CN108084174B - Preparation method of nifuratel - Google Patents
Preparation method of nifuratel Download PDFInfo
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- CN108084174B CN108084174B CN201711215085.5A CN201711215085A CN108084174B CN 108084174 B CN108084174 B CN 108084174B CN 201711215085 A CN201711215085 A CN 201711215085A CN 108084174 B CN108084174 B CN 108084174B
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D307/70—Nitro radicals
- C07D307/71—Nitro radicals attached in position 5
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
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Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of nifuratel. The method comprises the following steps: taking epoxypropylmethyl sulfide as a starting material, and carrying out ring-opening reaction on the epoxypropylmethyl sulfide and tert-butyl carbazate to obtain N' - (2-hydroxy-3-methylthio-propyl) -tert-butyl carbazate; carrying out ring closing reaction with urea under the catalytic action of cuprous bromide to obtain a key intermediate N- (Boc-amino) -5-methylthiomethyl-2-oxazolidone; hydrolyzing 5-nitrofurfural diethyl ester under the action of trifluoroacetic acid to obtain 5-nitrofurfural, and condensing with N- (Boc-amino) -5-methylthiomethyl-2-oxazolidinone to obtain nifuratel. The process route of the invention adopts cheap and easily available reagents, reduces the operation difficulty and the treatment burden after reaction, reduces the environmental hazard, ensures the production safety, and is a simple, green and economic process route for preparing nifuratel.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of nifuratel.
Background
5- [ (methylthio) methyl ] -3- { [ (5-nitro-2-furan) methylene ] amino } -2-oxazolidinone, chinese name: nifuratel, english name: nifutatel is a drug developed and produced by Italian pril chemical company and mainly used for gynecological infection, is a broad-spectrum antibiotic, has a strong killing effect on common pathogens of gynecological infection such as gram-positive and gram-negative bacteria, trichomonas, mould, chlamydia, mycoplasma and the like, and has a good curative effect on treating common vaginal infection caused by trichomonas, Candida albicans, bacteria and the like in gynecology. At present, the Chinese medicine composition is made into tablet, capsule, suppository and other dosage forms and is marketed in China and other countries.
The chemical structure of nifuratel is as follows:
the synthetic routes reported by nifuratel are mainly as follows:
route one: belgium [ Belg Pat.635608(1963): CA61:16069c ], the synthetic route of nifuratel was first disclosed, as follows:
the method comprises the steps of firstly carrying out ring opening on chlorocyclopropane and methyl mercaptan to obtain a compound 3', then carrying out substitution reaction on the compound and hydrazine hydrate to obtain a compound 4, and reacting the compound 4 with diethyl carbonate under the catalytic action of metal sodium to obtain a compound 5. Decomposing 5-nitrofurfural diethyl ester under the action of sulfuric acid to prepare a compound 6, namely 5-nitrofurfural, condensing the compound 6 and the compound 5, and refining to obtain a nifuratel refined product.
And a second route: french patent [ Fr.M4544(1966): CA66:59221a ] on the basis of Belgian patent, methyl mercaptan was replaced by sodium methyl mercaptide, the synthetic route is shown below:
the route is similar to the first route, except that in the preparation of compound 4, sodium methyl mercaptide is used for substitution reaction, and then the compound is subjected to ring-opening reaction with hydrazine hydrate, and the sodium methyl mercaptide is used for replacing methyl mercaptan.
By thoroughly studying the two routes, it was found that the main problems in the two routes are:
(1) the separation process of the compound 3 and the compound 4 mostly adopts high vacuum distillation, has high requirements on equipment, large operation difficulty and low yield, and because the used methyl mercaptan and sodium methyl mercaptide have foul smell, the environment is extremely easy to damage, and the method has larger environmental protection pressure;
(2) in the process for preparing oxazolidinone, when the compound 5 is synthesized from the compound 4, a sodium methoxide/methanol system and metallic sodium are used, so that the safety hazard is great, the combustion and explosion are easily caused, and the feeding and production operation are strictly required.
And a third route: plum Shiwan et al, an improvement of the synthetic process of nifuratel, an anti-infective drug, Release military, Pharmacology, Vol 21, No. 4, 2005, on the basis of the two routes, dimethyl sulfate and thiourea are used for synthesizing thioether in order to avoid the use of malodorous methyl mercaptan and sodium methyl mercaptide.
