CN106397334A - Preparation method of fenbendazole which is benzimidazole anti-helminthic drug - Google Patents
Preparation method of fenbendazole which is benzimidazole anti-helminthic drug Download PDFInfo
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- CN106397334A CN106397334A CN201610770412.2A CN201610770412A CN106397334A CN 106397334 A CN106397334 A CN 106397334A CN 201610770412 A CN201610770412 A CN 201610770412A CN 106397334 A CN106397334 A CN 106397334A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
- C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
Abstract
The invention discloses a preparation method of fenbendazole which is a benzimidazole anti-helminthic drug. Fenbendazole is obtained by taking p-dichlorobenzene as a raw material through nitration, amination, condensation, reduction and ring-closure, and the final product content is 98-101%. The preparation method is simple and efficient, is safe to operate, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of novel preparation method of benzimidazole anthelmintic is and in particular to anti parasitic bulk drug benzene sulphur
The novel preparation method of imidazoles.
2nd, background technology
Fenbendazole, also known as Fenbendazole, chemical entitled 5- thiophenyl benzimidazolyl-2 radicals-methyl carbamate, is a kind of for animals
Broad-spectrum high efficacy anti-parasite medicine.Fenbendazole is used to kill animal gastrointestinal tract parasite, and it is not only to animal intestines and stomach
Road roundworm, hookworm, whipworm, part tapeworm and strongylid have height anthelmintic activity, and parasitic to part bronchial tree and lung
Worm（Cat lung worm and lung fluke）Also there is preferably curative effect.Fenbendazole has expelling parasite spectrum extensively, and toxicity is low, better tolerance, safe model
Enclose the advantages of width, good palatability.
Fenbendazole is initially and the seventies is by Hoechst Developed.The synthetic route of report can both at home and abroad at present
It is summarized as several classes as follows：
Route 1：
Route 2：
Route 3：
Above 3 kinds of routes are primarily present the deficiencies such as relatively costly, portion link is not easy to operate and impact of to environment is larger.
Content of the invention
It is an object of the invention to provide preparing a new process route of fenbendazole, it is desirable to provide one kind reduces into
This, be allowed to operate succinct safe, be even more acceptable industrial metaplasia and produce.
The technology contents of the present invention are：A kind of preparation method of fenbendazole, the present invention, with paracide as raw material, passes through
Nitrification, amination, condensation, reduction, closed loop obtain fenbendazole.
Comprise the following steps that：
(1) the preparation of 2- nitro -1,4- dichloro-benzenes：With paracide as raw material, in the presence of the concentrated sulfuric acid, plus nitron nitre
Change to obtain 2- nitro -1,4- dichloro-benzenes.Nitrating agent is nitric acid, and consumption is 1.02 ~ 1.06 times of the mole of paracide, preferably
1.04 again；Nitrification temperature is 0～30 DEG C, preferably 20～25 DEG C；Nitrification holding temperature is 30～60 DEG C, preferably 35～40 DEG C.
(2) the preparation of 2- nitro -4- chloroaniline：2- nitro -1,4- dichloro-benzenes obtains 2- nitre through aminating reaction in organic solvent
Base -4- chloroaniline.Reaction temperature is 78～150 DEG C, preferably 110～115 DEG C；Reaction pressure 0～4.0Mpa, preferably 1.5～
1.7Mpa.Organic solvent is selected from methyl alcohol, ethanol, propyl alcohol, isopropanol or dimethylbenzene, preferably ethanol, solvent load be 2- nitro-
2～5 times of weight ratios of Isosorbide-5-Nitrae-dichloro-benzenes, preferably 2.2 times；The mole of ammoniacal liquor is 2～8 times of 2- nitro-Isosorbide-5-Nitrae-dichloro-benzenes, excellent
Elect 3～4 times as；Amination reagent is selected from liquefied ammonia, ammoniacal liquor, preferably ammoniacal liquor.
(3) the preparation of 4- thiophenyl -2- nitroaniline：2- nitro -4- chloroaniline in the basic conditions, with benzenethiol, is condensed
Obtain 4- thiophenyl -2- nitroaniline.The consumption of benzenethiol is 1～3 times of the mole of 2- base -4- chloroaniline, preferably 1.2 times；
The consumption of solvent is 2～5 times of 2- base -4- chloroaniline weight ratio, preferably 3 times；The consumption of alkali is 2- base -4- chloroaniline mol ratio
1.2～3 times, preferably 1.5 times；The organic solvents such as solvent selected from methanol, ethanol, isopropanol, preferred alcohol；Alkali is selected from hydroxide
The inorganic bases such as sodium, potassium hydroxide, sodium carbonate, potassium carbonate, preferably NaOH or potassium hydroxide.
