CN116947838A - Production method of high-purity nifuratel - Google Patents

Production method of high-purity nifuratel Download PDF

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Publication number
CN116947838A
CN116947838A CN202310914718.0A CN202310914718A CN116947838A CN 116947838 A CN116947838 A CN 116947838A CN 202310914718 A CN202310914718 A CN 202310914718A CN 116947838 A CN116947838 A CN 116947838A
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nifuratel
purity
hydrazinolysis
producing high
product
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寇世超
孙雪兰
李誉军
王伟龙
张治中
王萌
张航
刘继远
黄明海
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Beijing Jincheng Taier Pharmaceutical Co ltd
Cangzhou Branch Of Beijing Jincheng Taier Pharm Co ltd
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Beijing Jincheng Taier Pharmaceutical Co ltd
Cangzhou Branch Of Beijing Jincheng Taier Pharm Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a production method of high-purity nifuratel. The method for producing the high-purity nifuratel comprises the steps of firstly reacting organic acid with hydrazine hydrate to generate hydrazine salt, then adding epoxypropyl methyl sulfide into the hydrazine salt to perform hydrazinolysis reaction to obtain hydrazinolysis salt solution, using alkali to free hydrazinolysis, extracting with a solvent to obtain an organic phase, concentrating, cyclizing and condensing to obtain a nifuratel crude product, and finally recrystallizing to obtain the high-purity nifuratel. The invention saves raw material hydrazine hydrate, is safe and environment-friendly, is simple to operate, and is easy for industrial production; the purity of the prepared nifuratel crude product can reach 99 percent, and the purity of the recrystallized nifuratel product can reach 100 percent.

Description

Production method of high-purity nifuratel
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a production method of high-purity nifuratel.
Background
Nifuratel formula C 10 H 11 N 3 O 5 S, relative molecular mass 285.28, chemical name 5- [ (methylthio) methyl]-3- [ (5-nitrofurfuryl) amino group]-2-oxazolidinone. Nifuratel is a nitrofuran antibiotic drug developed and developed in 60 s by the company poli industrial Chimica S.p.A, has remarkable effect of treating vaginal mixed infection, has the effect of killing trichomonas and being equivalent to metronidazole, has the antibacterial effect, can effectively kill chlamydia trachomatis and mycoplasma, and has certain activity on candida. The nifuratel oral administration and vaginal administration show that the nifuratel oral administration and vaginal administration have good tolerance and no drug resistance phenomenon, the cure rate of the nifuratel oral administration and vaginal administration on bacterial vaginitis is equivalent to that of ampicillin and carbenicillin, and the occurrence rate of adverse reaction is obviously lower than that of ampicillin and carbenicillin. Nifuratel is a broad-spectrum antibiotic, especially has strong killing effect on common pathogens of gynecological infection such as gram positive and negative bacteria, trichomonas, mould, chlamydia and mycoplasma, and has good treatment effect on vulva and vaginal infection and leucorrhea increase caused by bacteria, trichomonas, mould and candida, urinary system infection, digestive tract amoeba disease and giardiasis. At present, tablets, suppositories and ointments taking the extract as a main component are marketed in a plurality of countries at home and abroad. The structural formula is as follows:
chinese patent CN 103755696A discloses a nifuratel synthesis method, in which epichlorohydrin and sodium methyl mercaptide undergo substitution reaction under the action of a phase transfer catalyst to generate epoxypropylenesulfide; the method is characterized in that the concentrated hydrazinolysis product is distilled and reprocessed to improve the purity of the hydrazinolysis product and the quality of the product, but the method has the defects of low yield in the distillation process, danger in the process of distilling the hydrazinolysis product and the like.
Chinese patent CN103664923a discloses a nifuratel synthesis process, which uses epichlorohydrin as a raw material to obtain nifuratel product through substitution, hydrazinolysis, cyclization, hydrolysis and condensation, but the distillation process of the process is dangerous.
In the prior disclosed nifuratel preparation patent, the process for removing the di-substituent impurities in the process of generating the epoxypropyl methyl sulfide by the substitution reaction of the epoxychloropropane is not deeply researched, and the di-substituent can influence the purity of the subsequently synthesized hydrazinolysis product until the purity of the final product is influenced; the method for reducing the hydrazinolysis di-substituent impurity in the hydrazinolysis process is not studied in depth, the defect technology is studied in depth, the defect of the related technology of the product is overcome, and the method is safer and easy for industrial production.