Chinese patent CN100516063C also discloses a similar process route to the literature report, as follows:
route three has the greatest advantage over route one and route two in that compound 4 is prepared under the condition of using dimethyl sulfate and thiourea, so that the malodors generated in the using process of sodium methyl mercaptide and methyl mercaptan are avoided, but the route reported by leersin et al is long and the yield is low, and patent CN100516063C utilizes sodium hydride to prepare compound 5 through cyclization. Although the third route has certain advancement compared with the first two routes, certain disadvantages still exist:
(1) the toxicity of dimethyl sulfate is high, which causes the operation difficulty of the process to be increased;
(2) although metal sodium is not used in the cyclization reaction, sodium hydride has high danger and is extremely easy to spontaneously combust and explode;
(3) the separation process of the compound 4 and the compound 5 requires reduced pressure distillation, and the requirement on equipment is high.
In addition, research shows that the prior art generally utilizes 10 percent of H of 5-nitrofurfural diethyl ester2SO4Or heating to a higher temperature under the condition of Lewis acid for hydrolysis to prepare 5-nitrofurfural, wherein the 5-nitrofurfural is easy to discolor in light, and the aldehyde group is unstable, so that the discoloration speed can be caused under the heating conditionFaster, more side reactions, easy generation of polymer and poor product quality; meanwhile, the yield of the 5-nitrofurfural is reduced, which causes the quality of nifuratel to be poor, the color to be deepened and the yield to be reduced.
Disclosure of Invention
The invention aims to provide a preparation method of nifuratel, which avoids using high vacuum distillation in the process of separating an intermediate and improves the yield; high-risk metal sodium, sodium methoxide or sodium hydride used in the cyclization reaction is avoided; and high temperature is avoided in the preparation process of the 5-nitrofurfural, and the purity and the yield of the product are improved.
The preparation method of nifuratel provided by the invention comprises the following steps:
(1) taking epoxypropylthiomethyl sulfide as a starting material, and carrying out ring-opening reaction on the epoxypropylthiomethyl sulfide and tert-butyl carbazate to obtain N' - (2-hydroxy-3-methylthio-propyl) -tert-butyl hydrazinoformate;
(2) under the catalytic action of cuprous bromide, carrying out ring closure reaction on N' - (2-hydroxy-3-methylthio-propyl) -tert-butyl hydrazinoformate and urea to obtain N- (Boc-amino) -5-methylthiomethyl-2-oxazolidinone;
(3) under the action of trifluoroacetic acid, hydrolyzing 5-nitrofurfural diethyl ester to obtain 5-nitrofurfural, and carrying out condensation reaction on the 5-nitrofurfural and N- (Boc-amino) -5-methylthiomethyl-2-oxazolidinone to obtain nifuratel;
the synthesis process comprises the following steps:
wherein: the compound 3 is epoxypropylmethyl sulfide; compound 4 'is N' - (2-hydroxy-3-methylsulfanyl-propyl) -hydrazinecarboxylic acid tert-butyl ester; the compound 5' is N- (Boc-amino) -5-methylthiomethyl-2-oxazolidone; the compound 6 is 5-nitrofurfural; compound 1 is nifuratel.
The preparation method of the invention further comprises the following steps:
(1) taking a compound 3 as a starting material, taking water as a solvent, and carrying out a ring-opening reaction with tert-butyl carbazate at a certain temperature to obtain a compound 4';
(2) in a solvent, cuprous bromide is used as a catalyst, and the compound 4 'reacts with urea at a certain temperature to close the ring to obtain a compound 5';
(3) dissolving 5-nitrofurfural diethyl ester in a solvent, adding trifluoroacetic acid, and stirring at room temperature for a certain time to prepare 5-nitrofurfural reaction liquid; adding a compound 5' into the 5-nitrofurfural reaction liquid, stirring at room temperature to separate out yellow solid, and filtering to obtain nifuratel.
(4) Heating and dissolving nifuratel in glacial acetic acid, and cooling and crystallizing to obtain refined nifuratel product.
Wherein:
in the step (1), water is used as a solvent, epoxypropylthiomethyl ether is used as a starting material, and the ring-opening reaction is carried out on the epoxypropylthiomethyl ether and tert-butyl carbazate to obtain a compound 4'.
