CN111138354A - Preparation method of isoniazid - Google Patents
Preparation method of isoniazid Download PDFInfo
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- CN111138354A CN111138354A CN202010063653.XA CN202010063653A CN111138354A CN 111138354 A CN111138354 A CN 111138354A CN 202010063653 A CN202010063653 A CN 202010063653A CN 111138354 A CN111138354 A CN 111138354A
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- isoniazid
- isonicotinic acid
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- C—CHEMISTRY; METALLURGY
- 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 comprises the steps of firstly reacting isonicotinic acid ester generated by esterification reaction of isonicotinic acid, alcohol and an acylation reagent with an ether reagent in an alcohol solution of hydrogen chloride to generate isonicotinic acid ester hydrochloride, then condensing with hydrazine hydrate to generate a crude product of isoniazid, and refining to obtain a finished product; according to the method, the step of generating isonicotinic acid ester hydrochloride through isonicotinic acid ester reaction is added, so that on one hand, the subsequent condensation hydrazinolysis reaction time can be greatly shortened, the preparation efficiency is improved, on the other hand, the isonicotinic acid which is not fully reacted, isonicotinic amide and potential 2-picolinic acid impurities which are introduced into isonicotinic acid raw materials can be removed, the purity of the finally obtained isonicotinic acid is up to 99.99%, and the single impurity is less than 0.10%.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of isoniazid.
Background
Isoniazid (chemical name: 4-pyridine formhydrazide, INH for short) has good antibacterial effect on tubercle bacillus, good curative effect, small dosage, relatively low toxicity and easy acceptance by patients, and has the following chemical structural formula:
at present, there are three main synthetic routes of isoniazid, which are as follows:
the first method is the direct condensation preparation of isonicotinic acid and hydrazine hydrate (national raw material technology assembly 1980, 194-one 195.), and the method has the following disadvantages: the reaction temperature is high, the energy consumption is high, and the isonicotinic acid reaction is incomplete, so that the prepared isonicotinic acid has low purity.
The second one is prepared by using 4-cyanopyridine as raw material, hydrolyzing to isonicotinamide, and condensing with hydrazine hydrate (Sychevatp, Pavlova TN, Shehukia MN. Synthesis of isoniazid from 4-cyanopyralidine. Pharmachem J,1972:6:696-698.), and the disadvantages of the method are that: hydrolysis of 4-cyanopyridine is not easy to control, byproducts such as isonicotinic acid and 4-amino-3, 5-di (4-pyridine) -1,2, 4-triazole are easy to generate, and the purity of the prepared isoniazid is low.
The third one is prepared by using isonicotinic acid as a starting material, carrying out esterification reaction with alcohol and an acylating agent to obtain isonicotinic ester, and then condensing with hydrazine hydrate (CN105085390A), wherein the specific reaction route is as follows:
esterification reaction:
condensation reaction:
according to the technical scheme, in the esterification reaction, isonicotinic acid is used as a raw material, although the isonicotinic acid is produced on a large-scale and is convenient and easy to obtain, isonicotinic amide and potential 2-picolinic acid impurities often exist in the isonicotinic acid, and the 2-picolinic acid and the insufficiently reacted isonicotinic acid can transfer the reaction to influence the purity of the product. If the purity of the product is to be improved, the purity of the raw material isonicotinic acid and the addition amount can only be strictly controlled, so that the requirements on the preparation operation and the purity of the raw material are strict. In the condensation reaction, the crude product of the ethyl isonicotinate generated by the esterification reaction is directly condensed with hydrazine hydrate for hydrazinolysis, no solvent is added, the system is viscous, the stirring effect is poor, the reaction time is prolonged, and the production efficiency is low.
Therefore, how to develop a new synthetic route for isoniazid, which shortens the reaction time and improves the production efficiency on the basis of improving the purity of the prepared isoniazid, becomes a problem to be solved urgently.
Disclosure of Invention
In view of this, the invention provides a method for preparing isoniazid, which adopts a new synthesis route of isoniazid to shorten the reaction time and improve the production efficiency on the basis of improving the purity of the prepared isoniazid.
