CN112724081B - Preparation method of isoniazid - Google Patents
Preparation method of isoniazid Download PDFInfo
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- CN112724081B CN112724081B CN202011573013.XA CN202011573013A CN112724081B CN 112724081 B CN112724081 B CN 112724081B CN 202011573013 A CN202011573013 A CN 202011573013A CN 112724081 B CN112724081 B CN 112724081B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
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Abstract
The invention discloses a preparation method of isoniazid, which adopts the temperature control and the appropriate increase of the feeding proportion of hydrazine hydrate for reaction, solves the problems of narrow temperature range and difficult operability and controllability of the traditional condensation reaction, widens the reaction temperature to 129-138 ℃, and has high yield of isoniazid. Meanwhile, refining steps such as decolorization, washing, recrystallization and the like are combined, so that the impurity content in the isoniazid is remarkably reduced, and the requirement of related evaluation work of the raw material medicines is met. The method has wide reaction temperature range, improves the yield and the purity of the isoniazid, and provides a larger selection range for the operability and the controllability of the industrial production of the isoniazid.
Description
Technical Field
The invention belongs to the technical field of isoniazid preparation. More particularly, relates to a preparation method of isoniazid.
Background
Isoniazid (Isoniazid) has the chemical name: 4-pyridine carbohydrazide, together with rifampicin, ethambutol and pyrazinamide, are first-line antituberculosis drugs. Isoniazid was invented in 1952 as a chemical drug, which has fundamentally changed the treatment of tuberculosis, and most doctors still consider it to be an indispensable main drug for the treatment of tuberculosis in the history of about 70 years although some patients have developed drug resistance to tubercle bacillus infected with isoniazid.
At present, regardingThe synthesis of the niacinamide mainly comprises the following two methods: the first one is prepared by hydrolyzing 4-cyanopyridine into isonicotinamide and condensing with pure hydrazine (Sycheva TP, pavlova TN, shehukia MN. Synthesis of isoniazid from 4-cyanopyradine. Pharma Chem J, 1972) - ) The potential safety hazard exists because the human body is injured; the other method is prepared by directly condensing isonicotinic acid and pure hydrazine, and according to the synthesis method of isonicotinic acid recorded in the national pharmaceutical industry Association of technology (1980, 193-194), "2. Condensation and refining, isonicotinic acid is dissolved in pure hydrazine, and is distilled under reduced pressure until the temperature reaches 79-82 ℃/100-110 nm, and is raised to 129-130 ℃, and the reaction is carried out for 3 hours. In addition, when the method is used for refining, the reaction solution is diluted by the mother solution for preparing the isonicotinic acid in the previous step, based on the indiscriminate feeding, the impurities are accumulated and transferred to the product, and the impurities are accumulated and transferred in the subsequent processes of washing the crude product by the refined mother solution and adding hydrazine hydrate in the refining process, so that the quality of the product is difficult to ensure.
Therefore, the research and development of a relatively excellent isoniazid preparation process has become a problem to be solved urgently, and the production efficiency is improved on the basis of improving the purity of the prepared isoniazid.
Disclosure of Invention
The invention aims to solve the problems of narrow temperature range and difficult operability and controllability of the existing isoniazid synthesis method and provides a novel isoniazid preparation method. The method overcomes the problem of narrow temperature limit range of the traditional direct condensation reaction of isonicotinic acid and hydrazine hydrate, and widens the temperature from 129-130 ℃ which is narrow and difficult to control to 129-138 ℃ in the selection of the condensation reaction temperature, thereby providing a larger selection range for the operability and controllability of industrial production of isonicotinic acid.
