CN101570508B - Separation and purification of 4-hydroxy-3-nitropyridine by sublimation method - Google Patents
Separation and purification of 4-hydroxy-3-nitropyridine by sublimation method Download PDFInfo
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- CN101570508B CN101570508B CN2009100273050A CN200910027305A CN101570508B CN 101570508 B CN101570508 B CN 101570508B CN 2009100273050 A CN2009100273050 A CN 2009100273050A CN 200910027305 A CN200910027305 A CN 200910027305A CN 101570508 B CN101570508 B CN 101570508B
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Abstract
The invention relates to the technical field of preparation of medicinal intermediate, which comprises the following steps: heating 95.0 to 98.6 percent of 4-hydroxy-3-nitropyridine crude product in which inorganic salt accounts for less than or equal to 18.8 percent in percentage by mass under pressure reduction of a mechanical vacuum pump to sublimate the 4-hydroxy-3-nitropyridine so as to obtain a sublimated product, wherein the sublimated product is the purified 4-hydroxy-3-nitropyridine without the inorganic salt; measuring the sublimated product through efficient liquid chromatography, and purifying the crude 4-hydroxy-3-nitropyridine to more than 98 percent from 95.0 percent in percentage by mass with the yield of more than 95 percent; and under normal pressure (atmosphere), heatingthe sublimated product to sublimate the 4-hydroxy-3-nitropyridine so as to obtain a sublimated and purified product of more than 99.7 percent 4-hydroxy-3-nitropyridine in percentage by mass without t he inorganic salt. Compared with a wet separation method, the invention has high yield and low energy consumption, does not produce wastewater, and has social and economical effects.
Description
Technical field
The present invention relates to the preparing technical field of medicine intermediate, refer in particular to that subliming method is separated and purification of 4-hydroxy-3-nitropyridine, the present invention than wet method separation method (for example recrystallization method) yield height, energy consumption is low and do not have waste water, has society and economical effects.
Background technology
Pyridine and derivative thereof are the important intermediate of synthesizing heterocyclic compounds agricultural chemicals, medicine.Substitute the compound that obtains behind the phenyl ring with pyridine ring and often have higher biological activity or lower toxicity.In recent years, people particularly substitute the phenyl ring in the existing kind molecular structure with the pyridine group with various heterocycles or introduce other group in the pyridine group molecule and carry out derivatize in known containing, in the hope of obtaining new active compound.Nitration reaction be obtain nitro and amino these two nitrogen-containing functional groups, also be the important means that obtains the important source material of numerous pyridine derivate.The 4-hydroxy-3-nitropyridine is the derivative of synthetic β-Ka Lin and the raw material of 1L-8 receptor antagonist.4-hydroxy-3-nitropyridine massfraction＞97% of online spending abroad; 4-hydroxy-3-nitropyridine massfraction＞97% of domestic production and＜99%.Use the recrystallization method purification of 4-hydroxy-3-nitropyridine in the prior art, solvent is water, ethanol or water and alcoholic acid mixture.The shortcoming of recrystallization method is that efficient is low, yield is low, energy consumption is high and unavoidably sewage discharge is arranged and influence environment.The 4-hydroxy-3-nitropyridine has the distillation characteristic, and the distillation characteristic derives from its intramolecular hydrogen bond structure, has reduced Intermolecular Forces, and therefore under uniform temp, other isomery heights of its intrinsic standoff ratio are enough to realize to separate the purpose with purifying; This is just for having set up solid basis with subliming method separation and purification of 4-hydroxy-3-nitropyridine.Subliming method belongs to dry method, and do not need solvent, just not need to reclaim or handle solvent slop yet, so yield height, without sewage discharge.Do not need energy consumption has also just been saved in a large amount of solvent heating and cooling.
Summary of the invention
The purpose of this invention is to provide a kind of processing method, be used for separating and purification of 4-hydroxy-3-nitropyridine shortcomings such as prior art efficient is low, yield is low, energy consumption is high to overcome, contaminate environment.
The present invention can be 95.0%～98.6% 4-hydroxy-3-nitropyridine crude product (other isomer, other organism and the inorganic salt that contain the 4-hydroxy-3-nitropyridine in the crude product) with massfraction, inorganic salt massfraction≤18.8%; Under the oil-sealed rotary pump decompression, heating makes the distillation of 4-hydroxy-3-nitropyridine, the flores that obtains is the 4-hydroxy-3-nitropyridine that does not contain the purification of inorganic salt, measure through efficient liquid phase chromatographic analysis, it with massfraction 95.0% thick 4-hydroxy-3-nitropyridine, be purified to massfraction＞98%, yield＞95% through distillation; With massfraction is 98.6% thick 4-hydroxy-3-nitropyridine, is purified to massfraction＞98.6%, yield＞95% through distillation; Under normal pressure (atmosphere), 4-hydroxy-3-nitropyridine distillation purified product massfraction＞99.7% that does not contain inorganic salt that heating obtains the distillation of 4-hydroxy-3-nitropyridine.