Chinese patent CN108084174a discloses a method for preparing nifuratel, comprising the steps of: using epoxypropylthiofide as an initial raw material, and carrying out ring-opening reaction with tert-butyl hydrazinoformate to obtain N' - (2-hydroxy-3-methylthio-propyl) -tert-butyl hydrazinoformate; performing ring closure reaction with urea under the catalysis of cuprous bromide to obtain a key intermediate N- (Boc-amino) -5-methylthiomethyl-2-oxazolidone; hydrolyzing the diethyl 5-nitrofurfural under the action of trifluoroacetic acid to obtain 5-nitrofurfural, and condensing with N- (Boc-amino) -5-methylthiomethyl-2-oxazolidone to obtain nifuratel. The process route of the invention adopts cheap and easily available reagents, reduces the operation difficulty and the treatment burden after the reaction, reduces the environmental hazard, ensures the production safety, and is a simple, green and economic process route for preparing nifuratel. The above patent uses Boc anhydride to protect amino on one side of hydrazine hydrate, and uses tert-butyl hydrazinoformate and epoxypropyl methyl sulfide to make reaction, and the hydrazinolysis product obtained by the reaction has lower purity, so that the purity of nifuratel crude product and nifuratel product is affected.
Disclosure of Invention
The invention aims to provide a production method of high-purity nifuratel, which has the advantages of raw material saving, simple operation, high product purity, less impurities, good patent medicine property and easy industrial production.
The invention relates to a production method of high-purity nifuratel, which comprises the steps of firstly reacting organic acid with hydrazine hydrate to generate hydrazine salt, then adding epoxypropyl sulfide into the hydrazine salt to perform hydrazinolysis reaction to obtain hydrazinolysis salt solution, dissociating hydrazinolysis by using alkali, extracting the hydrazinolysis product by using a solvent to obtain an organic phase, concentrating, cyclizing and condensing to obtain a nifuratel crude product, and finally recrystallizing to obtain the high-purity nifuratel.
Wherein:
the organic acid is methanesulfonic acid, benzoic acid, phenylacetic acid or benzenesulfonic acid.
The molar ratio of the organic acid to the hydrazine hydrate is (0.8-1.2): 1.
The reaction temperature of the organic acid and the hydrazine hydrate is 5-25 ℃ and the reaction time is 30-40 min.
The molar ratio of the epoxypropylmethyl sulfide to the hydrazine hydrate is 1 (1.0-1.1).
The hydrazinolysis reaction temperature is 70-85 ℃, and the hydrazinolysis reaction time is 2-3 hours.
The alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
And (3) dissociating the hydrazinolysis product by using alkali under the conditions of the temperature of 5-25 ℃ and the pH value of 8-11.
The solvent is dichloromethane, dichloroethane, ethyl acetate or toluene.
During production, the propylene oxide methyl sulfide prepared by substitution of propylene oxide and sodium methyl mercaptide is subjected to rectification treatment, so that the content of di-substituent and propylene oxide in the propylene oxide methyl sulfide is reduced, and the propylene oxide methyl sulfide with higher purity is obtained.
The crude nifuratel product prepared by the method has higher purity and less impurity after recrystallization.
The invention firstly adds organic acid into hydrazine hydrate to generate corresponding hydrazine salt, and protects amino on one side so as to reduce the generation of hydrazinolysis di-substituent in the hydrazinolysis reaction process and reduce the consumption of hydrazine hydrate; slowly adding the purified epoxypropyl sulfide into the hydrazine salt, after the reaction is completed, dissociating hydrazine solution by using alkali liquor, and adding a solvent for extraction to obtain a water phase and an organic phase. The water phase is discarded, so that the generated salt and unreacted hydrazine hydrate can be removed, and the hydrazine hydrate and the subsequent hydrolysate are prevented from generating another impurity, thereby influencing the product quality. Concentrating the organic phase to obtain a high-purity hydrazinolysis product, concentrating, cyclizing and condensing to obtain a high-purity nifuratel crude product, and recrystallizing to obtain the high-purity nifuratel.
