CN115466221B - Treatment method of metronidazole hydroxylation reaction liquid - Google Patents
Treatment method of metronidazole hydroxylation reaction liquid Download PDFInfo
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- CN115466221B CN115466221B CN202211216382.2A CN202211216382A CN115466221B CN 115466221 B CN115466221 B CN 115466221B CN 202211216382 A CN202211216382 A CN 202211216382A CN 115466221 B CN115466221 B CN 115466221B
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Abstract
The invention relates to the technical field of medicine manufacturing, in particular to a method for treating a metronidazole hydroxylation reaction solution. The method comprises the steps of quenching a metronidazole hydroxylation reaction liquid, regulating the pH value to 1.6-1.9, adding at least one extractant in methyl tertiary butyl ether or chloroform for extraction, collecting filtrate, separating the filtrate to obtain a recovered extractant and a water phase, recycling the recovered extractant, regulating the pH value of the water phase to 6.5-7.5, and treating to obtain a crude metronidazole product. Wherein, after the pH value is adjusted to 1.6-1.9 at one time, an extractant is further added, which is favorable for the metronidazole to be further dissolved in the water phase, so that the 2-methyl-5-nitroimidazole is fully separated out for recycling; the pH is regulated to 6.5-7.5 to avoid the decomposition loss of the metronidazole under the alkaline condition, and the metronidazole in the crude mother liquor is fully separated out through cooling crystallization in the follow-up process.
Description
Technical Field
The invention relates to the technical field of medicine manufacturing, in particular to a method for treating a metronidazole hydroxylation reaction solution.
Background
Metronidazole (Metronidazole, molecular formula: C) 6 H 9 N 3 O 3 CAS number: 443-48-1), chinese name: 1- (2-hydroxyethyl) -2-methyl-5-nitroimidazole. Metronidazole is a nitroimidazole antiprotozoal and anaerobic drug, has strong killing effect on trichomonas in genitourinary system, intestinal canal and tissue internal amoeba, giardia and the like, and can also be used for treating diseases caused by trichomonas, amoebic dysentery, amoeba liver abscess and other protozoa. Metronidazole has effect in killing anaerobic microorganisms, and can be used for treating and preventing diseases caused by anaerobe, and for killing protozoa and anaerobe by breaking DNA chain or inhibiting synthesis of DNA. Metronidazole was selected by the world health organization as the primary drug against anaerobic infections in 1978.
The synthetic route of the metronidazole is that 2-methyl-5-nitroimidazole and ethylene oxide are prepared through hydroxylation reaction in formic acid and sulfuric acid environment. Ethylene oxide itself can be hydrolyzed into ethylene glycol, and esterification reaction can be carried out with formic acid under the acid condition, and the conversion rate of 2-methyl-5-nitroimidazole is difficult to continue to react after reaching a certain balance due to the competition side reaction, and the continuous introduction of ethylene oxide is only a byproduct for generating alcohols and esters, so that about one third of 2-methyl-5-nitroimidazole can not be converted into metronidazole. In the prior art, in order to improve the utilization rate of the ethylene oxide, two identical reaction kettles are additionally arranged at the upper part of the hydroxylation reaction kettle, so that three reaction kettles are arranged in series on equipment according to the upper, middle and lower parts, and the method improves the utilization rate of the ethylene oxide by 1 time. And a production method utilizing mother liquor is also provided, namely, the mother liquor is used for producing the metronidazole from which formic acid, sodium sulfate and water are removed, and part of formic acid solvent is replaced, so that the utilization rate of ethylene oxide is improved.
However, the problem of conversion rate of 2-methyl-5-nitroimidazole can not be fundamentally solved no matter the conversion rate of ethylene oxide is improved by modifying equipment or the yield is improved by using hydroxylation mother liquor. Therefore, the development of a method for reducing the residual quantity of 2-methyl-5-nitroimidazole and improving the yield and quality of metronidazole has very important significance.
Disclosure of Invention
Aiming at the problems of high 2-methyl-5-nitroimidazole residue and low yield of metronidazole in the prior art, the invention provides a method for treating a reaction solution for hydroxylation of metronidazole.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a method for treating a metronidazole hydroxylation reaction solution comprises the following steps:
step a, after quenching the metronidazole hydroxylation reaction liquid, regulating the pH value to 1.6-1.9 to neutralize the liquid;
step b, adding an extracting agent into the neutralization solution, cooling and crystallizing, and carrying out solid-liquid separation to obtain 2-methyl-5-nitroimidazole and filtrate; wherein the extractant is at least one of methyl tertiary butyl ether or chloroform;
c, standing the filtrate, and separating the filtrate to obtain a recovered extractant and a water phase;
and d, regulating the pH of the water phase to 6.5-7.5, cooling and crystallizing, and separating solid from liquid to obtain a crude metronidazole product.
