly finished product; One time highly finished product use the same method recrystallize once, and drying gets the vazadrine finished product.
Adopt the purity of the vazadrine finished product of HPLC method test gained, the content of relative substance, the result is following:
The purity of vazadrine finished product is 99.91%; Impurity INH-A does not detect, impurity INH-B does not detect, impurity INH-C does not detect, impurity INH-D does not detect, the content of impurity INH-E is 0.02%, the content of INH-F is 0.01%, the content of INH-G is 0.02%, impurity INH-H does not detect, impurity INH-I does not detect, the content of INH-J is 0.04%, all less than 0.1%; Not other single assorted not detecting; The content of total impurities is 0.09%, less than 0.3%.
The preparation of embodiment 3 INH-J
13g (0.1mol) Yi Yansuan is added the people in the 250ml flask, take by weighing 80g (1.6mol) Hydrazine Hydrate 80 again, be warming up to 140 ℃ of reaction 24h gradually.Obtain yellow oily liquid at last.Treat to use acetone recrystallization after the product cooled and solidified, obtain product 4g.
The product structure conclusive evidence:
Nuclear magnetic data:
The hydrogen spectrum (
1H-NMR) and the ownership
| Numbering | δ，ppm | Proton (proton) |
| 1，4，5，6 | 8.075-8.086 | 4 |
| 2，3，7，8 | 8.803 | 4 |
| 9 | 6.540 | 2 |
Ir data:
3299.10cm
-1：v?N-H
3173.13em
-1：v?N-H
1600.53cm
-1：v?C＝N
Mass-spectrometric data: quasi-molecular ion peak is [M-H] in spectrogram
+Total mass number be m/z237, the relative molecular mass of sample is 238, and is consistent with the molecular weight of impurity INH-J, the product that shows gained is impurity INH-J.
The preparation of embodiment 4 INH-J
It is raw material that enchashment has with the 4-cyanopyridine, gets the vazadrine through hydrolysis, condensation, again through refining vazadrine mother liquor (the Sycheva TP that produces; Pavlova TN, Shehukina MN.Synthesis of isoniazid from 4-cyanopyridine [J] .Pharma Chem J, 1972:6:696-698.); Be concentrated into 1/5th of vazadrine mother liquor volume; Reduce to room temperature, filter, filter cake promptly gets product with acetone recrystallization.
The product structure conclusive evidence:
Nuclear magnetic data:
The hydrogen spectrum (
1H-NMR) and the ownership
| Numbering | δ，ppm | Proton (proton) |
| 1，4，5，6 | 8.075-8.086 | 4 |
| 2，3，7，8 | 8.803 | 4 |
| 9 | 6.540 | 2 |
Ir data:
3299.10cm
-1：v?N-H
3173.13cm
-1：v?N-H
1600.53cm
-1：v?C＝N
Mass-spectrometric data: quasi-molecular ion peak is [M-H] in spectrogram
+Total mass number be m/z237, the relative molecular mass of sample is 238, and is consistent with the molecular weight of impurity INH-J, the product that shows gained is impurity INH-J.
The preparation of embodiment 5 INH-H
In the 2000ml there-necked flask, add 120g MnO
2, again that thermosol is good 600g 3-cyanopyridine and 360g water add, and are warming up to 95-105 ℃ of insulation and add water 600g after 1.5-3 hour, filter.Filtrating is carried out concentrating under reduced pressure, when reclaiming out about 720g water, stops to concentrate, and the inflated with nitrogen protection adds Hydrazine Hydrate 80, heats up, and 90 ℃ begin to clock, and 90-97 ℃ of insulation concentrated after 24 hours, got WS 102.
Structural identification:
Nuclear magnetic data:
The hydrogen spectrum (
1H-NMR) and the ownership
| Numbering | δ，ppm | Proton (proton) |
| 6 | 7.748 | 1 |
| 4 | 8.271 | 1 |
| 1，7 | 8.727～8.741 | 2 |
| 2，3 | 7.779～7.794 | 2 |
| 5 | 3.410 | 1 |
The product that shows gained is impurity INH-H, i.e. WS 102.