The technical scheme provided by the invention is specifically a preparation method of isoniazid, which comprises the following steps:
1) carrying out esterification reaction by using isonicotinic acid, alcohol and an acylation reagent as raw materials to obtain isonicotinic ester;
2) dripping the isonicotinate into an alcoholic solution of hydrogen chloride in an ether reagent, and reacting to obtain isonicotinate hydrochloride;
3) dissociating the isonicotinate hydrochloride, and then carrying out condensation hydrazinolysis reaction on the isonicotinate hydrochloride and hydrazine hydrate to obtain a crude product of isonicotinazide;
4) and refining the crude product of isoniazid to obtain a finished product.
Preferably, the ether reagent in step 2) is one of methyl tert-butyl ether, isopropyl ether or diethyl ether.
More preferably, the alcoholic solution of hydrogen chloride in step 2) is one of a methanol solution of hydrogen chloride, an ethanol solution of hydrogen chloride, or an isopropanol solution of hydrogen chloride.
More preferably, 8.0-20.0 ml of ether reagent is correspondingly added in the step 2) for every 1g of isonicotinic acid in the step 1).
Further preferably, the free isonicotinate hydrochloride and hydrazine hydrate are subjected to condensation hydrazinolysis reaction in solvent water in the step 3), wherein 1.0-2.0 ml of solvent water is added to 1g of free isonicotinate hydrochloride, and the molar ratio of the free isonicotinate hydrochloride to the hydrazine hydrate is 1: 1.4-3.
Further preferably, the temperature of the condensation hydrazinolysis reaction in the step 3) is 60-100 ℃, and the reaction time is 0.5-8 hours.
Further preferably, in step 4), after refining the crude isoniazid, a finished product is obtained, specifically: and refining the crude product of isoniazid by adopting an aqueous solution of alcohol to obtain a finished product.
More preferably, 6-15 ml of alcohol aqueous solution is added into each 1g of crude isoniazid.
More preferably, the volume ratio of the alcohol to the water in the alcohol aqueous solution is 97: 3-90: 10.
Further preferably, in the step 1), isonicotinic acid, alcohol and acylating agent are used as raw materials to perform esterification reaction to obtain isonicotinic acid ester, specifically:
adding isonicotinic acid into solvent and catalyst, dripping acylation reagent, and dripping alcohol for esterification reaction to obtain isonicotinic acid ester;
wherein the esterification reaction temperature is 10-50 ℃; adding 0.05-1.0 ml of catalyst into every 1g of isonicotinic acid; the molar ratio of the isonicotinic acid to the acylating reagent is 1: 1.3-3.0; the molar ratio of the isonicotinic acid to the alcohol is 1: 2.0-5.0.
The preparation method of isoniazid provided by the invention comprises the steps of firstly reacting isonicotinic acid ester generated by esterification reaction of isonicotinic acid, alcohol and an acylation reagent with an ether reagent in an alcoholic solution of hydrogen chloride to generate isonicotinic acid ester hydrochloride, dissociating, condensing with hydrazine hydrate to generate a crude product of isoniazid, and refining to obtain a finished product; according to the method, the step of generating isonicotinic acid ester hydrochloride through isonicotinic acid ester reaction is added, so that on one hand, the subsequent condensation hydrazinolysis reaction time can be greatly shortened, the preparation efficiency is improved, on the other hand, the isonicotinic acid which is not fully reacted, isonicotinic amide and potential 2-picolinic acid impurities which are introduced into isonicotinic acid raw materials can be removed, the purity of the finally obtained isonicotinic acid is up to 99.99%, and the single impurity is less than 0.10%.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
The embodiment provides a preparation method of isoniazid, which mainly comprises the following steps:
1) carrying out esterification reaction by using isonicotinic acid, alcohol and an acylation reagent as raw materials to obtain isonicotinic ester;
2) dripping isonicotinate into an alcoholic solution of hydrogen chloride in an ether reagent, and reacting to obtain isonicotinate hydrochloride;
3) after dissociating isonicotinate hydrochloride, carrying out condensation hydrazinolysis reaction on the isonicotinate hydrochloride and hydrazine hydrate to obtain a crude product of isonicotinazide;
4) and refining the crude product of isoniazid to obtain a finished product.
