CN105801429B - A kind of preparation method of the chloro- 2,4 difluorobenzene amine of 3,5- bis- - Google Patents
A kind of preparation method of the chloro- 2,4 difluorobenzene amine of 3,5- bis- Download PDFInfo
- Publication number
- CN105801429B CN105801429B CN201410854696.4A CN201410854696A CN105801429B CN 105801429 B CN105801429 B CN 105801429B CN 201410854696 A CN201410854696 A CN 201410854696A CN 105801429 B CN105801429 B CN 105801429B
- Authority
- CN
- China
- Prior art keywords
- reaction
- chloro
- bis
- preparation
- difluoroaniline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The present invention relates to organic synthesis fields, more particularly to the preparation method and its usage of chloro- 2, the 4- difluoroaniline of 3,5- of one kind bis-.The present invention provides the preparation method of chloro- 2,4- difluoroaniline of 3,5- of one kind bis-, includes the following steps: 1) nitration reaction；2) reduction reaction；3) diazo-reaction；4) nitration reaction；5) fluorination reaction；6) reduction reaction.The preparation method of chloro- 2, the 4- difluoroaniline (I) of 3,5- bis- provided by the present invention has the advantages that 1) reaction condition is mild, and stably and controllable, active site is few, is not susceptible to side reaction, and whole route yield and quality are preferable；2) supplementary material is cheap and easy to get, can be effectively reduced cost, energy saving, avoids the use of chlorine, environmental-friendly.
Description
Technical field
The present invention relates to organic synthesis fields, more particularly to the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- of one kind bis-
And application thereof.
Background technique
Teflubenzuron (teflubenzuron) developed listing by Celamerck GmbH&Co. company in 1984 for the first time, was
Important a kind of high-efficient low toxicity insecticide in process for preparation of benzoylurea compounds, it is main by inhibiting the synthesis of chitin to reach killing evil
The purpose of worm.Its mechanism of action is different from other insecticides, with insecticidal activity is high, insecticidal spectrum is wide, residual quantity is low, selectivity
By force, environmental-friendly feature.Since it is more friendly to people and animals, there is high bioactivity, further develop Teflubenzuron
Preparation method has positive meaning.Teflubenzuron chemical structural formula is as follows:
3,5- bis- chloro- 2,4- difluoroanilines are the important intermediate for synthesizing Teflubenzuron, it and 2,6- difluorobenzoyl isocyanide
Acid esters addition obtains Insecticide Triflubenzuron, it is specific the preparation method is as follows:
Other than the important synthetic intermediate as Teflubenzuron, 3,5- bis- chloro- 2,4- difluoroanilines are in medicine, material etc.
Also there is preferable application in field.Patent WO02/059094 report, it is anti-that 3,5- bis- chloro- 2,4- difluoroanilines can be used as quinolones
The raw material of drug candidate is infected, patent US8853186 then reports it and is used to prepare anti-parasite medicine bioactive molecule.Wherein ammonia
Base can connect further derivatization as chemical active radical with other structures, and fluorine, chlorine can participate in building pharmacological activity
Position.
The synthetic route of chloro- 2, the 4- difluoroaniline of a variety of 3,5- bis-, such as patent are disclosed in the prior art
(CN102617360A) it reports and 3,5- bis- is obtained through chlorinated with chlorine, potassium fluoride fluorination, reduction with the chloro- 3- fluoronitrobenzene of 2,4- bis-
Chloro- 2,4 difluorobenzene amine.In the route, raw material 2, the chloro- 3- fluoronitrobenzene price of 4- bis- is not easy to obtain, and logical chlorine is anti-
It answers condition very harsh (being dissolved in polar solvent together with iodine chlorine reaction 1-20 hours logical in 100-180 DEG C), is not suitable for big
Production.
The chloro- 2,4- of 3,5- bis- is made through chlorination, hydrogenating reduction with 2,4- difluoro nitrobenzene in patent (CN1683318A) report
Difluoroaniline.In the route, 2,4- difluoro nitrobenzene cost of material are expensive, high expensive, generally passed through by 2,4- dichloronitrobenzene
Fluorination is made.In addition, logical chlorine reaction condition is harsh (to be dissolved in 120-160 DEG C of logical chlorine reaction 6-8 in polar solvent together with iodine
Hour), reaction is easily incomplete, usually rests on intermediate state, final product accounting is few, is also not suitable for mass production.
In addition, Liu Changchun report with 1,2,4- trichloro-benzenes for starting material, through nitrification, chlorination, fluorination and reduction
The chloro- 2,4 difluorobenzene amine of 3,5- bis- is synthesized.The difficult point of this route is in this step of chlorination, and steric hindrance is very big, and reaction not exclusively, leads to pair
There are many product, it is also difficult to realize the industrialization of production.
In the route of patent US5081288 report, with 1,2,3,4- tetrachlorobenzene for starting material, is nitrified, be fluorinated and go back
The obtained chloro- 2,4 difluorobenzene amine of 3,5- bis- of original.The polarization nitrified in the reaction route is good, generates without isomers, but mesh
Preceding 1,2,3,4- tetrachloro benzene raw materials in the market do not have sterling, only following several isomers compositions mixture (VII, VIII,
IX).Therefore, laboratory stage is only rested in the route.