The above purpose of the invention is realized by the following technical scheme:
the preparation method of isoniazid comprises the steps of synthesis and refining, and specifically comprises the following steps:
s1, synthesis: carrying out condensation reaction on isonicotinic acid and pure hydrazine, and quenching after the reaction is finished to obtain an isonicotinic acid crude product suspension;
s2, refining:
s2-1, decoloring: heating and dissolving the crude isoniazid suspension obtained in the step S1, adding a decolorizing agent, stirring for 10-30 min, filtering with hot filter cloth, and cooling and crystallizing the filtrate to 5-10 ℃ within 2-3 h;
s2-2, washing: adding ethanol, and performing suction filtration to obtain a crude product of isoniazid;
s2-3, recrystallizing: adding water into the crude product of isoniazid obtained in S2-2, adding a decolorizing agent, heating for dissolving, stirring for 10-30 min, filtering with hot filter cloth, and cooling and crystallizing the filtrate to 5-10 ℃ within 2-3 h;
s2-4, washing: adding ethanol, and performing suction filtration;
s2-5, drying to obtain an isoniazid refined product;
wherein in the step S1, the condensation reaction is carried out, and the reaction temperature is controlled to be 129-138 ℃;
in the step S1, the weight ratio of the isonicotinic acid to the pure hydrazine is 1.40-0.48;
step S1, quenching, namely adding water with the weight 1.09-1.69 times that of isonicotinic acid to quench;
step S2-2, the dosage of the ethanol is 0.2 to 0.8 time of the weight of the isonicotinic acid;
step S2-3, the amount of water is 0.9-1.5 times of the weight of the crude product of isoniazid;
step S2-4, the dosage of the ethanol is 0.1-0.4 time of the weight of the crude product of the isoniazid;
in the step S2-1 and the step S2-3, the aperture and the mesh number of the filter cloth are 300-400 meshes.
The invention is improved based on the traditional direct condensation route of isonicotinic acid and hydrazine hydrate, breaks through the limited range of the traditional condensation reaction temperature, is widened to 129-138 ℃ from 129-130 ℃ which is narrow and difficult to control in the selection of the condensation reaction temperature, and has high yield of the isonicotinic hydrazine obtained by synthesis and relatively low impurity content. Meanwhile, the method combines the refining steps of decoloration, washing, recrystallization and the like, controls the conditions of material consumption, temperature, filter cloth size and the like, and can effectively ensure the yield and quality of the isoniazid.
The inventor researches in practice to find out that the reason why the temperature is limited between 129 and 130 ℃ in the traditional synthesis route can be as follows: from the analysis of the reaction formula, the condensation of isonicotinic acid and hydrazine hydrate produces impurity compound I and impurity compound II besides target product isonicotinic acid and generated water, and the reaction formula is shown as follows.
Reaction formula 3 impurity compound II reaction formula
Wherein the impurity compound I is formed by condensing 2 molecules of isonicotinic acid and one molecule of pure hydrazine in a reaction formula 2, and the melting point is 260-265 ℃; the impurity compound II is further cyclized by dihydrazide and pure hydrazine in a reaction formula 3, and the melting point is 330-333 ℃. These two impurity compounds are not recorded in the chinese pharmacopoeia, the united states pharmacopoeia, the european pharmacopoeia and the japanese pharmacopoeia, and both of the impurity compounds are white crystalline powders and have extremely low solubility in water. In practice, it has been found that increasing the reaction temperature or increasing the hydrazine hydrate feed ratio increases the contents of the two impurity compounds, thereby affecting the clarity and quality of the final product. Therefore, the temperature in the traditional synthetic route is limited between 129 ℃ and 130 ℃, and a limited balance between the yield of the target product and the difficulty degree of impurity removal is also selected.
In order to solve the problem that the temperature range of the isoniazid synthesis method is limited narrowly, the invention controls the condensation reaction temperature and properly increases the feeding proportion of hydrazine hydrate to carry out condensation reaction. The weight ratio of the isonicotinic acid to the pure hydrazine is within the range of 1.40-0.48, when the reaction temperature is too high, the reaction liquid is more viscous, impurity filter residues are increased, certain difficulty is brought to the subsequent refining process, and the yield and the purity of the isonicotinic acid and the pure hydrazine are reduced; the reaction temperature is 129-138 ℃, so that the yield of isoniazid can be effectively increased and the content of impurities can be reduced.
