CN101475527B - Method for preparing isonicotinic acid and pyrazinamide by non-catalytic hydrolyzing isonicotinonitrile in near-critical water medium - Google Patents
Method for preparing isonicotinic acid and pyrazinamide by non-catalytic hydrolyzing isonicotinonitrile in near-critical water medium Download PDFInfo
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Abstract
The invention discloses a method for simultaneously preparing pyrazinamide and isonicotinic acid through uncatalyzed hydrolysis of isonicotinic nitrile in a near critical water medium. The method comprises the following steps: adding deionized water and the isonicotinic nitrile into a high-pressure reaction kettle, stirring the mixture, raising the temperature to the boiling point at normal pressure, and opening an exhaust valve for 2 to 5 minutes; closing the exhaust valve, continuously raising the temperature to be between 200 and 300 DEG C, and hydrolyzing for 10 to 150 minutes; cooling hydrolysate, adjusting the pH value of the hydrolysate to be between 3 and 4, performing crystallization and filtration on the hydrolysate and obtaining coarse isonicotinic acid and filtrate; making the coarse isonicotinic acid subjected to hot-water dissolution, activated carbon decolorization, secondary crystallization and vacuum drying and obtaining isonicotinic acid products; adjusting the pH value of the filtrate to be between 8 and 9, performing crystallization and obtaining coarse pyrazinamide; and making the coarse pyrazinamide subjected to hot-water dissolution, activated carbon decolorization, secondary crystallization and vacuum drying and obtaining pyrazinamide products. The method does not add any catalyst during reaction, solves the pollution problem of acid and alkali catalyzed hydrolysis, has simple and green process, and has high purity and yield of the products.
Description
Technical field
The present invention relates to amides and carboxylic-acid, relate in particular to that different cigarette nitrile does not have the method that catalysis prepares Isonicotinamide and Yi Yansuan simultaneously in a kind of near critical aqueous medium.
Background technology
Isonicotinamide (Isonicotinamide; Pyridine-4-carboxylic acid amide), CAS NO.:1453-82-3, chemical name 4-pyridine carboxamide, molecular formula is C
6H
6N
2O, molecular weight: 122.12, structural formula is:
White or off-white color crystalline powder, fusing point 155-157 ℃.
Isonicotinamide is mainly used in synthetic cephalosporins medicine as medicine intermediate, and its similar niacinamide enters cell and can play germicidal action.As the two wires antitubercular agent, do not have cross resistance with other antitubercular agent in the past, and be mainly used in through the invalid case of line medicine treatment alive, list easily produces resistance with Isonicotinamide and needs and other antitubercular agent combined utilization.But to have gradually grown up be a line antitubercular agent to Isonicotinamide in recent years, and characteristics are that anti-microbial activity obviously strengthens in the pair cell and under the sour environment, is used for the patient that just controls invalid resistant tuberculosis patient or be used for can not tolerating other drug, tuberculous meningitis etc.
Synthesizing of Isonicotinamide, can be divided into 4-cyanopyridine hydrolysis method, nicotinic acid evaporation, methylpent diamines method, 2-methyl isophthalic acid, 5 pentamethylene diamine methods etc. from reaction raw materials.From synthetic method, can be divided into reagent method, ammonia oxidation hydrolysis method, microbial hydrolytic method etc.The method of industrial main employing mainly is 4-cyanopyridine hydrolysis method, Yi Yansuan evaporation and microbial hydrolytic method.4-cyanopyridine hydrolysis method technological process causes serious environmental to pollute because of using a large amount of alkali catalysts, and liquid waste disposal and catalyst recovery are not perfect; Yi Yansuan evaporation technology current consumption is big, the production cost height; Though the microbial method pollutant emission is few, the technology more complicated, and also reaction conditions is harsh, is difficult to large-scale commercial production.