To sum up a variety of causes, current bis- chloro- 2, the 4- difluoroaniline country 3,5- only have the production of 1-2 family, and yield is not caught up with, matter
It measures also not high.So it is extremely urgent to develop one kind fluoro- 3,5- dichloroaniline technique of cost-effective 2,4- bis-.
Summary of the invention
In view of the foregoing deficiencies of prior art, the purpose of the present invention is to provide chloro- 2, the 4- difluoros of 3,5- of one kind bis-
The preparation method of aniline, for solving the problems of the prior art.The preparation method phase of the chloro- 2,4 difluorobenzene amine of the 3,5- bis-
, safety more economical for existing synthetic route and environmental protection also reduce costs while improving yield and quality, save
Resource and the energy, the technique for being suitble to heavy industrialization.
In order to achieve the above objects and other related objects, first aspect present invention provides chloro- 2, the 4- difluoro of 3,5- of one kind bis-
The preparation method of aniline, includes the following steps:
1) with 1,2,3- trichloro-benzenes for raw material, nitration reaction prepares 2,3,4- trichloronitrobenzenes；Reaction equation is such as
Under:
2) 2,3,4- trichloronitrobenzenes are restored, prepares 2,3,4- trichloroanilines；Reaction equation is as follows:
3) 2,3,4- trichloroanilines prepare 1,2,3,4- tetrachlorobenzenes by diazo-reaction；Reaction equation is as follows:
4) 1,2,3,4- tetrachlorobenzene is nitrified, reaction obtains 2,3,4,5- tecnazenes；Reaction equation is as follows:
5) 2,3,4,5- tecnazenes are prepared into chloro- 2, the 4- difluoro nitrobenzene of 3,5- bis- by fluorination reaction；Instead
Answer equation as follows:
6) chloro- 2, the 4- difluoro nitrobenzene of 3,5- bis- is restored, that is, prepares chloro- 2, the 4- difluoroaniline of 3,5- bis-.Reaction
Equation is as follows:
Preferably, the preparation method of chloro- 2, the 4- difluoroaniline of 3, the 5- bis- specifically comprises the following steps:
1) nitration reaction: 1,2,3- trichloro-benzenes being dissolved in reaction dissolvent, then nitration mixture is added dropwise, and nitration reaction prepares 2,
3,4- trichloronitrobenzenes, the nitration mixture are the mixed liquor of nitric acid and the concentrated sulfuric acid.
It is furthermore preferred that the weight ratio of nitric acid and the concentrated sulfuric acid is 1:3-10 in mixed liquor in the step 1.
It is furthermore preferred that during nitration mixture is added dropwise, reaction temperature is 50-60 DEG C in the step 1.
It is furthermore preferred that after nitration mixture is added dropwise, keeping the temperature 30-45min at 40-60 DEG C in the step 1.
Under normal circumstances, reaction temperature is kept during being added dropwise.To the 1,2,3- trichlorine in solvent in reaction process
Benzene is monitored, and controls reaction process.
It is furthermore preferred that in the step 1, described 1, the weight ratio of 2,3- trichloro-benzenes and nitration mixture is 1:1.5-2.
It is furthermore preferred that the reaction dissolvent of nitration reaction includes but is not limited to dichloroethanes, tetrahydrofuran in the step 1
With one of 1,4- dioxane or a variety of combinations.
In a preferred embodiment, the reaction dissolvent is dichloroethanes.
It is furthermore preferred that the post-processing step in the step 1 are as follows: extract gained reaction solution using organic solvent, will have
Machine is mutually washed till alkalescent, and separation obtains organic phase and removes solvent up to step 1 product.
It is further preferred that also being recrystallized after removing solvent.In a preferred embodiment, recrystallization is made
Solvent is preferably n-hexane.
2) reduction reaction: reducing agent, salt electrolyte and water being mixed with reaction dissolvent, then are added portionwise 2,3,4- trichlorines
Nitrobenzene carries out reduction and prepares 2,3,4- trichloroaniline.
It is furthermore preferred that during 2,3,4- trichloronitrobenzene is added, reaction temperature is 40-70 DEG C in the step 2.
Be added portionwise can be it is point multiple batches of feed intake, also 2,3,4- trichloronitrobenzenes can be dissolved in appropriate reaction dissolvent
In, it is added in reaction system by way of dropwise addition.After the completion of the charging of 2,3,4- trichloronitrobenzenes, reaction system is protected
Temperature, and monitor reaction process.Preferred holding temperature is 50-70 DEG C, and soaking time is 1-4 hours.It is preferred real in the present invention one
It applies in example, the time of heat preservation is 2 hours or so.
It is furthermore preferred that in the step 2,2,3,4- trichloronitrobenzenes are with reducing agent, water, the electrolytelike weight ratio of salt
1:0.5-1.0:8-12:0.15-0.3.
It is furthermore preferred that the reducing agent is selected from iron powder or palladium charcoal in the step 2.
In a preferred embodiment, reducing agent is iron powder.
It is furthermore preferred that the salt electrolyte includes but is not limited to one of ammonium chloride, ammonium sulfate in the step 2
Or a variety of combination.
In a preferred embodiment, salt electrolyte is ammonium chloride.
It is furthermore preferred that the reaction dissolvent of reduction reaction includes but is not limited to dichloroethanes, toluene, first in the step 2
One of alcohol, ethyl alcohol or a variety of combinations.
In a preferred embodiment, the reaction dissolvent is dichloroethanes.
It is furthermore preferred that the post-processing step in the step 2 are as follows: filtering by filtrate water extracting and washing, is layered and merges
Organic phase removes solvent up to step 2 product.