In addition, the weight ratio of the isonicotinic acid to the pure hydrazine is within the range of 1.40-0.48, on one hand, the isonicotinic hydrazine is not increased along with the excessive increase of the feeding amount of the hydrazine hydrate, and on the other hand, the cost is increased due to the excessive increase of the feeding amount of the pure hydrazine. When the weight ratio of isonicotinic acid to pure hydrazine exceeds a certain range, the feeding amount of hydrazine hydrate is increased, the yield of isonicotinic hydrazine is improved, but the generation amount of impurity filter residues is increased, and the time for water evaporation under reduced pressure is correspondingly prolonged, so that the purity of isonicotinic hydrazine is influenced, and the cost is increased; when the weight ratio of isonicotinic acid to pure hydrazine is lower than a certain range, the feeding amount of hydrazine hydrate is reduced, although impurity filter residues are reduced, the isonicotinic acid which does not participate in the reaction is gradually increased, the water solubility of the isonicotinic acid is poor, and by-products, namely dihydrazide and triazole, can be further produced, so that the clarity of a finished product is influenced, the weight of impurities is increased, and the yield and the purity of the isonicotinic acid are reduced. Therefore, considering the balance between input and output suitable for industrial production, the weight ratio of isonicotinic acid to pure hydrazine in the step S1 is controlled to be 1.
In order to make the feeding amount of hydrazine hydrate uniform and applicable, the pure hydrazine of the invention does not contain crystal water, and a person skilled in the art can convert 40-80% of hydrazine hydrate into the pure hydrazine by calculation.
Meanwhile, the method combines the refining steps of decolorization, washing, recrystallization and the like, and controls the conditions of material consumption, temperature, filter cloth size and the like, so that the yield and quality of the isoniazid can be effectively ensured, the purity of the isoniazid is up to 99.64 percent, the impurity content meets the pharmacopoeia limit of raw material medicines, the total impurity content in the isoniazid is less than 1 percent, and the single impurity content is less than 0.35 percent.
In the step S1, water which is 1.09-1.69 times of the weight of isonicotinic acid is added for quenching reaction, and in the step S2-3, the using amount of the water is 0.9-1.5 times of the weight of crude isoniazid. In the step S1, the yield of the isoniazid is mainly influenced by the amount of quenched water and the amount of water in the step S2-3, and when the amount of water is larger, more isoniazid is dissolved in the mother liquor, the yield of the isoniazid is reduced; too little water will cause the isoniazid to crystallize too early or too quickly during the hot filtration process and thus be trapped on the filter cloth together with the impurities. Therefore, when the addition amount of water is within a certain range, the impurity compounds can be well removed. And the dosage of the solvent is less, so that the impurity removal effect is ensured, the cost is reduced, and the economy is good.
In order to better remove higher impurities in isoniazid, in the refining step, step S2-1 and step S2-3, the temperature of the filtrate is reduced to 5-10 ℃ within 2-3 h for crystallization. When the crystallization temperature is too low, the product is too hard to be frozen, so that the product is not beneficial to transfer and filtration, and energy conservation and environmental protection are not enough; when the crystallization temperature is too high, the yield is lowered. In addition, in the process of cooling crystallization to 5-10 ℃, isoniazid begins to be separated out at 20-25 ℃, and when the cooling time is too fast, the crystal form beauty of isoniazid can be influenced, and impurities can be wrapped and coprecipitated to bring influence to subsequent ethanol washing. Therefore, the temperature reduction and crystallization process of the filtrate needs to be controlled within 2-3 h.
In order to ensure complete crystallization, in the step S2-1 and the step S2-3, the filtrate is cooled for 2-3 h and crystallized to 5-10 ℃, and then is kept warm for 1-2 h.
The amount of ethanol used in step S2-2 and step S2-4 affects the yield and purity of isoniazid. In step S2-2 and step S2-4, the isonicotinic acid which is not completely reacted in the condensation reaction still exists in the crystalline solid, the whole crystal is light yellow, and a certain amount of ethanol is added for washing, so that the isonicotinic acid in the crystal can be effectively removed, and the impurity compound I and the impurity compound II which are not crystallized and have extremely low solubility in water are further removed. Therefore, in the step S2-2, the dosage of the ethanol is 0.2-0.8 time of the weight of the crude product of the isoniazid, and in the step S2-4, the dosage of the ethanol is 0.1-0.4 time of the weight of the crude product of the isoniazid.
In addition, it should be noted that the vacuum filtration cannot be started immediately after the ethanol is added, and the vacuum filtration needs to be started when the ethanol naturally drips, otherwise, the ethanol washing effect can be influenced by too early filtration.
