CN1807415A - 4-aminopyridine preparation method - Google Patents
4-aminopyridine preparation method Download PDFInfo
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- CN1807415A CN1807415A CN 200510002407 CN200510002407A CN1807415A CN 1807415 A CN1807415 A CN 1807415A CN 200510002407 CN200510002407 CN 200510002407 CN 200510002407 A CN200510002407 A CN 200510002407A CN 1807415 A CN1807415 A CN 1807415A
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- aminopyridine
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Abstract
The invention relates to a Method for preparation of 4-aminopyridine. This invention is based on the Hofmann degradation rezction of iosniacinamide to prepare 4-aminopyridine, making catalyzer by low-cost iodine or alkali metal iodide, sodium hydroxide orporassium hudroxide and bromine according to certain proportion and condition. The productivity of Hofmann degradation rezction of iosniacinamide is improved above 90%, the purity of 4-aminopyridine is higher than 99%. This can not only improve the productivity of 4-aminopyridine which is made by isonicotinic acid, but also reduce the cost of catalyzer greatly. It has important application-value to prepare 4-aminopyridine which is made by isonicotinic acid.
Description
Technical field:
The present invention relates to a kind of preparation method of 4-aminopyridine.
Background technology:
4-aminopyridine (claiming aminopyridine again) is the important intermediate of synthetic medicine, agricultural chemicals, dyestuff, also can be used as the additive of food and the raw material of efficient acylation catalyst 4-Dimethylamino pyridine.
At present, the method for synthetic 4-aminopyridine mainly contains two kinds, and a kind of is to be starting raw material with the pyridine, makes the nitrogen pyridine oxide through oxidation, makes 4-nitrate pyridine oxide through mixed acid nitrification again, and reduction at last obtains 4-aminopyridine.This method synthetic route is longer, and uses a large amount of strong acid during mixed acid nitrification, environmental pollution big (Progress in synthesis of 4-aminopyridine and application thereof, modern chemical industry, 2004, Vol.24 (5), pp.16-18); Another kind is to be starting raw material with the Yi Yansuan, makes 4-aminopyridine through esterification, amidation, Hofmann degradation.This method reaction conditions gentleness, but overall yield lower (synthesis technique of 4-aminopyridine progress, Liaoning chemical industry, 2003, Vol.32 (1), pp.34-35).And the committed step that influences yield is one step of Hofmann degradation.Zheng Sihua etc. studies show that, the yield of Yi Yansuan esterification is 78.5%, and amidated yield is 97.8%, the yield of Hofmann degradation be 50% (4-aminopyridine synthetic, Institutes Of Technology Of Tianjin's journal, 1999, Vol.15 (supplementary issue), pp.80-82).Studies show that of the round grade of Yang, if Hofmann degradation one step add iodobenzene as catalyzer, the yield of 4-aminopyridine can reach 83-85% (improvement of 4-aminopyridine synthetic method, applied chemistry, 2004, Vol.21 (5), pp.530-531).But the price of iodobenzene is more expensive relatively, and the yield of hoffman degradation reaction neither be very high.
The present invention use low-cost iodine or alkaline metal iodide, sodium hydroxide or potassium hydroxide and bromine by a certain percentage, the catalyzer made under certain condition, be used for the Isonicotinamide hoffman degradation reaction, the yield of this reaction has been brought up to more than 90%, too big the raising with the Yi Yansuan is the overall yield of feedstock production 4-aminopyridine, simultaneously, reduced the cost of Isonicotinamide hoffman degradation reaction catalyzer, this is to being that raw material is produced 4-aminopyridine and had important use and be worth with the Yi Yansuan.
Summary of the invention:
The object of the present invention is to provide a kind of method for preparing 4-aminopyridine based on Isonicotinamide through hoffman degradation reaction, adopting the aqueous mixture of iodine or alkaline metal iodide, sodium hydroxide or potassium hydroxide, bromine is catalyzer, under the certain reaction condition, make Isonicotinamide generation hoffman degradation reaction, preparation high purity 4-aminopyridine.Chemical equation is as follows:
The present invention is a kind of preparation method of 4-aminopyridine, adopt the method for Isonicotinamide Hofmann degradation, Isonicotinamide was carried out stirring reaction 45-50 minute with catalyzer under 0-5 ℃ of condition, the temperature of reaction that slowly raises again is to 70-80 ℃, continue to stir 50-60 minute, then, adding dilute hydrochloric acid to pH value of reaction system in reaction system is 1-2, under agitation condition, reaction system is reduced to room temperature, adding dilute sodium hydroxide or rare potassium hydroxide solution to pH value of reaction system again is 12-13, after portion water is removed in the reaction solution underpressure distillation, through cooling, filtration obtains the thick product of 4-aminopyridine; Thick product after vacuum-drying, obtains the pure product of 4-aminopyridine again through the benzene recrystallization.