Compared with the prior art, the method for treating the metronidazole hydroxylation reaction liquid provided by the invention has the advantages that the pH value of the quenched metronidazole hydroxylation reaction liquid is regulated to be 1.6-1.9, the solubility of 2-methyl-5-nitroimidazole is increased, and the 2-methyl-5-nitroimidazole is fully separated out through subsequent cooling crystallization; then adding a specific extractant into the neutralization solution, separating alcohols such as glycol and glycol diformate, ester byproducts and related organic impurities in the metronidazole hydroxylation reaction solution from the neutralization solution, changing the polarity of the neutralization solution system, fully precipitating and recycling 2-methyl-5-nitroimidazole, and further promoting the dissolution of the metronidazole in the water phase, wherein the quenched metronidazole hydroxylation reaction solution is regulated to a specific pH value and combined with the specific extractant, so that the 2-methyl-5-nitroimidazole can be maximally precipitated, the metronidazole can be prevented from being precipitated as much as possible, and the yield and quality of the metronidazole can be further improved; in the second neutralization, the pH of the water phase is regulated to 6.5-7.5, so that the metronidazole in the crude mother liquor can be fully separated out, meanwhile, the decomposition loss of the metronidazole under the alkaline condition is avoided, the neutral pH is also favorable for the dissolution of 2-methyl-5-nitroimidazole, and the content of 2-methyl-5-nitroimidazole in the crude metronidazole is reduced; meanwhile, as the extractant separates out byproducts such as alcohols, esters and the like, the polarity of the water phase is changed, so that the solubility of materials is reduced, the precipitation of metronidazole is ensured, the yield of the metronidazole is improved, and the complicated process of recycling the materials from crude mother liquor is avoided. The yield of the crude metronidazole can reach 75.92%, the purity of the metronidazole can reach 99.44%, and the problems of high cost and low yield of the existing method for preparing the metronidazole by using the formic acid method are solved.
It should be noted that the reaction solution of the metronidazole is prepared by hydroxylation reaction of 2-methyl-5-nitroimidazole and ethylene oxide in formic acid and sulfuric acid environment.
Preferably, the volume ratio of the metronidazole hydroxylation reaction liquid to the extractant is 1:0.6-1:0.9.
The preferred adding volume ratio of the metronidazole hydroxylation reaction liquid and the extractant can further improve the precipitation of the 2-methyl-5-nitroimidazole and reduce the use cost.
Preferably, in the step a, water is added to the metronidazole hydroxylation reaction solution for quenching.
Further, the volume ratio of the metronidazole hydroxylation reaction solution to the water is 1:0.3-1:0.6.
It should be noted that the reaction temperature at the pH adjustment in step a is not more than 35 ℃.
Preferably, in the step b, the extractant is a mixed solution of methyl tertiary butyl ether and chloroform.
Further, the volume ratio of the methyl tertiary butyl ether to the chloroform is 0.5:1-1:1.
The preferred ratio of the extractant to the extractant can be increased, and the extractant can be increased to extract alcohols such as glycol, glycol diformate and the like, ester byproducts and related organic impurities from the primary neutralization liquid, so that the yield of the metronidazole is further increased.
Preferably, in the step b, the temperature of the cooling crystallization is 15-20 ℃.
It should be noted that the extractant is added in the step b and stirred for 30min to 35min.
Preferably, in step c, the standing time is 20min-25min.
It should be noted that the pH adjustment is carried out by using 30% -42% sodium hydroxide aqueous solution.
Preferably, the temperature of the cooling in step d is 15 ℃ to 25 ℃.
It should be noted that the reaction temperature in step d does not exceed 40 ℃.
Preferably, in step c, the recovered extractant is recycled to step b and continued as extractant for the next batch of neutralisation liquid.