Further, the content of impurities in isoniazid is mainly affected by the size of the filter diameter of the filter medium during heat filtration. The inventor finds in practice that the pore size of the filter cloth needs to be controlled in the step S2-1 and the step S2-3 of recrystallization during hot filtration, and when the pore size of the filter cloth is larger, the pore size becomes smaller, the product filtration is more difficult, and the yield is influenced; when the pore size of the filter cloth is smaller, the pore size is larger, and the passing amount of impurities is increased. Therefore, the aperture and the mesh of the filter cloth are important parameters influencing the content of impurities in isoniazid and need to be strictly controlled, and when the aperture and the mesh of the filter cloth are 300-400 meshes, a better filtering effect can be achieved.
Preferably, in the step s1, the weight ratio of the isonicotinic acid to the pure hydrazine is 1.
Preferably, in step s1. The quenching is performed by adding water in an amount of 1.09 to 1.49 times the weight of isonicotinic acid.
Preferably, in the step S2-2, the dosage of the ethanol is 0.2 to 0.5 time of the weight of the crude product of isoniazid.
Preferably, in the step S2-3, the amount of the water is 0.9-1.3 times of the weight of the crude product of isoniazid.
Preferably, in the step S2-4, the dosage of the ethanol is 0.1-0.2 time of the weight of the crude product of isoniazid.
Preferably, in the step S2-1 and the step S2-3, the decolorizing agent is activated carbon, silica gel or alumina.
More preferably, in step S2-1 and step S2-3, the decolorizing agent is activated carbon.
Preferably, in the step S2-2 and the step S2-4, the ethanol content is 90-97%.
The content of impurities in the crude product obtained in the step S2-1 is different from that in the step S2-3, the content of the impurities in the step S2-1 is relatively higher, the solubility of the main component is influenced, and the hot filtration is required under the condition of higher temperature.
Preferably, in the step S2-1, the heating and dissolving temperature is 70-80 ℃.
Preferably, in the step S2-3, the heating and dissolving temperature is 60-65 ℃.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a preparation method of isoniazid, which is based on the improvement of the traditional direct condensation reaction of isonicotinic acid and hydrazine hydrate, adopts the reaction temperature control and the appropriate increase of the feeding proportion of hydrazine hydrate for reaction, solves the problems of narrow temperature range and difficult operability and controllability of the traditional condensation reaction, widens the reaction temperature to 129-138 ℃, and has high yield of isoniazid. Meanwhile, the method combines the refining steps of decolorization, washing, recrystallization and the like, so that the impurity content in the isoniazid is obviously reduced, the requirement of the related evaluation work of the raw material medicines is met, and the quality of the isoniazid is extremely important in the consistency evaluation. The method has wide reaction temperature range, provides a larger selection range for operability and controllability of the industrial production of the isoniazid, and can effectively improve the yield and quality of the isoniazid.
Detailed Description
The present invention is further illustrated by the following specific examples, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
EXAMPLE 1 preparation of Isoniazid
S1, synthesis of isoniazid
Dissolving 150kg of isonicotinic acid in 258kg of 40% hydrazine hydrate, carrying out reduced pressure distillation to 79-82 ℃, changing to a normal pressure environment, rapidly heating a reaction system to 129 ℃, reacting for 3h, adding 193.5kg of purified water, and quenching for reaction to obtain crude isonicotinic acid suspension.
S2, isoniazid purification
S2-1, decoloring: cooling the isoniazid crude product suspension obtained in the step S1 at normal temperature for 4h, heating the cooled crude product suspension to 70-80 ℃ for dissolving, adding 2% of activated carbon, stirring for 15min, filtering with filter cloth with the pore size of 325 meshes while hot, quickly transferring filtrate into a crystallization kettle, gradually cooling and crystallizing until the system temperature is 5-10 ℃, controlling the cooling and crystallizing time to be 2.5h, and keeping the temperature at 5-10 ℃ for 2h;
s2-2, washing: adding 52.5kg of 95% ethanol into the crystals obtained in the crystallization kettle in the step S2-1, starting vacuum filtration when ethanol drops at the lower end of the crystallization kettle, and performing suction filtration until no more filtrate drops to obtain 146.66kg of crude isoniazid, wherein the yield is 97.4%, and the purity is 98.52%;
s2-3, recrystallizing: step S2-2, adding 167.24kg of purified water and 0.5% of activated carbon into the crude isoniazide product without drying, heating to 60-65 ℃ for redissolving, stirring for 10min, filtering with filter cloth with the pore size of 325 meshes while the product is hot, quickly transferring the filtrate into another crystallization kettle, gradually cooling and crystallizing until the system temperature is 5-10 ℃, controlling the cooling and crystallizing time to be 2.5h, and keeping the temperature at 5-10 ℃ for 2h;
s2-4, washing: adding 30.41kg of 95% ethanol into the crystallization kettle in the step S2-3, starting vacuum filtration when ethanol drips at the lower end of the crystallization kettle, and performing vacuum filtration until no filtrate drips any more to obtain 139.18kg of isoniazid filter cake, wherein the yield is 94.9%;
s2-5, drying: and (5) transferring the step S2-4, drying the obtained filter cake at the temperature of between 60 and 65 ℃ to obtain 132.35kg of the refined isoniazid product, wherein the yield is 79.2 percent, and the purity is 99.61 percent.
