CN102241635A - Preparation method for anthelmintic benzimidazole fenbendazole - Google Patents
Preparation method for anthelmintic benzimidazole fenbendazole Download PDFInfo
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Abstract
The invention discloses a preparation method for anthelmintic benzimidazole fenbendazole. The method is characterized in that: p-dichlorobenzene is used as a starting raw material which is subjected to nitration, amination, condensation, reduction and ring-closure reactions so as to obtain fenbendazole (the content of the final product being 98% to 101%). The novel preparation method has the characteristics of a simple and highly efficient process and safe operation, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of novel preparation method of benzimidazoles insect repellent, be specifically related to the novel preparation method of parasiticide bulk drug benzene sulphur imidazoles.
Background technology
Benzene sulphur imidazoles has another name called fenbendazole, and chemistry 5-thiophenyl benzimidazolyl-2 radicals-Urethylane by name is a kind of anti-parasite medicine of broad-spectrum high efficacy for animals.Benzene sulphur imidazoles is used to kill the animal gastrointestinal tract parasite, it not only has the height anthelmintic activity to animal gastrointestinal tract roundworm, hookworm, whipworm, part tapeworm and strongylid, and part bronchial tree and lung parasite (cat lung worm and lung fluke) are also had preferable curative effect.Benzene sulphur imidazoles has the expelling parasite spectrum extensively, and toxicity is low, better tolerance, and safety range is wide, advantages such as good palatability.
Benzene sulphur imidazoles is initial and succeeded in developing by Hoechst company the seventies.The synthetic route of report can reduce following a few class both at home and abroad at present:
Route 1:
Route 2:
Route 3:
More than 3 kinds of routes have mainly that cost is higher, the part link is not easy to operate and to deficiency such as the influence of environment is bigger.
Summary of the invention
The object of the present invention is to provide a new operational path of preparation benzene sulphur imidazoles, aim to provide a kind of succinct safe, qualified suitability for industrialized production especially that reduces cost, makes it to operate.
Technology contents of the present invention is: a kind of preparation method of benzene sulphur imidazoles, the present invention are raw material with the santochlor, get benzene sulphur imidazoles through nitrated, amination, condensation, reduction, closed loop; Concrete steps are as follows:
⑴ 2-nitro-1, the preparation of 4-dichlorobenzene: with the santochlor is raw material, in the presence of the vitriol oil, adds nitrated 2-nitro-1, the 4-dichlorobenzene of getting of nitron.Nitrating agent is a nitric acid, and consumption is 1.02 ~ 1.06 times of molar weight of santochlor, preferred 1.04 times; Nitrated temperature is 0～30 ℃, preferred 20～25 ℃; Nitrated holding temperature is 30～60 ℃, preferred 35～40 ℃.
⑵ the preparation of 2-nitro-4-chloroaniline: 2-nitro-1,4-dichlorobenzene get 2-nitro-4-chloroaniline through amination reaction in organic solvent.Temperature of reaction is 78～150 ℃, preferred 110～115 ℃; Reaction pressure 0～4.0Mpa, preferred 1.5～1.7Mpa.Organic solvent is selected from methyl alcohol, ethanol, propyl alcohol, Virahol or dimethylbenzene, is preferably ethanol, and solvent load is a 2-nitro-1,2～5 times of weight ratios of 4-dichlorobenzene, preferred 2.2 times; The molar weight of ammoniacal liquor is a 2-nitro-1, and 2～8 times of 4-dichlorobenzene are preferably 3～4 times; Amination reagent is selected from liquefied ammonia, ammoniacal liquor, is preferably ammoniacal liquor.
⑶ the preparation of 4-thiophenyl-2-N-methyl-p-nitroaniline: 2-nitro-4-chloroaniline is under alkaline condition, and with thiophenol, condensation gets 4-thiophenyl-2-N-methyl-p-nitroaniline.The consumption of thiophenol is 1～3 times of molar weight of 2-base-4-chloroaniline, preferred 1.2 times; The consumption of solvent is 2～5 times of 2-base-4-chloroaniline weight ratio, preferred 3 times; The consumption of alkali is 1.2～3 times of 2-base-4-chloroaniline mol ratio, preferred 1.5 times; Solvent is selected from organic solvents such as methyl alcohol, ethanol, Virahol, preferred alcohol; Alkali is selected from mineral alkalis such as sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, preferred sodium hydroxide or potassium hydroxide.