According to the invention, further intensive research is carried out under the technical condition of CN108084174A, relatively cheap organic acid is used for replacing Boc anhydride to protect amino on one side of hydrazine hydrate, the reaction mechanism is different, the salifying protection process by using the organic acid is simpler, the generation of impurities in the reaction process is reduced, the industrialization is easier, the addition amount of the hydrazine hydrate is reduced, and the cost is saved.
Meanwhile, N' - (2-hydroxy-3-methylthio-propyl) -hydrazinecarboxylic acid tert-butyl ester is obtained in CN108084174A for process optimization, the hydrazinecarboxylic acid solution is dissociated by alkali liquor after hydrazinolysis, then a solvent is added for extraction to obtain a water phase and an organic phase, the generated salt and unreacted hydrazine hydrate are removed by the water phase, and the organic phase is concentrated to obtain a high-purity hydrazinecarboxylic acid solution, so that the steps of filtering, drying and the like are avoided.
Further, the preparation method of the high-purity nifuratel comprises the following steps:
(1) Adding epichlorohydrin, methylene dichloride and tetrabutylammonium bromide into a four-mouth bottle, adding methyl sodium mercaptide solution under the protection of nitrogen, heating to room temperature, stirring and reacting for 2-3 hours, taking an organic phase for rectification treatment, controlling P= -0.095 to-0.1 MPa, and collecting fractions with the temperature of 51-61 ℃ at the top of the tower to obtain the high-purity epoxypropylmethyl sulfide;
(2) Adding organic acid into hydrazine hydrate, controlling the temperature of the adding process to be 10-20 ℃, and stirring and reacting for 30-40 min after the adding process is finished to generate hydrazine benzoate; adding the epoxypropylthiofide into hydrazine benzoate at the temperature of between 60 and 70 ℃, heating to between 70 and 80 ℃ after the addition, stirring for 2 to 3 hours to obtain a hydrazinolysis salt solution, cooling, controlling the temperature to between 10 and 15 ℃, adding alkali into the reaction solution, adjusting the pH value of the reaction solution to between 8 and 11, adding a solvent for extraction, discarding a water phase, concentrating an organic phase at the temperature of less than 40 ℃ under reduced pressure until no liquid flows out, and obtaining the remainder as the hydrazinolysis product;
(3) Adding dimethyl carbonate and sodium methoxide methanol solution into the hydrazinolysis product, controlling the temperature to be 45-55 ℃ and stirring for reaction for 3-4 hours to obtain cyclization reaction liquid, and cooling for later use;
(4) Adding 5-nitro-2-furfural diacetate, ethanol, sulfuric acid and water into a four-mouth bottle, heating to reflux reaction for 1.5-2.5 hours under the protection of nitrogen to obtain 5-nitro furfural hydrolysate, and cooling for later use;
(5) Adding the cyclization reaction liquid into the hydrolysate at room temperature, wherein solid is continuously generated in the adding process, stirring for 3-4 hours at room temperature after the adding is finished, and filtering, leaching and drying to obtain a nifuratel crude product;
(6) Adding the nifuratel crude product, activated carbon and acetic acid into a four-mouth bottle, heating to reflux, filtering into another four-mouth bottle, cooling to crystallize, cooling to room temperature, filtering, leaching and drying to obtain nifuratel product.
The beneficial effects of the invention are as follows:
1. the nifuratel product prepared by the invention has high purity and better patentability.
2. The preparation method of the high-purity nifuratel saves raw material hydrazine hydrate, is safe and environment-friendly, is simple to operate, and is easy for industrial production.
3. The purity of the nifuratel crude product prepared by the invention can reach 99 percent, and the purity of the nifuratel product after recrystallization can reach 100 percent.
