CN104262278A - Preparation method of isoxaflutole - Google Patents
Preparation method of isoxaflutole Download PDFInfo
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- CN104262278A CN104262278A CN201410443186.8A CN201410443186A CN104262278A CN 104262278 A CN104262278 A CN 104262278A CN 201410443186 A CN201410443186 A CN 201410443186A CN 104262278 A CN104262278 A CN 104262278A
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- OYIKARCXOQLFHF-UHFFFAOYSA-N CS(c(cc(C(F)(F)F)cc1)c1C(c1c(C2CC2)[o]nc1)=O)(=O)=O Chemical compound CS(c(cc(C(F)(F)F)cc1)c1C(c1c(C2CC2)[o]nc1)=O)(=O)=O OYIKARCXOQLFHF-UHFFFAOYSA-N 0.000 description 1
- LJAPBTJZVJLHBR-UHFFFAOYSA-N CSc(cc(C(F)(F)F)cc1)c1C(c1c(C2CC2)[o]nc1)=O Chemical compound CSc(cc(C(F)(F)F)cc1)c1C(c1c(C2CC2)[o]nc1)=O LJAPBTJZVJLHBR-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of isoxaflutole. The structure of the isoxaflutole is disclosed as Formula (II). The method comprises the following step: contacting a compound disclosed as Formula (I) with an oxidizer, wherein the oxidizer contains peroxy organic acid; the peroxy organic acid is a compound disclosed as Formula (III), wherein X, Y and Z are identical or different and respectively independently hydrogen, halogen, or C1-C3 substituted or non-substituted alkyl group. The preparation method disclosed by the invention has the advantages of short reaction time, thorough reaction, high reaction yield, low raw material cost, mild reaction conditions and the like.
Description
Technical field
The invention belongs to chemical industry and pharmacy field, relate to the preparation method of a kind of isoxazole humulone (4-(4-trifluoromethyl-2-sulfonyloxy methyl benzoyl)-5-cyclopropyl isoxazole) particularly.
Background technology
Rhone-Poulenc Agriculture Ltd of France disclosed in 1989 has weeding activity isoxazole herbicide (EP0418175); CN1069268A disclosed benzoyl isooxazole class weedicide in 1992; wherein isoxazole humulone (isoxaflutole); better active; its chemistry 4-(4-trifluoromethyl-2-sulfonyloxy methyl benzoyl)-5-cyclopropyl isoxazole by name, trade name is that (Balance) is thought in hundred agricultures.The biological activity of isoxazole humulone makes it as the good maize and soybean Tian Kuanye class weedicide of selectivity, and its preparation and application are just subject to extensive concern at present.
CN1069268A also discloses three kinds of synthetic methods of isoxazole herbicide, wherein a kind of oxidation style for being shown below, R
1represent cyclopropyl, R
2represent chlorine, bromine or trifluoromethyl:
Also mention in the specification sheets of CN1069268A, employing methylene dichloride is solvent, and metachloroperbenzoic acid is that oxygenant carries out oxidizing reaction at-40 DEG C to 0 DEG C.
But metachloroperbenzoic acid the oxidant feed being not suitable as suitability for industrialized production use because m-chloro-benzoic acid peroxide not only price is high expensive, price per ton is about 400,000, and consumption is large.Because the mol ratio of compound shown in oxygenant and formula (V) is more than 2:1, the molecular weight of metachloroperbenzoic acid is 172, in such production, the unit consumption of metachloroperbenzoic acid can exceed the unit consumption of formula (V), product photooxidant raw materials cost about about 400,000 per ton, and the temperature of negative 40 DEG C also not easily reaches in general factory.Therefore be difficult to promote in the Chemicals that routinize are produced.
Therefore, existing market needs a kind of with low cost method preparing isoxazole humulone of exploitation badly.
Summary of the invention
The object of this invention is to provide a kind of preparation method of isoxazole humulone, the method can overcome the defect of cost intensive when adopting prior art to prepare isoxazole humulone, and the method for the present invention has the advantage such as low raw-material cost, reaction conditions gentleness, speed is fast, yield is high, production safety.
The present inventor finds under study for action, according to the method for prior art, in the process of the compound shown in a compounds accepted way of doing sth (II) shown in employing formula (I), compound shown in formula (I) is also unstable, when temperature is more than 70 DEG C, open loop side reaction will be accelerated greatly, forms the compound impurities shown in formula (IV), and the yield of the compound shown in formula (II) is reduced.