⑷ the preparation of 4-thiophenyl O-Phenylene Diamine: 4-thiophenyl-2-N-methyl-p-nitroaniline is reduced under catalyst action, generates 4-thiophenyl O-Phenylene Diamine.Solvent load is the weight ratio of 2～5 times of 4-thiophenyls-2-N-methyl-p-nitroaniline, preferred 3 times; The reduction reagent dosage is 1.2～3 times a mol ratio of 4-thiophenyl-2-N-methyl-p-nitroaniline, preferred 2 times; Solvent is selected from methyl alcohol, ethanol, Virahol etc., particular methanol; Also original reagent is selected from following reagent: Sodium Sulphide such as sodium sulphite, potassium sulphide, Sodium sulfhydrate, potassium bisulfide, iron powder and hydrazine hydrate etc., preferred hydrazine hydrate.
⑸ the preparation of benzene sulphur imidazoles: 4-thiophenyl O-Phenylene Diamine closed loop under acidic conditions gets benzene sulphur imidazoles.The consumption of acid is 0.8～1.5 times of weight ratio of 4-thiophenyl-2-N-methyl-p-nitroaniline, preferred 0.9; Solvent load is 3～5 times of weight ratios of 4-thiophenyl-2-N-methyl-p-nitroaniline, preferred 3 times; The cyclization reagent dosage is 1.1～2 times of molar weights of 4-thiophenyl-2-N-methyl-p-nitroaniline, preferred 1.3 times; Temperature of reaction is 40 ℃～80 ℃, preferred 75 ℃; 1～5 hour reaction times, preferred 3 hours; 0.5～5 hour recrystallization time, preferred 1 hour.The acids acids is selected from organic acids such as oxalic acid, acetate, formic acid, tartrate, preferable formic acid; Reaction solvent is selected from organic solvents such as trichloromethane, methylene dichloride, toluene, preferred toluene; Recrystallization solvent is selected from alcohols such as methyl alcohol, ethanol, Virahol, particular methanol; Cyclization reagent is selected from S-methyl-isothiourea methyl-formiate, O-methyl-isourea methyl-formiate, cyanamide base methyl-formiate etc., preferred S-methyl-isothiourea methyl-formiate.
The reaction formula of above-mentioned concrete making benzene sulphur imidazoles step is as follows:
1. nitrated:
2. amination:
3. condensation:
4. reduction:
5. closed loop:
The invention has the advantages that: present method is starting raw material with the santochlor, obtain benzene sulphur imidazoles (the finished product content 98% ~ 101%) through nitrated, amination, condensation, reduction, closed loop, succinct efficient, the operational safety of this new synthetic process is fit to suitability for industrialized production.
Embodiment
Following type reaction is used for illustrating the present invention, within the technical scheme that those skilled in the art all belong to the present invention to simple replacement that the present invention did or improvement etc. and protected.
Embodiment 1
Step 1:2-nitro-1, the preparation of 4-dichlorobenzene
In 500 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, open and stir, add the 120.0g santochlor successively, 0.8 the weight ratio vitriol oil doubly, dripping molar weight is 1.04 times of nitric acid of dichlorobenzene, and the control dropping temperature is at 20～25 ℃, dropwise, 35～40 ℃ of insulation reaction 1 hour, GC followed the tracks of and reacts completely, and divided sub-cloud spent acid layer; Add 1 times of purifying washing of santochlor weight ratio, branch vibration layer; Be neutralized to neutrality with liquid caustic soda again, cast out water layer.Get 2-nitro-1,4-dichlorobenzene 153.1g is directly used in next step reaction.This step yield is 97.7%.
The preparation of step 2:2-nitro-4-chloroaniline
In 1000 milliliters autoclave, add the 153.1g2-nitro-1 that previous step gets successively, the 4-dichlorobenzene, 2.2 2-nitro-1 doubly, the ethanol of 4-dichlorobenzene weight ratio, 2-nitro-1, the ammoniacal liquor of 3～4 times of molar weights of 4-dichlorobenzene, temperature is controlled at 110～115 ℃, reaction pressure was reacted 24 hours at 1.5～1.7Mpa; The purified water that adds 2 times of 2-nitro-4-chloroaniline weight ratios in 2000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, the feed liquid that reaction is finished add in 2000 milliliters the four-hole boiling flask, finish cooling, centrifugal, washing, oven dry gets 2-nitro-4-chloroaniline dry product 130.1g.Yield is 94.5%.