The present embodiment provides a new synthetic route for isoniazid, in view of the fact that the prior isoniazid finished product has the isonicotinic acid which is not fully reacted, isonicotinic amide and potential 2-picolinic acid impurities which are introduced from isonicotinic acid raw materials, and the isonicotinic acid and the 2-picolinic acid can both transfer reaction, resulting in the lower purity of the prepared isoniazid, therefore, the above embodiment is further provided with a step of reacting isonicotinic acid ester with an ether reagent in an alcoholic solution of hydrogen chloride to generate isonicotinic acid ester hydrochloride after the esterification reaction of isonicotinic acid, alcohol and an acylating reagent to generate isonicotinic acid ester, at this time, the incompletely reacted isonicotinic acid and the 2-picolinic acid in isonicotinic acid can correspondingly generate nicotinic acid ethyl ester hydrochloride and 2-picolinic acid ethyl ester hydrochloride, and the two substances have better solubility in the alcoholic solution of ether, the isonicotinic acid raw material is removed by reacting isonicotinic acid amide introduced in the condensation hydrazinolysis reaction with hydrazine hydrate to generate an isonicotinic acid crude product, and finally the high-purity isonicotinic acid with the purity of 99.99 percent is obtained by refining.
Carrying out esterification reaction on the isonicotinic acid, the alcohol and the acylating agent in the step 1) in a solvent and a catalyst, wherein the alcohol can be one of methanol, ethanol, butanol or isopropanol, and is preferably ethanol; the acylating agent can be oxalyl chloride; the solvent can be dichloromethane; the catalyst can be N, N-dimethylformamide.
The esterification reaction is specifically as follows: adding isonicotinic acid into a solvent and a catalyst, dropwise adding an acylation reagent, and then dropwise adding alcohol to perform an esterification reaction to obtain isonicotinic acid ester, wherein the esterification reaction temperature is 10-50 ℃, and the preferable temperature is 15-40 ℃; adding 0.05-1.0 ml of catalyst into every 1g of isonicotinic acid, preferably adding 0.05-0.2 ml of catalyst into every 1g of isonicotinic acid; the molar ratio of the isonicotinic acid to the acylating reagent is 1: 1.3-3.0, preferably 1: 1.3-1.5; the molar ratio of isonicotinic acid to alcohol is 1: 2.0-5.0, preferably 1: 2.0-3.0.
In the step 2), the ether reagent can be one of methyl tert-butyl ether, isopropyl ether or diethyl ether, preferably methyl tert-butyl ether, and because the solubility of the nicotinic acid ethyl ester hydrochloride and the 2-picolinic acid ethyl ester hydrochloride in the alcohol solution of the methyl tert-butyl ether is the highest, the corresponding removal effect is the best; the alcoholic solution of hydrogen chloride in the step 2) is one of a methanol solution of hydrogen chloride, an ethanol solution of hydrogen chloride or an isopropanol solution of hydrogen chloride.
Adding 8.0-20.0 ml of ether reagent to every 1g of isonicotinic acid in the step 1) and correspondingly adding 10.0-15.0 ml of ether reagent to every 1g of isonicotinic acid in the step 2), preferably to every 1g of isonicotinic acid in the step 1) and correspondingly adding the ether reagent in the step 2).
The isonicotinate hydrochloride after the dissociation in the step 3) and hydrazine hydrate are subjected to condensation hydrazinolysis reaction in solvent water, so that the reaction system is adjusted within a proper concentration range and fully reacts; wherein 1.0-2.0 ml of solvent water is correspondingly added into every 1g of dissociated isonicotinic acid ester hydrochloride, and 1.2-1.5 ml of solvent water is preferably added into every 1g of dissociated isonicotinic acid ester hydrochloride; the molar ratio of the free isonicotinate hydrochloride to the hydrazine hydrate is 1: 1.4-3, preferably 1: 1.5-2.0.
The temperature of the condensation hydrazinolysis reaction in the step 3) is 60-100 ℃, preferably 60-80 ℃, and the reaction time is 0.5-8 hours, preferably 0.5-4 hours.