3) diazo-reaction: 2,3,4- trichloroanilines, inorganic acid, ammonium chloride are dissolved in reaction dissolvent, Asia is added portionwise
Nitrate carries out diazotising；Gained reaction solution is added dropwise in the mixed liquor of concentrated hydrochloric acid and stannous chloride, it is anti-by sandmeyer
1,2,3,4- tetrachlorobenzene should be prepared.
It is furthermore preferred that the nitrite is selected from one of sodium nitrite, potassium nitrite or a variety of in the step 3
Selection.Be added portionwise can be it is point multiple batches of feed intake, nitrite can be also dissolved in appropriate solvent, pass through dropwise addition
Mode is added in reaction system.The process that feeds intake of nitrite need to generally be completed at low temperature.In one embodiment of the present invention
In, the nitrite is sodium nitrite or potassium nitrite, and the solvent is water, temperature model during nitrous acid aqueous solution is added dropwise
System is contained at -5-5 DEG C.
In a preferred embodiment, nitrite is sodium nitrite.
It is furthermore preferred that the inorganic acid includes but is not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, crosses chlorine in the step 3
One of acid and fluoboric acid or a variety of combinations.
In a preferred embodiment, salt used in the mixed liquor of the inorganic acid, hydrochloric acid and stannous chloride
Acid is 36~38% concentrated hydrochloric acid.
It is furthermore preferred that in the step 3, -5-5 DEG C of heat preservation 1-2h after nitrite is added.
It is furthermore preferred that in the step 3, in the mixed liquor that gained reaction solution is added dropwise to hydrochloric acid and stannous chloride
Dropping temperature is 40-60 DEG C, and 70-90 DEG C is warming up to after being added dropwise to complete, and keeps the temperature 1-2h.
It is furthermore preferred that 2,3,4- trichloroanilines, inorganic acid, ammonium chloride are dissolved in reaction dissolvent in the step 3, point
Batch be added nitrite carry out it is diazotizing during, the weight of 2,3,4- trichloroanilines, inorganic acid, ammonium chloride, sodium nitrite
Than for 1:2-3:0.2-0.4:0.4-0.6.
It is furthermore preferred that gained reaction solution being added dropwise in the mixed liquor of hydrochloric acid and stannous chloride, being passed through in the step 3
During sandmeyer reaction prepares 1,2,3,4- tetrachlorobenzenes, the weight of 2,3,4- trichloroanilines, hydrochloric acid, stannous chloride
Than for 1:5-7:0.6-1.
It is furthermore preferred that the post-processing step in the step 3 are as follows: extract gained reaction solution using organic solvent, separate
It obtains organic phase and removes organic solvent up to step 3 product.
4) nitration reaction: 1,2,3,4- tetrachlorobenzene is dissolved in reaction dissolvent, then nitration mixture is added dropwise, nitration reaction prepares
2,3,4,5- tecnazenes, the nitration mixture are the mixed liquor of nitric acid and the concentrated sulfuric acid.
It is furthermore preferred that the weight ratio of nitric acid and the concentrated sulfuric acid is 1:3-4 in mixed liquor in the step 4.
It is furthermore preferred that during nitration mixture is added dropwise, reaction temperature is 40-50 DEG C in the step 4.
It is furthermore preferred that after nitration mixture is added dropwise, keeping the temperature 8-12 hours at 40-60 DEG C in the step 4.
Under normal circumstances, reaction temperature is kept during being added dropwise.To the 1,2,3,4- tetra- in solvent in reaction process
Chlorobenzene is monitored, and controls reaction process.
It is furthermore preferred that in the step 4, described 1, the weight ratio of 2,3,4- tetrachlorobenzenes and nitration mixture is 1:1.5-2.
It is furthermore preferred that the reaction dissolvent of nitration reaction includes but is not limited to dichloroethanes, tetrahydrofuran in the step 4
With one of 1,4- dioxane or a variety of combinations.
It is furthermore preferred that the post-processing step in the step 4 are as follows: extract gained reaction solution using organic solvent, will have
Machine is mutually washed till alkalescent, and separation obtains organic phase and removes solvent up to step 4 product.
5) fluorination reaction: 2,3,4,5- tecnazene, fluorization agent and phase transfer catalyst are carried out in reaction dissolvent
Fluorination reaction prepares the chloro- 2,4- difluoro nitrobenzene of 3,5- bis-.
It is furthermore preferred that fluorization agent is selected from one of potassium fluoride, sodium fluoride and ammonium fluoride or a variety of in the step 5
Combination.
In a preferred embodiment, the fluorization agent is potassium fluoride.
It is furthermore preferred that in the step 5, phase transfer catalyst be selected from tetrabutylammonium bromide, trimethylphenyl ammonium chloride and
One of hexadecyl tributyl phosphonium phosphine or a variety of combinations.
It is furthermore preferred that in the step 5,2,3,4,5- tecnazenes, fluorization agent, phase transfer catalyst weight ratio be
1:0.58-0.8:0.09-0.15 reaction condition is to react 12-20h at 120-150 DEG C.
It is furthermore preferred that the reaction dissolvent of fluorination reaction includes but is not limited in sulfolane, DMSO and DMF in the step 5
One or more combinations.
In a preferred embodiment, the reaction dissolvent is sulfolane.