Referring to the preparation method of example 1, the inventors have searched experimental conditions for isoniazid synthesis, and the specific experimental conditions are shown in table 1.
TABLE 1 influence of different condensation temperatures and ratios on isoniazid formation rate and impurity residue amount
Wherein, the generation rate = the weight of all products generated by the reaction/theoretical yield multiplied by 100%, and the amount of impurity filter residue = the weight of the impurity filter residue/the weight of the fed isonicotinic acid multiplied by 100%;
comparative example 8 of table 1 refers to the synthesis method of isoniazid as recorded in "national raw material process compilation", and adopts a reaction temperature of 129-130 ℃, isonicotinic acid: hydrazine hydrate (100%) = 1.31 weight ratio which is calculated to correspond to the weight ratio of isonicotinic acid to pure hydrazine of the present invention 1.
As can be seen from Table 1, from the results of examples 1 to 4, when the weight ratio of isonicotinic acid to pure hydrazine is 1.44, the productivity of isonicotinic acid is improved by increasing the condensation reaction temperature within the range of 129-138 ℃ in the invention; however, when the condensation temperature is higher than 140 ℃, it can be seen from the results of comparative examples 1 and 2 that the isoniazid formation rate is rather decreased, probably because the increase of the condensation temperature is advantageous for the formation of impurities.
From the results of examples 3, 5 and 6, it is found that when the weight ratio of isonicotinic acid to pure hydrazine is in the range of 0.40 to 1. When the weight ratio of isonicotinic acid to pure hydrazine is within the range of 1.28-1; and when the weight ratio of isonicotinic acid to pure hydrazine is in the range of 1.
Compared with the embodiments 1 to 6 of the invention, the yield of isoniazid of the invention is obviously improved, and the quality is also improved.
Therefore, the reaction temperature is controlled to be 129-138 ℃, the weight ratio of the isonicotinic acid to the pure hydrazine is 1.40-1.
Example 7 preparation of Isoniazid
S1, synthesis of isoniazid
Dissolving 150kg of isonicotinic acid in 258kg of 40% hydrazine hydrate, carrying out reduced pressure distillation to 79-82 ℃, changing to a normal pressure environment, rapidly heating a reaction system to 135 ℃, reacting for 3h, adding 223.5kg of purified water, and quenching for reaction to obtain crude isonicotinic acid suspension.
S2, refining isoniazid
S2-1, decoloring: cooling the crude isoniazid suspension obtained in the step S1 at normal temperature for 4h, heating the cooled crude suspension to 70-80 ℃ for dissolution, adding 2% of activated carbon, stirring for 15min, filtering with filter cloth with the pore size of 325 meshes while hot, quickly transferring filtrate into a crystallization kettle, gradually cooling and crystallizing until the system temperature is 5-10 ℃, controlling the cooling and crystallizing time to be 2.5h, and keeping the temperature at 5-10 ℃ for 2h;
s2-2, washing: adding 52.5kg of 95% ethanol into the crystals obtained in the crystallization kettle in the step S2-1, starting vacuum filtration when ethanol is dripped at the lower end of the crystallization kettle, and performing suction filtration until no more filtrate is dripped to obtain 146.25kg of crude isoniazid, wherein the yield is 93.4% and the purity is 98.55%;
s2-3, recrystallizing: step S2-2, the crude isoniazide product obtained in the step S does not need to be dried, 160.88kg of purified water is added, 0.5% of activated carbon is added, the mixture is heated to 60-65 ℃ for redissolution, stirred for 10min, filtered by filter cloth with the pore size of 325 meshes while hot, the filtrate is quickly transferred to another crystallization kettle, gradually cooled and crystallized until the system temperature is 5-10 ℃, the cooling and crystallization time is controlled to be 2.5h, and the temperature is kept at 5-10 ℃ for 2h;
s2-4, washing: adding 29.25kg of 95% ethanol into the crystallization kettle in the step S2-3, starting vacuum filtration when ethanol drips at the lower end of the crystallization kettle, and performing suction filtration until no filtrate drips any more to obtain 138.50kg of isoniazid filter cake, wherein the yield is 94.7%;
s2-5, drying: transferring the filter cake obtained in the step S2-4, and drying at 60-65 ℃ to obtain 132.52kg of isoniazid refined product, wherein the yield is 79.3%, and the purity is 99.62%.
Referring to the above preparation method, except that different amounts of water are used in step S1. Or different amounts of ethanol are used in step S2-2. To prepare isoniazid, the rest parameters or operation refer to example 2. See table 2 for specific data and experimental results.
TABLE 2 influence of Water usage in step S1. And ethanol usage in step S2-2. On yield and purity of isoniazid
As can be seen from Table 3, in the serial numbers 1-20, the amount of the water used in the step S1. And the amount of the ethanol used in the step S2-2. Are within the range defined by the invention, the amount of the water used in the step S1. Is 1.09-1.69 times, and the amount of the ethanol used in the step S2-2. Is 0.2-0.8 times, so that the yield of the prepared crude product and the refined product of isoniazid is high, and the impurity removal effect is good. Wherein, the using amount of the water in the step S1 is 1.29 times, the using amount of the ethanol in the step S2-2 is 0.35 times (number 14), and the yield and the purity of the prepared crude product and the refined product of the isoniazid are high.
EXAMPLE 8 preparation of Isoniazid
S1, synthesis of isoniazid
150kg of isonicotinic acid is dissolved in 258kg of 40% hydrazine hydrate, reduced pressure distillation is carried out until the temperature reaches 79-82 ℃, then the normal pressure environment is changed, the reaction system is rapidly heated to 135 ℃, the reaction is carried out for 3h, 193.5kg of purified water is added for quenching reaction, and crude isoniazid suspension is obtained.
S2, refining isoniazid
S2-1, decoloring: cooling the crude isoniazid suspension obtained in the step S1 at normal temperature for 4h, heating the cooled crude suspension to 70-80 ℃ for dissolution, adding 2% of activated carbon, stirring for 15min, filtering with filter cloth with the pore size of 325 meshes while hot, quickly transferring filtrate into a crystallization kettle, gradually cooling and crystallizing until the system temperature is 5-10 ℃, controlling the cooling and crystallizing time to be 2.5h, and keeping the temperature at 5-10 ℃ for 2h;
s2-2, washing: adding 52.5kg of 95% ethanol into the crystals obtained in the crystallization kettle in the step S2-1, starting vacuum filtration when ethanol naturally drips at the lower end of the crystallization kettle, and performing suction filtration until no filtrate drips any more to obtain 152.04kg of crude isoniazid, wherein the yield is 97.1%, and the purity is 98.51%;
s2-3, recrystallizing: s2-2, adding 197.65kg of purified water and 0.5% of activated carbon into the crude isoniazide product without drying, heating to 60-65 ℃ for redissolving, stirring for 10min, filtering with filter cloth with the pore size of 325 meshes while the product is hot, quickly transferring the filtrate into another crystallization kettle, gradually cooling and crystallizing until the system temperature is 5-10 ℃, controlling the cooling and crystallizing time to be 2.5h, and keeping the temperature at 5-10 ℃ for 2h;
s2-4, washing: adding 30.41kg of 95% ethanol into the crystallization kettle in the step S2-3, starting vacuum filtration when ethanol is dripped at the lower end of the crystallization kettle, and performing suction filtration until no more filtrate is dripped to obtain 138.96kg of isoniazid filter cake with the yield of 91.4%; (ii) a
S2-5, drying: and (5) transferring the step S2-4, drying the obtained filter cake at the temperature of 60-65 ℃ to obtain 133.35kg of isoniazid refined product with the yield of 79.8 percent and the purity of 99.62 percent.