Refining the crude product of isoniazid in the step 4) to obtain a finished product, which specifically comprises the following steps: refining the crude product of isoniazid by adopting an aqueous solution of alcohol to obtain a finished product; wherein 6-15 ml of alcohol aqueous solution is correspondingly added into each 1g of crude isoniazid, and 8-12 ml of alcohol aqueous solution is preferably correspondingly added into each 1g of crude isoniazid; the volume ratio of the alcohol to the water in the alcohol aqueous solution is 97: 3-90: 10, preferably 95:5, and the alcohol aqueous solution is preferably an ethanol aqueous solution.
The isoniazid prepared by the method provided by the embodiment has good product quality, and the single impurity of isonicotinic acid and isonicotinamide is controlled below 0.10%. The free hydrazine remained in finished products of isoniazid can be controlled to be less than 10ppm, and the requirements of European pharmacopoeia EP9.5 on isoniazid and isoniazid single impurity of not more than 0.15 percent and free hydrazine of not more than 15ppm are completely met.
In the processes of generating isoniazid by reacting isoniazid hydrochloride with hydrazine hydrate and refining and purifying, the reaction time is controlled to be 0.5-8 hours, and the reaction time is obviously shortened.
The preparation method of isoniazid provided in the above embodiment corresponds to the following synthetic route, wherein, some reagents are only expressed as a specific component, but are not used to limit the specific selection of the reagent components:
esterification and hydrochloride formation:
condensation reaction:
the present invention is further illustrated by the following specific examples, which are not intended to limit the scope of the invention.
EXAMPLE 1 preparation of Ethyl isonicotinate hydrochloride
To a 3000ml four-necked flask were added 200g (1.62mol) of isonicotinic acid, 1600ml of methylene chloride and 10ml of N, N-dimethylformamide to obtain a white suspension. 620g (4.86mol) of oxalyl chloride is slowly dripped, stirring is carried out for 4 hours at the temperature of 10-50 ℃ after dripping is finished, then 150.4g (3.24mol) of absolute ethyl alcohol is dripped, stirring is carried out for 30 minutes after dripping is finished, the reaction is completed, sodium carbonate aqueous solution prepared in advance (220g of sodium carbonate is dissolved in 800ml of water) is dripped until the pH value is 7-8, liquid separation is carried out, and the organic phase at the lower layer is washed by 600g of 15% sodium chloride aqueous solution. Concentrating the organic phase at 45 ℃ under reduced pressure until no obvious fraction is obtained, adding 400ml of methyl tert-butyl ether, concentrating at 50 ℃ under reduced pressure until no obvious fraction is obtained, adding 3200ml of methyl tert-butyl ether to dilute the concentrate, dripping 151.6g (1.62mol) of ethanol solution of hydrogen chloride with the hydrogen chloride content of 0.39g/g, stirring for 1 hour after dripping, carrying out suction filtration, leaching the filter cake with 400ml of methyl tert-butyl ether, and drying the filter cake at 50 ℃ by air blowing for 3 hours to obtain 288.7g of ethyl isonicotinate hydrochloride white solid powder, wherein the yield is 94.7 percent and the purity is 99.92 percent.
EXAMPLE 2 preparation of crude Isoniazid
Adding 250g (1.33mol) of isonicotinic acid ethyl ester hydrochloride prepared in example 1 and 250ml of purified water into a 2000ml three-necked bottle, stirring to dissolve the mixture clearly, dropwise adding a sodium carbonate aqueous solution prepared in advance (42.5g of sodium carbonate is dissolved in 500ml of water) until the pH value is 7-8, then adding 250ml of dichloromethane, separating, collecting a lower organic phase, adding 300ml of purified water, dropwise adding 116.5g (1.87mol) of 80% hydrazine hydrate, heating to 60-100 ℃, separating low-boiling-point fractions such as dichloromethane and the like while heating, preserving heat at 60-100 ℃ for 0.5-4 hours, cooling to 0-5 ℃ after complete reaction, preserving heat for 1 hour, performing suction filtration, leaching with 250ml of absolute ethyl alcohol to obtain white solid powder, and drying by blowing at 50 ℃ for 3 hours to obtain 148.9g of crude isonicotinic hydrazine, wherein the yield is 81.6% and the purity is 99.