The present inventor also finds; in the reaction by the compound shown in the preparation of compounds of formula (II) shown in formula (I); according to the methylene dichloride of prior art to coordinate with hydrogen peroxide system and/or metachloroperbenzoic acid react time; reaction is carried out slowly; or selectivity is poor; even if raised temperature is to normal temperature (25 DEG C), reacts after 5 hours, also only can generate the intermediate shown in a small amount of formula (M343).When wanting the compound described in synthesis type (II), the higher solvent of other boiling point such as chlorobenzene etc. can only be replaced with, even if but after temperature of reaction is brought up to about 100 DEG C, the reaction times still can be very long, and the yield of compound described in formula (II) is not high.And oxidizing reaction has much harm when at high temperature carrying out.Time such as using aqueous hydrogen peroxide solution as oxygenant, MSDS (chemical producting safety specification sheets) shows, and when temperature is to more than 100 DEG C, the hydrogen peroxide in aqueous hydrogen peroxide solution sharply decomposes, discharge a large amount of oxygen and heat, make to produce the very large security risk of existence.
The present inventor also finds, carry out to make reaction milder and adopt active lower oxygenant to carry out above-mentioned reaction time, when selecting lower temperature to react, have again and there is another kind of security risk: when temperature is lower than certain activation temperature, the oxygenant in batches added just can not consume in time, and in reaction system, oxygenant can constantly be accumulated; If now reaction conditions slight change, when such as raising reacting liquid temperature, once arrive the initiation point of reaction, reaction system can continue heat release, the temperature of reaction solution is improved constantly, and speed of response is also constantly accelerated, simultaneous oxidation agent fast decoupled, release the gases such as a large amount of oxygen, so just may cause the security risks such as punching material, blast.
When the present inventor is surprised to find that the oxygenant of peroxide organic acid as above-mentioned reaction adopting specific organic acid and hydrogen peroxide donor to be formed after having drawn above-mentioned experience and lessons, can ensure to react the generation carrying out and can guarantee not having this kind of by product shown in formula IV at a lower temperature; And the organic acid added fast corresponding to specific peroxide organic acid of the present invention can make to react quick generation, thus constantly consume hydrogen peroxide donor, it is not accumulated, and removed the heat of generation in time, so just there is no security risk; And the reaction times is short and thorough, reaction yield is high.
In addition, organic acid corresponding to peroxide organic acid of the present invention or this organic acid aqueous solution itself have good solvability to the compound shown in formula (I), also reaction can be made even if therefore do not add organic solvent to carry out smoothly as reaction medium, and the by product of reaction is mainly the nontoxic by product such as water, carbonic acid gas, boric acid, so technique of the present invention very environmental protection.
To achieve these goals, the invention provides a kind of preparation method of isoxazole humulone, the structure of described isoxazole humulone is such as formula shown in (II), and the method comprises the compound shown in formula (I) and oxidising agent, containing peroxide organic acid in described oxygenant; Described peroxide organic acid is the compound shown in formula (III), and in formula (III), X, Y and Z are identical or different, is the one in the substituted or unsubstituted alkyl of hydrogen, halogen, C1-C3 independently of one another,
The reaction conditions gentleness adopting method provided by the invention to prepare isoxazole humulone can be found out from the result of embodiments of the invention, and can make in the short period of time to be swift in response, feed stock conversion all can reach more than 98.7%, even can reach 100%, the purity of product can reach more than 90%, and the yield of product also can reach more than 91%.Trace it to its cause, may be because above-mentioned specific peroxide organic acid oxidisability is strong, the temperature of reaction system is reduced greatly, thus makes to ensure to react the generation carrying out and can guarantee not having this kind of by product shown in above-mentioned formula IV at a lower temperature; And when adding corresponding to above-mentioned specific peroxide organic acid organic acid fast, can make to react quick generation, thus the hydrogen peroxide donor constantly in consumption reaction system, make it can not continue accumulation, there is no security risk; And preparation can be made to have the advantages such as the reaction times is short, reaction is thorough, reaction yield is high, low raw-material cost, reaction conditions are gentle such as formula the humulone of isoxazole shown in (II).
Other features and advantages of the present invention are described in detail in embodiment part subsequently.