Referring to the above preparation method, except that different amounts of water are used in the step S2-3, or different amounts of ethanol are used in the step S2-4, to prepare isoniazid, the remaining parameters or operations refer to example 3. See table 3 for specific data and experimental results.
TABLE 3 influence of the amount of water used in step S2-3 and the amount of ethanol used in step S2-4 on the yield and purity of isoniazid
As can be seen from table 4, as shown in serial numbers 3, 4, 7, 8, 11, 12, 15, and 16, the amount of water used in step S2-3 and the amount of ethanol used in step S2-4 are within the range defined in the present invention, the amount of water used in step S2-3 is 0.9-1.5 times, and the amount of ethanol used in step S2-4 is 0.1-0.4 times, the yield of isoniazid obtained by the preparation is high, both of which are above 81.5%, and the total content of isoniazid is less than 0.59%, and the maximum content of single impurity is less than 0.24%, which meets the limit (total content of impurity is 1%, single impurity content is 0.35%) specified in the pharmaceutical pharmacopoeia. Wherein the dosage of the water in the step S2-3 is 1.1 times, the dosage of the ethanol in the step S2-4 is 0.2 times (serial number 12), and the yield and the purity of the prepared isoniazid are both high.
EXAMPLE 9 preparation of Isoniazid
S1, synthesis of isoniazid
150kg of isonicotinic acid is dissolved in 258kg of 40% hydrazine hydrate, reduced pressure distillation is carried out until the temperature reaches 79-82 ℃, then the normal pressure environment is changed, the reaction system is rapidly heated to 135 ℃, the reaction is carried out for 3h, 193.5kg of purified water is added for quenching reaction, and crude isoniazid suspension is obtained.
S2, isoniazid purification
S2-1, decoloring: cooling the crude isoniazid suspension obtained in the step S1 at normal temperature for 4h, heating the cooled crude suspension to 70-80 ℃ for dissolution, adding 2% of activated carbon, stirring for 15min, filtering with filter cloth with the pore size of 325 meshes while hot, quickly transferring filtrate into a crystallization kettle, gradually cooling and crystallizing until the system temperature is 5-10 ℃, controlling the cooling and crystallizing time to be 2.5h, and keeping the temperature at 5-10 ℃ for 2h;
s2-2, washing: adding 52.5kg of 95% ethanol into the crystals obtained in the crystallization kettle of the step S2-1, starting vacuum filtration when ethanol is dripped at the lower end of the crystallization kettle, and performing suction filtration until no more filtrate is dripped to obtain 152.04kg of crude isoniazid, wherein the yield is 97.1% and the purity is 98.51%;
s2-3, recrystallizing: step S2-2, adding 167.24kg of purified water and 0.5% of activated carbon into the crude isoniazide product without drying, heating to 60-65 ℃ for redissolving, stirring for 10min, filtering with filter cloth with the pore size of 325 meshes while the product is hot, quickly transferring the filtrate into another crystallization kettle, gradually cooling and crystallizing until the system temperature is 5-10 ℃, controlling the cooling and crystallizing time to be 2.5h, and keeping the temperature at 5-10 ℃ for 2h;
s2-4, washing: adding 30.41kg of 95% ethanol into the crystallization kettle in the step S2-3, starting vacuum filtration when ethanol drips at the lower end of the crystallization kettle, and performing suction filtration until no more filtrate drips to obtain 143.98kg of isoniazid filter cake, wherein the yield is 94.7%;
s2-5, drying: transferring the filter cake obtained in the step S2-4, and drying at the temperature of 60-65 ℃ to obtain 138.37kg of refined isoniazid product with the yield of 82.8 percent and the purity of 99.61 percent.
Referring to the preparation method, the influence of the mesh number of the filter cloth in the step S2-1 and the step S2-3 on the crude product and the refined product of isoniazid is examined, and specific data and experimental results are shown in tables 4 and 5.
TABLE 4S 2-1. Influence of mesh number of middle filter cloth on crude product of isoniazid
Wherein, the crude isoniazid yield of table 4 is calculated as follows: crude isoniazid (not dried)/total product weight generated by reaction x 100%.