EXAMPLE 3 preparation of finished Isoniazid
Adding 143.9g of crude isoniazid obtained in example 2 and 2159ml of 97% ethanol into a 2000ml three-necked bottle, heating to 70-80 ℃, stirring for dissolving, keeping the temperature of 70-80 ℃ for 30 minutes after dissolving, cooling to 20-25 ℃, performing suction filtration, and performing forced air drying on a filter cake at 50 ℃ to obtain 121.1g of finished isoniazid, wherein the recovery rate is 84.2%, and the purity is 99.99%.
EXAMPLE 4 preparation of Ethyl isonicotinate hydrochloride
100g (0.81mol) of isonicotinic acid, 0.2g of nicotinic acid, 0.2g of 2-picolinic acid, 800ml of dichloromethane and 100ml of N, N-dimethylformamide were added to a 2000ml three-necked flask to obtain a white suspension. Slowly dropwise adding 134g (1.05mol) of oxalyl chloride, after dropwise adding, controlling the temperature to be 15-40 ℃, stirring for 4 hours, then dropwise adding 186.6g (4.05mol) of absolute ethyl alcohol, stirring for 30 minutes after dropwise adding to completely react, dropwise adding a sodium carbonate aqueous solution prepared in advance (110g of sodium carbonate is dissolved in 400ml of water) to the pH value of 7-8, separating, and washing a lower organic phase by using 300g of a 15% sodium chloride aqueous solution. And (2) concentrating the organic phase at 45 ℃ under reduced pressure until no obvious fraction is obtained, adding 100ml of methyl tert-butyl ether, concentrating at 50 ℃ under reduced pressure until no obvious fraction is obtained, adding 500ml of methyl tert-butyl ether to dilute the concentrate, dropwise adding 75.8g (0.81mol) of ethanol solution of hydrogen chloride with the hydrogen chloride content of 0.39g/g, stirring for 1 hour after dropwise adding, carrying out suction filtration, leaching the filter cake with 200ml of methyl tert-butyl ether, and carrying out forced air drying on the filter cake at 50 ℃ for 2 hours to obtain 136g of ethyl isonicotinate hydrochloride white solid powder, wherein the yield is 89.2%, and the.
EXAMPLE 5 preparation of crude Isoniazid
Adding 100g (0.53mol) of isonicotinic acid ethyl ester hydrochloride prepared in example 4 and 200ml of purified water into a 1000ml three-necked bottle, stirring to dissolve the mixture clearly, dropwise adding a sodium carbonate aqueous solution prepared in advance (32.2g of sodium carbonate is dissolved in 200ml of water) until the pH value is 7-8, then adding 100ml of dichloromethane, separating, collecting a lower organic phase, adding 120ml of purified water, dropwise adding 99.4g (1.59mol) of 80% hydrazine hydrate, heating to 60-80 ℃, separating low-boiling-point fractions such as dichloromethane and the like while heating, keeping the temperature at 60-80 ℃ for 1 hour, cooling to 0-5 ℃ after complete reaction, keeping the temperature for 1 hour, performing suction filtration, leaching by using 100ml of absolute ethyl alcohol to obtain white solid powder, and drying by blowing at 50 ℃ for 5 hours to obtain 57.4g of crude isonicotinic acid hydrazine, wherein the yield is 78.5% and.
EXAMPLE 6 preparation of finished Isoniazid
Adding 50g of the crude isoniazid obtained in the example 5 and 300ml of 90% ethanol into a 1000ml three-necked bottle, heating to 70-80 ℃, stirring for dissolving, keeping the temperature for 30 minutes at 70-80 ℃ after dissolving, cooling to 20-25 ℃, performing suction filtration, and performing forced air drying on a filter cake at 50 ℃ to obtain 41.7g of finished isoniazid, wherein the recovery rate is 83.4%, and the purity is 99.99%.