Compared with the prior art, the treatment method of the metronidazole hydroxylation reaction liquid provided by the invention has the following invention points:
(1) The pH value is adjusted to be 1.6-1.9 in the first neutralization, the consumption of liquid alkali is reduced compared with the treatment of the metronidazole hydroxylation reaction liquid in the prior art, and under the condition, the solubility of the 2-methyl-5-nitroimidazole is very low, so that the maximum precipitation of the 2-methyl-5-nitroimidazole is further ensured;
(2) After the pH value is regulated to 1.6-1.9 at one time, an extractant is further added, alcohol and ester byproducts such as glycol, glycol diformate and the like in the system can be selectively extracted to an organic phase, the proportion of an organic solvent in a metronidazole hydroxylation reaction liquid system is reduced, so that the polarity of a neutralization liquid system is changed, the incompletely precipitated 2-methyl-5-nitroimidazole is fully separated out and recycled, the metronidazole is further dissolved in a water phase, and the yield and quality of the metronidazole are further improved;
(3) The aqueous phase does not contain organic byproducts such as alcohols, lipids and the like, and the decomposition loss of the metronidazole under the alkaline condition can be avoided by adjusting the pH of the aqueous phase to 6.5-7.5, so that the metronidazole in the crude mother liquor is fully separated out, and the yield and the quality of the metronidazole are further improved; and the neutral pH is also beneficial to the dissolution of the 2-methyl-5-nitroimidazole, so that the content of the 2-methyl-5-nitroimidazole in the crude product of the metronidazole is reduced.
The invention has reasonable design, and solves the problems of high cost and low yield of the existing method for preparing the metronidazole by the formic acid method.
Detailed Description
The following description of the present invention will be made clearly and fully with the understanding that the specific examples described herein are intended to provide a thorough understanding of the present invention and are not intended to limit the invention to the embodiments described.
The following examples and comparative examples were prepared by hydroxylation of 159.06g of 2-methyl-5-nitroimidazole with 101.8g of ethylene oxide in a formic acid and sulfuric acid environment.
Example 1
A method for treating a metronidazole hydroxylation reaction solution comprises the following steps:
adding 150mL of water into 500mL of metronidazole hydroxylation reaction solution, quenching, controlling the temperature at 27 ℃ in the reaction, adding 30% sodium hydroxide aqueous solution to adjust the pH to 1.9, controlling the temperature at 32 ℃ in the reaction, and neutralizing the solution;
adding 450mL of extracting agent into the neutralization solution, wherein the extracting agent is mixed solvent of methyl tertiary butyl ether and chloroform in a volume ratio of 0.5:1, stirring for 30min, cooling to 15 ℃, crystallizing, carrying out solid-liquid separation, collecting filtrate, and obtaining 49.25g of 2-methyl-5-nitroimidazole with the content of 99.58% and 46.59g of 2-methyl-5-nitroimidazole as the pure-folding content, wherein the filtrate is the unreacted 2-methyl-5-nitroimidazole;
standing the filtrate for 20min, separating to obtain a recovered extractant and a water phase, and recycling the recovered extractant to the step b, and continuously taking the recovered extractant as the extractant of the next batch of neutralizing liquid;
adding 30% sodium hydroxide aqueous solution into the aqueous phase to adjust the pH to 7.5, controlling the temperature to 40 ℃ in the reaction, cooling to 25 ℃, carrying out solid-liquid separation after crystallization is completed, and collecting filtrate as crude mother liquor to obtain a crystal which is a crude metronidazole product. Wherein the dry weight of the crude product of the metronidazole is 115.08g, the purity of the metronidazole is 99.44%, and the content of the 2-methyl-5-nitroimidazole is 0.16%; the content of 2-methyl-5-nitroimidazole in the crude mother liquor is 0.12 percent, and the content of metronidazole is 0.15 percent; the yield of the crude metronidazole is 75.92%.