Wherein said catalyzer adopts following method preparation: earlier that iodine or alkaline metal iodide is at room temperature soluble in water, after reducing to 0～5 ℃, add sodium hydroxide or potassium hydroxide, bromine successively, the mol ratio that makes iodine or alkaline metal iodide, sodium hydroxide or potassium hydroxide, bromine, water is 1: 50～70: 25～30: 500～600, makes catalyzer through fully stirring; Used alkaline metal iodide is lithium iodide, sodium iodide or potassiumiodide.
It is 1/20～1/25 that above-mentioned catalyst consumption makes the mol ratio of iodine or alkaline metal iodide and Isonicotinamide.
Through fusing point,
1H NMR, infrared measurement, the purity of the 4-aminopyridine of the present invention's preparation is greater than 99%, and yield can be up to more than 90%.
The present invention compares with the method for existing preparation 4-aminopyridine, has following remarkable advantage:
1. under similar reaction conditions, the yield of the target product 4-aminopyridine that method of the present invention obtains can improve 6～8%, and the purity of product is very high, is particularly suitable for industrialization and amplifies.
2. the catalyzer that reacts used is cheap, thereby can reduce the cost of synthetic 4-aminopyridine greatly, and the reaction conditions gentleness, environment is not polluted, " three wastes " seldom.
The invention will be further described below in conjunction with embodiment.
Embodiment:
Embodiment 1
(1) takes by weighing commercially available analytically pure iodine 2.54g (0.01mol) and put into the 500ml there-necked flask, add deionized water 18g (1mol) and make its dissolving, then, there-necked flask put into 0～5 ℃ ice-water bath, add commercially available analytically pure sodium hydroxide 22g (0.55mol), agitation condition adds deionized water 90g (5mol) down makes its dissolving, slowly drips commercially available analytically pure bromine 39.95g (0.25mol) again, after stirring, be the catalyzer for preparing.
(2) take by weighing commercially available chemical pure Isonicotinamide 26.87g (0.22mol), add above-mentioned filling in the there-necked flask for preparing catalyzer, keep temperature of reaction at 0～5 ℃, stirring reaction 45min, the temperature of reaction to 80 that slowly raises again ℃, and maintenance 50min, then, the dilute hydrochloric acid solution that adds 1N is to strongly-acid (the pH value is 1～2), be cooled to room temperature under the agitation condition, the diluted sodium hydroxide solution that adds 1N again is to strong basicity (the pH value is 12～13), and portion water is removed in underpressure distillation, cooled and filtered obtains the thick product of 4-aminopyridine.
(3) with the thick product of 4-aminopyridine benzene recrystallization, after the vacuum-drying, obtain the pure product 19.42g of 4-aminopyridine, yield is 93.77% (calculating with the Isonicotinamide of throwing).160～162 ℃ of fusing points,
1H NMR spectrum, infrared spectra conform to the standard spectrogram.
Embodiment 2
(1) takes by weighing commercially available analytically pure potassiumiodide 1.66g (0.01mol) and put into the 500ml there-necked flask, add deionized water 27g (1.5mol) and make its dissolving, then, there-necked flask put into 0～5 ℃ ice-water bath, add commercially available analytically pure potassium hydroxide 28.06g (0.50mol), agitation condition adds deionized water 72g (4mol) down makes its dissolving, slowly drips commercially available analytically pure bromine 47.94g (0.30mol) again, after stirring, be the catalyzer for preparing.