Yi Yansuan (Isonicotinic acid, 4-Picolinic acid, Pyridine-4-carboxylic acid, CAS No.:55-22-1) has another name called isonicotine acid, chemical name pyridine-4-carboxylic acid, and molecular formula is C
6H
5NO
2, molecular weight is 123.11, structural formula is:
The white, needle-shaped crystals powder, tasteless; 319 ℃ of fusing points, 260 ℃ (2kPa) distillation; Be dissolved in hot water, be slightly soluble in cold water, be dissolved in benzene, ether etc. hardly.This material is an amphoteric substance, both has been dissolved in acid, also is dissolved in alkali, generates pyridinium salt with acid-respons, generates carboxylate salt with alkali reaction.Pyridine carboxylic acid all with inner salt, promptly exists with zwitterionic form in the aqueous solution.
Yi Yansuan is a kind of intermediate of widespread use, mainly as the raw material of line antitubercular agents such as vazadrine (rimifon), Triludan and iso-nicotinate, also can be used as corrosion inhibitor, electroplating additive, photosensitive resin stablizer, polychloroethylene heat stabilizer and non-ferro metals floatation medicament etc.Yi Yansuan and hydrazine hydrate condensation, fusion dehydration can be made the vazadrine, there is good anti-microbial effect the vazadrine to tubercule bacillus, curative effect is better, consumption is less, toxicity is relatively low, be used for various phthisical progressive stage, dissolve and send out phase, good absorption refunding, also can be used for the outer tuberculosis of tuberculous meningitis and other lungs etc., preparation has tablet, injection etc.
Synthetic Yi Yansuan can be divided into 4-picoline method, nicotine method, quinoline method, 2-methyl-5-ethylpyridine method etc. from reaction raw materials.From synthetic method, mainly contain liquid-phase oxidation and catalytic gas phase oxidation two big methods.Liquid phase oxidation mainly is divided into reagent oxidation and catalyzed oxidation again, and catalytic gas phase oxidation then is divided into ammonia oxidation-hydrolysis method and direct catalytic oxidation.Synthetic method commonly used at present mainly comprises potassium permanganate oxidation method, nitric acid oxidation method, ammonia oxidation-hydrolysis method, ozone oxidation method, electrooxidation method etc., and wherein ammonia oxidation-hydrolysis method is the method in industrial widespread usage.
Ammonia oxidation-hydrolysis method mainly is to be raw material with the 4-picoline, under the catalyst action based on Vanadium Pentoxide in FLAKES, carries out high temperature oxidation with ammonia and AIR MIXTURES, generates the 4-cyanopyridine, and hydrolysis obtains acid under alkaline condition then.This technological process significant disadvantages is a complex process, has strengthened facility investment, and reaction process uses a large amount of alkali catalysts to cause serious environmental to pollute, and peroxidation is serious, and not perfect in preparation, selection and the recovery of metal catalyst.
Near-critical water typically refers to the compressed liquid water of temperature between 200～350 ℃.Water has following three key properties in this zone:
1) self have the function of acid catalysis and base catalysis: depress at saturated vapo(u)r, the ionization constant of near-critical water has a maximum value to be about 10 near 275 ℃
-11(molkg)
2, its value is 1000 times of normal temperature and pressure water, and ionization constant increases the [H in the near-critical water with the increase of pressure
3O
+] and [OH
-] near weak acid or weak base, self have the function of acid catalysis and base catalysis, therefore can make some acid-base catalyzed reaction needn't add acid base catalysator, thereby avoid the neutralization of soda acid, the operations such as processing of salt;
2) simultaneously dissolved organic matter and inorganics: depress at saturated vapo(u)r, the specific inductivity of 20 ℃ of water is 80.1, and has only 23.5 275 ℃ the time.Although the specific inductivity of near-critical water is still bigger, solubilized even ionized salts, enough little of dissolved organic matter, (275 ℃ of saturated vapo(u)rs density of depressing water is 0.76g/cm to add that the density of near-critical water is big
3, the specific inductivity of near-critical water, density and acetone are close), so near-critical water has extraordinary solubility property, has the characteristic of dissolved organic matter and inorganics simultaneously.This can carry out the building-up reactions in many near critical aqueous mediums in homogeneous phase, thereby eliminates resistance to mass transfer, improves speed of response, and the reaction back only needs simple cooling just can realize the wax water sepn simultaneously, and water can be recycled;
3) rerum natura adjustability: physicochemical property such as the specific inductivity of near-critical water, ion-product constant, density, viscosity, spread coefficient, solubleness are adjustable continuously in the scope of broad with temperature, pressure, the rerum natura that is near-critical water has controllability, therefore as reaction medium, near-critical water has different solvent properties and reactivity worth at different states.