(4) the preparation of 4- thiophenyl o-phenylenediamine：4- thiophenyl -2- nitroaniline is reduced under catalyst action, generates
4- thiophenyl o-phenylenediamine.Solvent load is the weight ratio of 2～5 times of 4- thiophenyl -2- nitroaniline, preferably 3 times；Go back original reagent
Consumption is the mol ratio of 1.2～3 times of 4- thiophenyl -2- nitroaniline, preferably 2 times；Solvent selected from methanol, ethanol, isopropanol
Deng preferably methyl alcohol；Go back original reagent is selected from following reagent：The akali sulphide such as vulcanized sodium, potassium sulfide, NaHS, potassium bisulfide, iron powder
And hydrazine hydrate etc., preferably hydrazine hydrate.
(5) the preparation of fenbendazole：Closed loop obtains fenbendazole to 4- thiophenyl o-phenylenediamine in acid condition.The consumption of acid
For 0.8～1.5 times of weight ratio of 4- thiophenyl -2- nitroaniline, preferably 0.9；Solvent load is 4- thiophenyl -2- nitroaniline
3～5 times of weight ratios, preferably 3 times；Cyclization reagent consumption is 1.1～2 times of moles of 4- thiophenyl -2- nitroaniline, preferably
1.3 again；Reaction temperature is 40 DEG C～80 DEG C, preferably 75 DEG C；1～5 hour reaction time, preferably 3 hours；The recrystallization time 0.5
～5 hours, preferably 1 hour.Acids acids is selected from the organic acid such as ethanedioic acid, acetic acid, formic acid, tartaric acid, preferably formic acid；Reaction
Solvent is selected from the organic solvent such as chloroform, dichloromethane, toluene, preferably toluene；Recrystallization solvent is selected from methyl alcohol, ethanol, different
The alcohols such as propyl alcohol, preferably methyl alcohol；Cyclization reagent is selected from S- methyl isothiourea methyl formate, O- methyl-isourea methyl formate, cyanamide
Base methyl formate etc., preferably S- methyl isothiourea methyl formate；.
The reaction equation of above-mentioned concrete making fenbendazole step is as follows：
1st, nitrify：
2nd, amination：
3rd, it is condensed：
4th, reduce：
5th, closed loop：
It is an advantage of the current invention that：This method with paracide as initiation material, through nitrification, amination, condensation, reduction, closed loop
Obtain fenbendazole（Final products content 98% ~ 101%）, this new technique for synthesizing is succinctly efficient, safe operation, is suitable for industry metaplasia
Produce.
Specific embodiment
Following typical reaction is used for illustrating the present invention, and it is simple that technical staff in the art is done to the present invention
Replace or improve etc. and belong within the technical scheme that the present invention is protected.
Embodiment 1
Step 1：The preparation of 2- nitro -1,4- dichloro-benzenes
In 500 milliliters of four-hole boiling flasks carrying thermometer and agitating device, open stirring, sequentially add 120.0g to dichloro
Benzene, than the concentrated sulfuric acid, dropping mole is 1.04 times of nitric acid of dichloro-benzenes to 0.8 times of weight, controls dropping temperature at 20～25 DEG C, dropping
Finish, in 35～40 DEG C of insulation reaction 1 hour, GC followed the tracks of reaction completely, point sub-cloud spent acid layer；Add paracide weight ratio
1 times purifies washing, branch vibration layer；It is neutralized to neutrality with liquid caustic soda again, cast out water layer.Obtain 2- nitro-Isosorbide-5-Nitrae-dichloro-benzenes 153.1g, directly
Connect for next step reaction.This step yield is 97.7%.