EXAMPLE 7 preparation of Ethyl isonicotinate hydrochloride
To a 3000ml four-necked flask were added 200g (1.62mol) of isonicotinic acid, 1800ml of methylene chloride and 40ml of N, N-dimethylformamide to obtain a white suspension. 310g (2.43mol) of oxalyl chloride is slowly dripped, stirring is carried out for 4 hours at the temperature of 15-40 ℃ after dripping is finished, then 225.6g (4.86mol) of absolute ethyl alcohol is dripped, stirring is carried out for 30 minutes after dripping is finished, the reaction is completed, a sodium carbonate aqueous solution prepared in advance (220g of sodium carbonate is dissolved in 800ml of water) is dripped until the pH value is 7-8, liquid separation is carried out, and the organic phase at the lower layer is washed by 600g of 15% sodium chloride aqueous solution. Concentrating the organic phase at 45 ℃ under reduced pressure until no obvious fraction is obtained, adding 300ml of methyl tert-butyl ether, concentrating at 50 ℃ under reduced pressure until no obvious fraction is obtained, adding 1200ml of methyl tert-butyl ether to dilute the concentrate, dripping 151.6g (1.62mol) of ethanol solution of hydrogen chloride with the hydrogen chloride content of 0.39g/g, stirring for 1 hour after dripping, carrying out suction filtration, leaching the filter cake with 500ml of methyl tert-butyl ether, and carrying out forced air drying on the filter cake at 50 ℃ for 3 hours to obtain 291.5g of ethyl isonicotinate hydrochloride white solid powder, wherein the yield is 95.2% and the purity is 99.95%.
EXAMPLE 8 preparation of crude Isoniazid
Adding 250g (1.33mol) of isonicotinic acid ethyl ester hydrochloride prepared in example 7 and 300ml of purified water into a 2000ml three-necked bottle, stirring to dissolve the mixture clearly, dropwise adding a sodium carbonate aqueous solution prepared in advance (42.5g of sodium carbonate is dissolved in 500ml of water) until the pH value is 7-8, then adding 250ml of dichloromethane, separating, collecting a lower organic phase, adding 300ml of purified water, dropwise adding 165.7g (2.66mol) of 80% hydrazine hydrate, heating to 60-80 ℃, separating low-boiling-point fractions such as dichloromethane and the like while heating, preserving heat at 60-80 ℃ for 0.5-1 hour, cooling to 0-5 ℃ after complete reaction, preserving heat for 1 hour, performing suction filtration, leaching with 250ml of absolute ethyl alcohol to obtain white solid powder, and drying by blowing at 50 ℃ for 2 hours to obtain 149.6g of crude isonicotinic acid hydrazine, wherein the yield is 83.6% and the purity is.
EXAMPLE 9 preparation of finished Isoniazid
Adding 145.1g of crude isoniazid obtained in example 8 and 1161ml of 95% ethanol into a 2000ml three-necked bottle, heating to 70-80 ℃, stirring for dissolving, keeping the temperature of 70-80 ℃ for 30 minutes after dissolving, cooling to 20-25 ℃, performing suction filtration, and performing forced air drying on a filter cake at 50 ℃ to obtain 123.5g of finished isoniazid, wherein the recovery rate is 85.1%, and the purity is 99.99%.
EXAMPLE 10 preparation of Ethyl isonicotinate hydrochloride
100g (0.81mol) of isonicotinic acid, 750ml of dichloromethane and 15ml of N, N-dimethylformamide were added to a 2000ml three-necked flask to obtain a white suspension. Slowly dropwise adding 134g (1.05mol) of oxalyl chloride, controlling the temperature to be 15-35 ℃ and stirring for 4 hours after dropwise adding, then dropwise adding 74.7g (1.62mol) of absolute ethyl alcohol, stirring for 30 minutes after dropwise adding to completely react, dropwise adding a sodium carbonate aqueous solution prepared in advance (110g of sodium carbonate is dissolved in 400ml of water) to the pH value of 7-8, separating, and washing a lower organic phase by using 300g of a 15% sodium chloride aqueous solution. And (2) concentrating the organic phase at 45 ℃ under reduced pressure until no obvious fraction is obtained, adding 200ml of methyl tert-butyl ether, concentrating at 50 ℃ under reduced pressure until no obvious fraction is obtained, adding 1000ml of methyl tert-butyl ether to dilute the concentrate, dropwise adding 75.8g (0.81mol) of ethanol solution of hydrogen chloride with the hydrogen chloride content of 0.39g/g, stirring for 1 hour after dropwise adding, carrying out suction filtration, leaching the filter cake with 300ml of methyl tert-butyl ether, and carrying out forced air drying on the filter cake at 50 ℃ for 2 hours to obtain 136g of ethyl isonicotinate hydrochloride white solid powder, wherein the yield is 90.1%, and the.