It is furthermore preferred that the post-processing step in the step 5 are as follows: it is added toluene in gained reaction solution, cooled and filtered,
Solid phase is washed with toluene, and washing lotion merges with filtrate, removes solvent up to step 5 product.
6) reduction reaction: reducing agent, salt electrolyte and water are mixed with reaction dissolvent, then are added portionwise 3,5- bis- is chloro-
2,4- difluoro nitrobenzenes are restored, that is, prepare chloro- 2, the 4- difluoroaniline of 3,5- bis-.
It is furthermore preferred that 3,5- bis- chloro- 2,4- difluoro nitrobenzenes and reducing agent, water, salt are electrolytelike in the step 6
Weight ratio is 1:0.5-1.0:8-12:0.15-0.3, and reaction temperature is 70-100 DEG C.
It is furthermore preferred that the reducing agent is selected from iron powder or palladium charcoal in the step 6.
In a preferred embodiment, reducing agent is iron powder.
It is furthermore preferred that the salt electrolyte includes but is not limited to one of ammonium chloride, ammonium sulfate in the step 6
Or a variety of combination.
In a preferred embodiment, salt electrolyte is ammonium chloride.
It is furthermore preferred that the reaction dissolvent of reduction reaction includes but is not limited to dichloroethanes, tetrahydrofuran in the step 6
With one of 1,4- dioxane or a variety of combinations.
In a preferred embodiment, the reaction dissolvent is dichloroethanes.
It is furthermore preferred that reaction temperature is 70-90 DEG C during chloro- 2, the 4- difluoro nitrobenzene of 3,5- bis- is added.
Be added portionwise can be it is point multiple batches of feed intake, chloro- 2, the 4- difluoro nitrobenzene of 3,5- bis- can be also dissolved in right amount
In reaction dissolvent, it is added in reaction system by way of dropwise addition.It is right after the completion of 3,5- bis- chloro- 2,4- difluoro nitrobenzene chargings
Reaction system is kept the temperature, and monitors reaction process.Preferred holding temperature is 80-100 DEG C, and soaking time is 2-5 hours.?
In one embodiment of the present invention, the time of heat preservation is 2 hours or so.
It is furthermore preferred that the post-processing step in the step 6 are as follows: filtering, by filtrate water extracting and washing, layering is associated with
Machine phase, solvent evaporated is up to step 6 product.
As described above, the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- bis- provided by the present invention be extremely easy to industrial production,
Cost is relatively low, the route of safety and environmental protection.The preparation method is that starting is former with cheap chemical products 1,2,3- trichloro-benzenes
Material, through nitrification, reduction, diazotising chlorination three-step reaction be made high-purity 1,2,3,4- tetrachlorobenzenes, then again it is perfluorinated and also
The obtained chloro- 2,4 difluorobenzene amine of 3,5- bis- of original.Each step reaction is all popular response, and yield is very high；And it gets around on chlorine
The reaction of chlorine, uses chlorine in diazotising instead, and reaction condition as mild as a dove, is suitble to large-scale production.
Second aspect of the present invention provides the preparation method of the chloro- 2,4 difluorobenzene amine of the 3,5- bis- in Teflubenzuron, quinolone
The purposes of the preparation fields such as class candidates against infection, anti-parasite medicine bioactive molecule.
The purposes refers specifically to
Intermediate, synthesis Teflubenzuron, quinolones candidates against infection, anti-parasite medicine bioactive molecule etc..
The preparation method of the chloro- 2,4 difluorobenzene amine (I) of 3,5- bis- provided by the present invention has the advantages that
1) reaction condition is mild, stably and controllable, and active site is few, is not susceptible to side reaction, whole route yield and quality
Preferably
2) supplementary material is cheap and easy to get, can be effectively reduced cost, energy saving, avoids the use of chlorine, environment friend
It is good.
Specific embodiment
Illustrate embodiments of the present invention below by way of specific specific example, those skilled in the art can be by this specification
Other advantages and efficacy of the present invention can be easily understood for disclosed content.The present invention can also pass through in addition different specific realities
The mode of applying is embodied or practiced, the various details in this specification can also based on different viewpoints and application, without departing from
Various modifications or alterations are carried out under spirit of the invention.
It should be clear that in the following example not specifically dated process equipment or device be all made of conventional equipment in the art or
Device；All pressure values and range all refer to absolute pressure.
In addition, it should also be understood that, one or more method and step mentioned in the present invention does not repel before and after the combination step
It can also be inserted into other methods step there may also be other methods step or between these explicitly mentioned steps, unless separately
It is described；It should also be understood that the combination connection relationship between one or more equipment/device mentioned in the present invention is not repelled
The two equipment/devices specifically mentioned before and after the unit equipment/device there may also be other equipment/device or at these it
Between can also be inserted into other equipment/device, unless otherwise indicated.Moreover, unless otherwise indicated, the number of various method steps is only
Identify the convenient tool of various method steps, rather than for the arrangement order of limitation various method steps or limits the enforceable model of the present invention
It encloses, relativeness is altered or modified, and without material changes in technical content, when being also considered as, the present invention is enforceable
Scope.
Embodiment 1:
The preparation (II) of intermediate 2,3,4- trichloronitrobenzene
The preparation of nitration mixture: putting into 80g nitric acid in the there-necked flask of 500ml, cools to 0 DEG C or so, instills the 240g concentrated sulfuric acid,
It controls temperature and is no more than 10 DEG C.