Example 2
A method for treating a metronidazole hydroxylation reaction solution comprises the following steps:
adding 300mL of water into 500mL of metronidazole hydroxylation reaction solution, quenching, controlling the temperature at 32 ℃ in the reaction, adding 42% sodium hydroxide aqueous solution to adjust the pH to 1.6, controlling the temperature at 27 ℃ in the reaction, and neutralizing the solution;
adding 300mL of an extractant into the neutralization solution, wherein the extractant is a mixed solvent of methyl tertiary butyl ether and chloroform in a volume ratio of 1:1, stirring for 35min, cooling to 20 ℃, crystallizing, carrying out solid-liquid separation, collecting filtrate, and obtaining 48.13g of 2-methyl-5-nitroimidazole with a content of 99.44% and a pure 2-methyl-5-nitroimidazole content of 45.47g for the next synthesis, wherein the filtrate is obtained as the crystal;
standing the filtrate for 25min, separating to obtain a recovered extractant and a water phase, and recycling the recovered extractant to the step b, and continuously taking the recovered extractant as the extractant of the next batch of neutralizing liquid;
adding 42% sodium hydroxide aqueous solution into the aqueous phase to adjust the pH to 6.5, controlling the temperature to 35 ℃ in the reaction, cooling to 15 ℃, carrying out solid-liquid separation after crystallization is completed, and collecting filtrate as crude mother liquor to obtain a crystal which is a crude metronidazole product. Wherein the dry weight of the crude product of the metronidazole is 112.44g, the purity of the metronidazole is 99.32%, and the content of the 2-methyl-5-nitroimidazole is 0.28%; the content of 2-methyl-5-nitroimidazole in the crude mother liquor is 0.33 percent, and the content of metronidazole is 0.19 percent; the yield of the crude metronidazole is 73.45%.
Example 3
A method for treating a metronidazole hydroxylation reaction solution comprises the following steps:
adding 280mL of water into 500mL of metronidazole hydroxylation reaction solution, quenching, controlling the temperature to be 30 ℃ in the reaction, adding 38% sodium hydroxide aqueous solution to adjust the pH to 1.7, controlling the temperature to be 31 ℃ in the reaction, and neutralizing the solution;
adding 400mL of an extractant into the first neutralization solution, wherein the extractant is a mixed solvent of methyl tertiary butyl ether and chloroform in a volume ratio of 0.8:1, stirring for 33min, cooling to 18 ℃, crystallizing, carrying out solid-liquid separation, and collecting filtrate, wherein the crystallized substance is unreacted and completely 2-methyl-5-nitroimidazole for the next synthesis, and 48.2g of 2-methyl-5-nitroimidazole with a content of 99.21% and a pure 2-methyl-5-nitroimidazole folding content of 45.43g are obtained;
standing the filtrate for 22min, separating to obtain a recovered extractant and a water phase, and recycling the recovered extractant to the step b, and continuing to serve as the extractant of the next batch of neutralizing liquid;
adding 38% sodium hydroxide aqueous solution into the aqueous phase to adjust the pH to 6.8, controlling the temperature to 37 ℃ in the reaction, cooling to 21 ℃, carrying out solid-liquid separation after crystallization is completed, and collecting filtrate as crude mother liquor to obtain a crystal which is a crude metronidazole product. Wherein the dry weight of the crude product of the metronidazole is 113.07g, the purity of the metronidazole is 99.34 percent, and the content of the 2-methyl-5-nitroimidazole is 0.31 percent; the content of 2-methyl-5-nitroimidazole in the crude mother liquor is 0.24 percent, and the content of metronidazole is 0.26 percent; the yield of the crude metronidazole is 73.84%.
Example 4
A method for treating a metronidazole hydroxylation reaction solution comprises the following steps:
adding 150mL of water into 500mL of metronidazole hydroxylation reaction solution, quenching, controlling the temperature at 27 ℃ in the reaction, adding 30% sodium hydroxide aqueous solution to adjust the pH to 1.9, controlling the temperature at 32 ℃ in the reaction, and neutralizing the solution;
adding 450mL of extracting agent into the neutralization solution, wherein the extracting agent is chloroform solvent, stirring for 30min, cooling to 15 ℃ for crystallization, carrying out solid-liquid separation, collecting filtrate, and obtaining 45.35g of 2-methyl-5-nitroimidazole with the content of 98.68% and the folded purity content of the 2-methyl-5-nitroimidazole of 42.51g, wherein the crystal is unreacted completely 2-methyl-5-nitroimidazole;
standing the filtrate for 20min, separating to obtain a recovered extractant and a water phase, and recycling the recovered extractant to the step b, and continuously taking the recovered extractant as the extractant of the next batch of neutralizing liquid;
adding 30% sodium hydroxide aqueous solution into the aqueous phase to adjust the pH to 7.5, controlling the temperature to 40 ℃ in the reaction, cooling to 25 ℃, carrying out solid-liquid separation after crystallization is completed, and collecting filtrate as crude mother liquor to obtain a crystal which is a crude metronidazole product. Wherein the dry weight of the crude product of the metronidazole is 108.03g, the purity of the metronidazole is 98.52 percent, and the content of the 2-methyl-5-nitroimidazole is 0.6 percent; the content of 2-methyl-5-nitroimidazole in the crude mother liquor is 0.52 percent, and the content of metronidazole is 0.35 percent; the yield of the crude metronidazole is 68.78%.