EXAMPLE 11 preparation of crude Isoniazid
Adding 100g (0.53mol) of isonicotinic acid ethyl ester hydrochloride prepared in example 10 and 120ml of purified water into a 1000ml three-necked bottle, stirring to dissolve the mixture clearly, dropwise adding a sodium carbonate aqueous solution prepared in advance (32.2g of sodium carbonate is dissolved in 200ml of water) until the pH value is 7-8, then adding 100ml of dichloromethane, separating, collecting a lower organic phase, adding 120ml of purified water, dropwise adding 50.0g (0.8mol) of 80% hydrazine hydrate, heating to 60-80 ℃, separating low-boiling-point fractions such as dichloromethane and the like while heating, keeping the temperature at 60-80 ℃ for 1 hour, cooling to 0-5 ℃ after complete reaction, keeping the temperature for 1 hour, performing suction filtration, leaching by using 100ml of absolute ethyl alcohol to obtain white solid powder, and drying by blowing at 50 ℃ for 5 hours to obtain 57.4g of crude isonicotinic acid hydrazine, wherein the yield is 79.4% and.
EXAMPLE 12 preparation of finished Isoniazid
Adding 55g of the crude isoniazid obtained in the example 11 and 660ml of 95% ethanol into a 1000ml three-necked bottle, heating to 70-80 ℃, stirring for dissolving, keeping the temperature for 30 minutes at 70-80 ℃ after dissolving, cooling to 20-25 ℃, performing suction filtration, and performing forced air drying on a filter cake at 50 ℃ to obtain 47.6g of finished isoniazid, wherein the recovery rate is 86.5%, and the purity is 99.99%.
Comparative example 1
Adding 200g (1.62mol) of isonicotinic acid, 1800g of ethanol and 16.4g (0.162mol) of triethylamine into a 3000ml three-necked bottle, stirring and cooling to 5-10 ℃, slowly dropwise adding 295g (2.48mol) of thionyl chloride, after dropwise adding, controlling the temperature to 5-10 ℃, preserving the temperature for 2 hours, then heating to 25-30 ℃, preserving the temperature for 24 hours, after the reaction is finished, concentrating under reduced pressure to obtain an oily substance, adding 158g (3.2mol) of hydrazine hydrate, heating to 75-80 ℃, preserving the temperature for 10 hours, adding a diluent (350 g) into the mixture, properly heating and dissolving to obtain an aqueous solution of a crude product of isonicotinyl hydrazine, adding 10g of activated carbon, preserving the temperature for half an hour at 70-75 ℃, filtering, naturally cooling the filtrate for 6 hours, slowly cooling to 0-5 ℃, filtering, and drying to obtain a finished product of isonicotinyl hydrazine, wherein the yield is 87% and the purity.
Example 13 test comparison
From the test results, the purity of the finished product in the embodiment is obviously superior to that of the comparative example, meanwhile, in the production process, the subsequent reaction time of the intermediate and hydrazine hydrate in the process is obviously shortened, and the finishing process is optimized on the premise of ensuring the product quality.
In the above examples and comparative examples, the determination methods of purity and content of related substances are conventional techniques, and the chromatographic conditions are as follows:
1. purity of isonicotinic acid to isonicotinic acid ethyl ester hydrochloride and isonicotinic acid ethyl ester hydrochloride
Octadecylsilane chemically bonded silica was used as a filler (5 μm, 250 mm. times.4.6 mm); 0.02mol/L disodium hydrogen phosphate solution (pH value is adjusted to 6.0 by phosphoric acid) -acetonitrile (70:30) is used as a mobile phase, the column temperature is 40 ℃, the detection wavelength is 262nm, and the sample amount is 10 mu L.
