CN106045876A - Synthetic method for 4-chlorophenylhydrazine hydrochloride - Google Patents
Synthetic method for 4-chlorophenylhydrazine hydrochloride Download PDFInfo
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Abstract
The invention discloses a synthetic method for 4-chlorophenylhydrazine hydrochloride. The synthetic method comprises the following steps: 4-bromochlorobenzene and hydrazine hydrate are taken as reaction raw materials, and a phase transfer catalyst, a solvent and a catalyst are added for a reaction; after the reaction, solids are filtered and separated, and a solvent is removed from a filtrate through distillation; hydrochloric acid is added to residues obtained after distillation, and the mixture is stirred and filtered; filter residues are washed with water and dried, and 4-chlorophenylhydrazine hydrochloride is obtained. The synthetic method aims to solve the problem of generation of a large amount of wastewater due to adoption of a current commonly used method for reduction acidification after diazotization of 4-chloroaniline, 4-bromochlorobenzene and hydrazine hydrate are taken as the reaction raw materials, the phase transfer catalyst, the solvent and the catalyst are added for the reaction, the reaction steps are simple, the wastewater produced in a 4-chlorophenylhydrazine synthetic method is reduced remarkably, sulfur dioxide is prevented from being produced through reduction of sodium sulfite, excessive hydrazine hydrate and solvent can be recovered and reused after reaction, and the method is environment-friendly.
Description
Technical field
The present invention is the synthetic method of a kind of p-hydrochloride, is specifically related to synthesizing pyrazole kresoxim-methyl intermediate chlorine
The method of hydrazinobenzene hydrochloride salt, belongs to the synthesis field of organic compound.
Background technology
To chlorophenyl hydrazine, molecular formula is C6H7ClN2, structural formula is, it is the important conjunction of pyraclostrobin
Become intermediate, parachloroanilinum obtain through diazotising, bisulfite sodium reduction, hydrolysis, and the method uses long-standing.Example
As:
The preparation method of a patent documentation CN104926682A(p-hydrochloride, 2015.09.23) disclosed with to chlorine
Aniline is raw material, after diazotising, reduction, with non-polar solven toluene or benzene, dichloromethane, chloroform, dichloroethanes
Aqueous phase extracted remove impurity, then aqueous phase salt adding acid hydrolysis obtains p-hydrochloride, and cooling, filtration drying i.e. obtains chlorobenzene hydrazonium salt
Hydrochlorate.The present invention compared with prior art, selects the nonpolar solvent extraction removal of impurity, products obtained therefrom yield and purity high, right
Chlorophenylhydxazine hydrochloride purity > 99%, yield > 86%.As long as filtering once, simple to operate.Wastewater flow rate reduces than prior art
One times, environmental protection pressure reduces, but uses solvent to add processing procedure, and yield is on the low side.
The preparation method of patent documentation CN102993044A(p-hydrochloride, 2013.03.27) disclosed by chlorine
Aniline is after diazo-reaction, reduction reaction, acidification reaction, then through filtration, washing, discharging, drying, obtains chlorophenyl hydrazine hydrochloric acid
Salt finished product, during, use ammonium sulfite aqueous solution as reducing agent, it is easy to operation；In acidification reaction generate ammonium chloride and
Ammonium hydrogen sulfate dissolubility in water is big, makes product crystallization late, reduces side reaction；Product crystallization is loose, and good fluidity easily goes out
Material, washing, be effectively improved product quality and yield.
The preparation method of a patent documentation CN103910650A(p-hydrochloride, 2014.07.09) disclosed with
Parachloroanilinum is raw material, through diazonium, reduce, be acidified, lower the temperature, filter, wash, discharging, dry to obtain finished product.Reduction reaction uses Asia
Ammonium sulfate solution makees reducing agent, solves former technique sodium sulfite solids and feeds intake the most easy-operating difficult problem of easily luming；Acidifying
Ammonium chloride and ammonium hydrogen sulfate dissolubility in water that reaction generates are big, and crystallization is late, and beneficially acidification reaction enters in the solution
OK, side reaction is reduced；Product crystallization is loose, and good fluidity, easy discharging, washing, product quality and yield are superior to produce
Level.