(2) take by weighing commercially available chemical pure Isonicotinamide 30.53g (0.25mol), add above-mentioned filling in the there-necked flask for preparing catalyzer, keep temperature of reaction at 0～5 ℃, stirring reaction 50min, the temperature of reaction to 75 that slowly raises again ℃, and maintenance 55min, then, the dilute hydrochloric acid solution that adds 1N is to strongly-acid (the pH value is 1～2), be cooled to room temperature under the agitation condition, the rare potassium hydroxide solution that adds 1N again is to strong basicity (the pH value is 12～13), and portion water is removed in underpressure distillation, cooled and filtered obtains the thick product of 4-aminopyridine.
(3) with the thick product of 4-aminopyridine benzene recrystallization, after the vacuum-drying, obtain the pure product 21.62g of 4-aminopyridine, yield is 91.89% (calculating with the Isonicotinamide of throwing).160～162 ℃ of fusing points,
1H NMR spectrum, infrared spectra conform to the standard spectrogram.
Embodiment 3
(1) takes by weighing commercially available analytically pure sodium iodide 1.50g (0.01mol) and put into the 500ml there-necked flask, add deionized water 18g (1mol) 22ml deionized water and make its dissolving, then, there-necked flask put into 0～5 ℃ ice-water bath, add commercially available analytically pure sodium hydroxide 28g (0.70mol), agitation condition adds deionized water 72g (4mol) down makes its dissolving, slowly drips commercially available analytically pure bromine 43.15g (0.27mol) again, after stirring, be the catalyzer for preparing.
(2) take by weighing commercially available chemical pure Isonicotinamide 25.65g (0.21mol), add above-mentioned filling in the there-necked flask for preparing catalyzer, keep temperature of reaction at 0～5 ℃, stirring reaction 45min, the temperature of reaction to 70 that slowly raises again ℃, and maintenance 60min, then, the dilute hydrochloric acid solution that adds 1N is to strongly-acid (the pH value is 1～2), be cooled to room temperature under the agitation condition, the rare potassium hydroxide solution that adds 1N again is to strong basicity (the pH value is 12～13), and portion water is removed in underpressure distillation, cooled and filtered obtains the thick product of 4-aminopyridine.
(3) with the thick product of 4-aminopyridine benzene recrystallization, after the vacuum-drying, obtain the pure product 18.25g of 4-aminopyridine, yield is 92.32% (calculating with the Isonicotinamide of throwing).160～162 ℃ of fusing points,
1H NMR spectrum, infrared spectra conform to the standard spectrogram.
Embodiment 4
(1) takes by weighing commercially available analytically pure lithium iodide 1.34g (0.01mol) and put into the 500ml there-necked flask, add deionized water 21.6g (1.2mol) and make its dissolving, then, there-necked flask put into 0～5 ℃ ice-water bath, add commercially available analytically pure potassium hydroxide 33.67g (0.60mol), agitation condition adds deionized water 72g (4mol) down makes its dissolving, slowly drips commercially available analytically pure bromine 46.34g (0.30mol) again, after stirring, be the catalyzer for preparing.
(2) take by weighing commercially available chemical pure Isonicotinamide 24.43g (0.20mol), add above-mentioned filling in the there-necked flask for preparing catalyzer, keep temperature of reaction at 0～5 ℃, stirring reaction 50min, the temperature of reaction to 70 that slowly raises again ℃, and maintenance 50min, then, the dilute hydrochloric acid solution that adds 1N is to strongly-acid (the pH value is 1～2), be cooled to room temperature under the agitation condition, the diluted sodium hydroxide solution that adds 1N again is to strong basicity (the pH value is 12～13), and portion water is removed in underpressure distillation, cooled and filtered obtains the thick product of 4-aminopyridine.
(3) with the thick product of 4-aminopyridine benzene recrystallization, after the vacuum-drying, obtain the pure product 17.06g of 4-aminopyridine, yield is 90.61% (calculating with the Isonicotinamide of throwing).160～162 ℃ of fusing points,
1H NMR spectrum, infrared spectra conform to the standard spectrogram.
