CN102952094A - Method of preparing 1,2-benzisothiazole-3-ketone compound - Google Patents
Method of preparing 1,2-benzisothiazole-3-ketone compound Download PDFInfo
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- CN102952094A CN102952094A CN2012103043461A CN201210304346A CN102952094A CN 102952094 A CN102952094 A CN 102952094A CN 2012103043461 A CN2012103043461 A CN 2012103043461A CN 201210304346 A CN201210304346 A CN 201210304346A CN 102952094 A CN102952094 A CN 102952094A
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Abstract
The invention provides a method of preparing a 1,2-benzisothiazole-3-ketone compound simply and economically at a high purity and a high yield, wherein a reaction mixture obtained by acting a 2-(alkyl sulphanyl) cyanobenzene compound and a halogenating agent at the presence of water is maintained at a low temperature about -20 DEG C to 40 DEG C, and an obtained solid content is recovered.
Description
Technical field
The present invention relates to the preparation method of BIT compound.Further specifically relating to can be with the preparation method of very high yield acquisition as the useful BIT compound such as antiseptic-germicide, anti-mycotic agent.
Background technology
In the patent documentation 1, as industrial favourable and do not use high price and the upper dangerous high material of operation, simple and easy and prepare economically 1, the method of 2-benzisothiazole-3-ketone compound discloses the method that 2-(alkylthio) cyanobenzene compound and halogenating agent are reacted in the presence of water.
Disclose in the patent documentation 2, in patent documentation 1 in the disclosed method, when 2-(alkylthio) cyanobenzene compound and halogenating agent are reacted in the presence of water, by the mineral acids such as hydrochloric acid, sulfuric acid, nitric acid are existed, thereby suppress the generation of by product, the method for preparing highly purified BIT compound.
The prior art document
[patent documentation]
[patent documentation 1] Japanese kokai publication hei 8-134051 communique
[patent documentation 2] TOHKEMY 2002-088072 communique.
Summary of the invention
The problem that invention will solve
Disclosed method is compared with method for making in the past in the patent documentation 1, can and obtain with high yield 1 with short operation, 2-benzisothiazole-3-ketone compound, but be difficult to the by product that generates in the reaction is fully removed by process for purification such as partial crystallizations, thereby obtain 1, the purity of 2-benzisothiazole-3-ketone compound is low, also has the leeway of improvement.
And then, the disclosed method in the patent documentation 2 of patent documentation 1 of having improved can suppress by product generation, obtain 1 with high purity, 2-benzisothiazole-3-ketone compound, but yield is not high, have 1, the loss of 2-benzisothiazole-3-ketone compound itself, economy is low, also has the leeway of improvement.
Thereby, the object of the invention is to, provide a kind of with higher yield, simple and easy and prepare economically the method for BIT compound.
The technique means of dealing with problems
The inventor etc. conduct in-depth research in order to solve aforementioned problems, found that, in the method for patent documentation 1 or 2 records, preparation 1, during 2-benzisothiazole-3-ketone compound, in order to obtain highly purified BIT compound, need to be than higher temperatures, filter under 40 ℃ the temperature etc. such as surpassing.Yet, the problem that the method exists yield to reduce.Here, by keeping the low temperature about-20～40 ℃, reactant with solid substance form filtering separation from reaction mixture, can be obtained the BIT compound with very high yield, thereby finished the present invention.
Further, the inventor etc. find first, in the solid substance that obtains by method of the present invention, except 1 of target, beyond the 2-benzisothiazole-3-ketone compound, also contain the dimer N that the BIT compound of 2 molecules is combined into by methylene radical, N '-methylene-bis (BIT) compound.
In addition, confirmed this N, N '-methylene-bis (BIT) compound is also useful as antiseptic-germicide, anti-mycotic agent etc.
Therefore, do not need aforementioned dimer is removed from the solid substance that obtains by method of the present invention as impurity, can suppress the loss of removing the BIT compound itself that operation causes owing to aforementioned impurity.