Comparative example 1
A method for treating a metronidazole hydroxylation reaction solution comprises the following steps:
adding 150mL of water into 500mL of metronidazole hydroxylation reaction solution, quenching, controlling the temperature at 27 ℃ in the reaction, adding 30% sodium hydroxide aqueous solution to adjust the pH to 2.8, controlling the temperature at 32 ℃ in the reaction, and neutralizing the solution;
450mL of extracting agent is added into the neutralization solution, wherein the extracting agent is mixed solvent of methyl tertiary butyl ether and chloroform in a volume ratio of 0.5:1, the mixture is stirred for 30min, the mixture is cooled to 15 ℃ and then crystallized, solid-liquid separation is carried out, filtrate is collected, the crystallized substance is unreacted complete 2-methyl-5-nitroimidazole and is used for the next synthesis, and 41.35g of 2-methyl-5-nitroimidazole with the content of 98.03% and the folded purity content of 2-methyl-5-nitroimidazole is 38.51g;
standing the filtrate for 20min, separating to obtain a recovered extractant and a water phase, and recycling the recovered extractant to the step b, and continuously taking the recovered extractant as the extractant of the next batch of neutralizing liquid; adding 30% sodium hydroxide aqueous solution into the aqueous phase to adjust the pH to 7.5, controlling the temperature to 40 ℃ in the reaction, cooling to 25 ℃, carrying out solid-liquid separation after crystallization is completed, and collecting filtrate as crude mother liquor to obtain a crystal which is a crude metronidazole product. Wherein the dry weight of the crude product of the metronidazole is 109.96g, the purity of the metronidazole is 97.22%, and the content of the 2-methyl-5-nitroimidazole is 1.4%; the content of 2-methyl-5-nitroimidazole in the crude mother liquor is 0.82 percent, and the content of metronidazole is 0.39 percent; the yield of the crude metronidazole was 67.68%.
Comparative example 2
A method for treating a metronidazole hydroxylation reaction solution comprises the following steps:
adding 150mL of water into 500mL of metronidazole hydroxylation reaction solution, quenching, controlling the temperature at 27 ℃ in the reaction, adding 30% sodium hydroxide aqueous solution to adjust the pH to 1.9, controlling the temperature at 32 ℃ in the reaction, and neutralizing the solution;
adding 450mL of extracting agent into the neutralization solution, wherein the extracting agent is mixed solvent of methyl tertiary butyl ether and chloroform in a volume ratio of 0.5:1, stirring for 30min, cooling to 15 ℃, crystallizing, carrying out solid-liquid separation, collecting filtrate, and obtaining 49.17g of 2-methyl-5-nitroimidazole with the content of 99.50% and 46.48g of 2-methyl-5-nitroimidazole as the pure-folding content, wherein the filtrate is the unreacted 2-methyl-5-nitroimidazole;
standing the filtrate for 20min, separating to obtain a recovered extractant and a water phase, and recycling the recovered extractant to the step b, and continuously taking the recovered extractant as the extractant of the next batch of neutralizing liquid;
adding 30% sodium hydroxide aqueous solution into the aqueous phase to adjust the pH to 11, controlling the temperature to 40 ℃ in the reaction, cooling to 25 ℃, carrying out solid-liquid separation after crystallization is completed, and collecting filtrate as crude mother liquor to obtain a crystal which is a crude product of metronidazole. Wherein the dry weight of the crude product of the metronidazole is 108.66g, the purity of the metronidazole is 97.22%, and the content of the 2-methyl-5-nitroimidazole is 0.31%; the content of 2-methyl-5-nitroimidazole in the crude mother liquor is 0.12 percent, and the content of metronidazole is 0.34 percent; the yield of the crude metronidazole was 71.61%.