Claims (3)
1. the preparation method of a 4-aminopyridine, adopt the method for Isonicotinamide Hofmann degradation, Isonicotinamide was carried out stirring reaction 45-50 minute with catalyzer under 0-5 ℃ of condition, the temperature of reaction that slowly raises again is to 70-80 ℃, continue to stir 50-60 minute, then, adding dilute hydrochloric acid to pH value of reaction system in reaction system is 1-2, under agitation condition, reaction system is reduced to room temperature, adding dilute sodium hydroxide or potassium hydroxide solution to pH value of reaction system again is 12-13, after portion water is removed in the reaction solution underpressure distillation, through cooling, filtration obtains the thick product of 4-aminopyridine;
Said catalyzer adopts following method preparation: earlier that iodine or alkaline metal iodide is at room temperature soluble in water, after reducing to 0～5 ℃, add sodium hydroxide or potassium hydroxide, bromine successively, the mol ratio that makes iodine or alkaline metal iodide, sodium hydroxide or potassium hydroxide, bromine, water is 1: 50～70: 25～30: 500～600, makes catalyzer through fully stirring;
It is 1/20～1/25 that above-mentioned catalyst consumption makes the mol ratio of iodine or alkaline metal iodide and Isonicotinamide.
2. according to the preparation method of claim 1, it is characterized in that: thick product benzene recrystallization after vacuum-drying, obtains the pure product of 4-aminopyridine.
3. according to the preparation method of claim 1 or 2, it is characterized in that: alkaline metal iodide is lithium iodide, sodium iodide or potassiumiodide.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011108009A2 (en) | 2010-03-05 | 2011-09-09 | Enaltec Labs Pvt. Ltd. | Process for the preparation of fampridine |
| EP2394994A1 (en) | 2010-06-08 | 2011-12-14 | Procos S.p.A. | One-pot process for the synthesis of dalfampridine |
| CN101863829B (en) * | 2009-04-16 | 2012-02-15 | 上海联友制药技术有限公司 | Synthesis method of 3-fluorine-4-aminopyridine |
| CN101723892B (en) * | 2008-10-22 | 2012-05-30 | 苏州开元民生科技股份有限公司 | Preparation method of 2-alkyl thioisonicotinamide |
| WO2012095691A1 (en) * | 2011-01-15 | 2012-07-19 | Jubilant Life Sciences Ltd. | An improved process for producing aminopyridines |
| CN106554306A (en) * | 2015-09-29 | 2017-04-05 | 深圳翰宇药业股份有限公司 | The preparation method of 4AP |
| CN111138352A (en) * | 2020-01-08 | 2020-05-12 | 山东泓达生物科技有限公司 | Preparation method and post-treatment process of 4-aminopyridine |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB382327A (en) * | 1931-07-27 | 1932-10-27 | Ernst Koenigs | Process for the manufacture of pyridine derivatives |
| CN1311185A (en) * | 2000-03-03 | 2001-09-05 | 山东新华制药股份有限公司 | Method for preparing 4-amino pyridine and its derivatives |
-
2005
- 2005-01-21 CN CNB2005100024079A patent/CN1319947C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101723892B (en) * | 2008-10-22 | 2012-05-30 | 苏州开元民生科技股份有限公司 | Preparation method of 2-alkyl thioisonicotinamide |
| CN101863829B (en) * | 2009-04-16 | 2012-02-15 | 上海联友制药技术有限公司 | Synthesis method of 3-fluorine-4-aminopyridine |
| WO2011108009A2 (en) | 2010-03-05 | 2011-09-09 | Enaltec Labs Pvt. Ltd. | Process for the preparation of fampridine |
| EP2394994A1 (en) | 2010-06-08 | 2011-12-14 | Procos S.p.A. | One-pot process for the synthesis of dalfampridine |
| WO2012095691A1 (en) * | 2011-01-15 | 2012-07-19 | Jubilant Life Sciences Ltd. | An improved process for producing aminopyridines |
| CN106554306A (en) * | 2015-09-29 | 2017-04-05 | 深圳翰宇药业股份有限公司 | The preparation method of 4AP |
| CN106554306B (en) * | 2015-09-29 | 2019-02-26 | 深圳翰宇药业股份有限公司 | The preparation method of dalfampridine |
| CN111138352A (en) * | 2020-01-08 | 2020-05-12 | 山东泓达生物科技有限公司 | Preparation method and post-treatment process of 4-aminopyridine |
| CN111138352B (en) * | 2020-01-08 | 2023-03-24 | 山东泓达生物科技有限公司 | Preparation method and post-treatment process of 4-aminopyridine |
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| CN1319947C (en) | 2007-06-06 |
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