Drawings
FIG. 1 is a synthetic process scheme of example 1;
FIG. 2 is a GC purity profile of propylene oxide sulfide after rectification of example 1;
FIG. 3 is a HPLC purity profile of crude nifuratel prepared in example 1;
FIG. 4 is an HPLC purity profile of nifuratel product prepared in example 1;
FIG. 5 is a HPLC purity profile of crude nifuratel prepared in example 2;
FIG. 6 is an HPLC purity profile of nifuratel product prepared in example 2;
FIG. 7 is a HPLC purity profile of crude nifuratel prepared in example 3;
FIG. 8 is an HPLC purity profile of nifuratel product prepared in example 3;
FIG. 9 is a HPLC purity profile of crude nifuratel prepared in example 4;
FIG. 10 is an HPLC purity profile of nifuratel product prepared in example 4;
FIG. 11 is a HPLC purity profile of crude nifuratel prepared in comparative example 1;
FIG. 12 is a nuclear magnetic resonance spectrum of nifuratel product prepared in example 1.
Detailed Description
The present invention is specifically described and illustrated below with reference to examples.
Example 1
(1) Adding 100g of epichlorohydrin, 300ml of dichloromethane and 5g of tetrabutylammonium bromide into a four-mouth bottle, slowly adding 585g of methyl sodium mercaptide solution (with the concentration of 20 wt%) under the protection of nitrogen, heating to room temperature, stirring for reacting for 2 hours, taking an organic phase for rectification treatment, controlling the P= -0.095 to-0.1 MPa, and collecting a fraction with the temperature of 51-61 ℃ at the top of the bottle to obtain 85g of propylene oxide methyl sulfide with higher purity and 99.069 percent of purity;
(2) Slowly adding 99.7g of benzoic acid into 51.1g of hydrazine hydrate (concentration of 80 wt.%) at a process control temperature of 20 ℃, and stirring for reaction for 30min after the addition to generate hydrazine benzoate; slowly adding 85g of epoxypropylthiofide into hydrazine benzoate at the temperature of 70 ℃, heating to 80 ℃ after the addition, stirring for 2 hours to obtain a hydrazinolysis salt solution, slowly adding 5wt.% sodium hydroxide solution into the reaction solution at the temperature of 10 ℃ after cooling, adjusting the pH value of the reaction solution to 9-10, adding 300g of dichloromethane for extraction, discarding a water phase, concentrating an organic phase at the temperature of 40 ℃ under reduced pressure until no liquid flows out, and obtaining 103.9g of hydrazinolysis; the yield thereof was found to be 93.5% and the purity thereof was found to be 94.1%.
(3) 81g of dimethyl carbonate and 51.9g of sodium methoxide methanol (with the concentration of 30 wt.%) solution are added into the hydrazinolysis substance, the temperature is controlled to be 45 ℃ and the mixture is stirred and reacted for 4 hours, so as to obtain a cyclization reaction solution, and the temperature is reduced for standby;
(4) Adding 158g of 5-nitro-2-furfural diacetate, 400ml of ethanol, 30.6g of sulfuric acid and 400g of water into a four-mouth bottle, heating to reflux reaction for 1.5 hours under the protection of nitrogen to obtain 5-nitro furfural hydrolysate, and cooling for later use;
(5) Slowly adding the cyclization reaction liquid into the hydrolysate at room temperature, wherein solid is continuously generated in the adding process, stirring for 3 hours at room temperature after the adding is finished, filtering, leaching and drying to obtain 175g of nifuratel crude product with the purity of 99.12%;
(6) 175g of nifuratel crude product, 5g of active carbon and 1750g of acetic acid are added into a four-mouth bottle, heated to reflux, filtered into another four-mouth bottle, slowly cooled for crystallization, filtered, leached and dried to obtain 161g of nifuratel product with the yield of 92% and the purity of 100% after the temperature is reached to room temperature.
The GC purity of the rectified epoxypropylthiofide is shown in figure 2, the HPLC purity of the obtained nifuratel crude product is shown in figure 3, and the HPLC purity of the obtained nifuratel product is shown in figure 4.
Making nuclear magnetic resonance of the obtained nifuratel product, wherein the nuclear magnetic resonance spectrum is shown in figure 12, and the nuclear magnetic resonance spectrum is analyzed as follows: δh7.86 (1H, s,), δh7.788 (1H, dj=3.6 Hz); δh 7.152 (1H, dj=3.6 Hz), δh 5.006 (1H, m,); δH4.112,3.696, (2H, t, dd,), 2.944, (2H, m), 2.168, (3H, s).