The preparation of step 3:4-thiophenyl-2-N-methyl-p-nitroaniline
In 1000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, open and stir, add 130.1g 2-nitro-4-chloroaniline successively, the thiophenol that molar weight is 1.2 times, the methyl alcohol of 3 times of 2-nitro-4-chloroaniline weight ratios adds the potassium hydroxide aqueous solution of the content 40% of 1.5 times of 2-bases-4-chloroaniline mol ratio; Finished back flow reaction 4 hours, the reaction finish be cooled to 20 ℃ the insulation 1 hour, centrifugal, wash, dry 4-thiophenyl-2-N-methyl-p-nitroaniline dry product 158.6g, yield is 85.4%.
The preparation of step 4:4-thiophenyl O-Phenylene Diamine
In 1000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, add weight ratio successively and be the methyl alcohol of 3 times of 4-thiophenyls-2-N-methyl-p-nitroaniline, 90.0g4-thiophenyl-2-N-methyl-p-nitroaniline, weight ratio is the Raney's nickel of 0.05 times of 4-thiophenyl-2-N-methyl-p-nitroaniline, open and stir, drip mol ratio and be the hydrazine hydrate of 2 times of 4-thiophenyls-2-N-methyl-p-nitroaniline, dripped complete back flow reaction 6 hours, filter the catalyzer Raney's nickel, pressure reducing and steaming methyl alcohol, get 4-thiophenyl O-Phenylene Diamine 74.9g, be directly used in next step reaction, yield is 94.8%.
Step 5: the preparation of benzene sulphur imidazoles
The 4-thiophenyl O-Phenylene Diamine that obtains is extracted with toluene and water, cast out water, organic phase adds in 1000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, open and stir, adding weight ratio is the acetate of 0.9 times of 4-thiophenyl O-Phenylene Diamine, adding mol ratio is the cyanamide base methyl-formiate of 1.3 times of 4-thiophenyl O-Phenylene Diamines, and 75 ℃ were reacted 3 hours, and boiled off toluene, the methyl alcohol that adds 3 times of 4-thiophenyl O-Phenylene Diamine weight ratios, refluxed 1 hour, and be cooled to normal temperature, centrifugal, washing, dry 86.1g, yield is 83.1%, content 99.6%.
Embodiment 2.
Step 1:2-nitro-1, the preparation of 4-dichlorobenzene
In 500 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, open and stir, add the 120.0g santochlor successively, 0.8 the weight ratio vitriol oil doubly, dripping molar weight is 1.04 times of nitric acid of dichlorobenzene, and the control dropping temperature is at 20～25 ℃, dropwise, 35～40 ℃ of insulation reaction 1 hour, GC followed the tracks of and reacts completely, and divided sub-cloud spent acid layer; Add 1 times of purifying washing of santochlor weight ratio, branch vibration layer; Be neutralized to neutrality with liquid caustic soda again, cast out water layer.Get 2-nitro-1,4-dichlorobenzene 153.4g is directly used in next step reaction.This step yield is 97.9%.
The preparation of step 2:2-nitro-4-chloroaniline
In 1000 milliliters autoclave, add the 153.4g2-nitro-1 that previous step gets successively, the 4-dichlorobenzene, 2.2 2-nitro-1 doubly, the dimethylbenzene of 4-dichlorobenzene weight ratio, 2-nitro-1, the ammoniacal liquor of 3～4 times of molar weights of 4-dichlorobenzene, temperature is controlled at 110～115 ℃, reaction pressure was reacted 24 hours at 1.5～1.7Mpa; The purified water that adds 2 times of 2-nitro-4-chloroaniline weight ratios in 2000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, the feed liquid that reaction is finished add in 2000 milliliters the four-hole boiling flask, finish cooling, centrifugal, washing, oven dry gets 2-nitro-4-chloroaniline dry product 130.5g.Yield is 94.6%.
The preparation of step 3:4-thiophenyl-2-N-methyl-p-nitroaniline
In 1000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, open and stir, add 130.5g 2-nitro-4-chloroaniline successively, the thiophenol that molar weight is 1.2 times, the ethanol of 3 times of 2-nitro-4-chloroaniline weight ratios adds the aqueous sodium hydroxide solution of the content 40% of 1.5 times of 2-bases-4-chloroaniline mol ratio; Finished back flow reaction 4 hours, the reaction finish be cooled to 20 ℃ the insulation 1 hour, centrifugal, wash, dry 4-thiophenyl-2-N-methyl-p-nitroaniline dry product 159.4g, yield is 85.6%.