2. Purity of isonicotinic acid ethyl ester hydrochloride to isoniazid and isoniazid
Octadecylsilane chemically bonded silica was used as a filler (5 μm, 250 mm. times.4.6 mm); 0.02mol/L disodium hydrogen phosphate solution (pH value is adjusted to 6.0 by phosphoric acid) -acetonitrile (97:3) is used as a mobile phase, the flow rate is 1.0ml/min, the column temperature is 30 ℃, the detection wavelength is 262nm, and the sample amount is 10 mu L.
Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. This application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
It is to be understood that the present invention is not limited to what has been described above, and that various modifications and changes may be made without departing from the scope thereof. The scope of the invention is limited only by the appended claims.
Claims (10)
1. A preparation method of isoniazid is characterized by comprising the following steps:
1) carrying out esterification reaction by using isonicotinic acid, alcohol and an acylation reagent as raw materials to obtain isonicotinic ester;
2) dripping the isonicotinate into an alcoholic solution of hydrogen chloride in an ether reagent, and reacting to obtain isonicotinate hydrochloride;
3) dissociating the isonicotinate hydrochloride, and then carrying out condensation hydrazinolysis reaction on the isonicotinate hydrochloride and hydrazine hydrate to obtain a crude product of isonicotinazide;
4) and refining the crude product of isoniazid to obtain a finished product.
2. The method for preparing isoniazid according to claim 1, characterized in that, the ether reagent in step 2) is one of methyl tert-butyl ether, isopropyl ether or diethyl ether.
3. The method for preparing isoniazid according to claim 1, wherein the alcoholic solution of hydrogen chloride in step 2) is one of a methanol solution of hydrogen chloride, an ethanol solution of hydrogen chloride or an isopropanol solution of hydrogen chloride.
4. The method for preparing isoniazid according to claim 1, characterized in that 8.0-20.0 ml of ether reagent is added in step 2) for every 1g of isoniazid in step 1).
5. The method for preparing isoniazid according to claim 1, characterized in that, in step 3), the dissociated isoniazid hydrochloride and hydrazine hydrate are subjected to condensation hydrazinolysis reaction in solvent water, wherein 1.0-2.0 ml of solvent water is added for every 1g of dissociated isoniazid hydrochloride, and the molar ratio of the dissociated isoniazid hydrochloride to the hydrazine hydrate is 1: 1.4-3.
6. The method for preparing isoniazid according to claim 1, wherein the condensation hydrazinolysis reaction in step 3) is carried out at a temperature of 60-100 ℃ for 0.5-8 hours.
7. The method for preparing isoniazid according to claim 1, characterized in that, the finished product is obtained after refining the crude product of isoniazid in step 4), and specifically comprises the following steps: and refining the crude product of isoniazid by adopting an aqueous solution of alcohol to obtain a finished product.
8. The method for preparing isoniazid according to claim 7, characterized in that 6-15 ml of alcohol aqueous solution is added for each 1g of crude isoniazid.
9. A preparation method of isoniazid according to claim 7 or 8, characterized in that, the volume ratio of alcohol to water in the alcohol aqueous solution is 97: 3-90: 10.
10. The method for preparing isoniazid according to claim 1, wherein in step 1), isonicotinic acid, alcohol and acylating reagent are used as raw materials to perform esterification reaction to obtain isoniazid, specifically:
adding isonicotinic acid into solvent and catalyst, dripping acylation reagent, and dripping alcohol for esterification reaction to obtain isonicotinic acid ester;
wherein the esterification reaction temperature is 10-50 ℃; adding 0.05-1.0 ml of catalyst into every 1g of isonicotinic acid; the molar ratio of the isonicotinic acid to the acylating reagent is 1: 1.3-3.0; the molar ratio of the isonicotinic acid to the alcohol is 1: 2.0-5.0.
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Cited By (1)
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| CN112724081A (en) * | 2020-12-24 | 2021-04-30 | 广州白云山明兴制药有限公司 | Preparation method of isoniazid |
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| CN112724081A (en) * | 2020-12-24 | 2021-04-30 | 广州白云山明兴制药有限公司 | Preparation method of isoniazid |
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