Example 2
(1) Adding 100g of epichlorohydrin, 300ml of dichloromethane and 5g of tetrabutylammonium bromide into a four-mouth bottle, slowly adding 585g of methyl sodium mercaptide solution (with the concentration of 20 wt%) under the protection of nitrogen, heating to room temperature, stirring and reacting for 2 hours, taking an organic phase for rectification treatment, controlling the pressure to be P= -0.095 to-0.1 MPa, collecting a fraction with the temperature of 51-61 ℃ at the top of the tower, obtaining 85.7g of propylene oxide methyl sulfide with higher purity and 99.051%, and taking 85g for subsequent experiments;
(2) Slowly adding 79.8g of benzoic acid into 51.1g of hydrazine hydrate (concentration of 80 wt.%), controlling the temperature of the adding process to be 20 ℃, and stirring and reacting for 30min after the adding is finished to generate hydrazine benzoate; slowly adding 85g of epoxypropylthiofide into hydrazine benzoate at the temperature of 70 ℃, heating to 80 ℃ after the addition, stirring for 2 hours to obtain a hydrazinolysis salt solution, slowly adding 5wt.% sodium hydroxide solution into the reaction solution at the temperature of 10 ℃ after cooling, adjusting the pH value of the reaction solution to 9-10, adding 300g of dichloromethane for extraction, discarding a water phase, concentrating an organic phase at the temperature of 40 ℃ under reduced pressure until no liquid flows out, and obtaining 102.7g of hydrazinolysis; yield 92.4% and purity 93.5%;
(3) 81g of dimethyl carbonate and 51.9g of sodium methoxide methanol solution (with the concentration of 30 wt.%) are added into the hydrazinolysis substance, the mixture is stirred and reacted for 4 hours at the temperature of 45 ℃ to obtain cyclization reaction liquid, and the temperature is reduced for standby;
(4) Adding 158g of 5-nitro-2-furfural diacetate, 400ml of ethanol, 30.6g of sulfuric acid and 400g of water into a four-mouth bottle, heating to reflux reaction for 1.5 hours under the protection of nitrogen to obtain 5-nitro furfural hydrolysate, and cooling for later use;
(5) Slowly adding the cyclization reaction liquid into the hydrolysate at room temperature, wherein solid is continuously generated in the adding process, stirring for 3 hours at room temperature after finishing the adding, filtering, leaching and drying to obtain 172g of nifuratel crude product with the purity of 99.02%;
(6) 172g of nifuratel crude product, 5g of active carbon and 1720g of acetic acid are added into a four-mouth bottle, heated to reflux, filtered into another four-mouth bottle, slowly cooled for crystallization, filtered, leached and dried to obtain 158.3g of nifuratel product with the yield of 92 percent and the purity of 100 percent after the temperature is reached to the room temperature.
The HPLC purity of the obtained nifuratel crude product is shown in figure 5, and the HPLC purity of the obtained nifuratel product is shown in figure 6.
Example 3
(1) Adding 100g of epichlorohydrin, 300ml of dichloromethane and 5g of tetrabutylammonium bromide into a four-mouth bottle, slowly adding 585g of methyl sodium mercaptide solution (with the concentration of 20 wt%) under the protection of nitrogen, heating to room temperature, stirring and reacting for 2 hours, taking an organic phase for rectification treatment, controlling the pressure of P= -0.095 to-0.1 MPa, collecting fractions with the temperature of 51-61 ℃ at the top of the tower, obtaining 85.4g of propylene oxide methyl sulfide with higher purity and 99.012%, and taking 85g for subsequent experiments;
(2) Slowly adding 119.6g of benzoic acid into 51.1g of hydrazine hydrate (concentration of 80 wt.%), controlling the temperature of the adding process to be 20 ℃, and stirring and reacting for 30min after the adding is finished to generate hydrazine benzoate; slowly adding 85g of epoxypropylthiofide into hydrazine benzoate at the temperature of 70 ℃, heating to 80 ℃ after the addition, stirring for 2 hours to obtain a hydrazinolysis salt solution, slowly adding 5wt.% sodium hydroxide solution into the reaction solution at the temperature of 10 ℃ after cooling, adjusting the pH value of the reaction solution to 9-10, adding 300g of dichloromethane for extraction, discarding a water phase, concentrating an organic phase at the temperature of 40 ℃ under reduced pressure until no liquid flows out, and obtaining 104.5g of hydrazinolysis; the yield thereof was found to be 94.0% and the purity thereof was found to be 93.8%.