The preparation of embodiment 6 vazadrine
In the 2000ml there-necked flask, add 100g MnO
2(the HPLC chromatographic purity is 99.9% to again that thermosol is good 600g (5.76mol) 4-cyanopyridine; Record wherein that the content of impurity INH-C is 0.04%, the content of impurity INH-D is 0.03%, and the content of impurity INH-B is 0.03%) and 360g water add; Be warming up to 105 ℃ of insulations and add water 600g after 1.5 hours, filter.Filtrating is carried out concentrating under reduced pressure, when reclaiming out about 720g water, stops to concentrate that (HPLC records in the enriched material, and the content of INH-A is 0.20%; The content of INH-F is 0.91%), the inflated with nitrogen protection adds 577g (11.52mol) Hydrazine Hydrate 80, heats up; 97 ℃ begin to clock, and 97 ℃ of insulations added diluent (water 450g) after 1.5 hours; Suitably heat up, dissolving, (HPLC records wherein, and the content of INH-E is 0.92% to get the vazadrine aqueous solution of crude; The content of INH-F is 1.83%, and the content of INH-J is 0.31%), vazadrine bullion yield 96%.
Making with extra care of embodiment 7 vazadrine
In the 2000ml there-necked flask, add the vazadrine aqueous solution of crude that embodiment 6 makes, add gac 5g, be heated to 95 ℃; After insulation half a hour, filter the first naturally cooling 4 hours of filtrating; Be chilled to 10 ℃ again, filter, get highly finished product; One time highly finished product use the same method recrystallize once, and drying gets the vazadrine finished product.
Adopt the purity of the vazadrine finished product of HPLC method test gained, the content of relative substance, the result is following:
The purity of vazadrine finished product is 99.95%; Impurity INH-A does not detect, impurity INH-B does not detect, impurity INH-C does not detect, impurity INH-D does not detect, the content of impurity INH-E is 0.01%, the content of INH-F is 0.01%, the content of INH-G is 0.01%, impurity INH-H does not detect, impurity INH-I does not detect, the content of impurity INH-J is 0.02%, all less than 0.1%; Not other single assorted not detecting; The content of total impurities is 0.05%, less than 0.3%.
The preparation of embodiment 8 vazadrine
In the 2000ml there-necked flask, add 85.8g MnO
2(the HPLC chromatographic purity is 99.8% to again that thermosol is good 600g (5.76mol) 4-cyanopyridine; Record wherein that the content of impurity INH-C is 0.08%, the content of impurity INH-D is 0.06%, and the content of impurity INH-B is 0.06%) and 360g water add; Be warming up to 100 ℃ of insulations and add water 600g after 2.2 hours, filter.Filtrating is carried out concentrating under reduced pressure, when reclaiming out about 720g water, stops to concentrate that (HPLC records in the enriched material, and the content of INH-A is 0.45%; The content of INH-F is 1.35%), the inflated with nitrogen protection adds 1153g (23.04mol) Hydrazine Hydrate 80, heats up; 93 ℃ begin to clock, and 93 ℃ of insulations added diluent (water 450g) after 2 hours; Suitably heat up, dissolving, (HPLC records wherein, and the content of INH-E is 1.25% to get the vazadrine aqueous solution of crude; The content of INH-F is 2.43%, and the content of INH-J is 0.51%), vazadrine bullion yield 93.8%.
Making with extra care of embodiment 9 vazadrine
In the 2000ml there-necked flask, add the vazadrine aqueous solution of crude that embodiment 8 makes, add gac 5g, be heated to 85 ℃; After insulation half a hour, filter the first naturally cooling 4 hours of filtrating; Be chilled to 5 ℃ again, filter, get highly finished product; One time highly finished product use the same method recrystallize once, and drying gets the vazadrine finished product.
Adopt the purity of the vazadrine finished product of HPLC method test gained, the content of relative substance, the result is following:
The purity of vazadrine finished product is 99.88%; Impurity INH-A does not detect, impurity INH-B does not detect, impurity INH-C does not detect, impurity INH-D does not detect, the content of impurity INH-E is 0.03%, the content of impurity INH-F is 0.02%, the content of INH-G is 0.01%, impurity INH-H does not detect, impurity INH-I does not detect, the content of impurity INH-J is 0.06%; All less than 0.1%; Not other single assorted not detecting; The content of total impurities is 0.12%, less than 0.3%.