In the step (1), the ring-opening reaction time is 4-8 hours, preferably 5-6 hours, and the ring-opening reaction temperature is 70-90 ℃, preferably 80-90 ℃.
In the step (1), the molar ratio of the epoxypropylmethyl sulfide to the tert-butyl carbazate is 1.0: 1.2-2.0, preferably 1.0: 1.3-1.5.
In the step (2), N-dimethylformamide is used as a solvent, and the compound 4 'and urea undergo a ring closure reaction under the catalytic action of cuprous bromide to obtain a compound 5'.
In the step (2), the ring closing reaction time is 4-8 h, preferably 6-8 h, and the ring closing reaction temperature is 70-120 ℃, preferably 80-100 ℃.
In the step (2), the molar ratio of the compound 4', the cuprous bromide and the urea is 1.0: 0.2-0.6: 1.5-3.0, preferably 1.0: 0.3-0.5: 1.8-2.0.
In the step (3), under the condition of room temperature, 5-nitrofurfural diethyl ester is firstly dissolved in a solvent, and then hydrolyzed under the action of trifluoroacetic acid to prepare 5-nitrofurfural.
In step (3), the solvent is 95wt.% methanol or 95wt.% ethanol, preferably 95wt.% ethanol.
In the step (3), the molar ratio of the 5-nitrofurfural diethyl ester to the trifluoroacetic acid is 1.0: 1.0-2.0, preferably 1.0: 1.2-1.5; the hydrolysis time is 6-10 h, preferably 6-8 h, and the condensation reaction time is 2-3 h.
In the step (3), hydrolysis is performed at room temperature in the absence of light.
The inventor of the invention proves that: the oxazolidinone (compound 5 ') is successfully synthesized at low temperature by using CuBr as a catalyst and using the compound 4' in the presence of urea, so that the use of dangerous reagents such as metallic sodium, sodium methoxide, sodium hydride and the like is avoided, and the operation is simple and convenient. In addition, under the condition of trifluoroacetic acid, the 5-nitrofurfural diethyl ester is hydrolyzed at room temperature to prepare the 5-nitrofurfural, so that the decomposition and condensation of the 5-nitrofurfural at high temperature are avoided, and the purity and the yield are improved.
The invention has the beneficial effects that:
(1) the method avoids the use of high-vacuum-degree reduced pressure distillation in the separation process of the intermediate, uses simpler and easier-to-implement operations such as filtration and the like, and improves the yield.
(2) The invention avoids using flammable and explosive hazardous reagents such as sodium metal, sodium methoxide, sodium hydride and the like in the cyclization reaction, and uses a system consisting of mild cuprous bromide and urea to carry out the cyclization reaction so as to prepare a key intermediate, the yield is stable, the operation is simple, the raw material reagent is cheap and easy to obtain, more importantly, the production environment is improved, and the production safety is ensured.
(3) According to the invention, in the preparation process of the 5-nitrofurfural, a process route of preparing the 5-nitrofurfural by performing high-temperature hydrolysis by using inorganic acid and Lewis acid is avoided, and a process of hydrolyzing the 5-nitrofurfural by using trifluoroacetic acid at room temperature is adopted, so that the occurrence of side reactions is further reduced, and the purity and the yield of the 5-nitrofurfural are improved by reducing the reaction temperature.
(4) The intermediate N- (Boc-amino) -5-methylthiomethyl-2-oxazolidinone and 5-nitrofurfural prepared by the method have higher yield and purity, are directly used for synthesizing nifuratel, and the Boc protective group in the N- (Boc-amino) -5-methylthiomethyl-2-oxazolidinone is condensed with 5-nitrofurfural after being rapidly deprotected in the presence of trifluoroacetic acid to obtain nifuratel. The nifuratel purity reaches more than 99.0 percent, and the yield reaches more than 95.0 percent.
(5) The total yield of the method is 65-70% calculated by the epoxypropylthiomethyl ether, is obviously higher than that of the existing process route, and the cost is greatly reduced.
The invention provides a reasonable and feasible industrial production route based on the concept of green, environmental protection and safe production. The process route selects safe and cheap reagents, avoids using dangerous and virulent reagents, reduces environmental hazards, reduces operation difficulty and treatment burden after reaction, ensures production safety, is a simple, green and economic process route for preparing nifuratel, has high product yield and good purity, and is suitable for industrial mass production of nifuratel.