1,2,3- trichloro-benzenes (1.10mol) of 200g, 200g dichloroethanes, control temperature are added in the four-hole bottle of 1000ml
Degree is in 50-60 DEG C of dropwise addition nitration mixture, and time for adding 2h, after heat preservation 30 minutes, sampling GC analysis: 1,2,3- trichloro-benzenes is less than 1%.
Layering: organic layer is separated, and twice with dichloroethanes extraction acid layer.Merge organic layer, washes pH=7- with saturated sodium bicarbonate
8, anhydrous sodium sulfate dries, filters, and 700g n-hexane is added after being evaporated recycling dichloroethanes, and heat up dissolved clarification, then cools to 15
DEG C or so, suction filtration dries to obtain 216g finished product, GC analysis 99.4%, yield 86%.1H-NMR(400MHz,CDCl3) δ ppm:7.55
(d, 1H, J=8.8Hz), 7.71 (d, 1H, J=8.8Hz).
Embodiment 2:
The preparation of intermediate 2,3,4- trichloroaniline (III):
Investment 8g iron powder (0.14mol), 80g dichloroethanes, 100g water and 2g ammonium chloride in the four-hole bottle of 500ml.?
2,3,4- trichloronitrobenzene 11.5g (0.051mol) and 20g dichloroethane solution are added dropwise in the case of reflux, is kept the temperature after being added dropwise to complete
2 hours, GC analysis, reaction was basically completed.Filtrate water extracting and washing is layered and is merged organic phase by filtering, after solvent evaporated
Obtain 8.2g finished product, yield 83%.1H-NMR (400MHz, MeOD) δ ppm:7.28 (d, 1H, J=8Hz), 7.55 (d, 1H, J=
8Hz)。
Embodiment 3:
The preparation of intermediate 1,2,3,4- tetrachlorobenzene (IV):
2,3,4- trichloroaniline 10g (0.051mol), concentrated hydrochloric acid 21g are put into the four-hole bottle of 500ml.Control temperature
The aqueous solution of 4g sodium nitrite is added dropwise in -5-5 DEG C of ranges, is added dropwise to complete, heat preservation 1 hour spare.
50g concentrated hydrochloric acid is put into the four-hole bottle of an other 1000ml, 6g stannous chloride is added dropwise at 50 DEG C or so
The nitrosation solution of front is warming up to 80 DEG C after adding, keep the temperature 1 hour, be then cooled to 30 DEG C, with dichloroethanes extraction point
Layer is evaporated to obtain 1,2,3,4- 98% or more tetrachlorobenzene 9g, GC analyses, yield 82%.1H-NMR (400MHz, MeOD) δ ppm:
7.90(s,2H)。
Embodiment 4:
The preparation of intermediate 2,3,4,5- tecnazene (V):
The preparation of nitration mixture: putting into 5.1g nitric acid in the there-necked flask of 500ml, cools to 0 DEG C or so, instills the dense sulphur of 15.4g
Acid, control temperature are no more than 10 DEG C.
1,2,3,4- tetrachlorobenzene 14g (0.065mol), the dichloroethanes of 80g, control temperature are put into the four-hole bottle of 500ml
The mixed acid solution for being added dropwise and preparing at 40-50 DEG C is spent, the reaction time 10 hours, GC detection reaction was completed.Layering, uses dichloroethanes
It extracting acid layer twice, merges organic layer, sodium bicarbonate washing, anhydrous sodium sulfate dries, filters, and concentration of organic layers obtains 2,3,4,
5- tecnazene 16.5g, yield 97%.1H-NMR (400MHz, MeOD) δ ppm:8.25 (s, 1H).
Embodiment 5:
The preparation of the chloro- 2,4- difluoro nitrobenzene (VI) of intermediate 3,5- bis-:
2,3,4,5- tecnazene 13g (0.05mol), anhydrous potassium fluoride 7.55g (0.13mol), tetrabutylammonium bromide
In 135 DEG C of reaction 16h in 30g sulfolane, cooling reaction solution is added 100ml toluene to 115 DEG C, mixes, continue to cool down 1.2g
To 10 DEG C, sulfolane, potassium fluoride and solid potassium chloride are precipitated, filtering, and are washed twice with 0 DEG C of toluene 50ml.It is molten that toluene is concentrated
Liquid is evaporated to obtain chloro- 2, the 4- difluoro nitrobenzene 10.4g of 3,5- bis-, yield 91%.1H-NMR (400MHz, MeOD) δ ppm:8.36
(t, J=8Hz, 1H).
Embodiment 6:
The preparation of the chloro- 2,4 difluorobenzene amine (I) of 3,5- bis-:
Investment 8g iron powder (0.14mol), 80g dichloroethanes, 100g water and 2g ammonium chloride in the four-hole bottle of 500ml.?
Chloro- 2, the 4- difluoro nitrobenzene 11.4g (0.05mol) of 3,5- bis- and 20g dichloroethane solution are added dropwise in the case of reflux, is added dropwise to complete
2 hours are kept the temperature afterwards, GC analysis, reaction is basically completed.Filtering, by filtrate water extracting and washing, is layered and merges organic phase, be evaporated
9.5g, yield 96% are obtained after solvent, GC purity is 96%.1H-NMR (400MHz, MeOD) δ ppm:6.87 (m, 1H).