Comparative example 3
A method for treating a metronidazole hydroxylation reaction solution comprises the following steps:
adding 150mL of water into 500mL of metronidazole hydroxylation reaction solution, quenching, controlling the temperature at 27 ℃ in the reaction, adding 30% sodium hydroxide aqueous solution to adjust the pH to 1.9, controlling the temperature at 32 ℃ in the reaction, and neutralizing the solution;
adding 450mL of extracting agent into the neutralization solution, wherein the extracting agent is tetrahydrofuran solvent, stirring for 30min, cooling to 15 ℃ for crystallization, carrying out solid-liquid separation, collecting filtrate, and obtaining 43.29g of 2-methyl-5-nitroimidazole with the content of 99.02% and the folded purity content of the 2-methyl-5-nitroimidazole of 40.72g, wherein the crystallized substance is unreacted completely 2-methyl-5-nitroimidazole;
standing the filtrate for 20min, separating to obtain a recovered extractant and a water phase, and recycling the recovered extractant to the step b, and continuously taking the recovered extractant as the extractant of the next batch of neutralizing liquid;
adding 30% sodium hydroxide aqueous solution into the aqueous phase to adjust the pH to 7.5, controlling the temperature to 40 ℃ in the reaction, cooling to 25 ℃, carrying out solid-liquid separation after crystallization is completed, and collecting filtrate as crude mother liquor to obtain a crystal which is a crude metronidazole product. Wherein the dry weight of the crude product of the metronidazole is 107.83g, the purity of the metronidazole is 98.12 percent, and the content of the 2-methyl-5-nitroimidazole is 0.37 percent; the content of 2-methyl-5-nitroimidazole in the crude mother liquor is 0.74 percent, and the content of metronidazole is 0.37 percent; the yield of the crude metronidazole is 67.61%.
According to the method for treating the metronidazole hydroxylation reaction liquid, the extracted metronidazole hydroxylation reaction liquid is regulated to have the pH value of 1.6-1.9, a specific extractant is further used for extraction, the pH value is regulated to be 6.5-7.5, the precipitation purity of 2-methyl-5-nitroimidazole reaches 99.58%, the purity of the metronidazole in the crude product of the metronidazole reaches 99.44%, the content of 2-methyl-5-nitroimidazole is as low as 0.12%, the purity of the metronidazole in the mother liquor of the crude product is as low as 0.15%, and the yield of the crude product of the metronidazole is 75.92%, so that the problems of high cost and low yield of the existing method for preparing the metronidazole by using the formic acid are solved.
The above embodiments are only preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, but any modifications, equivalents, or improvements made within the spirit and principles of the present invention should be included in the scope of the present invention.
Claims (8)
1. The method for treating the metronidazole hydroxylation reaction liquid is characterized by comprising the following steps of:
step a, after quenching the metronidazole hydroxylation reaction liquid, regulating the pH value to 1.6-1.9 to neutralize the liquid;
step b, adding an extracting agent into the neutralization solution, cooling and crystallizing, and carrying out solid-liquid separation to obtain 2-methyl-5-nitroimidazole and filtrate;
c, standing the filtrate, and separating the filtrate to obtain a recovered extractant and a water phase;
step d, regulating the pH of the water phase to 6.5-7.5, cooling and crystallizing, and carrying out solid-liquid separation to obtain a crude metronidazole product;
in the step b, the extractant is a mixed solution of methyl tertiary butyl ether and chloroform in a volume ratio of 0.5:1-1:1.
2. The method for treating a metronidazole hydroxylation reaction solution as claimed in claim 1, wherein the volume ratio of the metronidazole hydroxylation reaction solution to the extractant is 1:0.6-1:0.9.
3. The method for treating a reaction solution for hydroxylation of metronidazole as claimed in claim 1, wherein in the step a, water is added to the reaction solution for hydroxylation of metronidazole for quenching.
4. The method for treating a metronidazole hydroxylation reaction solution as claimed in claim 3, wherein the volume ratio of the metronidazole hydroxylation reaction solution to water is 1:0.3-1:0.6.
5. The method for treating a reaction solution for hydroxylation of metronidazole as claimed in claim 1, wherein in the step b, the temperature of the cooling crystallization is 15℃to 20 ℃.
6. The method for treating a reaction solution for hydroxylation of metronidazole as claimed in claim 1, wherein the standing time in the step c is 20min to 25min.
7. The method for treating a reaction solution for hydroxylation of metronidazole as claimed in claim 1, wherein in the step d, the temperature of the cooling crystallization is 15℃to 25 ℃.
8. The method for treating a reaction solution for hydroxylation of metronidazole as claimed in claim 1, wherein in the step c, the recovered extractant is recycled to the step b and is continued as extractant in the next neutralization solution.
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