(3) 81g of dimethyl carbonate and 51.9g of sodium methoxide methanol solution (with the concentration of 30 wt.%) are added into the hydrazinolysis substance, the mixture is stirred and reacted for 4 hours at the temperature of 45 ℃ to obtain cyclization reaction liquid, and the temperature is reduced for standby;
(4) Adding 158g of 5-nitro-2-furfural diacetate, 400ml of ethanol, 30.6g of sulfuric acid and 400g of water into a four-mouth bottle, heating to reflux reaction for 1.5 hours under the protection of nitrogen to obtain 5-nitro furfural hydrolysate, and cooling for later use;
(5) Slowly adding the cyclization reaction liquid into the hydrolysate at room temperature, wherein solid is continuously generated in the adding process, stirring for 3 hours at room temperature after the adding is finished, filtering, leaching and drying to obtain 173.5g of nifuratel crude product with the purity of 99.12%;
(6) 173.5g of nifuratel crude product, 5g of active carbon and 1735g of acetic acid are added into a four-mouth bottle, heated to reflux, filtered into another four-mouth bottle, slowly cooled for crystallization, filtered, leached and dried to obtain 159.5g of nifuratel product with the yield of 91.9 percent and the purity of 100 percent after the temperature is reduced to room temperature.
The HPLC purity of the obtained nifuratel crude product is shown in figure 7, and the HPLC purity of the obtained nifuratel product is shown in figure 8.
Example 4
(1) Adding 100g of epichlorohydrin, 300ml of dichloromethane and 5g of tetrabutylammonium bromide into a four-mouth bottle, slowly adding 585g of methyl sodium mercaptide solution (with the concentration of 20 wt%) under the protection of nitrogen, heating to room temperature, stirring for reaction for 3 hours, taking an organic phase for rectification treatment, controlling the pressure to be between P= -0.095 and-0.1 MPa, collecting fractions with the temperature of between 51 and 61 ℃ at the top of the bottle, obtaining 86.1g of propylene oxide methyl sulfide with higher purity and 99.058 percent of purity, and taking 85g for subsequent experiments;
(2) Slowly adding 129.2g of benzenesulfonic acid into 51.1g of hydrazine hydrate (concentration is 80 wt.%), adding process control temperature is 10 ℃, stirring and reacting for 40min to generate benzenesulfonic acid hydrazine salt, then controlling temperature to 60 ℃, slowly adding 85g of epoxypropylmethyl sulfide into benzenesulfonic acid hydrazine salt, after adding, heating to 70 ℃, stirring for 3 hours to obtain hydrazinolysis salt solution, slowly adding 5wt.% of sodium hydroxide solution into the reaction solution after cooling, controlling temperature to 15 ℃, regulating pH value of the reaction solution to 9-10, adding dichloromethane to 300g for extraction, discarding aqueous phase, taking organic phase, controlling temperature to 40 ℃, concentrating under reduced pressure until no liquid flows out, and obtaining 103.8g of hydrazinolysis product; yield 93.4%, purity 93.7%;
(3) 81g of dimethyl carbonate and 51.9g of sodium methoxide methanol solution (with the concentration of 30 wt.%) are added into the hydrazinolysis substance, the mixture is stirred and reacted for 3 hours at the temperature of 55 ℃ to obtain cyclization reaction liquid, and the temperature is reduced for standby;
(4) Adding 158g of 5-nitro-2-furfural diacetate, 400ml of ethanol, 30.6g of sulfuric acid and 400g of water into a four-mouth bottle, heating to reflux reaction for 2.5 hours under the protection of nitrogen to obtain 5-nitro furfural hydrolysate, and cooling for later use;
(5) Slowly adding the cyclization reaction liquid into the hydrolysate at room temperature, wherein solid is continuously generated in the adding process, stirring for 4 hours at room temperature after the adding is finished, filtering, leaching and drying to obtain 177.6g of nifuratel crude product with the purity of 99.26%;
(6) 177.5g of nifuratel crude product, 5g of active carbon and 1775g of acetic acid are added into a four-mouth bottle, heated to reflux, filtered into another four-mouth bottle, slowly cooled for crystallization, filtered, leached and dried to obtain 162.5g of nifuratel product with the yield of 91.5 percent and the purity of 100 percent after the temperature is reduced to room temperature.