The preparation of step 4:4-thiophenyl O-Phenylene Diamine
In 1000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, add weight ratio successively and be the methyl alcohol of 3 times of 4-thiophenyls-2-N-methyl-p-nitroaniline, 90.0g4-thiophenyl-2-N-methyl-p-nitroaniline, weight ratio is the Raney's nickel of 0.05 times of 4-thiophenyl-2-N-methyl-p-nitroaniline, open and stir, drip mol ratio and be the hydrazine hydrate of 2 times of 4-thiophenyls-2-N-methyl-p-nitroaniline, dripped complete back flow reaction 6 hours, filter the catalyzer Raney's nickel, pressure reducing and steaming methyl alcohol, get 4-thiophenyl O-Phenylene Diamine 75.2g, be directly used in next step reaction, yield is 95.2%.
Step 5: the preparation of benzene sulphur imidazoles
The 4-thiophenyl O-Phenylene Diamine that obtains is extracted with toluene and water, cast out water, organic phase adds in 1000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, open and stir, adding weight ratio is the acetate of 0.9 times of 4-thiophenyl O-Phenylene Diamine, adding mol ratio is the cyanamide base methyl-formiate of 1.3 times of 4-thiophenyl O-Phenylene Diamines, and 75 ℃ were reacted 3 hours, and boiled off toluene, the methyl alcohol that adds 3 times of 4-thiophenyl O-Phenylene Diamine weight ratios, refluxed 1 hour, and be cooled to normal temperature, centrifugal, washing, dry 86.7g, yield is 83.3%, content 99.8%
Embodiment 3.
Step 1:2-nitro-1, the preparation of 4-dichlorobenzene
In 1000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, open and stir, add the 240.0g santochlor successively, 0.8 the weight ratio vitriol oil doubly, dripping molar weight is the nitric acid of 1.04 times of santochlor, and the control dropping temperature is at 20～25 ℃, dropwise, 35～40 ℃ of insulation reaction 1 hour, GC followed the tracks of and reacts completely, and divided sub-cloud spent acid layer; Add 1 times of purifying washing of santochlor weight ratio, branch vibration layer; Be neutralized to neutrality with liquid caustic soda again, cast out water layer.Get 2-nitro-1,4-dichlorobenzene 307.2g is directly used in next step reaction.This step yield is 98.0%.
The preparation of step 2:2-nitro-4-chloroaniline
In 2000 milliliters autoclave, add the 307.2g2-nitro-1 that previous step gets successively, the 4-dichlorobenzene, 2.2 2-nitro-1 doubly, the ethanol of 4-dichlorobenzene weight ratio, 2-nitro-1, the ammoniacal liquor of 3～4 times of molar weights of 4-dichlorobenzene, temperature is controlled at 110～115 ℃, reaction pressure was reacted 24 hours at 1.5～1.7Mpa; The purified water that adds 2 times of 2-nitro-4-chloroaniline weight ratios in 4000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, the feed liquid that reaction is finished add in 4000 milliliters the four-hole boiling flask, finish cooling, centrifugal, washing, oven dry gets 2-nitro-4-chloroaniline dry product 262.9g.Yield is 95.2%.
The preparation of step 3:4-thiophenyl-2-N-methyl-p-nitroaniline
In 1000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, open and stir, add 156.7g 2-nitro-4-chloroaniline successively, the thiophenol that molar weight is 1.2 times, the ethanol of 3 times of 2-nitro-4-chloroaniline weight ratios adds the aqueous sodium hydroxide solution of the content 40% of 1.5 times of 2-bases-4-chloroaniline mol ratio; Finished back flow reaction 4 hours, the reaction finish be cooled to 20 ℃ the insulation 1 hour, centrifugal, wash, dry 4-thiophenyl-2-N-methyl-p-nitroaniline dry product 190.3g, yield is 85.1%.
The preparation of step 4:4-thiophenyl O-Phenylene Diamine
In 1000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, add weight ratio successively and be the methyl alcohol of 3 times of 4-thiophenyls-2-N-methyl-p-nitroaniline, 90g4-thiophenyl-2-N-methyl-p-nitroaniline, weight ratio is the Raney's nickel of 0.05 times of 4-thiophenyl-2-N-methyl-p-nitroaniline, open and stir, drip mol ratio and be the hydrazine hydrate of 2 times of 4-thiophenyls-2-N-methyl-p-nitroaniline, dripped complete back flow reaction 6 hours, filter the catalyzer Raney's nickel, pressure reducing and steaming methyl alcohol, get 4-thiophenyl O-Phenylene Diamine 75.3g, be directly used in next step reaction, yield is 95.3%.