That is, the present invention relates to following general formula (2):
(in the formula, R
2R in expression and the following general formula (1)
2Identical atom or group) shown in the preparation method of BIT compound, it is characterized in that, comprise making following general formula (1):
(in the formula, R
1The alkyl of expression carbonatoms 1～4, R
2Expression hydrogen atom, the alkyl of carbonatoms 1～4, alkoxyl group, nitro, carboxyl or its ester or the halogen atom of carbonatoms 1～4) shown in 2-(alkylthio) cyanobenzene compound and halogenating agent in the presence of water, react the reaction process of acquisition reaction mixture; With
The previous reaction mixture is maintained low temperature, reclaim the recovery process of the solid substance that obtains.
In the preparation method's of the BIT compound of the present invention concrete example, reaction process carries out under-20～170 ℃.
In the preparation method's of the BIT compound of the present invention concrete example, recovery process carries out under-20～40 ℃.
Of the present invention 1, in the preparation method's of 2-benzisothiazole-3-ketone compound the aspect, the solid substance that obtains is for containing 1 shown in the general formula (2), N shown in 2-benzisothiazole-3-ketone compound and the following general formula (3), N '-methylene-bis (1, the 2-benzisothiazole-3-ketone) composition of compound
(in the formula, R
2R in expression and the aforementioned formula (1)
2Identical atom or group).
In the preparation method's of the BIT compound of the present invention aspect, 2-(alkylthio) cyanobenzene compound and the halogenating agent shown in the general formula (1) reacted in the presence of water and mineral acid.
The effect of invention
According to the present invention, provide a kind of by 2-(alkylthio) cyanobenzene compound and halogenating agent are reacted in the presence of water, obtain reaction mixture, the previous reaction mixture is maintained low temperature reclaim solid substance, thereby with very high yield, simple and easy and prepare economically the method for BIT compound.
Embodiment
Of the present invention 1, the preparation method of 2-benzisothiazole-3-ketone compound is by reacting 2-(alkylthio) cyanobenzene compound and the halogenating agent shown in the general formula (1) in the presence of water, thereby the BIT compound shown in the preparation general formula (2).
Among the present invention, the R in 2-(alkylthio) the cyanobenzene compound shown in the general formula (1)
1The alkyl of expression carbonatoms 1～4.As the alkyl of aforementioned carbonatoms 1～4, can list such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl etc.Wherein, preferable methyl, ethyl, n-propyl and the tertiary butyl.
R in 2-(alkylthio) the cyanobenzene compound shown in the general formula (1)
2Expression hydrogen atom, the alkyl of carbonatoms 1～4, alkoxyl group, nitro, carboxyl or its ester or the halogen atom of carbonatoms 1～4.As the alkyl of aforementioned carbonatoms 1～4, can list such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl etc.As the alkoxyl group of aforementioned carbonatoms 1～4, can list such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy etc.As the ester of aforementioned carboxyl, can list such as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl and butoxy carbonyl etc.As aforementioned halogen atom, can list such as chlorine atom and bromine atoms etc.Wherein, preferred hydrogen atom, methyl, ethyl, the tertiary butyl, methoxyl group, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, chlorine atom and nitro.
Concrete example as 2-(alkylthio) the cyanobenzene compound shown in the general formula (1), can list, for example the 2-(methylthio group) cyanobenzene, the 2-(ethylmercapto group) cyanobenzene, the positive rosickyite base of 2-() cyanobenzene, 2-(tertiary butyl sulfenyl) cyanobenzene, 3-methyl-2-(methylthio group) cyanobenzene, the 5-tertiary butyl-2-(methylthio group) cyanobenzene, 4-methoxyl group-2-(methylthio group) cyanobenzene, 3-nitro-2-(methylthio group) cyanobenzene, 3-nitro-2-(tertiary butyl sulfenyl) cyanobenzene, 4-chloro-2-(methylthio group) cyanobenzene, 4-carboxyl-2-(methylthio group) cyanobenzene and 4-methoxycarbonyl-2-(methylthio group) cyanobenzene etc.Wherein, from the viewpoint of the germ resistance excellence of easy acquisition, resultant, preferably use the 2-(methylthio group) cyanobenzene, 3-methyl-2-(methylthio group) cyanobenzene, the 5-tertiary butyl-2-(methylthio group) cyanobenzene, 4-methoxyl group-2-(methylthio group) cyanobenzene, 3-nitro-2-(tertiary butyl sulfenyl) cyanobenzene, 4-chloro-2-(methylthio group) cyanobenzene and 4-methoxycarbonyl-2-(methylthio group) cyanobenzene.
Need to prove, aforementioned 2-(alkylthio) cyanobenzene compound can use by any method this compound of preparation, for example can as record in the patent documentation 1, make general formula (4):
(in the formula, R
2R in expression and the general formula (1)
2Identical atom or group, X represent chlorine or bromine atoms.) shown in 2-halogeno-benzene formonitrile HCN compound and general formula (5):
(in the formula, R
1R in expression and the formula (1)
1Identical group.) shown in alkanethiol (alkanethiol) in the presence of alkali, react with nonhomogeneous system, thereby preparation.
Among the preparation method of BIT compound of the present invention,, can list such as chlorine, bromine, SULPHURYL CHLORIDE and sulfuryl bromide etc. as halogenating agent.Wherein, from the viewpoint grade of economy, preferably use chlorine or SULPHURYL CHLORIDE.
With respect to 1 mole of 2-(alkylthio) cyanobenzene compound, the usage ratio of aforementioned halogenating agent is preferably 0.8～3 mole, more preferably 1～2 mole.During 0.8 mole of the usage ratio deficiency of halogenating agent, there is unreacted 2-(alkylthio) cyanobenzene compound to become possibility many, that yield reduces, when the usage ratio of halogenating agent is above 3 moles in addition, the possibility of easy generation side reaction, yield reduction arranged.
Of the present invention 1, among the preparation method of 2-benzisothiazole-3-ketone compound, when 2-(alkylthio) the cyanobenzene compound shown in the general formula (1) and halogenating agent are reacted in the presence of water, with respect to 1 mole of 2-(alkylthio) cyanobenzene compound, the usage ratio of water is preferably 0.8～5 mole, more preferably 1～3 mole.During 0.8 mole of the usage ratio deficiency of water and when surpassing 5 moles, have to produce the possibility that side reaction, yield reduce.
Of the present invention 1, among the preparation method of 2-benzisothiazole-3-ketone compound, when 2-(alkylthio) the cyanobenzene compound shown in the general formula (1) and halogenating agent are reacted, can in water, add mineral acid in the presence of water, use with the inorganic acid aqueous solution form.By add mineral acid in water, the selectivity during reaction improves, and can suppress the generation of by product.
As aforementioned mineral acid, can list, such as, hydrochloric acid, sulfuric acid and nitric acid etc.
The concentration of aforementioned inorganic acid aqueous solution is not particularly limited, and usually, can preferably use 10 quality %～saturation concentrations in the situation of hydrochloric acid, can preferably use 10～50 quality % in the situation of sulfuric acid or nitric acid.
The consumption of aforementioned mineral acid is preferably 0.1～1.5 mole according to the kind of the mineral acid that uses, concentration and difference with respect to 1 mole of 2-(alkylthio) cyanobenzene compound, is 0.01～2 mole.But with respect to 1 mole of 2-(alkylthio) cyanobenzene compound, the amount of the water that contains in the mineral acid is preferably used below 5 moles.
Among the preparation method of BIT compound of the present invention, not necessarily need to use solvent, can use as required solvent.By using solvent, the situation that reaction is carried out smoothly is more.As solvent, be not particularly limited, can list hydro carbons such as normal hexane, hexanaphthene and normal heptane; The halogenated hydrocarbons such as ethylene dichloride, methylene dichloride and chloroform; Benzene,toluene,xylene and monochloro benzene etc. are aromatic hydrocarbon based; DMF and dimethyl sulfoxide (DMSO) etc.Wherein, can preferably use toluene and monochloro benzene.
With respect to 2-(alkylthio) cyanobenzene compound 100 mass parts, the consumption of aforementioned solvents is generally 20～3000 mass parts.During usefulness quantity not sufficient 20 mass parts of solvent, responding is difficult to the possibility of carrying out smoothly.In addition, when the consumption of solvent surpasses 3000 mass parts, the possibility that has volumetric efficiency to worsen.
Temperature of reaction in the previous reaction is generally-20～170 ℃, is preferably 0～150 ℃.Temperature of reaction is not enough-20 ℃ the time, and the speed that responds is slow, and reaction needed for a long time may.In addition, when temperature of reaction surpasses 170 ℃, there is side reaction to become incidental possible.Reaction times is generally 1～40 hour according to temperature of reaction etc. and different.
Resulting reaction mixture is maintained low temperature, reclaim resulting solid substance.Method as reclaiming resulting solid substance can list, the method that the solid substance that direct partial crystallization is obtained filters, with the alkali extracting (
) after carry out acid out and method that the solid substance that obtains filters etc.
Maintain low temperature and the temperature of low temperature during the solid substance that obtains is generally-20～40 ℃ as recovery, be preferably-10～30 ℃, more preferably-10～25 ℃.When temperature surpasses 40 ℃, there be the loss of BIT compound in filtrate to become many, the possibility that yield reduces.Temperature is not enough-20 ℃ the time, and the effect that can not get matching with it is unfavorable on economy.
As 1 shown in the general formula (2) of the target compound that obtains like this, the concrete example of 2-benzisothiazole-3-ketone compound, can list, for example 1,2-benzisothiazole-3-ketone, 7-methyl isophthalic acid, 2-benzisothiazole-3-ketone, the 5-tertiary butyl-1,2-benzisothiazole-3-ketone, 6-methoxyl group-1,2-benzisothiazole-3-ketone, 7-nitro-1,2-benzisothiazole-3-ketone, 6-chloro-1,2-benzisothiazole-3-ketone, 6-carboxyl-BIT and 6-methoxycarbonyl-BIT etc.
According to the preparation method of BIT compound of the present invention, the solid substance that obtains is for containing the BIT compound shown in the general formula (2) and following general formula (3):
(in the formula, R
2R in expression and the aforementioned formula (1)
2Identical atom or group.) shown in N, the composition of N '-methylene-bis (BIT) compound.
Containing 1 shown in the general formula (2), N shown in 2-benzisothiazole-3-ketone compound and the general formula (3), N '-methylene-bis (1, the 2-benzisothiazole-3-ketone) in the composition of compound, N shown in the general formula (3), the content of N '-methylene-bis (BIT) compound is generally 0.2～5 quality %, is preferably 0.5～5 quality %, 2～5 quality % more preferably.
As the N shown in the general formula (3), the concrete example of N '-methylene-bis (BIT) compound can list, N for example, N '-methylene-bis (BIT) etc.
The N that contains in the BIT compound of the present invention, N '-methylene-bis (BIT) compound can be used as antibiotic and/or anti-mycotic agent composition and preferred the use.This compound can with the same purposes of BIT compound in use, for example can directly use separately a kind, also can with other components matching, use as containing the antibiotic of this compound and/or anti-mycotic agent composition.That is, this compound also can cooperate with solvent or solid carrier, as antibiotic and/or anti-mycotic agent composition and use.As preferred solvent, can list such as water, ethylene glycol, propylene glycol, glycol ether, dipropylene glycol, polyoxyethylene glycol, polypropylene glycol, glycol ether, methyl alcohol, ethanol, propyl alcohol, phenylethyl alcohol, phenoxypropanol, acetone, methylethylketone, vinyl acetic monomer, N-BUTYL ACETATE, triacetyl citric acid (Network エ Application acid ト リ ア セ チ Le), glycerine triacetate, Texacar PC and methylcarbonate etc.These solvents can use separately a kind, also can will be used in combination more than 2 kinds.For N of the present invention, N '-methylene-bis (1, the 2-benzisothiazole-3-ketone) compound, its using method and purposes are not limited, after it is dissolved in organic solvent, with this organic solution dilution, contain this compound antibiotic and/or anti-mycotic agent composition use thereby can be used as by the use solvent.In addition, aforementioned antibiotic and/or anti-mycotic agent composition also can further contain other compositions of at least a kind such as antiseptic-germicide, anti-mycotic agents such as BIT compounds.Aforementioned antibiotic and/or anti-mycotic agent composition can be acid, neutral or alkaline.
As preferred solid carrier, can list, for example cyclodextrin, silicon-dioxide, diatomite, wax, cellulose-based material, alkali and alkali earths (for example, sodium, magnesium, potassium) metal-salt (for example, muriate, nitrate, bromide, vitriol) and charcoal etc.In addition, as the stablizer of composition, can contain at least a kind thickening material, frostproofer, dispersion agent, tensio-active agent, inhibitor or alkali metal hydroxide etc.
Contain N, the antibiotic and/or anti-mycotic agent composition of N '-methylene-bis (BIT) compound for example can be used as industrial process waters (
), the fluid of condensing tower, draining processing, water ballast (Ballast water), heat exchanger, paper pulp and used for paper processing and additive, plastics, coating, latex, coating agent, spackling, caking agent, sensitizer (
), printing fluid, household supplies, industrial detergent, metal processing uses with fluid, agricultural antiseptic-germicide, the anti-mycotic agent with the preservation of the preservation of auxiliary, tensio-active agent, medical instruments etc. with fluid, leather and leatherware, textile article, timber and woodwork, petroleum refinement.
Contained N in the BIT compound that obtains by the present invention, N '-methylene-bis (BIT) compound exhibits goes out anti-microbial activity and anti-mycotic activity.Such as demonstrating comprising streptococcus pyogenes K(Streptococcus pyogenes K) the gram-positive microorganism such as suis (Streptococcus) and such as the high anti-microbial activity of the Gram-negative bacterias such as Salmonellas (Salmonella) that comprise salmonella dublin (Salmonella dublin).In addition, demonstrate with the Candida (Candida) that for example comprises Candida albicans (Candida alvicans) of pass the United Nations General Assembly of people, domestic animal with comprise the high anti-mycotic activity of the Trichophyton (Trichophyton) of trichophyton mentagrophytes (Trichophyton mentagrophytes).In addition, this compound demonstrates activity in large pH scope, and its activity is subjected to the impact of body fluid such as bile, serum etc. hardly.N, N '-methylene-bis (BIT) compound is also effective to phytopathogen.Can list, the seedling of the disease of the oat that for example wheat powdery mildew mutation (Erysiphe graminis var. avenae) causes, the tobacco that tobacco downy mildew (Peronospora tabacina) causes (
) in disease and the disease in the seedling of the wheat that causes of puccinia triticinia (Puccinia triticina), these can pass through N of the present invention, N '-methylene-bis (BIT) compound and effectively prevention.
These N, N '-methylene-bis (BIT) compound can be directly or indirectly be used for by be confined to skin, hair, nail etc. have keratic shallow keratinized tissue (
) the middle skin wire-like bacteria that infects (
) caused tinea alba (
), for example a tinea alba (
), sufficient tinea alba (
), the first tinea alba (
) etc. topical therapeutic, perhaps as common sterilizing agent or urinary tract sterilizing agent.
Embodiment
Below further describe the present invention by preparation example, embodiment, but the present invention is not subjected to the restriction of these embodiment etc.
Preparation example ［ 2-(methylthio group) cyanobenzene synthetic ］
Under nitrogen atmosphere, in the four neck flasks of the internal volume 500ml that possesses stirrer, thermometer, dropping funnel and prolong, adding 2-chlorobenzonitrile 27.5g(0.2 mole), the tetra-n-butyl ammonium bromide aqueous solution 1.0g of monochloro benzene 30.0g, 50 quality %, stir on one side, lower to the sodium-salt aqueous solution 51.4g(0.22 mole that dripped 30 quality % thiomethyl alcohols in 5 hours at 60～65 ℃ on one side), after dripping end, further under uniform temp, reacted 12 hours.
After reaction finishes, reaction solution is cooled to room temperature, heat up in a steamer desolventizing after, carry out underpressure distillation, thereby obtain the 2-(methylthio group) 139～140 ℃ of cyanobenzene 29.5g(boiling points/931Pa).Yield with respect to the 2-chlorobenzonitrile is 99%.
Embodiment 1
In the four neck flasks of the internal volume 500ml that possesses stirrer, thermometer and prolong, the 2-(methylthio group that adding obtains by the method identical with preparation example) cyanobenzene 29.8g(0.2 mole), monochloro benzene 50.0g and water 4.3g(0.24 mole), stir on one side, lower to being blown into chlorine 15.6g(0.22 mole in 2 hours at 45～50 ℃ on one side), further be heated to 65～70 ℃, reacted 1 hour.
After reaction finishes, under uniform temp, add 20 quality % aqueous sodium hydroxide solution 41.0g, be cooled to-10 ℃.With the crystal filtering separation of separating out, with the washing of monochloro benzene, carry out drying, obtain to contain N, the BIT 29.8g(0.197 mole of N '-methylene-bis (BIT) compound).With respect to the 2-(methylthio group) yield of cyanobenzene is 98.5%.By the purity of the resulting BIT of high effective liquid chromatography for measuring, the result is 97.1%, contains the N of 2.9 quality %, N '-methylene-bis (BIT).
Embodiment 2
In the four neck flasks of the internal volume 500ml that possesses stirrer, thermometer and prolong, the 2-(methylthio group that adding obtains by the method identical with preparation example) cyanobenzene 29.8g(0.2 mole), monochloro benzene 50.0g and 35 0.06 mole of quality % hydrochloric acid 6.6g(hydrochloric acid, 0.24 mole in water), stir on one side, lower to being blown into chlorine 15.6g(0.22 mole in 2 hours at 45～50 ℃ on one side), further be heated to 65～70 ℃, reacted 1 hour.
After reaction finishes, under uniform temp, add 20 quality % aqueous sodium hydroxide solution 41.0g, be cooled to 0 ℃.With the crystal filtering separation of separating out, with the washing of monochloro benzene, carry out drying, obtain to contain N, the BIT 29.9g(0.198 mole of N '-methylene-bis (BIT) compound).With respect to the 2-(methylthio group) yield of cyanobenzene is 99.0%.By the purity of the resulting BIT of high effective liquid chromatography for measuring, the result is 98.5%, contains the N of 1.5 quality %, N '-methylene-bis (BIT).
Embodiment 3
Under nitrogen atmosphere, in the four neck flasks of the internal volume 500ml that possesses stirrer, thermometer, dropping funnel and prolong, adding 2-chlorobenzonitrile 27.5g(0.2 mole), monochloro benzene 30.0g, 50 quality % tetra-n-butyl ammonium bromide aqueous solution 1.0g, stir on one side, lower to the sodium-salt aqueous solution 51.4g(0.22 mole that dripped 30 quality % thiomethyl alcohols in 5 hours at 60～65 ℃ on one side), after dripping end, further under uniform temp, reacted 12 hours.
After reaction finishes, reaction solution is cooled to 25 ℃, separatory obtains organic layer, in the organic layer that obtains, add 35 0.06 mole of quality % hydrochloric acid 6.6g(hydrochloric acid, 0.24 mole in water), stir on one side, lower to being blown into chlorine 15.6g(0.22 mole in 2 hours at 45～50 ℃ on one side), further be heated to 65～70 ℃, reacted 1 hour.
After reaction finishes, under uniform temp, add 20 quality % aqueous sodium hydroxide solution 41.0g, be cooled to 20 ℃.With the crystal filtering separation of separating out, with the washing of monochloro benzene, carry out drying, obtain to contain N, the BIT 29.8g(0.197 mole of N '-methylene-bis (BIT) compound).Yield with respect to the 2-chlorobenzonitrile is 98.5%.By the purity of the resulting BIT of high effective liquid chromatography for measuring, the result is 99.2%, contains the N of 0.8 quality %, N '-methylene-bis (BIT).
Embodiment 4
In the four neck flasks of the internal volume 500ml that possesses stirrer, thermometer and prolong, the 2-(methylthio group that adding obtains by the method identical with preparation example) cyanobenzene 29.8g(0.2 mole), monochloro benzene 50.0g and 35 0.06 mole of quality % hydrochloric acid 6.6g(hydrochloric acid, 0.24 mole in water), stir on one side, lower to being blown into chlorine 15.6g(0.22 mole in 2 hours at 45～50 ℃ on one side), further be heated to 65～70 ℃, reacted 1 hour.
After reaction finishes, under uniform temp, add 20 quality % aqueous sodium hydroxide solution 41.0g, be cooled to 30 ℃.With the crystal filtering separation of separating out, with the washing of monochloro benzene, carry out drying, obtain to contain N, the BIT 29.6g(0.196 mole of N '-methylene-bis (BIT) compound).With respect to the 2-(methylthio group) yield of cyanobenzene is 98.0%.By the purity of the resulting BIT of high effective liquid chromatography for measuring, the result is 99.5%, contains the N of 0.5 quality %, N '-methylene-bis (BIT).
Comparative example
In the four neck flasks of the internal volume 500ml that possesses stirrer, thermometer and prolong, adding 2-(methylthio group) cyanobenzene 29.8g(0.2 mole), monochloro benzene 50.0g and 35 0.06 mole of quality % hydrochloric acid 6.6g(hydrochloric acid, 0.24 mole in water), stir on one side, lower to being blown into chlorine 15.6g(0.22 mole in 2 hours at 45～50 ℃ on one side), further be heated to 65～70 ℃, reacted 1 hour.
After reaction finishes, under uniform temp, add 20 quality % aqueous sodium hydroxide solution 41.0g, be cooled to 45 ℃.With the crystal filtering separation of separating out, with the washing of monochloro benzene, carry out drying, obtain to contain N, the BIT 29.0g(0.192 mole of N '-methylene-bis (BIT) compound).With respect to the 2-(methylthio group) yield of cyanobenzene is 96.0%.By the purity of the resulting BIT of high effective liquid chromatography for measuring, the result is 99.9%, N, N '-methylene-bis (BIT) less than 0.1 quality %.
Embodiment 5
Mix dipropylene glycol 28g and water 3.7g among the solid substance 10g that obtains by filtration in the embodiment 1.Stir aforementioned mixture on one side, Yi Bian add 30 quality % aqueous sodium hydroxide solution 8.7g, obtain the insolubles of white.With the insolubles filtering separation that obtains, with methyl alcohol and water washing, the dry white crystal that obtains.The crystal that obtains is carried out NMR to be measured.By measurement result, be defined as general formula (6):
Shown N, N '-methylene-bis (BIT).
Embodiment 6
By in ball mill, comprising N, N '-methylene-bis (1, the 2-benzisothiazole-3-ketone) mixture that 1 part, 1 part of dispersion agent being formed by the mixture of methylene radical-dinaphthyl-β-disodium sulfonate and naphthalene-β-sodium sulfonate and water are 80 parts is pulverized the preparation dispersion.Add 9 parts of above-mentioned dispersions in 1000 parts in the water that the nonionogenic tenside that forms to the condenses that contains by oxyethane and alkylphenol is 0.15 part.After said composition being interspersed among the seedling of oat, the spore of inoculation wheat powdery mildew mutation.Afterwards, under the environment of the germination that is suitable for spore and infection, keep the seedling of aforementioned oat, find to be prevented fully by this fungus-caused oat disease.
Embodiment 7
Similarly to Example 6 operation, use N, N '-methylene-bis (BIT) prepares dispersion, in 1000 parts in the water that the nonionogenic tenside that forms to the condenses that contains by oxyethane and alkylphenol is 0.15 part, add 45 parts of above-mentioned dispersions.After said composition being interspersed among the seedling of tobacco, the spore of inoculation tobacco downy mildew.Afterwards, under the environment of the germination that is suitable for spore and infection, keep the seedling of aforementioned tobacco, find that the prevention rate by the disease in the seedling of this fungus-caused tobacco is 95%.
Embodiment 8
Similarly to Example 6 operation, use N, N '-methylene-bis (BIT) prepares dispersion, in 1000 parts in the water that the nonionogenic tenside that forms to the condenses that contains by oxyethane and alkylphenol is 0.15 part, add 9 parts of above-mentioned dispersions.After said composition being interspersed among the seedling of wheat, the spore of inoculation puccinia triticinia.Then, under the environment of the germination that is suitable for spore and infection, keep the seedling of aforementioned wheat, find to be prevented fully by the disease in the seedling of this fungus-caused wheat.
Claims (5)
1. the preparation method of BIT compound shown in the following general formula (2),
In the formula (2), R
2R in expression and the following general formula (1)
2Identical atom or group,
It is characterized in that, comprise that 2-(alkylthio) the cyanobenzene compound and the halogenating agent that make shown in the following general formula (1) react in the presence of water, obtain the reaction process of reaction mixture; With
The previous reaction mixture is maintained low temperature, reclaims the recovery process of the solid substance that obtains,
In the formula (1), R
1The alkyl of expression carbonatoms 1～4, R
2Expression hydrogen atom, the alkyl of carbonatoms 1～4, alkoxyl group, nitro, carboxyl or its ester or the halogen atom of carbonatoms 1～4.
2. the preparation method of BIT compound according to claim 1, wherein, reaction process carries out under-20～170 ℃.
3. the preparation method of BIT compound according to claim 1, wherein, recovery process carries out at-20～40 ℃.
4. according to claim 11, the preparation method of 2-benzisothiazole-3-ketone compound, wherein, the solid substance that obtains is for containing 1 shown in the general formula (2), N shown in 2-benzisothiazole-3-ketone compound and the following general formula (3), the composition of N '-methylene-bis (BIT) compound
In the formula, R
2Represent atom or the group identical with aforementioned formula (1).
5. the preparation method of BIT compound according to claim 1 wherein, reacts 2-(alkylthio) cyanobenzene compound and the halogenating agent shown in the general formula (1) in the presence of water and mineral acid.
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| CN102731428A (en) * | 2011-03-31 | 2012-10-17 | 住友精化株式会社 | N, n'-methylenebis(1,2-benzisothiazoline-3-ketone) compound and manufacture method thereof |
| CN115448860A (en) * | 2022-09-16 | 2022-12-09 | 上海海客宜家生物科技有限公司 | Synthetic method of o-methylthiobenzonitrile |
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| JP2013043882A (en) * | 2011-08-26 | 2013-03-04 | Sumitomo Seika Chem Co Ltd | Method for producing 1,2-benzisothiazolin-3-one compound |
| CN107162998B (en) * | 2014-05-26 | 2019-10-08 | 寿光新泰精细化工有限公司 | A kind of synthetic method of 1,2- benzisothiazole-3-ketone compound |
| US9334248B2 (en) | 2014-05-26 | 2016-05-10 | Shouguang Syntech Fine Chemical Co., Ltd. | Synthetic method for the preparation of 1, 2-benzisothiazolin-3-one |
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| JPS53111064A (en) * | 1977-03-08 | 1978-09-28 | Nippon Soda Co Ltd | Preparation of 3-chloro-1,2-benzoisothiazole-1,1-dioxide |
| CN1119645A (en) * | 1994-07-05 | 1996-04-03 | 住友精化株式会社 | Method for producing 1,2-benzisothiazol-3-ones 21678/01 |
| JP2002088072A (en) * | 2000-09-14 | 2002-03-27 | Sumitomo Seika Chem Co Ltd | Method for producing 1,2-benzisothiazol-3-one |
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| JP3152573B2 (en) * | 1994-11-09 | 2001-04-03 | 住友精化株式会社 | Method for producing 1,2-benzisothiazol-3-ones |
| CN1280279C (en) * | 2003-09-10 | 2006-10-18 | 北京大学药学院 | Dibenzo-isozaolone compounds and their synthesis process and application |
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| JPS53111064A (en) * | 1977-03-08 | 1978-09-28 | Nippon Soda Co Ltd | Preparation of 3-chloro-1,2-benzoisothiazole-1,1-dioxide |
| CN1119645A (en) * | 1994-07-05 | 1996-04-03 | 住友精化株式会社 | Method for producing 1,2-benzisothiazol-3-ones 21678/01 |
| JP2002088072A (en) * | 2000-09-14 | 2002-03-27 | Sumitomo Seika Chem Co Ltd | Method for producing 1,2-benzisothiazol-3-one |
| CN101602742A (en) * | 2009-07-02 | 2009-12-16 | 浙江化工科技集团有限公司 | A kind of 1, the synthetic method of 2-benzo isothiazole compound |
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| CN102731428A (en) * | 2011-03-31 | 2012-10-17 | 住友精化株式会社 | N, n'-methylenebis(1,2-benzisothiazoline-3-ketone) compound and manufacture method thereof |
| CN115448860A (en) * | 2022-09-16 | 2022-12-09 | 上海海客宜家生物科技有限公司 | Synthetic method of o-methylthiobenzonitrile |
| CN115448860B (en) * | 2022-09-16 | 2024-04-02 | 上海海客宜家生物科技有限公司 | Synthesis method of o-methylthio benzonitrile |
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