Detailed Description
The present invention is further described below with reference to examples.
Example 1
Preparation of compound 4':
adding 264.00g of tert-butyl carbazate and 260ml of purified water into a 1000ml reaction bottle, heating the system temperature to 60 ℃, dropwise adding 104.05g of epoxypropylmethyl sulfide at the temperature, controlling the dropwise adding speed to ensure that the temperature of the reaction system does not exceed 65 ℃, heating to 80 ℃ after the dropwise adding is finished, preserving the temperature for 4 hours, cooling to room temperature after the heat preservation is finished, continuously cooling to 5 ℃, separating out solids, leaching with cold water, and drying to obtain 212.30g of quasi-white solids, namely a compound 4', with the yield of 89.80% and the purity of 98.5%.
Example 2
Preparation of compound 4':
adding 159.00g of tert-butyl carbazate and 260ml of purified water into a 1000ml reaction bottle, heating the system temperature to 60 ℃, dropwise adding 104.02g of epoxypropylmethyl sulfide at the temperature, controlling the dropwise adding speed to ensure that the temperature of the reaction system does not exceed 65 ℃, heating to 80 ℃ after the dropwise adding is finished, preserving the temperature for 8 hours, cooling to room temperature after the heat preservation is finished, continuously cooling to 5 ℃, separating out solids, carrying out suction filtration, leaching with cold water, and drying to obtain 203.12g of quasi-white solids, namely a compound 4', the yield is 86.00%, and the purity is 98.7%.
Example 3
Preparation of compound 5':
adding 200.00g of the compound 4 'in example 1, 300ml of DMF, 7.32g of cuprous bromide and 76.27g of urea into a 2000ml reaction bottle, heating to 70 ℃, preserving heat for 8 hours, cooling to room temperature after heat preservation, dropwise adding 600ml of water under stirring, continuously cooling to below 10 ℃ after dropwise adding, and performing suction filtration to obtain 195.30g of solid, namely the compound 5', with the yield of 87.83% and the purity of 98.5%.
Example 4
Preparation of compound 5':
adding 200.00g of the compound 4 'of example 2 into a 1000ml reaction bottle, adding 300ml of DMF, 2.44g of cuprous bromide and 152.54g of urea, heating to 120 ℃, preserving heat for 8 hours, cooling to room temperature after the heat preservation is finished, dropwise adding 600ml of water under stirring, continuously cooling to below 10 ℃ after the dropwise adding is finished, and performing suction filtration to obtain 201.05g of solid, namely the compound 5', the yield is 90.54% and the purity is 98.8%.
Example 5
Preparation of 5-nitrofurfural:
adding 365.00g of 5-nitrofurfural diethyl ester into a 2500ml reaction bottle, adding 1822ml of 95wt.% ethanol solvent, adding 171.23g of trifluoroacetic acid, stirring at room temperature in the dark for 10 hours, and leaving the mixture untreated for later use after the reaction.
Example 6
Preparation of 5-nitrofurfural:
in a 2500ml reaction bottle, 365.00g of 5-nitrofurfural diethyl ester, 1822ml of 95wt.% methanol as a solvent and 342.00g of trifluoroacetic acid are added, and the mixture is stirred at room temperature for 6 hours in a dark place and is not treated for standby after the reaction is finished.
Example 7
Preparation of nifuratel:
in a 2500ml reaction bottle, 5' 211.50g of the compound prepared in example 3 is added into the material obtained in example 5 in batches, yellow solid is gradually separated out, after the addition is finished, the temperature is kept for 2 hours, the filtration is carried out, a filter cake is rinsed by ethanol and dried, 410.40g of yellow solid, namely nifuratel is obtained, the yield is 96.10% and the purity is 99.1% according to the calculation of 5-nitrofurfural diethyl ester.
Example 8
Preparation of nifuratel:
in a 2500ml reaction bottle, 5' 211.50g of the compound prepared in example 4 is added into the material obtained in example 6 in batches, yellow solid is gradually separated out, after the addition is finished, the temperature is kept for 2 hours, the filtration is carried out, a filter cake is leached by methanol and dried, 409.50g of yellow solid, namely nifuratel is obtained, the yield is 95.90 percent and the purity is 99.2 percent according to the calculation of 5-nitrofurfural diethyl ester.