Step 5: the preparation of benzene sulphur imidazoles
The 4-thiophenyl O-Phenylene Diamine that obtains is extracted with toluene and water, organic phase adds in 1000 milliliters of four-hole boiling flasks that have thermometer and a whipping appts, adding weight ratio is the formic acid of 0.9 times of 4-thiophenyl O-Phenylene Diamine, adding mol ratio is the S-methyl-isothiourea methyl-formiate of 1.3 times of 4-thiophenyl O-Phenylene Diamines, 75 ℃ were reacted 3 hours, boil off toluene, the methyl alcohol that adds 3 times of 4-thiophenyl O-Phenylene Diamine weight ratios, refluxed 1 hour, and be cooled to normal temperature, centrifugal, washing, dry 87.5g, yield is 83.7%, content 99.8%.
Claims (11)
1. the preparation method of a benzimidazoles insect repellent benzene sulphur imidazoles mainly makes with the synthetic method, and it is characterized in that: step is as follows:
(1) is raw material with the santochlor, in the presence of the vitriol oil, obtains 2-nitro-1, the 4-dichlorobenzene through nitration reaction;
(2) 2-nitro-1, the 4-dichlorobenzene obtains 2-nitro-4-chloroaniline through amination reaction;
(3) 2-nitro-4-chloroaniline obtains 4-thiophenyl-2-N-methyl-p-nitroaniline with the thiophenol condensation reaction under alkaline condition;
(4) 4-thiophenyl-2-N-methyl-p-nitroaniline obtains 4-thiophenyl O-Phenylene Diamine through reduction reaction;
(5) 4-thiophenyl O-Phenylene Diamine closed loop obtains benzene sulphur imidazoles.
2. according to the benzene sulphur imidazoles preparation method described in the claim 1, it is characterized in that, in the reactions steps (1), nitrating agent is a nitric acid, its consumption is 1.02 ~ 1.06 times of molar weight of santochlor, and nitrated temperature is 0～30 ℃, and nitrated holding temperature is 30～60 ℃.
3. the preparation method of benzene sulphur imidazoles according to claim 2 is characterized in that, in the reactions steps (1), and 1.04 times of the preferred dichlorobenzene molar weights of nitrating agent, preferred 20～25 ℃ of nitrated temperature, preferred 35～40 ℃ of nitrated holding temperature.
4. the preparation method of benzene sulphur imidazoles according to claim 1 is characterized in that, in the reactions steps (2), the amination solvent is selected from following reagent: methyl alcohol or ethanol or propyl alcohol or Virahol or dimethylbenzene; Amination reagent is selected from following reagent: liquefied ammonia or ammoniacal liquor; The molar weight of amination reagent is a 2-nitro-1,2～8 times of 4-dichlorobenzene, and the consumption of solvent is a 2-nitro-1,2～5 times of 4-dichlorobenzene weight ratio, temperature of reaction is 78～150 ℃, reaction pressure 0～4.0MPa.
5. according to the benzene sulphur imidazoles preparation method described in the claim 4, it is characterized in that, the amination solvent is preferably ethanol, amination reagent is preferably ammoniacal liquor, the molar weight of amination reagent is preferably 2-nitro-1,3～4 times of 4-dichlorobenzene, the preferred 2-nitro-1 of the amount of solvent, 2.2 times of 4-dichlorobenzene weight ratio.
6. the preparation method of benzene sulphur imidazoles according to claim 1, it is characterized in that in the reactions steps (3), the consumption of thiophenol is 1～3 times of molar weight of 2-base-4-chloroaniline, the consumption of solvent is 2～5 times of 2-base-4-chloroaniline weight ratio, the consumption of alkali is 1.2～2.5 times of 2-base-4-chloroaniline mol ratio, solvent is selected from ethanol, methyl alcohol, Virahol, and organic solvents such as propyl carbinol, alkali are selected from sodium hydroxide or potassium hydroxide or yellow soda ash or salt of wormwood class mineral alkali.
7. the preparation method of the benzene sulphur imidazoles of telling according to claim 6, it is characterized in that in the reactions steps (3), the consumption of thiophenol is preferably 1.2 times of molar weight of 2-base-4-chloroaniline, the consumption of solvent is preferably 3 times of 2-base-4-chloroaniline weight ratio, the consumption of alkali is preferably 1.5 times of 2-nitro-4-chloroaniline mol ratio, the solvent preferred alcohol, preferred sodium hydroxide of alkali or potassium hydroxide.