Realize that foregoing invention purpose technical scheme is:
With 4-hydroxy-3-nitropyridine crude product normal pressure (atmosphere) or the decompression under, be heated to 150 ℃～210 ℃ and make the distillation of 4-hydroxy-3-nitropyridine, and residual volatility relatively poor and do not have volatile impurity, (normal pressure is meant that sublimation process all carries out from start to finish to the 4-hydroxy-3-nitropyridine of gasification under normal pressure through 4-hydroxy-3-nitropyridine that condensation obtains purifying; Decompression is meant that sublimation process is initially located under the normal pressure, reduces pressure 1～5 * 10 in sublimation container after starting the vacuum pump decompression
3The pressure [1～5 * 10 of Pa
3Pa is that sublimation process can be kept the stable scope of pressure at last]).Known from the Study on Mathematic Model of 4-hydroxy-3-nitropyridine distillation characteristic and rate of sublimation: Heating temperature is low excessively, and the gasification rate of 4-hydroxy-3-nitropyridine is too low; Too high temperature will cause organic impurities content increase in the 4-hydroxy-3-nitropyridine flores, even cause the 4-hydroxy-3-nitropyridine to decompose.Because in the sublimation process, the speed of distillation is decided by the surface-area and the residing pressure of material of temperature, sublimate, correlation parameter is exactly: the surface-area of temperature, pressure and sublimate.Amass＜0.20gcm for 4-hydroxy-3-nitropyridine crude product quality/container section
-2, normal pressure or decompression down, distillation time≤4 hour (change according to the amount of material, surface-area, the temperature and pressure of the material that distils) till heating sublimation no longer includes the sublimate output to range estimation.Select for use normal pressure (atmosphere) can obtain better separating effect and the higher 4-hydroxy-3-nitropyridine of purity; Select for use higher vacuum tightness can improve production rate; Temperature is 150～200 ℃ under the decompression; Temperature is 200 ℃～210 ℃ under the normal pressure.
Embodiment
Below among each embodiment the usage quantity of 4-hydroxy-3-nitropyridine crude product be 0.29g～0.51g.The sectional area of sampling receptacle is 2.5cm
2Heating sublimation time＜4 hour (changing) according to the amount of material, surface-area, the temperature and pressure of distillation material.Under reduced pressure, the termination of sublimation process with estimate no longer include the sublimate output till; Under normal pressure, sublimation process is 4 hours.
The parameter of other terms and conditions is as follows in the technology:
A. raw material (4-hydroxy-3-nitropyridine crude product):
(1) 4-hydroxy-3-nitropyridine: massfraction 98.6%; Do not contain inorganic salt;
(2) 4-hydroxy-3-nitropyridine: massfraction 95%; Do not contain inorganic salt;
(3) 4-hydroxy-3-nitropyridine: massfraction 98.6%, inorganic salt (Na
2SO
4) be 5.7% of raw materials quality;
(4) 4-hydroxy-3-nitropyridine: massfraction 95%, inorganic salt (Na
2SO
4) be 18.8% of raw materials quality.
(5) 4-hydroxy-3-nitropyridine: massfraction 95%, this 4-hydroxy-3-nitropyridine are that one bath two stage process prepares, and the yield of preparation is 74%, wherein inorganic salt (Na
2SO
4) massfraction＜0.1%.