The Novel synthesis technology of patent documentation CN103848752A(p-hydrochloride, 2014.06.11) disclose with
Parachloroanilinum is raw material, through diazonium, reduces, is acidified, is cooled to room temperature, filters, and dries, obtains blush p-hydrochloride
Solid.The sodium sulfite used and the mixture of sodium sulfite are reducing agent so that the PH of system can stablize at pH=6-7,
Avoid course of reaction to regulate pH value with NaOH or HCl always；Need not in course of reaction repeatedly heat up, convenient temperature control operates,
And decreasing the consumption of water, wastewater displacement also greatly reduces, it is to avoid the improvement of later stage waste water, reduce cost.
Make defect in aforementioned manners include: in production process, owing to using substantial amounts of acid and sulphite, can produce huge
Big wastewater flow rate；There is potential safety hazard in diazotising and reduction process, the concentration of diazol can not be high, otherwise can improve the danger of production
Dangerous energy, in reduction process (such as CN103848752A) used by sulphite have by-product sulfur dioxide gas produce.Along with
Strengthening environmental conservation and the green consciousness produced in recent years, the raising day by day of safety requirements, the problem of safety and the three wastes becomes
The maximum restriction restrictive condition of diazotising hydrazine, to this end, the present invention arises at the historic moment.
Summary of the invention
For solve to reduce after the existing chloroaniline diazotising commonly used a large amount of wastewater problems that acidization tool brings with
And potential safety hazard, the invention provides the novel synthesis of a kind of p-hydrochloride, this synthetic method is with to bromochlorobenzene, water
Conjunction hydrazine is reaction raw materials, reacts after adding phase transfer catalyst, solvent, catalyst, and reactions steps is simple, significantly drops
The low wastewater flow rate to producing in chlorophenyl hydrazine building-up process, it is to avoid sulfite reducing agent and the uses of a large amount of acid, solvent and mistake
The hydrazine hydrate of amount can be with recycled, and catalyst is in simple process Returning reacting system, and whole technique produces without harmful gas,
Environmental protection.
The present invention is achieved through the following technical solutions: the synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, with to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer catalyst, solvent, catalyst react；
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent；
C, addition hydrochloric acid, filtration after stirring in step B gained residue；
D, by filtering residue wash, dry obtain p-hydrochloride.
Due to diazotising (acid adding becomes salt, sodium nitrite wiring solution-forming), (reducing agent sulphite is made into molten in advance in reduction
Liquid), acidifying (acid adding decomposition sulfonate), product become the step such as salt, washing to be required to use water.Synthetic method of the present invention then saves
Gone diazotising, reduce, acidifying etc. needs to bring in a large number the step of water, only becomes salt, washing to need to bring into part water at product, because of
This, synthetic method of the present invention considerably reduces the consumption of water and the generation of waste water compared with diazotising method.
The concentration of described hydrazine hydrate is 30～100%, and the described equivalent proportion to bromochlorobenzene Yu hydrazine hydrate is 1:(1～5), excellent
Select 1:(2～3).
Described is 1:(0.01～0.15 to bromochlorobenzene and phase transfer catalyst, the weight ratio of catalyst): (0.01～
0.2), preferably 1:(0.02～0.08): (0.05～0.10).
The described weight ratio to bromochlorobenzene Yu solvent is 1:(1～20), quantity of solvent is larger is conducive to dividing of reaction mass
Dissipate, improve reaction efficiency, preferably 1:(3～5).
Described phase transfer catalyst includes tetrabutylammonium chloride, tetrabutyl ammonium bromide, 4-butyl ammonium hydrogen sulfate, benzyl three second
Ammonium chloride, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, 18-crown-6,
The combination of one or more in benzo 18-crown-6,15-crown-5, PEG400, PEG600, PEG800.