8. the preparation method of benzene sulphur imidazoles according to claim 1, it is characterized in that solvent load in the reactions steps (4) is the weight ratio of 2～5 times of 4-thiophenyls-2-N-methyl-p-nitroaniline, the reduction reagent dosage is 1.2～3 times a mol ratio of 4-thiophenyl-2-N-methyl-p-nitroaniline, solvent is selected from methyl alcohol, ethanol, Virahol etc., goes back original reagent and is selected from following reagent: Sodium Sulphide, iron powder and hydrazine hydrates such as sodium sulphite, potassium sulphide, Sodium sulfhydrate, potassium bisulfide, vat powder.
9. benzene sulphur imidazoles preparation method according to claim 8 is characterized in that the consumption of solvent in the reactions steps (4) is preferably 3 times of 4-thiophenyl-2-N-methyl-p-nitroaniline, and the reduction reagent dosage is preferably 2 times of mol ratios of 4-thiophenyl-2-N-methyl-p-nitroaniline; The solvent particular methanol is gone back the original reagent preferably water and is closed hydrazine.
10. the preparation method of benzene sulphur imidazoles according to claim 1, it is characterized in that the acids acids is selected from organic acids such as oxalic acid, acetate, formic acid, tartrate in the reactions steps (5), reaction solvent is selected from organic solvents such as trichloromethane, methylene dichloride, toluene, recrystallization solvent is selected from alcohols such as methyl alcohol, ethanol, Virahol, and cyclization reagent is selected from S-methyl-isothiourea methyl-formiate, O-methyl-isourea methyl-formiate, cyanamide base methyl-formiate; Temperature of reaction is 40 ℃～150 ℃, 1～12 hour reaction times, 0.5～5 hour recrystallization time.
11. the preparation method of the benzene sulphur imidazoles of telling according to claim 10, it is characterized in that in the reactions steps (5), the acid preferable formic acid, the preferred toluene of reaction solvent, the recrystallization solvent particular methanol, the preferred S-methyl-isothiourea of cyclization reagent methyl-formiate, preferred 75 ℃ of temperature of reaction, preferred 3 hours of reaction times, preferred 1 hour of recrystallization time.
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| CN116496181A (en) * | 2023-06-27 | 2023-07-28 | 山东国邦药业有限公司 | Cyclization agent N- (methoxycarbonyl) dimethyl iminoformate and method for synthesizing fenbendazole by using same |
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| CN103073504A (en) * | 2013-01-09 | 2013-05-01 | 湖南欧亚生物有限公司 | Synthetic method of 5-substituted thiophenyl-benziminazole-2-N-methoxycarbonylamino compound |
| CN103044262A (en) * | 2013-01-27 | 2013-04-17 | 厦门大学 | Synthesis method for 2,5-dichloronitrobenzene |
| CN103242237A (en) * | 2013-05-10 | 2013-08-14 | 常州亚邦齐晖医药化工有限公司 | New preparation method for anthelmintic fenbendazole |
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| CN111349032A (en) * | 2020-04-23 | 2020-06-30 | 山东国邦药业有限公司 | Preparation method of fenbendazole intermediate 2-nitro-4-thiophenyl aniline |
| CN111349032B (en) * | 2020-04-23 | 2021-08-06 | 山东国邦药业有限公司 | Preparation method of fenbendazole intermediate 2-nitro-4-thiophenyl aniline |
| CN113248445B (en) * | 2021-06-28 | 2021-10-08 | 山东国邦药业有限公司 | Synthesis method of fenbendazole |
| CN113185436A (en) * | 2021-07-01 | 2021-07-30 | 山东国邦药业有限公司 | Preparation method of 4-thiophenyl-o-phenylenediamine |
| CN116063212A (en) * | 2023-01-28 | 2023-05-05 | 山东国邦药业有限公司 | Preparation method of 4-phenylthio-1, 2-phenylenediamine |
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| CN116496181A (en) * | 2023-06-27 | 2023-07-28 | 山东国邦药业有限公司 | Cyclization agent N- (methoxycarbonyl) dimethyl iminoformate and method for synthesizing fenbendazole by using same |
| CN116496181B (en) * | 2023-06-27 | 2023-09-01 | 山东国邦药业有限公司 | Cyclization agent N- (methoxycarbonyl) iminomethyl carbonate and method for synthesizing fenbendazole by using same |
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