Step 2：The preparation of 2- nitro -4- chloroaniline
153.1g2- nitro-Isosorbide-5-Nitrae-dichloro-benzenes that previous step obtains, 2.2 times of 2- nitre are sequentially added in 1000 milliliters of autoclave
The ethanol of base-Isosorbide-5-Nitrae-dichloro-benzenes weight ratio, the ammoniacal liquor of 2- nitro -3～4 times of moles of Isosorbide-5-Nitrae-dichloro-benzenes, temperature control 110～
115 DEG C, reaction pressure, in 1.5～1.7Mpa, is reacted 24 hours；Carry four mouthfuls of burnings of thermometer and agitating device at 2000 milliliters
The purified water of 2 times of 2- nitro -4- chloroaniline weight ratios is added, the feed liquid that reaction is finished adds 2000 milliliters of four mouthfuls of burnings in bottle
In bottle, finish cooling, centrifugation, washing, dry, obtain 2- nitro -4- chloroaniline dry product 130.1g.Yield is 94.5%.
Step 3：The preparation of 4- thiophenyl -2- nitroaniline
In 1000 milliliters of four-hole boiling flasks carrying thermometer and agitating device, open stirring, sequentially add 130.1g 2- nitre
Base -4- chloroaniline, the benzenethiol that 1.2 times of mole, the methyl alcohol of 3 times of 2- nitro -4- chloroaniline weight ratios, 1.5 times of 2- bases of addition -
The potassium hydroxide aqueous solution of the content 40% of 4- chloroaniline mol ratio；Finish back flow reaction 4 hours, reaction finishes and is cooled to 20 DEG C
Insulation 1 hour, is centrifuged, washs, drying and to obtain 4- thiophenyl -2- nitroaniline dry product 158.6g, and yield is 85.4%.
Step 4：The preparation of 4- thiophenyl o-phenylenediamine
In 1000 milliliters of four-hole boiling flasks carrying thermometer and agitating device, sequentially add weight ratio for 4- thiophenyl -2- nitre
The methyl alcohol that 3 times of base aniline, 90.0g4- thiophenyl -2- nitroaniline, weight is than for 0.05 times of 4- thiophenyl -2- nitroaniline
Raney's nickel, opens stirring, and dropping mol ratio is the hydrazine hydrate of 2 times of 4- thiophenyl -2- nitroaniline, drips complete back flow reaction 6 hours,
Filter catalyst Raney's nickel, decompression boils off methyl alcohol, obtains 4- thiophenyl o-phenylenediamine 74.9g, be directly used in next step reaction, yield
For 94.8%.
Step 5：The preparation of fenbendazole
By the 4- obtaining thiophenyl o-phenylenediamine toluene and water extraction, cast out aqueous phase, organic be added to 1000 milliliters carry temperature
In the four-hole boiling flask of degree meter and agitating device, open stirring, add weight than the acetic acid for 0.9 times of 4- thiophenyl o-phenylenediamine,
Add the cyanamide base methyl formate that mol ratio is 1.3 times of 4- thiophenyl o-phenylenediamine, 75 DEG C are reacted 3 hours, boil off toluene, add
The methyl alcohol of 3 times of 4- thiophenyl o-phenylenediamine weight ratios, flows back 1 hour, is cooled to normal temperature, centrifugation, and 86.1g is dried to obtain in washing, receives
Rate is 83.1%, content 99.6%.
Embodiment 2.
Step 1：The preparation of 2- nitro -1,4- dichloro-benzenes
In 500 milliliters of four-hole boiling flasks carrying thermometer and agitating device, open stirring, sequentially add 120.0g to dichloro
Benzene, than the concentrated sulfuric acid, dropping mole is 1.04 times of nitric acid of dichloro-benzenes to 0.8 times of weight, controls dropping temperature at 20～25 DEG C, dropping
Finish, in 35～40 DEG C of insulation reaction 1 hour, GC followed the tracks of reaction completely, point sub-cloud spent acid layer；Add paracide weight ratio
1 times purifies washing, branch vibration layer；It is neutralized to neutrality with liquid caustic soda again, cast out water layer.Obtain 2- nitro-Isosorbide-5-Nitrae-dichloro-benzenes 153.4g, directly
Connect for next step reaction.This step yield is 97.9%.
Step 2：The preparation of 2- nitro -4- chloroaniline
153.4g2- nitro-Isosorbide-5-Nitrae-dichloro-benzenes that previous step obtains, 2.2 times of 2- nitre are sequentially added in 1000 milliliters of autoclave
The dimethylbenzene of base-Isosorbide-5-Nitrae-dichloro-benzenes weight ratio, the ammoniacal liquor of 2- nitro -3～4 times of moles of Isosorbide-5-Nitrae-dichloro-benzenes, temperature control is 110
～115 DEG C, reaction pressure, in 1.5～1.7Mpa, is reacted 24 hours；Carry four mouthfuls of thermometer and agitating device at 2000 milliliters
The purified water of 2 times of 2- nitro -4- chloroaniline weight ratios is added, the feed liquid that reaction is finished adds four mouthfuls of 2000 milliliters in flask
In flask, finish cooling, centrifugation, washing, dry, obtain 2- nitro -4- chloroaniline dry product 130.5g.Yield is 94.6%.