The applied research of reacting in the near-critical water comprises that offal treatment, macromolecular material recycle, inorganic materials are synthetic, gelatin liquefaction and biomass as resources etc.Patent 200910095456.X discloses method (Lv Xiuyang, the Ren Haoming that different cigarette nitrile non-catalysis hydrolyzation in a kind of near critical aqueous medium prepares Yi Yansuan.Different cigarette nitrile non-catalysis hydrolyzation prepares the method for Yi Yansuan in the near critical aqueous medium, application number: the 200910095456.X applying date: on January 15th, 2009), the present invention is applied in different cigarette nitrile (chemical name 4-cyanopyridine with the characteristic of near-critical water equally, English name: 4-Cyanopyridine, Isonicotinonitrile, CAS No.:100-48-1, molecular formula is C
6H
4N
2, molecular weight is 104.11, structural formula is:
) hydrolysis on, preparation when realizing high purity Isonicotinamide and Yi Yansuan.Without acid-base catalysis, raw material and each product all can not pollute environment in this method reaction process, thereby realize the no catalysis of different cigarette nitrile, quick, green hydrolysis, enlarge the Application Areas of near-critical water.The reaction formula that different cigarette nitrile non-catalysis hydrolyzation prepares Isonicotinamide and Yi Yansuan simultaneously in the near-critical water is as follows:
Summary of the invention
The no catalysis, green, the effectively hydrolyzing that the purpose of this invention is to provide different cigarette nitrile in a kind of near critical aqueous medium prepare the method for Isonicotinamide and Yi Yansuan simultaneously.
The step of method is as follows:
1) add deionized water and different cigarette nitrile in autoclave, the mass ratio of deionized water and different cigarette nitrile is 2: 1～8: 1, opens stirring, is warming up to boiling under the normal pressure, opens vent valve 2～5 minutes;
2) close vent valve, continue to be warming up to 200～300 ℃ of hydrolysis 10～150min;
3) hydrolysate obtains thick Yi Yansuan and filtrate through cooling, adjust pH to 3～4, crystallization and filtration;
4) thick Yi Yansuan gets the Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying;
5) filtrate is transferred pH to 8～9, crystallization, obtains thick Isonicotinamide;
6) thick Isonicotinamide gets the Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying.
The preferred range of the mass ratio of deionized water described in the step 1) and different cigarette nitrile is 3: 1～6: 1; The preferred range of the hydrolysis temperature described in the step 2 is 220～280 ℃; The used reagent of adjust pH described in the step 3) is HCl or H
2SO
4Solution; The used reagent of adjust pH described in the step 5) is NaOH, KOH, Na
2CO
3Or NaHCO
3Solution.
The purpose that " is warming up to boiling under the normal pressure, opened vent valve 2-5 minute " in the step 1) of the present invention is to utilize water vapour to take away the interior oxygen of still, to reduce the generation of side reaction, improves the yield of product; The rotating speed that stirs in the reactor is 400 commentaries on classics/min.
Step 3), step 4), step 5), four steps of step 6) all relate to crystallisation by cooling, and the temperature during crystallization is 0 a ℃～room temperature, and the low more product yield of Tc is high more.
The present invention need not add any catalyzer in reaction process, self acid-base catalysis characteristic of utilizing near-critical water makes the hydrolysis in near-critical water of different cigarette nitrile generate Isonicotinamide and Yi Yansuan with characteristic that can dissolved organic matter, solved an acid-base catalysis hydrolysis pollution on the environment difficult problem, reaction process is simple, has realized the greenization of production process.Simultaneously, the yield of Isonicotinamide and Yi Yansuan can be adjustable with temperature of reaction and reaction times, the high and purity height of the total recovery of product Isonicotinamide and Yi Yansuan.
Description of drawings
Accompanying drawing is the process flow diagram that different cigarette nitrile non-catalysis hydrolyzation prepares Isonicotinamide and Yi Yansuan simultaneously in the near critical aqueous medium.