The HPLC purity of the obtained nifuratel crude product is shown in figure 9, and the HPLC purity of the obtained nifuratel product is shown in figure 10.
Comparative example 1
(1) 86.2g of pyrithione with the purity of 99.017% is obtained by the method of the step (1) of the example 1, and 85g is taken for subsequent experiments;
(2) Slowly adding 85g of pyrithione into 51.5g of hydrazine hydrate at the temperature of 70 ℃, heating to 80 ℃ after the addition, stirring for 2 hours to obtain a hydrazinolysis solution, concentrating under reduced pressure at the temperature of 40 ℃ until no liquid flows out, and obtaining 110.9g of hydrazinolysis as the remainder; yield 99.8% and purity 80%;
(3) 81g of dimethyl carbonate and 51.9g of sodium methoxide methanol solution (with the concentration of 30 wt.%) are added into the hydrazinolysis substance, the mixture is stirred and reacted for 4 hours at the temperature of 45 ℃ to obtain cyclization reaction liquid, and the temperature is reduced for standby;
(4) Adding 158g of 5-nitro-2-furfural diacetate, 400ml of ethanol, 30.6g of sulfuric acid and 400g of water into a four-mouth bottle, heating to reflux reaction for 1.5 hours under the protection of nitrogen to obtain 5-nitro furfural hydrolysate, and cooling for later use;
(5) Slowly adding the cyclization reaction liquid into the hydrolysate at room temperature, wherein solid is continuously generated in the adding process, stirring for 3 hours at room temperature after the adding is finished, filtering, leaching and drying to obtain 160.2g of nifuratel crude product with the purity of 94.917%.
The HPLC purity profile of the crude nifuratel obtained is shown in FIG. 11.

Claims (10)

1. The production method of the high-purity nifuratel is characterized by comprising the steps of firstly reacting organic acid with hydrazine hydrate to generate hydrazine salt, then adding epoxypropyl sulfide into the hydrazine salt to perform hydrazinolysis reaction to obtain hydrazinolysis salt solution, dissociating hydrazinolysis by using alkali, extracting the hydrazinolysis product by using a solvent to obtain an organic phase, concentrating, cyclizing and condensing to obtain a nifuratel crude product, and finally recrystallizing to obtain the high-purity nifuratel.
2. The method for producing high-purity nifuratel according to claim 1, wherein the organic acid is methanesulfonic acid, benzoic acid, phenylacetic acid or benzenesulfonic acid.
3. The process for producing high-purity nifuratel according to claim 1, wherein the molar ratio of the organic acid to hydrazine hydrate is 1 (0.8 to 1.2).
4. The method for producing high-purity nifuratel according to claim 1, wherein the reaction temperature of the organic acid and hydrazine hydrate is 5-25 ℃ and the reaction time is 30-40 min.
5. The method for producing high-purity nifuratel according to claim 1, wherein the molar ratio of the pyrithione to the hydrazine hydrate is 1 (1.0-1.1).
6. The method for producing high-purity nifuratel according to claim 1, wherein the hydrazinolysis reaction temperature is 70-85 ℃ and the hydrazinolysis reaction time is 2-3 hours.
7. The method for producing high-purity nifuratel according to claim 1, wherein the base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
8. The process for producing high purity nifuratel according to claim 1, wherein the hydrazinolysis product is released using a base at a temperature of 5 to 25 ℃ and a pH of 8 to 11.
9. The method for producing high-purity nifuratel according to claim 1, wherein the solvent is dichloromethane, dichloroethane, ethyl acetate or toluene.
10. The method for producing high-purity nifuratel according to claim 1, wherein the propylene oxide methyl sulfide is subjected to rectification treatment.
CN202310914718.0A 2023-07-25 2023-07-25 Production method of high-purity nifuratel Pending CN116947838A (en)

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