Claims (6)
1. the preparation method of a vazadrine may further comprise the steps:
Hydrolysis reaction:
Condensation reaction:
It is characterized in that chromatographic purity>=99.8% of 4-cyanopyridine raw material, the content of impurity INH-C≤0.1% wherein, the content of impurity INH-D≤0.1%, the content of impurity INH-B≤0.1%;
In the hydrolysis reaction step, control reaction temperature is 95 ℃-105 ℃, and the reaction times is 1.5 hours-3 hours;
In the step of condensation, control reaction temperature is 90 ℃-97 ℃, and the reaction times is 1.5 hours-2.5 hours;
The mol ratio of control 4-cyanopyridine and Hydrazine Hydrate 80 is: 1: 2-4;
Wherein, the structural formula of described INH-B, INH-C and INH-D is respectively as follows:
2. the preparation method of vazadrine according to claim 1 is characterized in that, in the hydrolysis reaction step, the content of INH-A is less than 0.5% in the product of hydrolysis reaction, and the content of INH-F is less than 2.5%;
Wherein, the structural formula of described INH-A and INH-F is respectively as follows:
3. the preparation method of vazadrine according to claim 1 is characterized in that, in the step of condensation, the content of INH-E is less than 3% in the product of condensation reaction, and the content of INH-F is less than 3.5%, and the content of INH-J is less than 0.7%;
Wherein, the structural formula of described INH-E, INH-F and INH-J is respectively as follows:
4. the preparation method of vazadrine according to claim 3 is characterized in that, in the step of condensation, the content of INH-E is less than 2% in the product of condensation reaction.
5. the preparation method of vazadrine according to claim 1; It is characterized in that; Related substance meets following requirement in the vazadrine that makes: the content of impurity INH-A, INH-B, INH-C, INH-D, INH-E, INH-F, INH-G, INH-H, INH-I, INH-J all≤0.1%; Other single assorted content≤0.1%, the content of total impurities≤0.3%;
Wherein, the structural formula of said impurity is following:
6. the preparation method of vazadrine according to claim 1 is characterized in that, control 4-cyanopyridine and catalyzer MnO
2Mass ratio be 5-7: 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108226323A (en) * | 2017-12-13 | 2018-06-29 | 重庆华邦胜凯制药有限公司 | A kind of method for measuring isoniazid starting material 4- cyanopyridines and its impurity content |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2830994A (en) * | 1955-06-29 | 1958-04-15 | Distillers Co Yeast Ltd | Process for manufacture of isonicotinic acid hydrazide from pyridine nitrile |
| CN1741997A (en) * | 2002-12-23 | 2006-03-01 | 科学与工业研究委员会 | Process for conversion of cyanopyridines tonicotinamides and catalyst therefor, process for preparing said catalyst |
-
2011
- 2011-09-30 CN CN2011102985019A patent/CN102391178A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2830994A (en) * | 1955-06-29 | 1958-04-15 | Distillers Co Yeast Ltd | Process for manufacture of isonicotinic acid hydrazide from pyridine nitrile |
| CN1741997A (en) * | 2002-12-23 | 2006-03-01 | 科学与工业研究委员会 | Process for conversion of cyanopyridines tonicotinamides and catalyst therefor, process for preparing said catalyst |
Non-Patent Citations (2)
| Title |
|---|
| T. P. SYCHEVA，等: "SYNTHESIS OF ISONIAZID FROM 4-CYANOPYRIDINE", 《J. PHARMA.CHEM》, vol. 6, no. 11, 30 November 1972 (1972-11-30), pages 696 - 698 * |
| 崔书文，等: "异烟肼合成方法的改进", 《黑龙江医药科学》, vol. 21, no. 5, 31 October 1998 (1998-10-31), pages 36 - 37 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108226323A (en) * | 2017-12-13 | 2018-06-29 | 重庆华邦胜凯制药有限公司 | A kind of method for measuring isoniazid starting material 4- cyanopyridines and its impurity content |
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Application publication date: 20120328 |