Embodiment
Among the present invention, product adopts high performance liquid chromatography (Agilent 1100 series) to analyze, and the concrete analysis condition is as follows: (4mmID * 250mm), column temperature is 35 ℃ to chromatographic column adopting KNAUER-C18 post; Moving phase be 0.3% (v/v) aqueous acetic acid-methyl alcohol-acetonitrile (70: 15: 15, v/v/v), flow velocity is 0.6mL/min; The detection wavelength is 268nm.The employing external standard method is quantitative.
Yield in following examples is a molar yield.
Below with embodiment processing method of the present invention is further described.Protection scope of the present invention is not subjected to the restriction of embodiment, and protection scope of the present invention is determined by claims.
Embodiment 1
In 500mL high pressure batch reactor, add 240g deionized water and the different cigarette nitrile of 120g (mass ratio of deionized water and different cigarette nitrile is 2: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 5min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 200 ℃ of reaction 150min; Reaction product cooling back adds HCl solution adjust pH to 3～4, and crystallization and filtration gets the Yi Yansuan crude product and contains Isonicotinamide filtrate.The Yi Yansuan crude product gets 25:8g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.5% (wt%) through the HPLC purity assay, and yield is 17.7%; Contain Isonicotinamide filtrate and add NaOH solution adjust pH to 8～9, crystallization, obtain thick Isonicotinamide; Thick Isonicotinamide gets 80.2g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.1% (wt%) through the HPLC purity assay, and yield is 55.3%.
Embodiment 2
In 500mL high pressure batch reactor, add 300g deionized water and the different cigarette nitrile of 100g (mass ratio of deionized water and different cigarette nitrile is 3: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 4min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 210 ℃ of reaction 135min; Reaction product cooling back adds H
2SO
4Solution adjust pH to 3～4, crystallization and filtration get the Yi Yansuan crude product and contain Isonicotinamide filtrate.The Yi Yansuan crude product gets 22.5g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.7% (wt%) through the HPLC purity assay, and yield is 18.6%; Contain Isonicotinamide filtrate and add Na
2CO
3Solution adjust pH to 8～9, crystallization obtain thick Isonicotinamide; Thick Isonicotinamide gets 69.0g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.2% (wt%) through the HPLC purity assay, and yield is 57.2%.
Embodiment 3
In 500mL high pressure batch reactor, add 300g deionized water and the different cigarette nitrile of 60g (mass ratio of deionized water and different cigarette nitrile is 5: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 3min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 220 ℃ of reaction 120min; Reaction product cooling back adds HCl solution adjust pH to 3～4, and crystallization and filtration gets the Yi Yansuan crude product and contains Isonicotinamide filtrate.The Yi Yansuan crude product gets 15.4g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.8% (wt%) through the HPLC purity assay, and yield is 21.2%; Contain Isonicotinamide filtrate and add KOH solution adjust pH to 8～9, crystallization, obtain thick Isonicotinamide; Thick Isonicotinamide gets 44.6g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.2% (wt%) through the HPLC purity assay, and yield is 61.6%.
Embodiment 4
In 500mL high pressure batch reactor, add 320g deionized water and the different cigarette nitrile of 40g (mass ratio of deionized water and different cigarette nitrile is 8: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 2min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 220 ℃ of reaction 110min; Reaction product cooling back adds H
2SO
4Solution adjust pH to 3～4, crystallization and filtration get the Yi Yansuan crude product and contain Isonicotinamide filtrate.The Yi Yansuan crude product gets 10.8g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 98.2% (wt%) through the HPLC purity assay, and yield is 22.4%; Contain Isonicotinamide filtrate and add NaHCO
3Solution adjust pH to 8～9, crystallization obtain thick Isonicotinamide; Thick Isonicotinamide gets 30.3g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.5% (wt%) through the HPLC purity assay, and yield is 63.0%.