B. temperature: (1) 150 ℃, (2) 155 ℃, (3) 175 ℃, (4) 200 ℃, (5) 210 ℃.
C. pressure: (1) decompression down, (2) normal pressure (atmosphere).
The operating process of embodiment
The decompression operation process
Accurately take by weighing a certain amount of 4-hydroxy-3-nitropyridine crude product and place sampling receptacle.Sampling receptacle is put into has in the standard ground-in sublimation container, sublimation container is had the conduit of standard grinding port plug beyond the Great Wall, be used for condensation and collect sublimate, the air cooling of conduit outer wall mat, the other end tool one standard ground of conduit, three arms of standard ground-in the other end tool, 1. one of them arm connects pressure instrument; 2. another arm passes through stop,threeway; 3. the 3rd arm be communicated with atmosphere through two logical pistons.One pipe coupling snubber, snubber of stop,threeway connect vacuum pump again; Another arm of stop,threeway is communicated with atmosphere; Stop,threeway can be modulated vacuum pump and be connected in one of two kinds of states: (1) and conduit are communicated with, but obstructed atmosphere; (2) obstructed conduit, but and atmosphere connection.After 3. arm be communicated with atmosphere, the sublimation container that installs sample receiver is put in the thermostatted; Control sublimation container temperature is the designated value of processing parameter B, temperature fluctuation＜± 2 ℃; Stop,threeway places state (1), the arm two logical obstructed atmosphere of piston 3..Start oil-sealed rotary pump, make the 4-hydroxy-3-nitropyridine distillation in the sample receiver, be condensate on the catheter wall.Range estimation is till no longer including the distillation material and freeze-outing (distillation time＜4 hour).Stop heating, stop,threeway placed state (2) after, disconnect the mechanical vacuum pumping source.When treating that sublimation container cools to nearly room temperature, carefully arm two logical pistons 3. are communicated with atmosphere, dismantle the grinding port plug of sublimation container, take out the material that is condensate on the catheter wall, obtain residue by sample receiver is weighed heavy, and it is heavy to calculate the distillation material in view of the above.Measure material on the catheter wall and the 4-hydroxy-3-nitropyridine content in the residue (, not measuring) with HPLC when level of residue seldom the time; The Na content of measuring in the distillation material with ICP-AES (is converted into Na
2SO
4), the Na content in the material that distils in all embodiments proves Na in the distillation material near measuring blank value
2SO
4Content＜0.01 quality %.Na in the residue
2SO
4Content then calculates by material balance.
Normal pressure (atmosphere) operating process
Accurately take by weighing a certain amount of 4-hydroxy-3-nitropyridine crude product and place sampling receptacle.Sampling receptacle is put into has in the standard ground-in sublimation container, sublimation container is had the conduit of standard grinding port plug beyond the Great Wall, and be used for condensation and collect sublimate, the air cooling of conduit outer wall mat, the other end of conduit is communicated with normal pressure (atmosphere).The sublimation container that installs sample receiver is put in the thermostatted; Control sublimation container temperature is the designated value of processing parameter B, temperature fluctuation＜± 2 ℃; , make the 4-hydroxy-3-nitropyridine distillation in the sample receiver, be condensate on the catheter wall.Distilled 4 hours, and stopped heating, when treating that sublimation container cools to nearly room temperature, dismantle the grinding port plug of sublimation container, take out the material that is condensate on the catheter wall, obtain residue by sample receiver is weighed heavy, and it is heavy to calculate the distillation material in view of the above.With material on the HPLC mensuration catheter wall and the 4-hydroxy-3-nitropyridine content in the residue; The Na content of measuring in the distillation material with ICP-AES (is converted into Na
2SO
4), the Na content in the material that distils in all embodiments proves Na in the distillation material near measuring blank value
2SO
4Massfraction＜0.01%.Na in the residue
2SO
4Content then calculates by material balance.
Embodiment 1
Accurately take by weighing A (1) 0.5071g; Processing parameter: B (2); C (1).Obtain pure product 4-hydroxy-3-nitropyridine 0.5030g, massfraction 99.6%, yield 99.6%, residue 0.0041g (amount is few, and 4-hydroxy-3-nitropyridine content is not analyzed).
Embodiment 2
Accurately take by weighing A (2) 0.3510g; Processing parameter: B (3); C (1).Obtain pure product 4-hydroxy-3-nitropyridine 0.3411g, massfraction 98.1%, yield 100.0% (calculating behind the 4-hydroxy-3-nitropyridine in the deduction residue), residue 0.0099g, 4-hydroxy-3-nitropyridine massfraction 12.8% in the residue wherein, yield 0.4%.The material balance 100.4% of 4-hydroxy-3-nitropyridine.
Embodiment 3
Present embodiment divides two sections distillations, for the first time the distillation amount near half, behind sampling analysis, proceed again.
Accurately take by weighing A (2) 0.3160g; Processing parameter: B (1); C (1).
Obtain for the first time pure product 4-hydroxy-3-nitropyridine 0.1548g, massfraction 99.7%, yield 51.3%, residue 0.1612g, 4-hydroxy-3-nitropyridine massfraction 87.6%.Residue 0.1429g behind the sampling analysis, purification distils under the same condition.Obtain for the second time pure product 4-hydroxy-3-nitropyridine 0.1269g, 4-hydroxy-3-nitropyridine massfraction 98.7%, yield 98.5% (calculating behind the 4-hydroxy-3-nitropyridine in the deduction residue), residue 0.016g, 4-hydroxy-3-nitropyridine massfraction 12.8% in the residue wherein, yield 1.5%.
Secondary joint account: obtain pure product 4-hydroxy-3-nitropyridine 0.2817g, massfraction 99.2%, yield 99.2% (calculating behind the 4-hydroxy-3-nitropyridine in the deduction residue), residue 0.016g, wherein 4-hydroxy-3-nitropyridine massfraction 12.8% in the residue.The material balance 100.7% of 4-hydroxy-3-nitropyridine.