In conclusion the present invention effectively overcomes various shortcoming in the prior art and has high industrial utilization value.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (13)
1. one kind 3, the preparation method of chloro- 2, the 4- difluoroaniline of 5- bis-, include the following steps:
1) nitration reaction: with 1,2,3- trichloro-benzenes for raw material, nitration reaction prepares 2,3,4- trichloronitrobenzenes；Reactional equation
Formula is as follows:
2) reduction reaction: 2,3,4- trichloronitrobenzenes are restored, 2,3,4- trichloroanilines are prepared；Reaction equation is as follows:
3) diazo-reaction: 2,3,4- trichloroanilines prepare 1,2,3,4- tetrachlorobenzenes by diazo-reaction；Reactional equation
Formula is as follows:
4) nitration reaction: 1,2,3,4- tetrachlorobenzene is nitrified, and reaction obtains 2,3,4,5- tecnazenes；Reaction equation is such as
Under:
5) fluorination reaction: by 2,3,4,5- tecnazenes by fluorination reaction, chloro- 2, the 4- difluoro nitro of 3,5- bis- is prepared
Benzene；Reaction equation is as follows:
6) reduction reaction: chloro- 2, the 4- difluoro nitrobenzene of 3,5- bis- is restored, that is, prepares chloro- 2, the 4- difluoroaniline of 3,5- bis-；
Reaction equation is as follows:
2. the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- bis- as described in claim 1, which is characterized in that specifically include as
Lower step:
1) nitration reaction: 1,2,3- trichloro-benzenes is dissolved in reaction dissolvent, then nitration mixture is added dropwise, nitration reaction prepares 2,3,4-
Trichloronitrobenzene, the nitration mixture are the mixed liquor of nitric acid and the concentrated sulfuric acid；
2) reduction reaction: reducing agent, salt electrolyte and water being mixed with reaction dissolvent, then are added portionwise 2,3,4- trichlorine nitros
Benzene carries out reduction and prepares 2,3,4- trichloroaniline；
3) diazo-reaction: 2,3,4- trichloroanilines, inorganic acid are dissolved in reaction dissolvent, and nitrite is added portionwise and carries out weight
Nitridation；Gained reaction solution is added dropwise in the mixed liquor of hydrochloric acid and stannous chloride, prepares 1,2 by sandmeyer reaction,
3,4- tetrachlorobenzene；
4) nitration reaction: 1,2,3,4- tetrachlorobenzene being dissolved in reaction dissolvent, then nitration mixture is added dropwise, and nitration reaction prepares 2,3,
4,5- tecnazenes, the nitration mixture are the mixed liquor of nitric acid and the concentrated sulfuric acid；
5) fluorination reaction: 2,3,4,5- tecnazene, fluorization agent and phase transfer catalyst are fluorinated in reaction dissolvent
Reaction prepares the chloro- 2,4- difluoro nitrobenzene of 3,5- bis-；
6) reduction reaction: reducing agent, salt electrolyte and water being mixed with reaction dissolvent, then are added portionwise 3,5- bis- chloro- 2,4-
Difluoro nitrobenzene is restored, that is, prepares chloro- 2, the 4- difluoroaniline of 3,5- bis-.
3. the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- bis- as claimed in claim 2, which is characterized in that the step 1
In, the weight ratio of nitric acid and the concentrated sulfuric acid is 1:3-10 in mixed liquor, and during nitration mixture is added dropwise, reaction temperature is 50-60 DEG C, drop
Add and keeps the temperature 30-45min after nitration mixture at 40-60 DEG C, described 1, the weight ratio of 2,3- trichloro-benzenes and nitration mixture is 1:1.5-2.
4. the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- bis- as claimed in claim 2, which is characterized in that the step 2
In, during 2,3,4- trichloronitrobenzene is added, reaction temperature is 40-70 DEG C, after the completion of the charging of 2,3,4- trichloronitrobenzenes,
Reaction system is kept the temperature, holding temperature is 50-70 DEG C, and soaking time is 1-4 hours, 2,3,4- trichloronitrobenzenes and reduction
Agent, water, the electrolytelike weight ratio of salt are 1:0.5-1.0:8-12:0.15-0.3.
5. the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- bis- as claimed in claim 2, which is characterized in that the step 2
In, the reducing agent is selected from iron powder or palladium charcoal, and the salt electrolyte is selected from ammonium chloride, one of ammonium sulfate or a variety of groups
It closes.
6. the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- bis- as claimed in claim 2, which is characterized in that the step 3
In, the inorganic acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, crosses one of chloric acid and fluoboric acid or a variety of combinations, institute
It states nitrite and is selected from one of sodium nitrite, potassium nitrite or a variety of combinations.
7. the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- bis- as claimed in claim 2, which is characterized in that the step 3
In, nitrite be added after in -5-5 DEG C of heat preservation 1-2h, it is described that gained reaction solution is added dropwise to mixing for the concentrated sulfuric acid and stannous chloride
Closing the dropping temperature in liquid is 40-60 DEG C, is warming up to 70-90 DEG C after being added dropwise to complete, and keeps the temperature 1-2h, described 2,3,4- trichloro-benzenes
Amine, concentrated hydrochloric acid, ammonium chloride, sodium nitrite weight ratio be 1:2-3:0.2-0.4:0.4-0.6, described 2,3,4- trichloroanilines,
Concentrated hydrochloric acid, stannous chloride weight ratio be 1:5-7:0.6-1.