TABLE 5 influence of step S2-3 of mesh number of intermediate filter cloth on refining
Wherein, the refining yield of table 5 is calculated by isoniazid filter cake (not dried)/crude isoniazid (not dried) x 100%.
As can be seen from tables 4 and 5, the pore size of the filter cloth is screened from 200 meshes to 600 meshes, and the filter cloth can be obtained from the serial numbers 3-5 and 3-5 in tables 4 and 5, the mesh number of the filter cloth is in the range of 300-400 meshes, so that a good filtering effect can be achieved, and when the mesh number of the selected filter cloth is 400-600 meshes (serial numbers 6-7 in tables 4 and 6-7 in tables 5), the pore size is reduced, the filtering difficulty is increased, and the yield is obviously reduced; the number of the filter cloth is 200-300 meshes (the numbers 1-2 in the table 4 and the numbers 1-2 in the table 5), the aperture is enlarged, the passing amount of impurities is increased, and the quality of the isoniazid is influenced. Therefore, the yield and the impurity removal effect are remarkably better when the mesh number of the filter cloth is 300-400 meshes.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. The preparation method of isoniazid is characterized by comprising the steps of synthesis and refining, and specifically comprises the following steps:
s1, synthesis: carrying out condensation reaction on isonicotinic acid and pure hydrazine, and quenching after the reaction is finished to obtain an isonicotinic acid crude product suspension;
s2, refining:
s2-1, decoloring: heating and dissolving the crude isoniazid suspension obtained in the step S1, adding a decolorizing agent, stirring for 10-30 min, filtering with hot filter cloth, and cooling and crystallizing the filtrate to 5-10 ℃ within 2-3 h;
s2-2, washing: adding ethanol, and performing suction filtration to obtain a crude product of isoniazid;
s2-3, recrystallizing: adding water into the crude isoniazid obtained in the step S2-2, adding a decolorizing agent, heating for dissolving, stirring for 10-30 min, filtering with hot filter cloth, and cooling and crystallizing the filtrate to 5-10 ℃ within 2-3 h;
s2-4, washing: adding ethanol, and performing suction filtration;
s2-5, drying to obtain an isoniazid refined product;
wherein in the step S1, the condensation reaction is carried out, and the reaction temperature is controlled to be 129-138 ℃;
in the step S1, the weight ratio of the isonicotinic acid to the pure hydrazine is 1.40-0.48;
step S1, quenching, namely adding water with the weight 1.09-1.69 times that of isonicotinic acid to quench;
step S2-2, the dosage of the ethanol is 0.2 to 0.8 time of the weight of the isonicotinic acid;
step S2-3, the amount of water is 0.9-1.5 times of the weight of the crude product of isoniazid;
step S2-4, wherein the dosage of the ethanol is 0.1-0.4 time of the weight of the crude product of isoniazid;
in the step S2-1 and the step S2-3, the aperture and the mesh number of the filter cloth are 300-400 meshes.
2. The method according to claim 1, wherein in step S1, the weight ratio of isonicotinic acid to pure hydrazine is 1.
3. The method of claim 1, wherein in step S1, the quenching is performed by adding water in an amount of 1.09 to 1.49 times the weight of the isonicotinic acid.
4. The method according to claim 1, wherein in step S2-1 and step S2-3, the decolorizing agent is activated carbon, silica gel, or alumina.
5. The method according to claim 1, wherein the amount of ethanol used in step S2-2 is 0.2 to 0.5 times the weight of isonicotinic acid.
6. The preparation method according to claim 1, wherein in the step S2-1 and the step S2-3, the temperature of the filtrate is reduced to 5-10 ℃ within 2-3 h for crystallization, and then the temperature is maintained for 1-2 h.
7. The method according to claim 1, wherein in step S2-3, the amount of water is 0.9-1.3 times the weight of the crude isoniazid.
8. The preparation method of claim 1, wherein in step S2-4, the amount of ethanol is 0.1-0.2 times of the weight of the crude isoniazid.
9. The method according to claim 1, wherein the temperature for the heat dissolution in step S2-1 is 70 to 80 ℃.
10. The method according to claim 1, wherein the ethanol is contained in an amount of 90 to 97% in the steps S2-2 and S2-4.
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| CN111138354A (en) * | 2020-01-20 | 2020-05-12 | 沈阳双鼎制药有限公司 | Preparation method of isoniazid |
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