Described solvent includes in water, ethylene glycol, propylene glycol, glycol monoethyl ether, glycol dimethyl ether, propylene glycol
Kind or multiple combination.
Described catalyst includes Nickel dichloride., copper sulfate, cobaltous chloride, Cu-lyt., copper chloride, copper bromide, cuprous bromide, iodine
Change cuprous in one or more.
In described step A, course of reaction includes: slowly heats up and controls temperature to 100～180 DEG C, atmospheric pressure reflux or
Pressurize is reacted, and keeps thermotonus 1～15h, sampling HPLC detection not extremely to be further added by chlorophenyl hydrazine, i.e. stopped reaction.The present invention
Reaction temperature is controlled at 100～180 DEG C, be conducive to being smoothed out of reaction, it is to avoid temperature is too high to be made chlorophenyl hydrazine and hydration
Hydrazine decomposes, and causes the failure of reaction.
In described step C, addition 15～the hydrochloric acid of 36% in step B gained residue, regulation pH value is 1～3, then
Filter after being sufficiently stirred for.
In described step D, filtering residue is washed, dries at 50～80 DEG C and obtain p-hydrochloride.
The present invention compared with prior art, has the following advantages and beneficial effect:
(1) synthetic method of the present invention with equivalent proportion as 1:(1～5) to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer
Catalyst, catalyst, solvent react, stopped reaction when chlorophenyl hydrazine is not extremely further added by by sampling HPLC detection, then through filtering,
Distill, be acidified, filter, wash, dry after available white chlorophenylhydxazine hydrochloride product, and meet HPLC content >=99%, receive
Rate >=80%.
(2) synthetic method of the present invention is simple, and course of reaction is to slowly warm up to 100～180 DEG C, then atmospheric pressure reflux or pressurize anti-
Answering 1～15h, to sampling HPLC detection, chlorophenyl hydrazine is not further added by rear stopped reaction, product is separated by filtration solid catalysis
Agent, be distilled off solvent, add hydrochloric acid stirring after filter, wash filtering residue, dry after i.e. can get chlorophenylhydxazine hydrochloride product, relatively
Existing commonly used with parachloroanilinum as raw material, through diazonium, reduce, be acidified, lower the temperature, filter, wash, discharging, dry
For the synthetic method of product, the consumption of about more than 90% water can be reduced and reduce the generation of more than 90% waste water, being proven, make
Often synthesize 1000kg chlorophenylhydxazine hydrochloride product by this synthetic method, water consumption can be controlled in 0.8～1.2m3, giving up of generation
The water yield can be controlled in 0.8～1.2m3。
(3) the raw materials used cleaning of synthetic method of the present invention, will not increase the output of the three wastes, it is to avoid sulfite reducing agent and
The use of a large amount of acid, the hydrazine hydrate of solvent and excess can be with recycled, and catalyst is in simple process Returning reacting system, whole
Individual technique produces without harmful gas, environmental protection.
(4) concentration of the present invention is the hydrazine hydrate of 30～100%, with equivalent proportion (1～5): 1 reacts with to bromochlorobenzene, special
For (2～3) in equivalent proportion: 1, control to bromochlorobenzene and phase transfer catalyst, weight ratio 1:(0.01 of catalyst～
0.15): (0.01～0.2), preferably 1:(0.02 ~ 0.08): (0.05 ~ 0.10), to weight ratio 1:(1 of bromochlorobenzene and solvent～
20), preferably 1:(3～5) in the case of, it is more beneficial for being smoothed out of reaction, improves the reaction efficiency to bromochlorobenzene.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited to this.
Embodiment 1:
The present embodiment proposes the synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, with to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer catalyst, solvent, catalyst react；
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent；
C, addition hydrochloric acid, filtration after stirring in step B gained residue；
D, by filtering residue wash, dry obtain p-hydrochloride.
Embodiment 2:
The present embodiment proposes the synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, with equivalent proportion as 1:5 to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer catalyst, solvent, catalyst enter
Row reaction, wherein, the concentration of hydrazine hydrate is 30%；
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent；
C, addition hydrochloric acid, filtration after stirring in step B gained residue；
D, by filtering residue wash, dry obtain p-hydrochloride.
Embodiment 3:
The present embodiment proposes the synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, with to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer catalyst, solvent, catalyst react, wherein,
It is 1:0.01:0.01 to bromochlorobenzene and phase transfer catalyst, the weight ratio of catalyst；
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent；
C, addition hydrochloric acid, filtration after stirring in step B gained residue；
D, by filtering residue wash, dry obtain p-hydrochloride.
Embodiment 4:
The present embodiment proposes the synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, with to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer catalyst, solvent, catalyst react, wherein,
Weight ratio to bromochlorobenzene Yu solvent is 1:20；
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent；
C, addition hydrochloric acid, filtration after stirring in step B gained residue；
D, by filtering residue wash, dry obtain p-hydrochloride.
Embodiment 5:
The present embodiment is with the difference of embodiment 1: the phase transfer catalyst that the present embodiment relates to can be selected for tetrabutylammonium chloride,
Tetrabutyl ammonium bromide, 4-butyl ammonium hydrogen sulfate, benzyltriethylammoinium chloride, tri-n-octyl methyl ammonium chloride, trimethyl
At least two in ammonium chloride, tetradecyl trimethyl ammonium chloride, such as: mass ratio is 1:4 tetrabutyl ammonium bromide and the tetrabutyl
The mixture of ammonium hydrogen sulfate composition, or mass ratio is 2:3:1 tetrabutylammonium chloride, Dodecyl trimethyl ammonium chloride and the tetradecane
The mixture of base trimethyl ammonium chloride composition.
Solvent can be selected for water and the mixed liquor of glycol dimethyl ether composition, and mixed liquid concentration is 80%.
Catalyst can be selected for slaine, if mass ratio is 1:1:1 copper sulfate, copper chloride, the mixture of copper bromide composition,.
Embodiment 6:
The present embodiment is with the difference of embodiment 2: the phase transfer catalyst that the present embodiment relates to can be selected for tetrabutylammonium chloride,
Tetrabutyl ammonium bromide, 4-butyl ammonium hydrogen sulfate, benzyltriethylammoinium chloride, tri-n-octyl methyl ammonium chloride, trimethyl
One in ammonium chloride, tetradecyl trimethyl ammonium chloride, such as: tetrabutylammonium chloride or Dodecyl trimethyl ammonium chloride.
Solvent can be selected for the one in water, alcohols or ethers, alcohols such as: ethylene glycol, propylene glycol or ethylene glycol, ethers such as:
One in monomethyl ether, glycol dimethyl ether or propylene glycol.
Catalyst can be selected for slaine, such as Nickel dichloride., copper sulfate, cobaltous chloride, Cu-lyt., copper chloride, copper bromide, bromination
One in cuprous, Hydro-Giene (Water Science)..
Embodiment 7:
The present embodiment is with the difference of embodiment 3: the phase transfer catalyst that the present embodiment relates to can be selected for PEG, such as:
One in PEG400, PEG600, PEG800.
Solvent can be selected for water and the mixed liquor of ethylene glycol composition, and the concentration of mixed liquor is 70%.
Catalyst can be selected for slaine, such as Nickel dichloride., copper sulfate, cobaltous chloride, Cu-lyt., copper chloride, copper bromide, bromination
At least two in cuprous, Hydro-Giene (Water Science)., such as: mass ratio is 1:2 Nickel dichloride. and the mixture of copper sulfate composition.
Embodiment 8:
The present embodiment is with the difference of embodiment 4: it is 3:1:3 that the phase transfer catalyst that the present embodiment relates to can be selected for mass ratio
The mixture of benzyltriethylammoinium chloride, 18-crown-6 and PEG composition.
Solvent can be selected for water and the molten mixed liquor of mixing of glycol dimethyl ether composition, and the concentration of mixed liquor is 90%.
Catalyst can be selected for slaine, such as Nickel dichloride., copper sulfate, cobaltous chloride, Cu-lyt., copper chloride, copper bromide, bromination
In cuprous, Hydro-Giene (Water Science). a kind of.
Embodiment 9:
The synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, with equivalent proportion as 1:1 to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer catalyst (tetrabutyl hydrogen sulfate
Ammonium), solvent (concentration is the glycol water of 85%), catalyst (mass ratio is the copper sulfate of 1:1, cobaltous chloride) react,
Wherein, the concentration of hydrazine hydrate is 100%, is 1:0.15:0.2 to bromochlorobenzene and phase transfer catalyst, the weight ratio of catalyst, right
Bromochlorobenzene is 1:1 with the weight ratio of solvent；
Course of reaction includes: slowly heating up and control temperature to 100 DEG C, atmospheric pressure reflux is reacted, and keeps thermotonus 1h, sampling
Chlorophenyl hydrazine is not extremely further added by by HPLC detection, i.e. stopped reaction.
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent.
C, add in step B gained residue 15% hydrochloric acid, regulation pH value is 1, then filters after being sufficiently stirred for.
D, filtering residue is washed, dry at 50 DEG C and obtain p-hydrochloride.
It is 80% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99%.
Embodiment 10:
The synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, with equivalent proportion as 1:3 to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer catalyst (mass ratio is 2:1's
Tetrabutyl ammonium bromide and 4-butyl ammonium hydrogen sulfate), solvent (glycol dimethyl ether), catalyst (copper bromide) react, wherein,
The concentration of hydrazine hydrate is 55%, is 1:0.08:0.12 to bromochlorobenzene and phase transfer catalyst, the weight ratio of catalyst, to bromochlorobenzene
It is 1:12 with the weight ratio of solvent；
Course of reaction includes: slowly heating up and control temperature to 150 DEG C, pressurize is reacted, and keeps thermotonus 10h, samples HPLC
Chlorophenyl hydrazine is not extremely further added by by detection, i.e. stopped reaction.
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent.
C, add in step B gained residue 28% hydrochloric acid, regulation pH value is 2.7, then filters after being sufficiently stirred for.
D, filtering residue is washed, dry at 60 DEG C and obtain p-hydrochloride.
It is 84.6% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.2%.
Embodiment 11:
The synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, with equivalent proportion as 1:4.5 to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer catalyst (mass ratio is 2:
The tri-n-octyl methyl ammonium chloride of 1:3,15-crown-5 and PEG400), the solvent propylene glycol aqueous solution of 85% (concentration be), catalyst
(Cu-lyt .) reacts, and wherein, the concentration of hydrazine hydrate is 88%, to bromochlorobenzene and phase transfer catalyst, the weight of catalyst
Ratio is 1:0.11:0.09, and the weight ratio to bromochlorobenzene Yu solvent is 1:8.6；
Course of reaction includes: slowly heating up and control temperature to 120 DEG C, atmospheric pressure reflux is reacted, and keeps thermotonus 9h, sampling
Chlorophenyl hydrazine is not extremely further added by by HPLC detection, i.e. stopped reaction.
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent.
C, add in step B gained residue 30% hydrochloric acid, regulation pH value is 2.5, then filters after being sufficiently stirred for.
D, filtering residue is washed, dry at 65 DEG C and obtain p-hydrochloride.
It is 85.0% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.1%.
Embodiment 12:
The synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, with equivalent proportion as 1:2.8 to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer catalyst (benzo 18-crown-
6), solvent (concentration is the aqueous solution of propylene glycol of 90%), catalyst (cuprous bromide) react, wherein, the concentration of hydrazine hydrate is
59.5%, it is 1:0.15:0.2 to bromochlorobenzene and phase transfer catalyst, the weight ratio of catalyst, the weight to bromochlorobenzene Yu solvent
Ratio is 1:16.6；
Course of reaction includes: slowly heating up and control temperature to 172 DEG C, pressurize is reacted, and keeps thermotonus 5h, sampling HPLC inspection
Survey to chlorophenyl hydrazine is not further added by, i.e. stopped reaction.
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent.
C, add in step B gained residue 24.8% hydrochloric acid, regulation pH value is 1.8, then filters after being sufficiently stirred for.
D, filtering residue is washed, dry at 70 DEG C and obtain p-hydrochloride.
It is 86.3% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.2%.
Embodiment 13:
The synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, in reaction vessel add reaction raw materials: 96.5g to bromochlorobenzene and the hydrazine hydrate of 4 equivalents, concentration of hydrazine hydrate is
40%, add the phase transfer catalyst (tetrabutylammonium chloride) of 12% weight ratio, the solvent (ethylene glycol) of 14 times of weight and 12% weight
The catalyst (copper sulfate) of amount, reacts；
Course of reaction includes: slowly heating up and control temperature to 162 DEG C, pressurize is reacted, and keeps thermotonus 8h, sampling HPLC inspection
Survey to chlorophenyl hydrazine is not further added by, i.e. stopped reaction.
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent.
C, add in step B gained residue 20.5% hydrochloric acid, regulation pH value is 2.2, then filters after being sufficiently stirred for.
D, filtering residue is washed, dry at 60 DEG C and obtain p-hydrochloride.
It is 84.6% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.3%.
Embodiment 14:
The synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, in reaction vessel add reaction raw materials: 98.25g to bromochlorobenzene and the hydrazine hydrate of 3.3 equivalents, concentration of hydrazine hydrate is
71%, add the phase transfer catalyst (PEG400) of 10% weight ratio, the solvent (propylene glycol) of 3 times of weight and urging of 20% weight
Agent copper sulfate and the cobaltous chloride of 3:1 (mass ratio be), reacts；
Course of reaction includes: slowly heats up and controls temperature to 152 DEG C, atmospheric pressure reflux or pressurize reaction, keeps thermotonus
10h, chlorophenyl hydrazine is not extremely further added by by sampling HPLC detection, i.e. stopped reaction.
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent.
C, add in step B gained residue 30% hydrochloric acid, regulation pH value is 3, then filters after being sufficiently stirred for.
D, filtering residue is washed, dry at 55 DEG C and obtain p-hydrochloride.
It is 88.1% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.29%.
Embodiment 15:
The synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, in reaction vessel add reaction raw materials: 95.36g to bromochlorobenzene and the hydrazine hydrate of 2 equivalents, concentration of hydrazine hydrate is
86%, (mass ratio is the 18-crown-6 of 1:5:1, PEG600, tetrabutyl phosphonium bromide to add the phase transfer catalyst of 14% weight ratio
Ammonium), the solvent of the 5 times of weight propylene glycol aqueous solution of 75% (concentration be) and the catalyst (copper chloride) of 2% weight, carry out anti-
Should；
Course of reaction includes: slowly heating up and control temperature to 180 DEG C, pressurize is reacted, and keeps thermotonus 4h, sampling HPLC inspection
Survey to chlorophenyl hydrazine is not further added by, i.e. stopped reaction.
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent.
C, add in step B gained residue 30% hydrochloric acid, regulation pH value is 1.5, then filters after being sufficiently stirred for.
D, filtering residue is washed, dry at 65 DEG C and obtain p-hydrochloride.
It is 85.0% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.6%.
Embodiment 16:
The synthetic method of a kind of p-hydrochloride, comprises the following steps:
A, in reaction vessel add reaction raw materials: 97.55g to bromochlorobenzene and the hydrazine hydrate of 1.8 equivalents, concentration of hydrazine hydrate is
80%, add 8% weight ratio phase transfer catalyst (mass ratio is the benzyltriethylammoinium chloride of 2:1, tetrabutyl ammonium bromide),
(mass ratio is the copper sulfate of 2:1:1, cobaltous chloride, protochloride for the solvent (ethylene glycol) of 6 times of weight and the catalyst of 19% weight
Copper), react；
Course of reaction includes: slowly heating up and control temperature to 120 DEG C, atmospheric pressure reflux is reacted, and keeps thermotonus 10h, sampling
Chlorophenyl hydrazine is not extremely further added by by HPLC detection, i.e. stopped reaction.
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent.
C, add in step B gained residue 35% hydrochloric acid, regulation pH value is 1.2, then filters after being sufficiently stirred for.
D, filtering residue is washed, dry at 70 DEG C and obtain p-hydrochloride.
It is 86. 2% that the present embodiment can realize the yield of p-hydrochloride, and HPLC content is 99.7%.
The above, be only presently preferred embodiments of the present invention, and the present invention not does any pro forma restriction, every depends on
Any simple modification of being made above example according to the technical spirit of the present invention, equivalent variations, each fall within the protection of the present invention
Within the scope of.
Claims (10)
1. the synthetic method of a p-hydrochloride, it is characterised in that: comprise the following steps:
A, with to bromochlorobenzene, hydrazine hydrate as reaction raw materials, add phase transfer catalyst, solvent, catalyst react；
After B, question response terminate, filtering and separate solid, filtrate is through being distilled off solvent；
C, addition hydrochloric acid, filtration after stirring in step B gained residue；
D, by filtering residue wash, dry obtain p-hydrochloride.
The synthetic method of a kind of p-hydrochloride the most according to claim 1, it is characterised in that: described hydrazine hydrate
Concentration is 30～100%, and the described equivalent proportion to bromochlorobenzene Yu hydrazine hydrate is 1:(1～5).
The synthetic method of a kind of p-hydrochloride the most according to claim 1, it is characterised in that: described to bromochlorobenzene
It is 1:(0.01～0.15 with the weight ratio of phase transfer catalyst, catalyst): (0.01～0.2).
The synthetic method of a kind of p-hydrochloride the most according to claim 1, it is characterised in that: described to bromochlorobenzene
It is 1:(1～20 with the weight ratio of solvent).
The synthetic method of a kind of p-hydrochloride the most according to claim 1, it is characterised in that: described phase transfer is urged
Agent includes tetrabutylammonium chloride, tetrabutyl ammonium bromide, 4-butyl ammonium hydrogen sulfate, benzyltriethylammoinium chloride, tricaprylmethyl
Ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, 18-crown-6, benzo 18-crown-6,15-crown-5,
The combination of one or more in PEG400, PEG600, PEG800.
The synthetic method of a kind of p-hydrochloride the most according to claim 1, it is characterised in that: described solvent includes
The combination of one or more in water, ethylene glycol, propylene glycol, glycol monoethyl ether, glycol dimethyl ether, propylene glycol.
The synthetic method of a kind of p-hydrochloride the most according to claim 1, it is characterised in that: described catalyst bag
Include the one in Nickel dichloride., copper sulfate, cobaltous chloride, Cu-lyt., copper chloride, copper bromide, cuprous bromide, Hydro-Giene (Water Science). or many
Kind.
The synthetic method of a kind of p-hydrochloride the most according to claim 1, it is characterised in that: in described step A
In, course of reaction includes: slowly heats up and controls temperature to 100～180 DEG C, atmospheric pressure reflux or pressurize reaction, keeps temperature anti-
Answering 1～15h, chlorophenyl hydrazine is not extremely further added by by sampling HPLC detection, i.e. stopped reaction.
The synthetic method of a kind of p-hydrochloride the most according to claim 1, it is characterised in that: in described step C
In, step B gained residue adds 15～the hydrochloric acid of 36%, regulation pH value is 1～3, then filters after being sufficiently stirred for.
The synthetic method of a kind of p-hydrochloride the most according to claim 1, it is characterised in that: in described step D
In, filtering residue is washed, dries at 50～80 DEG C and obtain p-hydrochloride.
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