Example 9
Refining nifuratel:
adding 100.00g of crude nifuratel and 600ml of acetic acid into a 2000ml reaction bottle, heating to reflux, adding 5g of activated carbon after dissolving, stirring for 1h, carrying out heat filtration, cooling the filtrate for crystallization, cooling to room temperature, and carrying out suction filtration to obtain 180.20g of refined nifuratel product, wherein the yield is 90.1%, and the purity is 99.8%.
The total yield is calculated by propylene oxide methyl sulfide: 68.07 percent.
Claims (8)
1. A preparation method of nifuratel is characterized by comprising the following steps:
(1) taking epoxypropylmethyl sulfide as a starting material, and carrying out ring-opening reaction on the epoxypropylmethyl sulfide and tert-butyl carbazate to obtain N' - (2-hydroxy-3-methylthio-propyl) -tert-butyl carbazate;
(2) under the catalytic action of cuprous bromide, carrying out ring closure reaction on N' - (2-hydroxy-3-methylthio-propyl) -tert-butyl hydrazinoformate and urea to obtain N- (Boc-amino) -5-methylthiomethyl-2-oxazolidinone;
(3) under the action of trifluoroacetic acid, hydrolyzing 5-nitrofurfural diethyl ester to obtain 5-nitrofurfural, and carrying out condensation reaction on the 5-nitrofurfural and N- (Boc-amino) -5-methylthiomethyl-2-oxazolidinone to obtain nifuratel;
the synthesis process comprises the following steps:
in the step (1), water is used as a solvent, epoxypropylmethyl sulfide is used as an initial raw material, and the initial raw material and tert-butyl carbazate undergo a ring-opening reaction to obtain N' - (2-hydroxy-3-methylthio-propyl) -tert-butyl hydrazinoformate;
in the step (2), N- (Boc-amino) -5-methylthiomethyl-2-oxazolidinone is obtained by using N, N-dimethylformamide as a solvent and carrying out a ring-closing reaction on N' - (2-hydroxy-3-methylthio-propyl) -tert-butyl hydrazinoformate and urea under the catalytic action of cuprous bromide.
2. A method of preparing nifuratel according to claim 1, characterized in that: in the step (1), the ring-opening reaction time is 4-8 h, and the ring-opening reaction temperature is 70-90 ℃.
3. A method of preparing nifuratel according to claim 1, characterized in that: in the step (1), the molar ratio of the epoxypropylmethyl sulfide to the tert-butyl carbazate is 1.0: 1.2-2.0.
4. A preparation method of nifuratel according to claim 1, characterized in that in step (2), the ring closure reaction time is 4-8 h, and the ring closure reaction temperature is 70-120 ℃.
5. A nifuratel preparation method according to claim 1, wherein in step (2), the molar ratio of N' - (2-hydroxy-3-methylthio-propyl) -hydrazinecarboxylic acid tert-butyl ester, cuprous bromide and urea is 1.0: 0.2-0.6: 1.5-3.0.
6. A nifuratel preparation method according to claim 1, characterized in that in step (3), 5-nitrofurfural diethyl ester is dissolved in a solvent at room temperature, and then hydrolyzed under the action of trifluoroacetic acid to prepare 5-nitrofurfural.
7. A process for the preparation of nifuratel according to claim 6, wherein in step (3), the solvent is 95wt.% methanol or 95wt.% ethanol.
8. A preparation method of nifuratel according to claim 6, characterized in that in step (3), the molar ratio of 5-nitrofurfural diethyl ester to trifluoroacetic acid is 1.0: 1.0-2.0, the hydrolysis time is 6-10 h, and the condensation reaction time is 2-3 h.
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Address after: 101399 Mintai Road, Beiwu Town, Shunyi District, Beijing (Science and Technology Innovation Functional Area) Applicant after: Beijing Jincheng Taier Pharmaceutical Co.,Ltd. Address before: 100020 Shuangqiao Road 559 Guanzhuang Township, Chaoyang District, Beijing Applicant before: BEIJING LANEVA PHARMACEUTICAL Co.,Ltd. |
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