Step 3：The preparation of 4- thiophenyl -2- nitroaniline
In 1000 milliliters of four-hole boiling flasks carrying thermometer and agitating device, open stirring, sequentially add 130.5g 2- nitre
Base -4- chloroaniline, the benzenethiol that 1.2 times of mole, the ethanol of 3 times of 2- nitro -4- chloroaniline weight ratios, 1.5 times of 2- bases of addition -
The sodium hydrate aqueous solution of the content 40% of 4- chloroaniline mol ratio；Finish back flow reaction 4 hours, reaction finishes and is cooled to 20 DEG C
Insulation 1 hour, is centrifuged, washs, drying and to obtain 4- thiophenyl -2- nitroaniline dry product 159.4g, and yield is 85.6%.
Step 4：The preparation of 4- thiophenyl o-phenylenediamine
In 1000 milliliters of four-hole boiling flasks carrying thermometer and agitating device, sequentially add weight ratio for 4- thiophenyl -2- nitre
The methyl alcohol that 3 times of base aniline, 90.0g4- thiophenyl -2- nitroaniline, weight is than for 0.05 times of 4- thiophenyl -2- nitroaniline
Raney's nickel, opens stirring, and dropping mol ratio is the hydrazine hydrate of 2 times of 4- thiophenyl -2- nitroaniline, drips complete back flow reaction 6 hours,
Filter catalyst Raney's nickel, decompression boils off methyl alcohol, obtains 4- thiophenyl o-phenylenediamine 75.2g, be directly used in next step reaction, yield
For 95.2%.
Step 5：The preparation of fenbendazole
By the 4- obtaining thiophenyl o-phenylenediamine toluene and water extraction, cast out aqueous phase, organic be added to 1000 milliliters carry temperature
In the four-hole boiling flask of degree meter and agitating device, open stirring, add weight than the acetic acid for 0.9 times of 4- thiophenyl o-phenylenediamine,
Add the cyanamide base methyl formate that mol ratio is 1.3 times of 4- thiophenyl o-phenylenediamine, 75 DEG C are reacted 3 hours, boil off toluene, add
The methyl alcohol of 3 times of 4- thiophenyl o-phenylenediamine weight ratios, flows back 1 hour, is cooled to normal temperature, centrifugation, and 86.7g is dried to obtain in washing, receives
Rate is 83.3%, content 99.8%
Embodiment 3.
Step 1：The preparation of 2- nitro -1,4- dichloro-benzenes
In 1000 milliliters of four-hole boiling flasks carrying thermometer and agitating device, open stirring, sequentially add 240.0g to dichloro
Benzene, 0.8 times of weight, than the concentrated sulfuric acid, drips the nitric acid that mole is 1.04 times of paracide, controls dropping temperature at 20～25 DEG C,
Completion of dropping, in 35～40 DEG C of insulation reaction 1 hour, GC followed the tracks of reaction completely, point sub-cloud spent acid layer；Add paracide weight
Amount purifies washing, branch vibration layer than 1 times；It is neutralized to neutrality with liquid caustic soda again, cast out water layer.Obtain 2- nitro -1,4- dichloro-benzenes
307.2g, is directly used in next step reaction.This step yield is 98.0%.
Step 2：The preparation of 2- nitro -4- chloroaniline
307.2g2- nitro-Isosorbide-5-Nitrae-dichloro-benzenes that previous step obtains, 2.2 times of 2- nitre are sequentially added in 2000 milliliters of autoclave
The ethanol of base-Isosorbide-5-Nitrae-dichloro-benzenes weight ratio, the ammoniacal liquor of 2- nitro -3～4 times of moles of Isosorbide-5-Nitrae-dichloro-benzenes, temperature control 110～
115 DEG C, reaction pressure, in 1.5～1.7Mpa, is reacted 24 hours；Carry four mouthfuls of burnings of thermometer and agitating device at 4000 milliliters
The purified water of 2 times of 2- nitro -4- chloroaniline weight ratios is added, the feed liquid that reaction is finished adds 4000 milliliters of four mouthfuls of burnings in bottle
In bottle, finish cooling, centrifugation, washing, dry, obtain 2- nitro -4- chloroaniline dry product 262.9g.Yield is 95.2%.
Step 3：The preparation of 4- thiophenyl -2- nitroaniline
In 1000 milliliters of four-hole boiling flasks carrying thermometer and agitating device, open stirring, sequentially add 156.7g 2- nitre
Base -4- chloroaniline, the benzenethiol that 1.2 times of mole, the ethanol of 3 times of 2- nitro -4- chloroaniline weight ratios, 1.5 times of 2- bases of addition -
The sodium hydrate aqueous solution of the content 40% of 4- chloroaniline mol ratio；Finish back flow reaction 4 hours, reaction finishes and is cooled to 20 DEG C
Insulation 1 hour, is centrifuged, washs, drying and to obtain 4- thiophenyl -2- nitroaniline dry product 190.3g, and yield is 85.1%.
Step 4：The preparation of 4- thiophenyl o-phenylenediamine
In 1000 milliliters of four-hole boiling flasks carrying thermometer and agitating device, sequentially add weight ratio for 4- thiophenyl -2- nitre
The methyl alcohol that 3 times of base aniline, 90g4- thiophenyl -2- nitroaniline, weight is than the thunder for 0.05 times of 4- thiophenyl -2- nitroaniline
Buddhist nun's nickel, opens stirring, and dropping mol ratio is the hydrazine hydrate of 2 times of 4- thiophenyl -2- nitroaniline, drips complete back flow reaction 6 hours, filter
Fall catalyst Raney's nickel, decompression boils off methyl alcohol, obtains 4- thiophenyl o-phenylenediamine 75.3g, be directly used in next step reaction, yield is
95.3%.
Step 5：The preparation of fenbendazole
By the 4- obtaining thiophenyl o-phenylenediamine toluene and water extraction, organic be added to 1000 milliliters carry thermometer and stirring
In the four-hole boiling flask of device, add weight than the formic acid for 0.9 times of 4- thiophenyl o-phenylenediamine, additions mol ratio is 4- thiophenyl
The S- methyl isothiourea methyl formate of 1.3 times of o-phenylenediamine, 75 DEG C are reacted 3 hours, boil off toluene, add 3 times of 4- thiophenyls adjacent
The methyl alcohol of phenylenediamine weight ratio, flows back 1 hour, is cooled to normal temperature, centrifugation, and 87.5g is dried to obtain in washing, and yield is 83.7%, contains
Amount 99.8%.
Claims (10)
1. a kind of preparation method of anthelmintic benzimidazole fenbendazole, mainly with synthesis method be obtained it is characterised in that：
Step is as follows：
（1）With paracide as raw material, in the presence of the concentrated sulfuric acid, obtain 2- nitro-Isosorbide-5-Nitrae-dichloro-benzenes through nitration reaction；
2- nitro -1,4- dichloro-benzenes obtains 2- nitro -4- chloroaniline through aminating reaction；
（2）2- nitro -4- chloroaniline in the basic conditions, obtains 4- thiophenyl -2- nitroaniline with benzenethiol condensation reaction；
（3）4- thiophenyl -2- nitroaniline obtains 4- thiophenyl o-phenylenediamine through reduction reaction；
（4）4- thiophenyl o-phenylenediamine closed loop obtains fenbendazole.
2. the fenbendazole preparation method according to claim 1 is it is characterised in that reactions steps（1）In, nitrating agent
For nitric acid, its consumption is 1.02 ~ 1.06 times of the mole of paracide, and nitrification temperature is 0～30 DEG C, and nitrification holding temperature is
30～60 DEG C.
3. the preparation method of fenbendazole according to claim 2 is it is characterised in that reactions steps（1）In, nitrating agent
1.04 times of preferred dichloro-benzenes mole, nitrify preferably 20～25 DEG C of temperature, nitrify preferably 35～40 DEG C of holding temperature.
4. the preparation method of fenbendazole according to claim 1 is it is characterised in that reactions steps（2）In, amination solvent
Selected from following reagent：Methyl alcohol or ethanol or propyl alcohol or isopropanol or dimethylbenzene；Amination reagent is selected from following reagent：Liquefied ammonia or ammonia
Water；The mole of amination reagent is 2～8 times of 2- nitro-Isosorbide-5-Nitrae-dichloro-benzenes, and the consumption of solvent is 2- nitro-Isosorbide-5-Nitrae-dichloro-benzenes
2～5 times of weight ratio, reaction temperature is 78～150 DEG C, reaction pressure 0～4.0MPa.