8. the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- bis- as claimed in claim 2, which is characterized in that the step 4
In, the weight ratio of nitric acid and the concentrated sulfuric acid is 1:3-4 in mixed liquor, and during nitration mixture is added dropwise, reaction temperature is 40-50 DEG C, drop
8-12 hours are kept the temperature at 40-60 DEG C after adding nitration mixture, described 1, the weight ratio of 2,3,4- tetrachlorobenzenes and nitration mixture is 1:1.5-2.
9. the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- bis- as claimed in claim 2, which is characterized in that the step 5
In, fluorization agent is selected from one of potassium fluoride, sodium fluoride and ammonium fluoride or a variety of combinations, and phase transfer catalyst is selected from the tetrabutyl
One of ammonium bromide, trimethylphenyl ammonium chloride and hexadecyl tributyl phosphonium phosphine or a variety of combinations.
10. the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- bis- as claimed in claim 2, which is characterized in that the step 5
In, 2,3,4,5- tecnazenes, fluorization agent, phase transfer catalyst weight ratio be 1:0.58-0.8:0.09-0.15, reaction
Condition is to react 12-20h at 120-150 DEG C.
11. the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- bis- as claimed in claim 2, which is characterized in that the step 6
In, during chloro- 2, the 4- difluoro nitrobenzene of 3,5- bis- is added, reaction temperature is 70-90 DEG C, 3,5- bis- chloro- 2,4- difluoro nitre
Base benzene charging after the completion of, reaction system is kept the temperature, holding temperature be 80-100 DEG C, soaking time be 2-5 hours, 3,5- bis-
Chloro- 2,4- difluoro nitrobenzene and reducing agent, water, the electrolytelike weight ratio of salt are 1:0.5-1.0:8-12:0.15-0.3, reaction
Temperature is 70-100 DEG C.
12. the preparation method of chloro- 2, the 4- difluoroaniline of 3,5- bis- as claimed in claim 2, which is characterized in that the step 6
In, the reducing agent is selected from iron powder or palladium charcoal, and the salt electrolyte is selected from ammonium chloride, one of ammonium sulfate or a variety of groups
It closes.
13. the preparation method of the chloro- 2,4 difluorobenzene amine of 3,5- bis- as described in claim 1-12 any claim is in volt worm
The purposes of grand, quinolones candidates against infection, anti-parasite medicine bioactive molecule preparation field.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410854696.4A CN105801429B (en) | 2014-12-31 | 2014-12-31 | A kind of preparation method of the chloro- 2,4 difluorobenzene amine of 3,5- bis- |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410854696.4A CN105801429B (en) | 2014-12-31 | 2014-12-31 | A kind of preparation method of the chloro- 2,4 difluorobenzene amine of 3,5- bis- |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105801429A CN105801429A (en) | 2016-07-27 |
| CN105801429B true CN105801429B (en) | 2019-09-24 |
Family
ID=56465211
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410854696.4A Active CN105801429B (en) | 2014-12-31 | 2014-12-31 | A kind of preparation method of the chloro- 2,4 difluorobenzene amine of 3,5- bis- |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105801429B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106854162A (en) * | 2016-12-13 | 2017-06-16 | 浙江海正化工股份有限公司 | A kind of nitroaniline of 2,3 dichloro 6 and preparation method thereof |
| CN106831460A (en) * | 2017-02-24 | 2017-06-13 | 青铜峡市嘉华化工有限公司 | The preparation method of the aminobenzoic acid of 3 methyl 4 |
| CN107722017A (en) * | 2017-11-03 | 2018-02-23 | 梯尔希（南京）药物研发有限公司 | A kind of preparation method of anagrelide derivative |
| CN107963995B (en) * | 2018-01-05 | 2020-01-10 | 江西师范大学 | Preparation method of melamine |
| CN108636319A (en) * | 2018-06-02 | 2018-10-12 | 张金河 | One kind 2,4,5- trichloroanilines process units and method |
| BR112021009123A2 (en) * | 2018-12-04 | 2021-08-10 | Basf Se | process for the preparation of 5-bromo-1,3-dichloro-2-fluoro-benzene and process for the preparation of compound of formula V |
| CN110028424A (en) * | 2019-05-15 | 2019-07-19 | 浙江长华科技股份有限公司 | Synthesis technology based on 2- amino -5- nitrobenzonitrile |
| CN110041228A (en) * | 2019-05-15 | 2019-07-23 | 浙江长华科技股份有限公司 | A kind of o-chloro benzonitrile nitration processes |
| CN110128295A (en) * | 2019-05-16 | 2019-08-16 | 浙江长华科技股份有限公司 | A kind of production technology based on micro- reaction synthesis chloro- 5- nitrobenzonitrile of 2- |
| CN110028425A (en) * | 2019-05-16 | 2019-07-19 | 浙江长华科技股份有限公司 | A kind of micro- reaction preparation process of 2- amino -5- nitrobenzonitrile |
| CN112047804B (en) * | 2020-09-10 | 2023-06-27 | 内蒙古永太化学有限公司 | Preparation method of 3, 5-dichloro-4-fluorobromobenzene compound |