Embodiment 5
In 500mL high pressure batch reactor, add 320g deionized water and the different cigarette nitrile of 80g (mass ratio of deionized water and different cigarette nitrile is 4: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 5min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 230 ℃ of reaction 95min; Reaction product cooling back adds HCl solution adjust pH to 3～4, and crystallization and filtration gets the Yi Yansuan crude product and contains Isonicotinamide filtrate.The Yi Yansuan crude product gets 21.2g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.6% (wt%) through the HPLC purity assay, and yield is 21.9%; Contain Isonicotinamide filtrate and add NaOH solution adjust pH to 8～9, crystallization, obtain thick Isonicotinamide; Thick Isonicotinamide gets 59.9g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 98.1% (wt%) through the HPLC purity assay, and yield is 62.6%.
Embodiment 6
In 500mL high pressure batch reactor, add 350g deionized water and the different cigarette nitrile of 50g (mass ratio of deionized water and different cigarette nitrile is 7: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 4min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 230 ℃ of reaction 85min; Reaction product cooling back adds H
2SO
4Solution adjust pH to 3～4, crystallization and filtration get the Yi Yansuan crude product and contain Isonicotinamide filtrate.The Yi Yansuan crude product gets 14.0g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.8% (wt%) through the HPLC purity assay, and yield is 23.2%; Contain Isonicotinamide filtrate and add Na
2CO
3Solution adjust pH to 8～9, crystallization obtain thick Isonicotinamide; Thick Isonicotinamide gets 38.4g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.5% (wt%) through the HPLC purity assay, and yield is 63.8%.
Embodiment 7
In 500mL high pressure batch reactor, add 300g deionized water and the different cigarette nitrile of 100g (mass ratio of deionized water and different cigarette nitrile is 3: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 3min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 240 ℃ of reaction 75min; Reaction product cooling back adds HCl solution adjust pH to 3～4, and crystallization and filtration gets the Yi Yansuan crude product and contains Isonicotinamide filtrate.The Yi Yansuan crude product gets 27.2g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.8% (wt%) through the HPLC purity assay, and yield is 22.5%; Contain Isonicotinamide filtrate and add KOH solution adjust pH to 8～9, crystallization, obtain thick Isonicotinamide; Thick Isonicotinamide gets 75.9g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.8% (wt%) through the HPLC purity assay, and yield is 63.3%.
Embodiment 8
In 500mL high pressure batch reactor, add 300g deionized water and the different cigarette nitrile of 50g (mass ratio of deionized water and different cigarette nitrile is 6: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 2min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 240 ℃ of reaction 70min; Reaction product cooling back adds H
2SO
4Solution adjust pH to 3～4, crystallization and filtration get the Yi Yansuan crude product and contain Isonicotinamide filtrate.The Yi Yansuan crude product gets 14.1g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 98.2% (wt%) through the HPLC purity assay, and yield is 23.4%; Contain Isonicotinamide filtrate and add NaHCO
3Solution adjust pH to 8～9, crystallization obtain thick Isonicotinamide; Thick Isonicotinamide gets 36.9g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 98.2% (wt%) through the HPLC purity assay, and yield is 61.8%.
Embodiment 9
In 500mL high pressure batch reactor, add 240g deionized water and the different cigarette nitrile of 120g (mass ratio of deionized water and different cigarette nitrile is 2: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 5min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 250 ℃ of reaction 60min; Reaction product cooling back adds HCl solution adjust pH to 3～4, and crystallization and filtration gets the Yi Yansuan crude product and contains Isonicotinamide filtrate.The Yi Yansuan crude product gets 32.4g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.6% (wt%) through the HPLC purity assay, and yield is 22.3%; Contain Isonicotinamide filtrate and add NaOH solution adjust pH to 8～9, crystallization, obtain thick Isonicotinamide; Thick Isonicotinamide gets 92.0g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.2% (wt%) through the HPLC purity assay, and yield is 63.5%.
Embodiment 10
In 500mL high pressure batch reactor, add 300g deionized water and the different cigarette nitrile of 60g (mass ratio of deionized water and different cigarette nitrile is 5: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 4min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 250 ℃ of reaction 55min; Reaction product cooling back adds H
2SO
4Solution adjust pH to 3～4, crystallization and filtration get the Yi Yansuan crude product and contain Isonicotinamide filtrate.The Yi Yansuan crude product gets 17.4g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.9% (wt%) through the HPLC purity assay, and yield is 24.0%; Contain Isonicotinamide filtrate and add Na
2CO
3Solution adjust pH to 8～9, crystallization obtain thick Isonicotinamide; Thick Isonicotinamide gets 45.5g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.6% (wt%) through the HPLC purity assay, and yield is 63.1%.
Embodiment 11
In 500mL high pressure batch reactor, add 300g deionized water and the different cigarette nitrile of 60g (mass ratio of deionized water and different cigarette nitrile is 5: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 3min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 260 ℃ of reaction 45min; Reaction product cooling back adds HCl solution adjust pH to 3～4, and crystallization and filtration gets the Yi Yansuan crude product and contains Isonicotinamide filtrate.The Yi Yansuan crude product gets 16.7g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.9% (wt%) through the HPLC purity assay, and yield is 23.0%; Contain Isonicotinamide filtrate and add KOH solution adjust pH to 8～9, crystallization, obtain thick Isonicotinamide; Thick Isonicotinamide gets 45.0g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 98.1% (wt%) through the HPLC purity assay, and yield is 62.7%.
Embodiment 12
In 500mL high pressure batch reactor, add 320g deionized water and the different cigarette nitrile of 40g (mass ratio of deionized water and different cigarette nitrile is 8: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 2min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 260 ℃ of reaction 40min; Reaction product cooling back adds H
2SO
4Solution adjust pH to 3～4, crystallization and filtration get the Yi Yansuan crude product and contain Isonicotinamide filtrate.The Yi Yansuan crude product gets 11.8g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 98.2% (wt%) through the HPLC purity assay, and yield is 24.5%; Contain Isonicotinamide filtrate and add NaHCO
3Solution adjust pH to 8～9, crystallization obtain thick Isonicotinamide; Thick Isonicotinamide gets 29.6g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.6% (wt%) through the HPLC purity assay, and yield is 61.6%.
Embodiment 13
In 500mL high pressure batch reactor, add 320g deionized water and the different cigarette nitrile of 80g (mass ratio of deionized water and different cigarette nitrile is 4: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 5min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 270 ℃ of reaction 35min; Reaction product cooling back adds HCl solution adjust pH to 3～4, and crystallization and filtration gets the Yi Yansuan crude product and contains Isonicotinamide filtrate.The Yi Yansuan crude product gets 22.8g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.6% (wt%) through the HPLC purity assay, and yield is 23.5%; Contain Isonicotinamide filtrate and add NaOH solution adjust pH to 8～9, crystallization, obtain thick Isonicotinamide; Thick Isonicotinamide gets 60.3g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.9% (wt%) through the HPLC purity assay, and yield is 62.9%.
Embodiment 14
In 500mL high pressure batch reactor, add 350g deionized water and the different cigarette nitrile of 50g (mass ratio of deionized water and different cigarette nitrile is 7: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 4min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 270 ℃ of reaction 30min; Reaction product cooling back adds H
2SO
4Solution adjust pH to 3～4, crystallization and filtration get the Yi Yansuan crude product and contain Isonicotinamide filtrate.The Yi Yansuan crude product gets 14.1g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 98.1% (wt%) through the HPLC purity assay, and yield is 23.4%; Contain Isonicotinamide filtrate and add Na
2CO
3Solution adjust pH to 8～9, crystallization obtain thick Isonicotinamide; Thick Isonicotinamide gets 37.3g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 98.2% (wt%) through the HPLC purity assay, and yield is 62.5%.
Embodiment 15
In 500mL high pressure batch reactor, add 300g deionized water and the different cigarette nitrile of 100g (mass ratio of deionized water and different cigarette nitrile is 3: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 3min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 280 ℃ of reaction 25min; Reaction product cooling back adds HCl solution adjust pH to 3～4, and crystallization and filtration gets the Yi Yansuan crude product and contains Isonicotinamide filtrate.The Yi Yansuan crude product gets 28.2g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.5% (wt%) through the HPLC purity assay, and yield is 23.3%; Contain Isonicotinamide filtrate and add KOH solution adjust pH to 8～9, crystallization, obtain thick Isonicotinamide; Thick Isonicotinamide gets 73.3g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.1% (wt%) through the HPLC purity assay, and yield is 60.7%.
Embodiment 16
In 500mL high pressure batch reactor, add 300g deionized water and the different cigarette nitrile of 50g (mass ratio of deionized water and different cigarette nitrile is 6: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 2min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 280 ℃ of reaction 20min; Reaction product cooling back adds H
2SO
4Solution adjust pH to 3～4, crystallization and filtration get the Yi Yansuan crude product and contain Isonicotinamide filtrate.The Yi Yansuan crude product gets 14.4g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.8% (wt%) through the HPLC purity assay, and yield is 23.8%; Contain Isonicotinamide filtrate and add NaHCO
3Solution adjust pH to 8～9, crystallization obtain thick Isonicotinamide; Thick Isonicotinamide gets 36.2g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.6% (wt%) through the HPLC purity assay, and yield is 60.2%.
Embodiment 17
In 500mL high pressure batch reactor, add 240g deionized water and the different cigarette nitrile of 120g (mass ratio of deionized water and different cigarette nitrile is 2: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 5min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 290 ℃ of reaction 15min; Reaction product cooling back adds HCl solution adjust pH to 3～4, and crystallization and filtration gets the Yi Yansuan crude product and contains Isonicotinamide filtrate.The Yi Yansuan crude product gets 34.2g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.7% (wt%) through the HPLC purity assay, and yield is 23.5%; Contain Isonicotinamide filtrate and add NaOH solution adjust pH to 8～9, crystallization, obtain thick Isonicotinamide; Thick Isonicotinamide gets 83.7g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.9% (wt%) through the HPLC purity assay, and yield is 58.2%.
Embodiment 18
In 500mL high pressure batch reactor, add 300g deionized water and the different cigarette nitrile of 60g (mass ratio of deionized water and different cigarette nitrile is 5: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 4min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 300 ℃ of reaction 10min; Reaction product cooling back adds H
2SO
4Solution adjust pH to 3～4, crystallization and filtration get the Yi Yansuan crude product and contain Isonicotinamide filtrate.The Yi Yansuan crude product gets 16.5g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.4% (wt%) through the HPLC purity assay, and yield is 22.7%; Contain Isonicotinamide filtrate and add Na
2CO
3Solution adjust pH to 8～9, crystallization obtain thick Isonicotinamide; Thick Isonicotinamide gets 39.1g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.9% (wt%) through the HPLC purity assay, and yield is 54.4%.
Embodiment 19
In 500mL high pressure batch reactor, add 300g deionized water and the different cigarette nitrile of 50g (mass ratio of deionized water and different cigarette nitrile is 6: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 3min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 250 ℃ of reaction 20min; Reaction product cooling back adds HCl solution adjust pH to 3～4, and crystallization and filtration gets the Yi Yansuan crude product and contains Isonicotinamide filtrate.The Yi Yansuan crude product gets 12.7g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.4% (wt%) through the HPLC purity assay, and yield is 20.9%; Contain Isonicotinamide filtrate and add NaOH solution adjust pH to 8～9, crystallization, obtain thick Isonicotinamide; Thick Isonicotinamide gets 31.9g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.9% (wt%) through the HPLC purity assay, and yield is 53.2%.
Embodiment 20
In 500mL high pressure batch reactor, add 300g deionized water and the different cigarette nitrile of 50g (mass ratio of deionized water and different cigarette nitrile is 6: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 3min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 250 ℃ of reaction 50min; Reaction product cooling back adds HCl solution adjust pH to 3～4, and crystallization and filtration gets the Yi Yansuan crude product and contains Isonicotinamide filtrate.The Yi Yansuan crude product gets 14.2g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.8% (wt%) through the HPLC purity assay, and yield is 23.5%; Contain Isonicotinamide filtrate and add NaOH solution adjust pH to 8～9, crystallization, obtain thick Isonicotinamide; Thick Isonicotinamide gets 36.5g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 98.1% (wt%) through the HPLC purity assay, and yield is 61.1%.
Embodiment 21
In 500mL high pressure batch reactor, add 300g deionized water and the different cigarette nitrile of 50g (mass ratio of deionized water and different cigarette nitrile is 6: 1), open stirring, be warming up to boiling under the normal pressure, open vent valve 3min, utilize water vapour to get rid of air in the still; Close vent valve, continue to be warming up to 250 ℃ of reaction 120min; Reaction product cooling back adds HCl solution adjust pH to 3～4, and crystallization and filtration gets the Yi Yansuan crude product and contains Isonicotinamide filtrate.The Yi Yansuan crude product gets 32.7g Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 97.9% (wt%) through the HPLC purity assay, and yield is 54.1%; Contain Isonicotinamide filtrate and add NaOH solution adjust pH to 8～9, crystallization, obtain thick Isonicotinamide; Thick Isonicotinamide gets 19.2g Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying, product is 98.2% (wt%) through the HPLC purity assay, and yield is 32.1%.
Claims (5)
1. different cigarette nitrile non-catalysis hydrolyzation prepares the method for Isonicotinamide and Yi Yansuan simultaneously in the near critical aqueous medium, it is characterized in that the step of method is as follows:
1) add deionized water and different cigarette nitrile in autoclave, the mass ratio of deionized water and different cigarette nitrile is 2: 1～8: 1, opens stirring, is warming up to boiling under the normal pressure, opens vent valve 2～5 minutes;
2) close vent valve, continue to be warming up to 200～300 ℃ of hydrolysis 10～150min;
3) hydrolysate obtains thick Yi Yansuan and filtrate through cooling, adjust pH to 3～4, crystallization and filtration;
4) thick Yi Yansuan gets the Yi Yansuan product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying;
5) filtrate is transferred pH to 8～9, crystallization, obtains thick Isonicotinamide;
6) thick Isonicotinamide gets the Isonicotinamide product after hot water dissolving, decolorizing with activated carbon, secondary crystal, vacuum-drying.
2. different cigarette nitrile non-catalysis hydrolyzation prepares the method for Isonicotinamide and Yi Yansuan simultaneously in a kind of near critical aqueous medium according to claim 1, and the mass ratio that it is characterized in that deionized water described in the step 1) and different cigarette nitrile is 3: 1～6: 1.
3. different cigarette nitrile non-catalysis hydrolyzation prepares the method for Isonicotinamide and Yi Yansuan simultaneously in a kind of near critical aqueous medium according to claim 1, it is characterized in that step 2) described in hydrolysis temperature be 220～280 ℃.
4. different cigarette nitrile non-catalysis hydrolyzation prepares the method for Isonicotinamide and Yi Yansuan simultaneously in a kind of near critical aqueous medium according to claim 1, it is characterized in that the used reagent of the adjust pH described in the step 3) is HCl or H
2SO
4Solution.
5. different cigarette nitrile non-catalysis hydrolyzation prepares the method for Isonicotinamide and Yi Yansuan simultaneously in a kind of near critical aqueous medium according to claim 1, it is characterized in that the used reagent of the adjust pH described in the step 5) is NaOH, KOH, Na
2CO
3Or NaHCO
3Solution.
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|---|---|---|---|
| CN2009100955878A CN101475527B (en) | 2009-01-22 | 2009-01-22 | Method for preparing isonicotinic acid and pyrazinamide by non-catalytic hydrolyzing isonicotinonitrile in near-critical water medium |
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|---|---|---|---|
| CN2009100955878A CN101475527B (en) | 2009-01-22 | 2009-01-22 | Method for preparing isonicotinic acid and pyrazinamide by non-catalytic hydrolyzing isonicotinonitrile in near-critical water medium |
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| CN104496897A (en) * | 2014-12-18 | 2015-04-08 | 天津汉德威药业有限公司 | Method for preparing high-purity pyrazinamide |
| CN104478796A (en) * | 2014-12-18 | 2015-04-01 | 天津汉德威药业有限公司 | Preparation method of isonicotinamide |
| CN104788450A (en) * | 2015-04-23 | 2015-07-22 | 湖南华腾制药有限公司 | Method for preparing pyridino-piperazine derivative |
| CN108440423A (en) * | 2018-04-26 | 2018-08-24 | 江苏四环生物制药有限公司 | A method of to the disposing mother liquor pyrazinamide containing pyrazinamide |
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