5. the fenbendazole preparation method according to claim 4 is it is characterised in that amination solvent is preferably ethanol, amine
Change reagent and be preferably ammoniacal liquor, the mole of amination reagent is preferably 3～4 times of 2- nitro-Isosorbide-5-Nitrae-dichloro-benzenes, and the amount of solvent is preferred
2.2 times of 2- nitro -1,4- dichloro-benzenes weight ratio.
6. the preparation method of fenbendazole according to claim 1 is it is characterised in that reactions steps（3）In, benzenethiol
Consumption is 1～3 times of the mole of 2- base -4- chloroaniline, and 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 selected from ethanol, methyl alcohol, isopropanol, and n-butanol etc. has
Machine solvent, alkali is selected from NaOH or potassium hydroxide or sodium carbonate or potassium carbonate class inorganic base.
7. the preparation method of the fenbendazole told according to claim 6 is it is characterised in that reactions steps（3）In, benzenethiol
Consumption is preferably 1.2 times of the mole of 2- base -4- chloroaniline, and the consumption of solvent is preferably the 3 of 2- base -4- chloroaniline weight ratio
Times, the consumption of alkali is preferably 1.5 times of 2- nitro -4- chloroaniline mol ratio, solvent preferred alcohol, the preferred NaOH of alkali or hydrogen
Potassium oxide.
8. the preparation method of fenbendazole according to claim 1 is it is characterised in that reactions steps（4）Middle solvent load is
The weight ratio of 2～5 times of 4- thiophenyl -2- nitroaniline, go back original reagent consumption is 1.2～3 times of 4- thiophenyl -2- nitroaniline
Mol ratio, solvent selected from methanol, ethanol, isopropanol etc., go back original reagent be selected from following reagent：Vulcanized sodium, potassium sulfide, sulphur hydrogenation
The akali sulphide such as sodium, potassium bisulfide, sodium hydrosulfite, iron powder and hydrazine hydrate.
9. fenbendazole preparation method according to claim 8 is it is characterised in that reactions steps（4）The consumption of middle solvent is excellent
Elect 4- thiophenyl -2- nitroaniline as 3 times, go back original reagent consumption is preferably 2 times moles of 4- thiophenyl -2- nitroaniline
Than；The preferred methyl alcohol of solvent, the preferred hydrazine hydrate of go back original reagent.
10. the preparation method of fenbendazole according to claim 1 is it is characterised in that reactions steps（5）Middle acids acids
Selected from organic acids such as ethanedioic acid, acetic acid, formic acid, tartaric acid, reaction dissolvent has selected from chloroform, dichloromethane, toluene etc.
Machine solvent, recrystallization solvent be selected from the alcohols such as methyl alcohol, ethanol, isopropanol, cyclization reagent be selected from S- methyl isothiourea methyl formate,
O- methyl-isourea methyl formate, cyanamide base methyl formate etc., reaction temperature is 40 DEG C～150 DEG C, 1～12 hour reaction time,
0.5～5 hour recrystallization time.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108402062A (en) * | 2018-01-16 | 2018-08-17 | 陕西康禾立丰生物科技药业有限公司 | A kind of pesticide of fenbendazole |
| CN110683966A (en) * | 2019-08-11 | 2020-01-14 | 沈阳百傲化学有限公司 | Process for preparing 2-cyano-4-nitroaniline by using microchannel reaction |
| CN112209885A (en) * | 2020-09-07 | 2021-01-12 | 宁夏大漠药业有限公司 | Production process and production device 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 |
-
2016
- 2016-08-31 CN CN201610770412.2A patent/CN106397334A/en not_active Withdrawn
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108402062A (en) * | 2018-01-16 | 2018-08-17 | 陕西康禾立丰生物科技药业有限公司 | A kind of pesticide of fenbendazole |
| CN110683966A (en) * | 2019-08-11 | 2020-01-14 | 沈阳百傲化学有限公司 | Process for preparing 2-cyano-4-nitroaniline by using microchannel reaction |
| CN112209885A (en) * | 2020-09-07 | 2021-01-12 | 宁夏大漠药业有限公司 | Production process and production device 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 |
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Application publication date: 20170215 |