Embodiment 4
Accurately take by weighing A (5) 0.3150g; Processing parameter: B (2); C (1).Obtain pure product 4-hydroxy-3-nitropyridine 0.2948g, massfraction 99.0%, yield 97.5%, residue 0.0202g, 4-hydroxy-3-nitropyridine massfraction 14.5% in the residue wherein, yield 1.0%.The material balance 98.5% of 4-hydroxy-3-nitropyridine.
A (5) is that the content in this method is synthetic is 95% with the synthetic product that obtains of one bath two stage process, yield can＞75%; One bath two stage process is purified in conjunction with subliming method, and can obtain 4-hydroxy-3-nitropyridine massfraction is 99.0%, 4-hydroxy-3-nitropyridine total recovery can＞70%, be higher than far away reported in literature＜50%; The yield that demonstrates the subliming method purification is far above crystallization process.
Embodiment 5
Accurately take by weighing A (4) 0.4360g; Processing parameter: B (2); C (1).Do not contained Na
2SO
4Pure product 4-hydroxy-3-nitropyridine 0.3332g, massfraction 98.2%, yield 97.5%, residue 0.1028g, 4-hydroxy-3-nitropyridine massfraction 14.5% in the residue wherein, yield 0.8%.The material balance 98.3% of 4-hydroxy-3-nitropyridine.
Embodiment 6
Accurately take by weighing A (3) 0.4400g; Processing parameter: B (2); C (1).Do not contained Na
2SO
4Pure product 4-hydroxy-3-nitropyridine 0.4130g, massfraction 98.7%, yield 100%, residue 0.0270g, 4-hydroxy-3-nitropyridine massfraction 7.4% in the residue wherein, yield 0.4%.The material balance 100.4% of 4-hydroxy-3-nitropyridine.
Embodiment 7
Accurately take by weighing A (1) 0.4440g; Processing parameter: B (5); C (2).Obtain pure product 4-hydroxy-3-nitropyridine 0.1134g, massfraction 99.8%, yield＜34%.
Embodiment 8
Accurately take by weighing A (1) 0.5g; Processing parameter: B (4); C (2).Can only obtain the minute quantity massfraction and be 99.8% the pure product of 4-hydroxy-3-nitropyridine, residue 4-hydroxy-3-nitropyridine massfraction 98.7%.
The present invention relates to massfraction is 95.0%～98.6% 4-hydroxy-3-nitropyridine crude product (agreement: measure the content in the total organic matter of 4-hydroxy-3-nitropyridine crude product with the high performance liquid chromatography area normalization method, this method can not be measured inorganic salt content); The inorganic salt that contain massfraction≤18.8% in the crude product, for example sodium sulfate.Heating 4-hydroxy-3-nitropyridine crude product under normal pressure (atmosphere) or decompression, be condensate in the receptor after making 4-hydroxy-3-nitropyridine distillation, become residue and residual than the organic impurities of 4-hydroxy-3-nitropyridine volatility difference and the inorganic salt that can not gasify and stay in the sublimation container; Thereby improved through the 4-of flores hydroxy-3-nitropyridine content and do not contained inorganic salt.After reducing pressure sublimation separation in 4 hours, only there is a small amount of 4-hydroxy-3-nitropyridine to remain in the residue.For massfraction is 95.0% thick 4-hydroxy-3-nitropyridine, through distillation purification massfraction＞98%, yield＞95%; For massfraction is 98.6% thick 4-hydroxy-3-nitropyridine, through distillation purification massfraction＞98.6%, yield＞95%; After normal pressure (atmosphere) sublimation separation, can obtain the 4-hydroxy-3-nitropyridine of massfraction 〉=99.8%.
Claims (2)
1. subliming method is separated and the method for purification of 4-hydroxy-3-nitropyridine, it is characterized in that: with 4-hydroxy-3-nitropyridine crude product normal pressure or the decompression under, be heated to 150 ℃～210 ℃ and make the distillation of 4-hydroxy-3-nitropyridine, distillation time≤4 hour, the 4-hydroxy-3-nitropyridine that the 4-hydroxy-3-nitropyridine of gasification obtains purifying through condensation, and residual volatility relatively poor and do not have volatile impurity, wherein a crude product quality/sampling receptacle sectional area＜0.20gcm
-2, wherein said decompression is meant that sublimation process is initially located under the normal pressure, reduces pressure 1～5 * 10 in sublimation container after starting the vacuum pump decompression
3The pressure of Pa.
2. preparation method according to claim 1 is characterized in that: decompression Heating temperature down is 150～200 ℃; Heating temperature is 200 ℃～210 ℃ under the normal pressure.
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