| CN114230471B (en) * | 2021-11-09 | 2024-01-26 | 河北科技大学 | Preparation method of 3, 4-dichloro-2-fluoroaniline |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4457943A (en) * | 1980-11-22 | 1984-07-03 | Celamerck Gmbh & Co. Kg | N-(2H-Difluoro-3,5-dichloro-phenyl)-N'-(2,6-difluorobenzoyl) urea derivative and pesticidal compositions containing same |
| US5081288A (en) * | 1986-12-11 | 1992-01-14 | Bayer Aktiengesellschaft | Process for the preparation of substituted 3,5-dichloro-2,4-difluoro-benzenes |
| US5847006A (en) * | 1991-02-08 | 1998-12-08 | Cambridge Neuroscience, Inc. | Therapeutic guanidines |
| CN1683318A (en) * | 2005-03-11 | 2005-10-19 | 浙江工业大学 | Synthetic method for 3,5-dichloro-2,4-difluoronitrobenzene and teflubenzuron |
| CN102617360A (en) * | 2012-03-01 | 2012-08-01 | 江西吉翔医药化工有限公司 | Synthetic method of 3, 5-dichloro-2, 4-difluoroaniline |
| CN103285856A (en) * | 2013-06-09 | 2013-09-11 | 南通市华峰化工有限责任公司 | Anti-dehalogenation ruthenium-based catalyst for preparing halogenated phenylamine and preparation method thereof |
-
2014
- 2014-12-31 CN CN201410854696.4A patent/CN105801429B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4457943A (en) * | 1980-11-22 | 1984-07-03 | Celamerck Gmbh & Co. Kg | N-(2H-Difluoro-3,5-dichloro-phenyl)-N'-(2,6-difluorobenzoyl) urea derivative and pesticidal compositions containing same |
| US5081288A (en) * | 1986-12-11 | 1992-01-14 | Bayer Aktiengesellschaft | Process for the preparation of substituted 3,5-dichloro-2,4-difluoro-benzenes |
| US5847006A (en) * | 1991-02-08 | 1998-12-08 | Cambridge Neuroscience, Inc. | Therapeutic guanidines |
| CN1683318A (en) * | 2005-03-11 | 2005-10-19 | 浙江工业大学 | Synthetic method for 3,5-dichloro-2,4-difluoronitrobenzene and teflubenzuron |
| CN102617360A (en) * | 2012-03-01 | 2012-08-01 | 江西吉翔医药化工有限公司 | Synthetic method of 3, 5-dichloro-2, 4-difluoroaniline |
| CN103285856A (en) * | 2013-06-09 | 2013-09-11 | 南通市华峰化工有限责任公司 | Anti-dehalogenation ruthenium-based catalyst for preparing halogenated phenylamine and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105801429A (en) | 2016-07-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105801429B (en) | A kind of preparation method of the chloro- 2,4 difluorobenzene amine of 3,5- bis- | |
| CN102617360B (en) | Synthetic method of 3, 5-dichloro-2, 4-difluoroaniline | |
| CN112707836B (en) | Preparation method of m-diamide compound | |
| CN102838535A (en) | Preparation method of nicotinoyl thiourea derivatives | |
| CN107188832A (en) | A kind of method that utilization carbon dioxide synthesizes the carbamate containing trifluoromethyl | |
| CN102786491B (en) | Preparation method of 2-methyl-4-isothiazolin-3-one | |
| CN105399663A (en) | 2, 3-dichloropyridine preparation method | |
| CN103694176A (en) | Preparation method of nilotinib intermediate | |
| CN102690223A (en) | Preparation method for 1-acetyl-7-cyanopyridine-5-(2-amino propyl) indoline | |
| CN102140095A (en) | Green new process for preparing tizanidine hydrochloride | |
| WO2010000856A1 (en) | Method for producing aminobiphenylene | |
| CN103601685A (en) | Preparation method of oxibendazole | |
| CN109232411A (en) | A method of preparing boscalid | |
| JP5965499B2 (en) | Halogenated aniline and process for producing the same | |
| CN107805256A (en) | Wei Patawei intermediates and preparation method and application | |
| CN102898358A (en) | Preparation method of fluoropyridine compounds | |
| CN105037172B (en) | A kind of 2（4 ' chlorphenyls）The preparation method of aniline | |
| CN107200707A (en) | A kind of Mo Fanselin preparation method | |
| JP2012518674A (en) | Process for producing nitrated aromatic compounds and mixtures thereof | |
| CN103044330B (en) | The new green synthesizing process of silaenafil intermediate 4- amino -1- methyl -3- n-propyl pyrazoles -5- formamides | |
| Tian et al. | Synthesis of 6‐halo‐5‐nitroquinoxalines | |
| CN105037186A (en) | Preparation method of aminomethylbenzoic acid | |
| JPH0840994A (en) | Production of nitrated arylamide and arylamine | |
| CN103965057B (en) | A kind of nitrile prepares the method for primary amine | |
| CN102516123A (en) | Method for preparing candesartan intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20161223 Address after: 247200 Anhui city of Chizhou province Dongzhi County Xiang Yu Zhen Chemical Industrial Park Applicant after: Anhui Changtai Chemical Co., Ltd. Address before: 201612 Shanghai City, Songjiang District new town 201 min Yick Road No. 12 building 4 layer Applicant before: Biocompounds Pharmaceutical Inc.(BPI) |
|
| TA01 | Transfer of patent application right | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 247200 East to Economic Development Zone, Chizhou City, Anhui Province Applicant after: Anhui New North Carolina Chemical Co., Ltd. Address before: 247200 Chemical Park, Xiangyu Town, Dongzhi County, Chizhou City, Anhui Province Applicant before: Anhui Changtai Chemical Co., Ltd. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |