CN105017098A - Preparation technology of alkyloxybenzsulfamide and its derivatives - Google Patents
Preparation technology of alkyloxybenzsulfamide and its derivatives Download PDFInfo
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Abstract
The invention discloses a preparation technology of alkyloxybenzsulfamide and its derivatives with a general formula (I). The preparation technology comprises that alkyloxybenzenesulfonyl chloride with a general formula (II) and its derivatives as raw materials undergo an ammonification agent ammonification reaction in the presence of a strong base compound. The ammonification technology does not utilize excess ammonium hydroxide, the reactants can completely react, the finished product does not contain ammonium hydroxide, the reaction product salt is prepared from strong acid and strong base, has stable properties and can be recovered easily, ammonium salt residue is avoided, produced waste water can be treated easily, ammonia gas is not released in production after ammonification, an operation environment is thoroughly improved, production operation is convenient, work environment protection is promoted, the problems of poor operation environment, high waste water treatment difficulty and complex processes are solved, raw materials can be obtained easily at home, processes are simple, operation is convenient, a cost is low, safety, high efficiency, energy saving and consumption reduction are realized and the preparation technology is suitable for industrial large-scale production.
Description
Technical field
The present invention relates to the preparation technology of alcoxyl base class benzsulfamide and derivative thereof, belong to technical field of organic synthesis.
Background technology
The alcoxyl base class benzsulfamide that general formula is (I) and derivative thereof are very important organic intermediates, are widely used in the fields such as medicine, agricultural chemicals, dyestuff.Such as 2-methoxybenzenesulphoismide, 3-methoxybenzenesulphoismide and 4-methoxybenzenesulphoismide all can be used for the medicine synthesizing treatment tumour.2-trifluoro-metoxybenzene sulfamide is mainly for the production of 2-(trifluoromethoxy) benzenesulfonyl isocyanate, and it is the important source material that sulfonylureas is produced.2-(2-chloroethoxy) benzsulfamide can for the synthesis of sulfonylurea herbicide triasulfuron.2-(2-methoxy ethoxy) benzsulfamide can for the synthesis of sulfonylurea herbicide cinosulfuron.2-chloro-5-methoxyl benzsulfamide can be used for synthesizing the medicine for parasitic nematode.4-methoxyl group-3-nitrobenzene sulfonamide can be used for the medicine synthesizing prevention and therapy various diseases.3-amino-4-methoxyl benzsulfamide can be used for the medicine synthesizing treatment dermatitis and the aspect such as prevention or Cardiovarscular.4-amino-2-methoxybenzenesulphoismide can be used for closing dispersed dye and pigment.5-amino-2-methoxybenzenesulphoismide can be used for synthesizing medicine cholesterol being had to classification regulating effect.2-amino-5-methoxybenzenesulphoismide can be used for synthesizing a kind of medicine suppressing hepatitis C virus polymerase.5-acetonyl-2-methoxybenzenesulphoismide can be used for the medicine tamsulosin hydrochloride synthesizing treatment prostatosis.2-methoxyl group-5-amino sulfonyl methyl benzoate can be used for synthesis antipsychotic class medicine Sulpiride.2,4-dimethoxybenzenesulfonamide can be used for the medicine synthesizing treatment tumour.3,4-dimethoxybenzenesulfonamide can be used for the medicines such as synthesis treatment asthma, anaphylactic disease, rheumatic arthritis, osteoarthritis and septic shock.2,5-dimethoxybenzenesulfonamide can be used for producing pigment.2,6-dimethoxybenzenesulfonamide can be used for synthetic herbicide.These compounds occupy suitable position in pharmaceutical chemistry.
At present, to use ammoniacal liquor to be the alcoxyl base class benzene sulfonyl chloride of (II) and derivative ammonification thereof by general formula be general formula is alcoxyl base class benzsulfamide and the derivative thereof of (I), almost becomes the preparation technology that these compounds are general.Its reaction process is as (3):
US4874894 provides one group and comprises 4-methoxybenzenesulphoismide, 4-phenetole sulphonamide, 4-propoxy-benzsulfamide, 4-butyl phenyl ether sulphonamide, by that analogy, and even n-Hexadecane oxygen base benzsulfamide is in the preparation method of interior alkoxy-benzenesuIfonamide, and this method uses ammoniacal liquor ammonification.The concrete preparation method providing 4-methoxybenzenesulphoismide is in instances, under-5 DEG C of conditions, 96.47g4-Methoxybenzenesulfonyl chloride is slowly joined in the mixture of 175.0ml strong aqua and 175.0g trash ice, reinforced complete, slowly be warming up to 70 DEG C, insulation 2.5h, then 10 DEG C are cooled to, keep 40min with sufficient crystallising, filter and with each 50ml frozen water drip washing three times, 97.37g4-methoxybenzenesulphoismide wet product is obtained after being filtered dry, then again with 50% sodium hydroxide solution to carry out alkali molten, activated carbon decolorizing, cross and filter gac, filtrate hcl acidifying, cool to 5 DEG C of sufficient crystallisings again, filter, filter cake obtains the 4-methoxybenzenesulphoismide of 70.93g white through vacuum-drying.
CN101671284 proposition ammoniacal liquor ammoniation process prepares the method for ortho-trifluoro-metoxybenzene sulfamide, the ammonification that this method is mentioned is the ammoniacal liquor 400 parts of input 20% in bottle, drip the adjacent trifluoromethoxy benzene sulfonyl chloride of homemade oily, in 38 ~ 42 DEG C of insulation 5h, filter to obtain crude product; Crude product is purified through recrystallization again, namely in bottle, drops into ethanol, gac, crude product, keeps 1h after temperature rising reflux, carry out press filtration, obtains the certified products containing a small amount of second alcohol and water, certified products yield 65%.
EP0044808 proposes the preparation method of one group of halo (comprising fluoro, chloro or bromo) alkoxyl group (comprising methoxy or ethoxy) benzsulfamide, and this method uses ammoniacal liquor ammonification.The concrete preparation method providing 2-difluoro-methoxy benzsulfamide is in instances, the mixture of rough for 80.3g 2-difluoro-methoxy benzene sulfonyl chloride and 50ml methylene dichloride is slowly joined in the material be made up of the ammoniacal liquor of 250ml methylene dichloride, 250ml water and 250ml30%, control exothermic heat of reaction, backflow 2h, organic phase is through washing, anhydrous sodium sulfate drying, solvent evaporated, refining methanol, finally obtains 40.5g2-difluoro-methoxy benzsulfamide.Also the concrete preparation method similarly providing 2-five fluorine phenetole sulphonamide is in instances, the mixture of homemade 2-five fluorine phenetole SULPHURYL CHLORIDE and 50ml methylene dichloride is slowly joined in the material be made up of the ammoniacal liquor of 250ml methylene dichloride, 250ml water and 250ml30%, control exothermic heat of reaction, backflow 2h, organic phase is through washing, anhydrous sodium sulfate drying, solvent evaporated, refining methanol, finally obtains 65.0g2-five fluorine phenetole sulphonamide.
US8735588 proposes the preparation method of 2-chloro-5-methoxyl benzsulfamide, and this method uses ammoniacal liquor ammonification.Specifically first 2.5g2-chloro-5-methoxyl benzene sulfonyl chloride is joined in 30ml tetrahydrofuran (THF), then 3.0ml30% ammoniacal liquor is dripped wherein, stir 15min, material becomes muddy, add 10ml water, after tetrahydrofuran (THF) is removed in underpressure distillation, obtain brown solid suspension liquid, more after filtration, washing after obtain 2.2g2-chloro-5-methoxyl benzsulfamide.Modern, the preparation method of 2004,3 (2), 13 ~ 14. proposition 5-chloro-2-(2-chloroethoxy) benzsulfamides, this method is also use ammoniacal liquor ammonification.4-(2-chloroethoxy) chlorobenzene is specifically first used to obtain the mixed solution of the chloro-2-of 5-(2-chloroethoxy) benzene sulfonyl chloride and chlorobenzene, under 40 DEG C of conditions, drip 43.8g strong aqua, control temperature is no more than 70 DEG C therebetween, dropwise, be cooled to 30 DEG C of insulation 3h, last suction filtration obtains the chloro-2-of 5-(2-chloroethoxy) benzsulfamide.
US8367667 proposes the preparation method of 2-methoxyl group-4-nitrobenzene sulfonamide, and this method uses ammoniacal liquor ammonification.Specifically the strong aqua of 2.5ml28% is carefully added drop-wise in 0.25g2-methoxyl group-4-nitrobenzene sulfonyl chloride, stir 24h, reacted product 50ml ammonium chloride solution and 50ml methylene dichloride extract at twice, extraction liquid after merging salt solution is cleaned, again through anhydrous sodium sulfate drying, concentrating under reduced pressure desolventizing, obtain the amber 2-methoxyl group of 0.16g-4-nitrobenzene sulfonamide crude product.
US6294558 proposes the preparation method of 4-acetylaminohydroxyphenylarsonic acid 2-methoxybenzenesulphoismide and 4-amino-2-methoxybenzenesulphoismide, and this method uses ammoniacal liquor ammonification.Concrete preparation method is, at whipped state at 0 DEG C, the chlorsulfonic acid of 0.5mol is added drop-wise in the 3-methoxyacetanilide of 0.1mol, be warmed up to 70 DEG C of reaction 6h, reaction mass is cooled to room temperature, add 50ml methylene dichloride and frozen water dilution, use 30ml dichloromethane extraction twice again, combining extraction liquid (4-acetylaminohydroxyphenylarsonic acid 2-Methoxybenzenesulfonyl chloride and methylene dichloride), it is added drop-wise in 20ml25% ammoniacal liquor at 0 DEG C, at room temperature stir 1h, reaction solution obtains 4-acetylaminohydroxyphenylarsonic acid 2-methoxybenzenesulphoismide after filtration.4-acetylaminohydroxyphenylarsonic acid 2-methoxybenzenesulphoismide put in aqueous sodium hydroxide solution and be heated to the 3h that refluxes, reaction solution, again through hcl acidifying, filtration, finally obtains 4-amino-2-methoxybenzenesulphoismide.
GB2006772 proposes the preparation method of 5-ethanoyl-2-methoxybenzenesulphoismide, and this method uses ammoniacal liquor ammonification.Concrete preparation method is, first 200g chlorsulfonic acid is cooled to 0 ~ 5 DEG C, 30g4-methoxyacetophenone is slowly added under stirring, and in room temperature for overnight, and then be warming up to 50 ~ 60 DEG C, insulation 3h, reaction solution pours crystallisation by cooling precipitation in frozen water into, use 500ml extraction into ethyl acetate again, after getting oil reservoir anhydrous magnesium sulfate drying, 37.1g faint yellow solid (5-ethanoyl-2-Methoxybenzenesulfonyl chloride) is obtained again after underpressure distillation desolventizing, faint yellow solid 150ml tetrahydrofuran (THF) dissolves, then the cold ammoniacal liquor of 300ml is added, material stirred overnight produces crystallization, crystallisate after filtration, washing, dry, finally obtain 25g5-ethanoyl-2-methoxybenzenesulphoismide.Similarly, CN1578761 proposes the preparation method of 5-acetonyl-2-methoxybenzenesulphoismide, and this method is also use ammoniacal liquor ammonification.Concrete preparation method is, first 426g chlorsulfonic acid is cooled to-10 ~ (-15) DEG C, 100g4-anisole acetone is added with certain speed, control temperature of reaction and be no more than 5 DEG C, reinforced complete, 2h is kept in room temperature, reaction solution pours stirred crystallization in 3100g frozen water into, leach crystallisate and use 200ml cold water washing, crystallisate is dissolved in 300ml ethyl acetate, the 600ml ammoniacal liquor being cooled to-5 DEG C is in advance added wherein again with certain speed, process control temp is no more than 5 DEG C, reinforced complete, be warming up to rt while stirring overnight, leach crystallization and use 200ml water and 100ml washing with alcohol, the crude product obtained uses ethyl alcohol recrystallization again, finally obtain 65g5-acetonyl-2-methoxybenzenesulphoismide.
Chinese Journal of Pharmaceuticals, 1996,27 (11), 487 ~ 488. and CN1884259 the preparation method of 2-methoxyl group-5-amino sulfonyl methyl benzoate is all proposed.The former is in 15min; the ammoniacal liquor of 120ml28% is instilled in homemade 26.5g5-chlorsulfonic acid-O-Anisic Acid methyl esters; generate white precipitate; stir 30min; filtration, precipitation are washed to without ammonia taste; dry at 80 DEG C, then vacuum-drying obtains 17.3g2-methoxyl group-5-amino sulfonyl methyl benzoate.And the latter passes into ammonia to reaction solution in alkalescence (pH=11) to homemade containing in the methylene dichloride band water mixture of 5-chlorsulfonic acid-O-Anisic Acid and 5-chlorsulfonic acid-O-Anisic Acid methyl esters; heat up and steam except methylene dichloride; add 200ml methyl alcohol and the 40g vitriol oil again; backflow 6h; steam except methyl alcohol; neutralize with saturated sodium carbonate; reaction solution is in alkalescence (pH=12); filter, washing, dry crude product, then through recrystallizing methanol, dry 196g2-methoxyl group-5-amino sulfonyl methyl benzoate.Although the latter directly uses ammonia, because having water in reaction system, this reaction is also ammoniacal liquor ammonification in fact.
J.Med.Chem., 1977,20 (10), 1235 ~ 1239. propose to comprise 2,4-dimethoxybenzenesulfonamide, 2,5-dimethoxybenzenesulfonamide and 3, the 4-dimethoxybenzenesulfonamide preparation method at interior one group of dimethoxybenzenesulfonamide.Preparation method be respectively by adjacent, p-dimethoxy benzene first carries out chlorosulphonation respectively obtained 3 with chlorsulfonic acid, 4-dimethoxybenzenesulfonyl chloride, 2,4-dimethoxybenzenesulfonyl chloride and 2,5-dimethoxybenzenesulfonyl chloride, and then respectively they are used ammoniacal liquor ammonification, finally obtain 3,4-dimethoxybenzenesulfonamide, 2,4-dimethoxybenzenesulfonamide and 2,5-dimethoxybenzenesulfonamide.
In addition, suitable document is also had to make relevant report to this kind of alcoxyl base class benzsulfamide and derivative thereof, wherein most of technique is ammoniacal liquor ammonification, such as US4709092, US4732711, US4806528, CN101462986, CN1588762, JP49132070 and JP7850139 etc., in addition also to have and adopt ammonia pressurization ammonification, and non-aminated technique, at this no longer Ao Shu.Although ammoniacal liquor ammonification technique is quite ripe, in its production implementation process, often there is following problem:
(1) because the consumption of ammoniacal liquor is excessive, have no small residual after the completion of reaction, a large amount of ammonia can be discharged at product separation and drying process, very large to the body harm of operator;
(2) owing to producing a large amount of ammonium chloride in aminating reaction process, this ammonia nitrogen waste water containing ammonium chloride is difficult, and processing cost is high, and environmental hazard is large;
(3) last handling process is too loaded down with trivial details, is unfavorable for industrialization.
Prior art ammoniacal liquor ammonification technique completes under weakly alkaline system, and reaction is undertaken by (3) formula;
Ammonification technique of the present invention then completes under strong basicity system, is undertaken by (1) formula or (2) formula;
(2) raw material of aminating reaction is different
Prior art ammoniacal liquor ammonification technique, except benzene sulfonyl chloride and derivative thereof, only uses ammoniacal liquor, the concentration of ammoniacal liquor often 20% ~ 30%;
Ammonification technique of the present invention is except alcoxyl base class benzene sulfonyl chloride and derivative, strong alkali compound and water, ammoniacal liquor can be used, also can not using ammoniacal liquor, will use ammonium salt when not using ammoniacal liquor, when using ammoniacal liquor, ammonia concn can be loosened to 5% ~ 30%;
(3) byproduct of reaction is different
During prior art aminating reaction, ammoniacal liquor ammonification technique will use ammoniacal liquor excessive greatly, otherwise alcoxyl base class benzene sulfonyl chloride and derivative thereof can not complete reactions, and in reaction final product except remained ammonia, also respond the ammonium chloride generated;
Ammonification technique ammoniacal liquor of the present invention need not be excessive, comprises strong alkali compound, and almost can add by the theoretical amount needed for reaction, alcoxyl base class benzene sulfonyl chloride and derivative thereof just can complete reactions.Almost do not have ammoniacal liquor in reaction final product, the salt that reaction generates is stable in properties and the strong acid and strong base salt easily reclaimed.
(4) aftertreatment technology complicacy is different
During the aftertreatment of prior art aminating reaction, ammoniacal liquor ammonification technique because having a large amount of ammonium chloride in system with alcoxyl base class benzene sulfonyl chloride and derivative together crystallization thereof, so product also needs the treating process through desalination, technological process relative complex;
During ammonification technique aftertreatment of the present invention, because of the often good water solubility of the salt in system, can not with alcoxyl base class benzene sulfonyl chloride and derivative together crystallization thereof, so product does not need to refine, technological process is relatively simple.
Compared with the present invention obtains ammoniacal liquor ammonification technique with alcoxyl base class benzene sulfonyl chloride and derivative thereof in prior art, advantage is the following aspects:
(1) the present invention does not have ammonia to discharge in the production operation process of ammonification aftertreatment, and operating environment is fundamentally improved, and is not only convenient to production operation, is also conducive to the protection of operating environment;
(2) the present invention is in ammonifying process, and ammonium salt can be fully used, can noresidue in ammonification waste water, and the waste water of generation easily processes, instead of reluctant ammonia nitrogen waste water;
(3) aminating reaction speed of the present invention is fast, and post-processing operation is easy, and production efficiency is high, good economy performance.
In sum, the present invention proposes the preparation technology that a kind of technique is more feasible, environment more has, economy better leads to formula I alcoxyl base class benzene sulfonyl chloride and derivative thereof.Overcome operating environment in prior art poor, waste water is difficult, and technique is loaded down with trivial details waits production defect.Method raw material provided by the invention is easy to get, and domesticly all can purchase, and technique is simple, and easy to operate, cost is low, and safe, efficient, energy-conservation, consumption reduction, thus be more suitable for industrial mass production.
Summary of the invention
For solve alcoxyl base class benzsulfamide and derivative thereof existing ammoniacal liquor ammonification preparation process in produce ammonia harm environmental and human health impacts, produce the higher ammonia nitrogen waste water of processing cost and the problem such as last handling process is complicated, the invention provides that a kind of raw material is easy to get, ammonifying process operating environment is fundamentally improved, do not produce ammonia nitrogen waste water, simplify last handling process, lower-cost preparation technology.
Technical scheme of the present invention is as follows: the preparation technology of logical formula I alcoxyl base class benzsulfamide and derivative thereof, with logical formula II alcoxyl base class benzene sulfonyl chloride and derivative thereof for raw material, under strong alkali compound exists, prepare through ammoniation agent aminating reaction;
Wherein, R represents (OCX
2cX
2)
mo (CX
2)
ncX
3;
R ' represents X or NO
2or NH
2or NHCOCH
3or COCH
3or CH
2cOCH
3or COOH or COOCH
3or COOCH
2cH
3or CX
3or OCX
3or OCX
2cX
3;
X represents hydrogen or halogen;
m＝0～100；
n＝0～15；
As preferably, described strong alkali compound is selected from alkali-metal oxide compound, alkali-metal oxyhydroxide, the oxide compound of alkaline-earth metal or the oxyhydroxide of alkaline-earth metal.
As preferably, described strong alkali compound is selected from least one in sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, hydrated barta, sodium oxide, potassium oxide, calcium oxide and barium oxide.
As preferably, described ammoniation agent is selected from ammoniacal liquor or ammonium salt; Described ammonium salt is selected from least one in ammonium chloride, ammonium sulfate, monoammonium sulfate, ammonium phosphate, ammonium hydrogen phosphate and primary ammonium phosphate.
As preferably, described preparation technology comprises the following steps:
1. ammonification: logical formula II alcoxyl base class benzene sulfonyl chloride and derivative, ammoniation agent, strong alkali compound, the obtained material containing leading to formula I alcoxyl base class benzsulfamide and derivative thereof of reaction at 0 ~ 100 DEG C;
2. be separated: material step 1. obtained cools to 0 ~ 10 DEG C, and crystallization refilters and obtains wet product;
3. dry: wet product step 2. obtained is dry at 30 ~ 100 DEG C;
The following reaction formula of its technological reaction process (1) or reaction formula (2):
The present invention, in ammonifying process, introduces strong alkali compound, ammonium salt is made full use of as aminating reaction raw material in the reaction system of former ammoniacal liquor ammonification technique.
The present invention, in last handling process, makes full use of logical formula I alcoxyl base class benzsulfamide and derivative fusing point is high, water-soluble is poor feature thereof, and adopt Crystallization Separation, water-washing desalting and solvent, process is simplified, and is more conducive to operation.In reaction process, introduce suitable solvent as dispersion agent and recrystallisation solvent, obvious facilitation effect is played to reaction and separation processes.
The present invention, in drying process, makes full use of logical formula I alcoxyl base class benzsulfamide and derivative fusing point is high, the not solvent-laden feature of wet product, improves drying temperature as far as possible, and process safety, operational cycle are short.
In the present invention, after described preparation process terminates, also can comprise the step of purification of products, as sedimentation, separatory and washing etc., be this area routine operation, known by technician, do not repeat at this.
As preferably, step 1. in also add solvent, the mass ratio of described logical formula II alcoxyl base class benzene sulfonyl chloride and derivative and solvent is 1:0 ~ 6.0; Described solvent is the mixture that water or water and organic solvent form; Wherein organic solvent is selected from least one in the similar homologue of methyl alcohol, ethanol, Virahol, ethyl formate, ethyl acetate, ether, isopropyl ether, methyl tertiary butyl ether, n-butyl ether, tetrahydrofuran (THF), hexanaphthene, methylcyclohexane, benzene, toluene, the above organic solvent or isomers; The mass ratio of water and organic solvent is 1:0 ~ 6.0.When reactant self can play solvent action, can not solubilizing agent.
As preferably, the concentration of described ammoniacal liquor is 5% ~ 30%.
As preferably, when described ammoniation agent is ammoniacal liquor, described logical formula II alcoxyl base class benzene sulfonyl chloride and derivative thereof, ammoniacal liquor are with NH
4 +meter, strong alkali compound are with the OH of complete water-soluble rear formation
-meter, mol ratio is 1:1.1 ~ 1.5:1.0 ~ 1.5.The ammoniacal liquor added and the feed way of strong alkali compound can be first add ammoniacal liquor, after add strong alkali compound, the two also or can mix simultaneously and add.
As preferably, when described ammoniation agent is ammonium salt, described logical formula II alcoxyl base class benzene sulfonyl chloride and derivative thereof, ammonium salt are with NH
4 +meter, strong alkali compound are with the OH of complete water-soluble rear formation
-meter, mol ratio is 1:1.0 ~ 1.2:2.0 ~ 2.4.
As preferably, described strong alkali compound directly in solid form or the solution being mixed with 10% ~ 50% be added in reaction system.
Present invention process is more feasible, environment more has, economy is better.
In the present invention and prior art, the difference of the ammoniacal liquor ammonification technique of alcoxyl base class benzene sulfonyl chloride and derivative thereof is the following aspects:
(1) reaction principle of aminating reaction is different
Accompanying drawing explanation
Accompanying drawing 1 width of the present invention,
Fig. 1 is the new preparation process flow process of alcoxyl base class benzsulfamide and derivative thereof,
In Fig. 1:
AW---represent ammoniacal liquor;
AS---represent ammonium salt;
B---represent oxide compound or the oxyhydroxide of basic metal or alkaline-earth metal;
BSC---represent alkoxy benzene SULPHURYL CHLORIDE and derivative thereof;
BSA---represent alkoxyl group benzene fulfonic amide and derivative thereof;
S---represent solvent.
Embodiment
Following non-limiting example can make the present invention of those of ordinary skill in the art's comprehend, but does not limit the present invention in any way.
The preparation of embodiment 1 4-methoxybenzenesulphoismide
1. ammonification: in 1000mL four-hole bottle, add 203g (1.07mol) 4-Methoxybenzenesulfonyl chloride and do bed material, after being warming up to 40 ~ 45 DEG C, under whipped state, be added drop-wise in bed material by the ammoniacal liquor of 200g (1.18mol) 10%, 1h dropwises, then is added drop-wise in reaction system by 160g (1.20mol) sodium hydroxide solution, 1h dropwises, insulation 1h.
2. be separated: under whipped state, material temperature adjustment to 5 ~ 10 DEG C sufficient crystallising step 1. obtained, filters and use 30g water wash, obtains the 4-methoxybenzenesulphoismide wet product of 273g (content 71%) off-white color.
3. dry: 4-methoxybenzenesulphoismide wet product step 2. obtained is dry at 75 ~ 85 DEG C, and obtain 190g4-methoxybenzenesulphoismide, product fusing point is 111 ~ 113 DEG C.
The preparation of embodiment 2 ortho-trifluoro-metoxybenzene sulfamide
1. ammonification: in 1000mL four-hole bottle, add 102g water successively and the adjacent trifluoromethoxy benzene sulfonyl chloride of 148g (0.5mol) does bed material, under whipped state, respectively by the ammoniacal liquor of 51g (0.75mol) 25% and 78.5g (0.51mol) sodium hydroxide solution at 20 ~ 30 DEG C, be added drop-wise in bed material in 1h simultaneously, ammoniacal liquor dropwises prior to sodium hydroxide solution, insulation 1h.
2. be separated: under whipped state, material temperature adjustment to 0 ~ 5 DEG C sufficient crystallising step 1. obtained, filters and use 30g water wash, obtains the ortho-trifluoro-metoxybenzene sulfamide wet product of 158g (content 67%) golden sheet.
3. dry: benzsulfamide wet product step 2. obtained is dry at 90 ~ 100 DEG C, and obtain 105g ortho-trifluoro-metoxybenzene sulfamide, product fusing point is 179 ~ 183 DEG C.
The preparation of embodiment 3 2-(2-chloroethoxy) benzsulfamide
1. ammonification: in 1000mL four-hole bottle, add 27.7g (0.50mol) ammonium chloride, 150g water, 350g toluene and 124g (0.48mol) 2-(2-chloroethoxy) benzene sulfonyl chloride successively and do bed material, under whipped state, by 132g (1.09mol) sodium hydroxide solution at 55 ~ 65 DEG C, be added drop-wise in bed material, 1h dropwises, insulation 1h.
2. be separated: under whipped state, material temperature adjustment to 0 ~ 5 DEG C sufficient crystallising step 1. obtained, filters and use 30g water wash, obtains 2-(2-chloroethoxy) the benzsulfamide wet product of 134g (content 74%).
3. dry: 2-(2-chloroethoxy) benzsulfamide wet product step 2. obtained is dry at 70 ~ 80 DEG C, and obtain 97g2-(2-chloroethoxy) benzsulfamide, product fusing point is 117 ~ 119 DEG C.
The preparation of embodiment 4 2-five fluorine phenetole sulphonamide
1. ammonification: in 1000mL four-hole bottle, add 300g ether, 161g (0.51mol) 2-five fluorine phenetole SULPHURYL CHLORIDE and 100g water successively and do bed material, under whipped state, the mixing solutions that ammoniacal liquor and 78.5g (0.51mol) sodium hydroxide solution in advance with 52g (0.76mol) 25% prepares is added drop-wise in bed material at 15 ~ 30 DEG C, 1h dropwises, insulation 1h.
2. be separated: under whipped state, material temperature adjustment to 5 ~ 10 DEG C sufficient crystallising step 1. obtained, filters and use 30g water wash, obtains the 2-five fluorine phenetole sulphonamide wet product of 159g (content 81%).
3. dry: 2-five fluorine phenetole sulphonamide wet product step 2. obtained is at 35 ~ 45 DEG C, and drying under reduced pressure under-0.096MPa, obtain the 2-five fluorine phenetole sulphonamide of 123g, product fusing point is 144 ~ 146 DEG C.
The preparation of embodiment 5 4-methoxyl group-3-nitrobenzene sulfonamide
1. ammonification: in 1000mL four-hole bottle, add 300g tetrahydrofuran (THF) successively and 128g (0.5mol) 4-methoxyl group-3-nitrobenzene sulfonyl chloride does bed material, under whipped state, the ammoniacal liquor of 51g (0.75mol) 25% is added drop-wise in bed material at 20 ~ 30 DEG C, and then 78.5g (0.51mol) sodium hydroxide solution is added drop-wise in bed material at 20 ~ 30 DEG C, 1h dropwises, insulation 1h.
2. be separated: under whipped state, in the material that 1. step obtains, add 200g water, then temperature adjustment to 0 ~ 5 DEG C sufficient crystallising, filter and use 30g water wash, obtain the 4-methoxyl group-3-nitrobenzene sulfonamide wet product of 122g (content 78%).
3. dry: 4-methoxyl group-3-nitrobenzene sulfonamide wet product step 2. obtained is at 35 ~ 45 DEG C, and drying under reduced pressure under-0.096MPa, obtain 93g4-methoxyl group-3-nitrobenzene sulfonamide, product fusing point is 134 ~ 136 DEG C.
The preparation of embodiment 6 4-acetylaminohydroxyphenylarsonic acid 2-methoxybenzenesulphoismide and 4-amino-2-methoxybenzenesulphoismide
1. ammonification: in 1000mL four-hole bottle, add 27.7g (0.50mol) ammonium chloride, 150g water, 200g ether and 128g (0.48mol) 4-acetylaminohydroxyphenylarsonic acid 2-Methoxybenzenesulfonyl chloride successively and do bed material, under whipped state, by 122g (1.0mol) sodium hydroxide solution at 15 ~ 30 DEG C, be added drop-wise in bed material, 1h dropwises, insulation 1h.
2. be separated: under whipped state, material temperature adjustment to 0 ~ 10 DEG C sufficient crystallising step 1. obtained, filters and use 30g water wash, obtains the 4-acetylaminohydroxyphenylarsonic acid 2-methoxybenzenesulphoismide wet product of 128g (content 79%).
3. molten, the acidifying of alkali: under whipped state, the sodium hydroxide of 370g (1.85mol) is joined in the 4-acetylaminohydroxyphenylarsonic acid 2-methoxybenzenesulphoismide of the 128g that 2. step obtains, be warming up to backflow 3h, be cooled to 50 DEG C, the hydrochloric acid of 176g30% is added (pH ≈ 7.5) in reactant again, in 50 DEG C of insulation 1h.
4. be separated: under whipped state, material temperature adjustment to 5 ~ 10 DEG C sufficient crystallising step 3. obtained, filters and use 30g water wash, obtains the 4-amino-2-methoxybenzenesulphoismide wet product of 119g (content 66%).
5. dry: 4-amino-2-methoxybenzenesulphoismide wet product step 4. obtained is 80 ~ 90 DEG C of dryings, and obtain 77g4-amino-2-methoxybenzenesulphoismide, product fusing point is 141 ~ 143 DEG C.
The preparation of embodiment 7-ethanoyl-2-methoxybenzenesulphoismide
1. ammonification: in 1000mL four-hole bottle; add 102g water, 200g ethyl acetate and 126g (0.5mol) 5-ethanoyl-2-Methoxybenzenesulfonyl chloride successively and do bed material; under whipped state; respectively by the ammoniacal liquor of 51g (0.75mol) 25% and 78.5g (0.51mol) sodium hydroxide solution at 35 ~ 45 DEG C; be added drop-wise in bed material in 1h simultaneously; ammoniacal liquor dropwises prior to sodium hydroxide solution, insulation 1h.
2. be separated: under whipped state, material temperature adjustment to 0 ~ 5 DEG C sufficient crystallising step 1. obtained, filters and use 30g water wash, obtains the 5-ethanoyl-2-methoxybenzenesulphoismide wet product of 139g (content 75%).
3. dry: 5-ethanoyl-2-methoxybenzenesulphoismide wet product step 2. obtained is at 50 ~ 60 DEG C, and drying under reduced pressure under-0.096MPa, obtain 103g5-ethanoyl-2-methoxybenzenesulphoismide, product fusing point is 143 ~ 146 DEG C.
The preparation of embodiment 8 2-methoxyl group-5-amino sulfonyl methyl benzoate
1. ammonification: in 1000mL four-hole bottle, add 27.7g (0.50mol) ammonium chloride, 150g water, 200g ethyl acetate and 115g (0.43mol) 5-chlorsulfonic acid-O-Anisic Acid methyl esters successively and do bed material, under whipped state, by 122g (1.0mol) sodium hydroxide solution at 35 ~ 45 DEG C, be added drop-wise in bed material, 1h dropwises, insulation 1h.
2. be separated: under whipped state, material temperature adjustment to 5 ~ 10 DEG C sufficient crystallising step 1. obtained, filters and use 30g water wash, obtains the 2-methoxyl group-5-amino sulfonyl methyl benzoate wet product of 116g (content 78%).
3. dry: 2-methoxyl group-5-amino sulfonyl methyl benzoate wet product step 2. obtained is at 50 ~ 60 DEG C, and drying under reduced pressure under-0.096MPa, obtain 89g2-methoxyl group-5-amino sulfonyl methyl benzoate, product fusing point is 174 ~ 176 DEG C.
The preparation of embodiment 92,4-dimethoxybenzenesulfonamide
1. ammonification: in 1000mL four-hole bottle, add ethanol 150g and 127g (0.53mol) 2,4-dimethoxybenzenesulfonyl chloride does bed material, after being warming up to 40 ~ 45 DEG C, under whipped state, the ammoniacal liquor of 100g (0.59mol) 10% is added drop-wise in bed material, 1h dropwises, be added drop-wise in reaction system by 80g (0.60mol) sodium hydroxide solution again, 1h dropwises, insulation 1h.
2. be separated: under whipped state, material temperature adjustment to 0 ~ 5 DEG C sufficient crystallising step 1. obtained, filters and use 30g water wash, obtains 2, the 4-dimethoxybenzenesulfonamide wet products of 119g (content 79%).
3. dry: 2,4-dimethoxybenzenesulfonamide wet products step 2. obtained are dry at 70 ~ 80 DEG C, and obtain 93g2,4-dimethoxybenzenesulfonamide, product fusing point is 165 ~ 167 DEG C.
Claims (10)
1. the preparation technology of logical formula I alcoxyl base class benzsulfamide and derivative thereof, with logical formula II alcoxyl base class benzene sulfonyl chloride and derivative thereof for raw material, under strong alkali compound exists, prepares through ammoniation agent aminating reaction;
Wherein, R represents (OCX
2cX
2)
mo (CX
2)
ncX
3;
R ' represents X or NO
2or NH
2or NHCOCH
3or COCH
3or CH
2cOCH
3or COOH or COOCH
3or COOCH
2cH
3or CX
3or OCX
3or OCX
2cX
3;
X represents hydrogen or halogen;
m＝0～100；
n＝0～15。
2. technique according to claim 1, is characterized in that, described strong alkali compound is selected from alkali-metal oxide compound, alkali-metal oxyhydroxide, the oxide compound of alkaline-earth metal or the oxyhydroxide of alkaline-earth metal.
3. technique according to claim 2, is characterized in that, described strong alkali compound is selected from least one in sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, hydrated barta, sodium oxide, potassium oxide, calcium oxide and barium oxide.
4. the technique according to claim 1 or 2 or 3, is characterized in that,
Described ammoniation agent is selected from ammoniacal liquor or ammonium salt;
Described ammonium salt is selected from least one in ammonium chloride, ammonium sulfate, monoammonium sulfate, ammonium phosphate, ammonium hydrogen phosphate and primary ammonium phosphate.
5. preparation technology according to claim 4, is characterized in that, described preparation technology comprises the following steps:
1. ammonification: logical formula II alcoxyl base class benzene sulfonyl chloride and derivative, ammoniation agent, strong alkali compound, the obtained material containing leading to formula I alcoxyl base class benzsulfamide and derivative thereof of reaction at 0 ~ 100 DEG C;
2. be separated: material step 1. obtained cools to 0 ~ 10 DEG C, and crystallization refilters and obtains wet product;
3. dry: wet product step 2. obtained is dry at 30 ~ 100 DEG C;
The following reaction formula of its technological reaction process (1) or reaction formula (2):
6. technique according to claim 5, is characterized in that, step 1. in also add solvent, the mass ratio of described logical formula II alcoxyl base class benzene sulfonyl chloride and derivative and solvent is 1:0 ~ 6.0; Described solvent is the mixture that water or water and organic solvent form; Wherein organic solvent is selected from least one in the similar homologue of methyl alcohol, ethanol, Virahol, ethyl formate, ethyl acetate, ether, isopropyl ether, methyl tertiary butyl ether, n-butyl ether, tetrahydrofuran (THF), hexanaphthene, methylcyclohexane, benzene, toluene, the above organic solvent or isomers;
The mass ratio of water and organic solvent is 1:0 ~ 6.0.
7. technique according to claim 4, is characterized in that, the concentration of described ammoniacal liquor is 5% ~ 30%.
8. technique according to claim 4, is characterized in that, when described ammoniation agent is ammoniacal liquor, described logical formula II alcoxyl base class benzene sulfonyl chloride and derivative thereof, ammoniacal liquor are with NH
4 +meter, strong alkali compound are with the OH of complete water-soluble rear formation
-meter, mol ratio is 1:1.1 ~ 1.5:1.0 ~ 1.5.
9. technique according to claim 4, is characterized in that, when described ammoniation agent is ammonium salt, described logical formula II alcoxyl base class benzene sulfonyl chloride and derivative thereof, ammonium salt are with NH
4 +meter, strong alkali compound are with the OH of complete water-soluble rear formation
-meter, mol ratio is 1:1.0 ~ 1.2:2.0 ~ 2.4.
10. technique according to claim 1, is characterized in that: described strong alkali compound directly in solid form or the solution being mixed with 10% ~ 50% be added in reaction system.
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| CN105439915A (en) * | 2015-12-30 | 2016-03-30 | 苏州诚和医药化学有限公司 | Preparation method of methyl 2-methoxy-5-sulfamoylbenzoate |
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| CN108117500A (en) * | 2017-11-24 | 2018-06-05 | 江苏慈星药业有限公司 | It is a kind of to reduce the method that aminating reaction technique generates waste water abraum salt in ammonia sulphur methyl esters production process |
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| CN109456231A (en) * | 2018-12-13 | 2019-03-12 | 临海市奥特休闲用品股份有限公司 | A kind of preparation method of 2- nitro-chlorobenzene -4- sulfonamide |
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