Embodiment
Below the specific embodiment of the present invention is described in detail.Should be understood that, embodiment described herein, only for instruction and explanation of the present invention, is not limited to the present invention.
The invention provides a kind of preparation method of isoxazole humulone, the structure of described isoxazole humulone is such as formula shown in (II), and the method comprises the compound shown in formula (I) and oxidising agent, containing peroxide organic acid in described oxygenant; Described peroxide organic acid is the compound shown in formula (III), and in formula (III), X, Y and Z are identical or different, is the one in the substituted or unsubstituted alkyl of hydrogen, halogen, C1-C3 independently of one another,
The preparation method of above-mentioned isoxazole humulone provided by the invention can ensure to react the generation carrying out and can guarantee not having or only having a small amount of by product at a lower temperature; And above-mentioned specific peroxide organic acid of the present invention can be consumed in the reaction fast, thus do not accumulate and do not have security risk, above-mentioned preparation method of the present invention also has the advantage that the reaction times is short, reaction is carried out thoroughly and reaction yield is high.
Under preferable case, in the preparation method of isoxazole humulone of the present invention, the condition of described contact can comprise: the temperature of contact is 0-95 DEG C; More preferably the temperature of described contact is 10-80 DEG C.
In the present invention, to time of described contact, there is no particular limitation, aforesaid method of the present invention can realization response in the short period of time carry out very thoroughly and reaction yield very high, therefore, those skilled in the art can control the reaction times according to practical situation.Under preferable case, in method of the present invention, in order to obtain the product of higher yield, the time of described contact is 1.5-8h; More preferably the time contacted is 1.5-5h.
The present inventor finds, when temperature of reaction is too low, such as, time lower than 0 DEG C, part peroxide of the present invention organic acid also has certain activity, but the production of cold condition makes production cost higher, is not best working condition.The present inventor also finds, when temperature of reaction is higher than 100 DEG C, easily induce reaction bumping, and peroxide organic acid fast decoupled, make peroxide organic acid utilization ratio not high, and the purity of the product obtained is lower.
Preferably, in the preparation method of isoxazole humulone of the present invention, in the organic acid shown in formula (III), described X, Y and Z can be identical or different, can be the one in the halo alkyl of hydrogen, fluorine, chlorine, methyl, ethyl, propyl group, sec.-propyl, C1-C3 independently of one another.
In the present invention, the halo alkyl of described C1-C3 can comprise the Halothane of the fluoro alkyl of C1-C3, the chloro alkyl of C1-C3, the bromo alkyl of C1-C3, the fluorine chloro alkyl of C1-C3 and C1-C3 at least one in alkyl.
In the present invention, described alkyl can comprise at least one in alkyl and thiazolinyl.
More preferably, in the preparation method of isoxazole humulone of the present invention, described peroxide organic acid is for being selected from least one in trifluoro Peracetic Acid, difluoro Peracetic Acid, a fluorine Peracetic Acid, difluoro monochloroperacetic acid, a fluorine dichloroperacetic acid, monochloroperacetic acid, dichloroperacetic acid, trichloroperacetic acid, a fluorine monochloroperacetic acid, 2-chlorine Perpropionic Acid, 3-chlorine Perpropionic Acid, 2,2-dichloro Perpropionic Acids, Perpropionic Acid, Perbutyric Acid and Peracetic Acid.
In the preparation method of isoxazole humulone of the present invention, preferred described peroxide organic acid is by obtaining the organic acid corresponding to the compound shown in formula (III) and hydrogen peroxide donor exposure.In the present invention, the organic acid corresponding to compound shown in described formula (III) is defined as the compound shown in following formula (VI):
Wherein, in formula (VI), X, Y in the compound shown in X, Y with the radical species represented by Z with formula (III) are identical with Z, and the present invention does not repeat them here.
In the preparation method of isoxazole humulone of the present invention, described hydrogen peroxide donor can be at least one in hydrogen peroxide, perborate, percarbonate and Urea Peroxide element and their solution (such as the aqueous solution etc.); Be more preferably hydrogen peroxide and/or Sodium peroxoborate and the aqueous solution thereof.In the present invention, described hydrogen peroxide donor refers to and can generate corresponding peroxide organic acid material to organic acid reaction.
Under preferable case, in the preparation method of isoxazole humulone of the present invention, described hydrogen peroxide donor is aqueous hydrogen peroxide solution, and in the hydrogen peroxide in described aqueous hydrogen peroxide solution, the mol ratio of the compound shown in described hydrogen peroxide and formula (I) is 2-10:1; Be preferably 2-5:1.
In method of the present invention, the concentration of preferred described aqueous hydrogen peroxide solution is 10-70 % by weight; Be more preferably 25-50 % by weight; Be particularly preferably 25-35 % by weight.
More preferably, in the preparation method of isoxazole humulone of the present invention, described peroxide organic acid can be at least one in dichloroperacetic acid, monochloroperacetic acid and Peracetic Acid.
Particularly preferably, in the preparation method of isoxazole humulone of the present invention, described peroxide organic acid is dichloroperacetic acid and Peracetic Acid.
According to the preparation method of isoxazole humulone of the present invention, when described peroxide organic acid be dichloroperacetic acid and Peracetic Acid time, preferred described peroxide organic acid is the consumption mol ratio of the corresponding respectively dichloro acetic acid of dichloroperacetic acid and Peracetic Acid and acetic acid is 0.5-4:1, is more preferably 1-3:1.
More preferably in situation, when described peroxide organic acid be dichloroperacetic acid and Peracetic Acid time, the condition of described contact comprises: the temperature of contact is 10-30 DEG C.
In the present invention, when described peroxide organic acid be dichloroperacetic acid and Peracetic Acid time, to contact there is no particular limitation time, under preferable case, in order to make the transformation efficiency of reaction raw materials higher, the time of described contact is 2-5h.
According to the preparation method of isoxazole humulone of the present invention, wherein, the described method by the compound shown in formula (I) and oxidising agent can comprise any one in following methods:
1) in advance the compound shown in formula (VI) and hydrogen peroxide donor exposure are obtained mixture solution, and then the compound shown in this mixture solution with formula (I) is contacted.Namely in the method, be equivalent to obtain the peroxide organic acid solution containing shown in formula (III) in advance.
2) compound shown in the compound shown in formula (VI), hydrogen peroxide donor with formula (I) is contacted.Namely, be equivalent in the method in reaction system, make often to generate the peroxide organic acid shown in a part of formula (III) just contact with the compound shown in formula (I) immediately (also namely those skilled in the art often say while generate, participate in reacting).To described organic acid existence form, there is no particular limitation in the present invention, can be such as solid and/or liquid form, the present invention, preferably when described organic acid is solid form, can adopt the dissolved solids organic acids such as the solvent such as water of arbitrary proportion, to form organic acid soln.
According to one of the present invention preferred embodiment, when described peroxide organic acid is Peracetic Acid, the method also comprises carries out in the presence of a mineral acid.In the present invention, it should be noted that, when the compound shown in used formula (III) is only Peracetic Acid, if the reaction times is longer and temperature of reaction is higher, structure isoxazole humulone shown in the formula (II) that just can obtain higher yields.But, in order to realize structure isoxazole humulone shown in quick production (II), and obtaining higher feed stock conversion, the present invention is preferably when the compound shown in used formula (III) is only Peracetic Acid, and described contact also comprises to be carried out in the presence of a mineral acid.And, in method of the present invention, when used oxygenant is for compound shown in Peracetic Acid and another or multiple formula (III), method of the present invention also can than the generation of isoxazole humulone that realize structure shown in formula (II) more quickly under relatively mild condition under the condition not adding mineral acid; And when working as the used compound shown in formula (III) for compound shown in Peracetic Acid and another or multiple formula (III), if add appropriate mineral acid again in system, reaction can be made to carry out quicker, and temperature of reaction is lower.Further, when the compound shown in formula (III) used in the method for the invention is at least one except Peracetic Acid, also can add proper inorganic acid in reaction system makes reaction carry out quicker, and the temperature of reacting generation can be made lower, but, in order to save production cost, in the method for the invention, when the organic acid shown in the formula (III) used is at least one except Peracetic Acid, described contact is carried out under the condition not adding mineral acid.
In particularly preferred situation, when described peroxide organic acid is Peracetic Acid, the condition of described contact comprises: the temperature of contact is 55-80 DEG C, and the time of contact is 2-5h.
In method of the present invention, the consumption mol ratio of the acetic acid that described mineral acid is corresponding with described Peracetic Acid can be 0.01-10:1; Be preferably 0.03-6:1; Be more preferably 0.03-1:1, be particularly preferably 0.05-0.6:1.
In method of the present invention, described mineral acid can comprise sulfuric acid, at least one replaced in sulfuric acid, substituted sulfonic acid, hydrochloric acid, hydroiodic acid HI, Hydrogen bromide, nitric acid, phosphoric acid, phosphorous acid, metaphosphoric acid and tetra-sodium; At least one that preferred described mineral acid is sulfuric acid and replaces in sulfuric acid.In the present invention, the replacement sulfuric acid that described replacement sulfuric acid can be replaced by alkyl at least one hydrogen atom in sulfuric acid can be such as methyl sulfate, sodium pyrosulfate, sal enixum etc.; Described substituted sulfonic acid can be such as that the present invention can be preferably methylsulphonic acid, ethylsulfonic acid, cumene, tosic acid etc. arbitrarily by the substituted sulfonic acid that alkyl replaces.
According to one of the present invention preferred embodiment, when described peroxide organic acid is trifluoro Peracetic Acid, the condition of described contact of the present invention comprises: the temperature of contact is 10-30 DEG C.
In the present invention, when described peroxide organic acid is trifluoro Peracetic Acid, the time of preferred described contact is 1.5-2h.
According to another preferred embodiment of the present invention, when described peroxide organic acid is dichloroperacetic acid, the condition of described contact of the present invention comprises: the temperature of contact is 15-30 DEG C.
In the present invention, when described peroxide organic acid is dichloroperacetic acid, the time of preferred described contact is 3-5h.
In method of the present invention, the consumption mol ratio of the organic acid corresponding to compound shown in described formula (III) and the compound shown in formula I can be 1-100:1; Can be preferably 4-60:1.
According to the preparation method of isoxazole humulone of the present invention, other acidity or non-acid medium or its mixture can also be added as reaction solvent in described reaction system, such as the compound shown in described formula (I) of the present invention and oxidising agent can also carry out under other solvent exists, and described solvent can be at least one in water, chloroform, methylene dichloride, chlorobenzene, toluene, toluene(mono)chloride and acetic acid.Also other solvent can not be added in method of the present invention, and adopt the organic acid (i.e. compound shown in formula (VI)) corresponding to compound shown in formula (III) to serve as solvent, there is no particular limitation to the organic acid amount of serving as solvent use for method of the present invention, selects after those skilled in the art can consider in comprehensive actual needs and cost etc. according to the amount of the solvent of this area routine use.
According to one of the present invention preferred embodiment, the preparation method of described isoxazole humulone comprises the organic acid corresponding to the compound shown in the compound shown in formula (I) and formula (III) and hydrogen peroxide donor exposure.
In method of the present invention, after completion of the reaction, a small amount of reductive agent can also be added to remove unreacted oxygenant completely in reaction system, to the kind of described reductive agent, there is no particular limitation in the present invention, can be various reductive agents conventional in this area, such as the present invention preferably can use S-WAT and/or sulfurous gas.
Reaction of the present invention is carried out degree and the conventional various methods used in this area can be adopted to detect, and such as the present invention preferably adopts high performance liquid chromatography (HPLC) to detect.
To the post-treating method reacted, there is no particular limitation in the present invention, the conventional various methods used in this area can be adopted to carry out aftertreatment, such as in the present invention, concentrating under reduced pressure can be adopted with removing or recycling design, obtain enriched material; Then use appropriate organic solvent such as methylene dichloride again to dissolve enriched material, and wash with water repeatedly; By organic phase concentrated after organic phase and aqueous phase separation, and adopted by obtained product the organic solvents such as ethanol to carry out recrystallization, then filter.
According to another preferred embodiment of the present invention, the preparation method of described isoxazole humulone comprises following reaction process:
By the compound shown in formula (I) and described organic acid or and described mineral acid be mixed together, obtain mixture solution, then hydrogen peroxide donor is added wherein, carry out insulation reaction, wherein, the consumption mol ratio of compound, organic acid, hydrogen peroxide donor and the mineral acid shown in preferred described formula (I) is 1:1-100:2-10:0.01-300; Be more preferably 1:1-60:2-5:0.1-50.
In above-mentioned another preferred embodiment, the amount ratio of compound, the temperature and time of insulation reaction etc. shown in the kind of described organic acid and mineral acid and hydrogen peroxide donor and they and formula (I) all can values arbitrarily in the scope in scheme disclosed by the invention.Such as, the temperature of insulation reaction can be 0 DEG C to 95 DEG C, and the reaction times can be 1.5-8h; And for example the temperature of described insulation reaction is preferably 10 DEG C to 80 DEG C, and the time of reaction is preferably 1.5-5h.
Below will be described the present invention by embodiment.In following examples, in case of no particular description, all ingredients used is commercially available product.
In the examples below; the method that described 4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole prior art provides prepares (Niu Jifeng; 2013; Master's thesis; the study on the synthesis of East China University of Science 《 isoxazole humulone "), the purity obtaining product after purification is 99.1%.
Embodiment 1
4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole 32.7g (0.1mol), dichloro acetic acid 150g is added, stirring and dissolving in 500ml reaction flask.Then in reaction flask, add the hydrogen peroxide (H of 30 % by weight
2o
2) be total to 45.3g (0.40mol), at 25 DEG C, carry out insulation reaction 3h, HPLC sampling detection find that feed stock conversion is 100%.Then in gained mixture, add a small amount of S-WAT to remove unnecessary oxygenant, decompression desolventizes in backward enriched material and adds 200g methylene dichloride, and with deionized water wash 2 times, each 50g, then remove methylene dichloride at reduced pressure conditions, then carry out recrystallization with ethanol, and filter.
Dried under infrared lamp by filtration gained solid, obtain white solid 35.5g, detecting product purity by HPLC is 97.5%, and yield is 96.3%.
Comparative example 1
4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole 32.7g (0.1mol), methylene dichloride 200g is added, stirring and dissolving in 500ml reaction flask.Then in reaction flask, add the hydrogen peroxide (H of 30 % by weight
2o
2) after 45.3g (0.40mol), at 25 DEG C of insulation reaction 3h.
HPLC sampling analysis, only generates the M343 intermediate of 1.3%, and does not have the product of isoxazole humulone shown in formula (II) to generate.Add the vitriol oil 10g of 98 % by weight again, be warmed up to backflow, HPLC sampling analysis again after insulation reaction 7h, find the M343 intermediate of generation 0.1% isoxazole humulone product and 4.3%.
Comparative example 2
4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole 32.7g (0.1mol), methylene dichloride 200g is added, stirring and dissolving in 500ml reaction flask.Then after adding 3-chloro-peroxy benzoic acid (0.40mol) in reaction flask, at subzero 10 DEG C of insulation reaction 5h.HPLC sampling analysis, isoxazole humulone shown in the M343 intermediate of generation 66.7% and 15.8% formula (II).
Comparative example 3
4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole 32.7g (0.1mol), methylene dichloride 200g is added, stirring and dissolving in 500ml reaction flask.Then after adding 3-chloro-peroxy benzoic acid (0.40mol) in reaction flask, at subzero 10 DEG C of insulation reaction 5h.HPLC sampling analysis, isoxazole humulone shown in the M343 intermediate of generation 66.7% and 15.8% formula (II).Be warmed up to 20 DEG C of insulation reaction 5h above freezing again.HPLC sampling analysis, isoxazole humulone shown in the M343 intermediate of generation 15.3% and the formula (II) of 65.2%.
Embodiment 2
4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole 32.7g (0.1mol), dichloro acetic acid 200g is added, stirring and dissolving in 500ml reaction flask.Add monohydrate sodium stannate (NaBO
3h
2o), after being total to 39.9g (0.40mol), at 30 DEG C, carrying out insulation reaction 5h, HPLC sampling detection find that feed stock conversion is 100%.Then in gained mixture, add a small amount of S-WAT to remove unnecessary oxygenant, after concentrating under reduced pressure, in enriched material, add 200g methylene dichloride, and with deionized water wash 2 times, each 50g, then remove methylene dichloride at reduced pressure conditions, then carry out recrystallization with ethanol, and filter.
Dried under infrared lamp by filtration gained solid, obtain white solid 35.8g, detecting product purity by HPLC is 97.3%, and yield is 97.0%.
Embodiment 3
Add in 500ml reaction flask 4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole 32.7g (0.1mol), 75 % by weight sulfuric acid 50g, acetic acid 50g, chlorobenzene 100g, stirring and dissolving.Then in reaction flask, add the hydrogen peroxide (H of 30 % by weight
2o
2) be total to 45.3g (0.40mol), at 80 DEG C, carry out insulation reaction 5h, HPLC sampling detection find that feed stock conversion is 100%.Then in gained mixture, add a small amount of S-WAT to remove unnecessary oxygenant, after concentrating under reduced pressure, in enriched material, add 200g methylene dichloride, and with deionized water wash 2 times, each 50g, then remove methylene dichloride at reduced pressure conditions, then carry out recrystallization with ethanol, and filter.
Dried at infrared lamp by filtration gained solid, obtain white solid 32.1g, detecting product purity by HPLC is 91.2%, and yield is 91.5%.
Embodiment 4
4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole 32.7g (0.1mol), acetic acid 90g, 98 % by weight vitriol oil 8g are added, stirring and dissolving in 500ml reaction flask.Then in reaction flask, add the hydrogen peroxide (H of 30 % by weight
2o
2) be total to 45.3g (0.40mol), at 65 DEG C, carry out insulation reaction 4h, HPLC sampling detection find that feed stock conversion is greater than 99.9%.Then in gained mixture, add a small amount of S-WAT to remove unnecessary oxygenant, after concentrating under reduced pressure, in enriched material, add 200g methylene dichloride, and with deionized water wash 2 times, each 50g, then remove methylene dichloride at reduced pressure conditions, then carry out recrystallization with ethanol, and filter.
Dried at infrared lamp by filtration gained solid, obtain white solid 34.8g, detecting product purity by HPLC is 98.1%, and yield is 95.1%.
Embodiment 5
4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole 32.7g (0.1mol), chlorobenzene 150g is added, stirring and dissolving in 500ml reaction flask.Then add in reaction flask and shift to an earlier date formulated peracetic acid soln by the vitriol oil 8g of the hydrogen peroxide of 30 % by weight (0.40mol) common 45.3g, acetic acid 100g and 98 % by weight.Be warmed up to 65 DEG C and carry out insulation reaction.HPLC samples detection, until feed stock conversion reaches 99.9%, coreaction 4.5h, then in gained mixture, add a small amount of S-WAT to remove unnecessary oxygenant, decompression precipitation recycling design, adds 20g methylene dichloride and uses deionized water wash 2 times, each 50g, then remove chlorobenzene at reduced pressure conditions, then carry out recrystallization with ethanol, and filter.
Dried at infrared lamp by filtration gained solid, obtain white solid 35.1g, detecting product purity by HPLC is 97.0%, and yield is 95.9%.
Embodiment 6
4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole 32.7g (0.1mol), trifluoroacetic acid 100g is added, stirring and dissolving in 500ml reaction flask.Then in reaction flask, add the hydrogen peroxide (H of 30 % by weight
2o
2) be total to 45.3g (0.40mol), at 15 DEG C, carry out insulation reaction 2h, HPLC sampling detection find that feed stock conversion is 100%.Then in gained mixture, add a small amount of S-WAT to remove unnecessary oxygenant, after concentrating under reduced pressure, in enriched material, add 200g methylene dichloride, and with deionized water wash 2 times, each 50g, then remove methylene dichloride at reduced pressure conditions, then carry out recrystallization with ethanol, and filter.
Dried at infrared lamp by filtration gained solid, obtain white solid 35.7g, detecting product purity by HPLC is 97.5%, and yield is 97.0%.
Embodiment 7
4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole 32.7g (0.1mol), a gifblaar poison 90g is added, stirring and dissolving in 500ml reaction flask.Then in reaction flask, add the hydrogen peroxide (H of 30 % by weight
2o
2) be total to 45.3g (0.40mol), at 20 DEG C, carry out insulation reaction 3h, HPLC sampling detection find that feed stock conversion is 100%.Then in gained mixture, add a small amount of S-WAT to remove unnecessary oxygenant, decompression desolventizes in backward enriched material and adds 200g methylene dichloride, and with deionized water wash 2 times, each 50g, then remove methylene dichloride at reduced pressure conditions, then carry out recrystallization with ethanol, and filter.
Dried under infrared lamp by filtration gained solid, obtain white solid 35.5g, detecting product purity by HPLC is 97.1%, and yield is 96.2%.
Embodiment 8
4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole 32.7g (0.1mol), 2,3-dichloro isopropylformic acids (1.16mol) are added, stirring and dissolving in 500ml reaction flask.Then in reaction flask, add the hydrogen peroxide (H of 30 % by weight
2o
2) be total to 45.3g (0.40mol), at 30 DEG C, carry out insulation reaction 1.5h, HPLC sampling detection find that feed stock conversion is 99.9%.Then in gained mixture, add a small amount of S-WAT to remove unnecessary oxygenant, decompression desolventizes in backward enriched material and adds 200g methylene dichloride, and with deionized water wash 2 times, each 50g, then remove methylene dichloride at reduced pressure conditions, then carry out recrystallization with ethanol, and filter.
Dried under infrared lamp by filtration gained solid, detecting product purity by HPLC is 97.3%, and yield is 96.3%.
Embodiment 9
The present embodiment adopts the method similar to embodiment 4 to carry out, and difference is, does not add 98 % by weight vitriol oils in the method for the present embodiment.
Detected by HPLC sampling carry out insulation reaction 4h at 60 DEG C after and find that feed stock conversion is 97.6%.Detected by HPLC sampling after continuing reaction 4h and find that feed stock conversion is 99.5%.
All the other steps are identical with the method in embodiment 4.
Detecting product purity by HPLC is 95.2%, and yield is 94.3%.
Embodiment 10
4-(4-trifluoromethyl-2-methylthio phenyl formyl radical)-5-cyclopropyl isoxazole 32.7g (0.1mol), dichloro acetic acid (0.77mol) and acetic acid (0.39mol) is added, stirring and dissolving in 500ml reaction flask.Then in reaction flask, add the hydrogen peroxide (H of 30 % by weight
2o
2) be total to 45.3g (0.40mol), at 30 DEG C, carry out insulation reaction 2h, HPLC sampling detection find that feed stock conversion is 100%.Then in gained mixture, add a small amount of S-WAT to remove unnecessary oxygenant, decompression desolventizes in backward enriched material and adds 200g methylene dichloride, and with deionized water wash 2 times, each 50g, then remove methylene dichloride at reduced pressure conditions, then carry out recrystallization with ethanol, and filter.
Dried under infrared lamp by filtration gained solid, detecting product purity by HPLC is 99.2%, and yield is 97.3%.
Embodiment 11
The present embodiment adopts the method similar to embodiment 10 to carry out.Difference is:
The dichloro acetic acid used in the present embodiment is 0.93mol, and acetic acid is 0.23mol, the hydrogen peroxide (H of 30 % by weight
2o
2) be total to 45.3g (0.40mol).
Detected by HPLC sampling carry out insulation reaction 2h at 30 DEG C after and find that feed stock conversion is 100%.
All the other steps are identical with the method in embodiment 10.
Detecting product purity by HPLC is 98.5%, and yield is 97.3%.
Embodiment 12
The present embodiment adopts the method similar to embodiment 10 to carry out.Difference is:
The dichloro acetic acid used in the present embodiment is 0.19mol, and acetic acid is 0.97mol, the hydrogen peroxide (H of 30 % by weight
2o
2) be total to 45.3g (0.40mol).
Detected by HPLC sampling carry out insulation reaction 2h at 30 DEG C after and find that feed stock conversion is 98.5%.Detected by HPLC sampling after continuing reaction 2h and find that feed stock conversion is 99.9%.
All the other steps are identical with the method in embodiment 10.
Detecting product purity by HPLC is 96.9%, and yield is 95.7%.
Can be found out by the result of above-described embodiment 1-12 and comparative example 1-3, method provided by the invention is adopted to prepare the reaction conditions gentleness of isoxazole humulone, and can make in the short period of time to be swift in response, feed stock conversion all can reach more than 98.7%, even can reach 100%, the purity of product can reach more than 90%, and the yield of product also can reach more than 91%.
More than describe the preferred embodiment of the present invention in detail; but the present invention is not limited to the detail in above-mentioned embodiment, within the scope of technical conceive of the present invention; can carry out multiple simple variant to technical scheme of the present invention, these simple variant all belong to protection scope of the present invention.
It should be noted that in addition, each concrete technical characteristic described in above-mentioned embodiment, in reconcilable situation, can be combined by any suitable mode, in order to avoid unnecessary repetition, the present invention illustrates no longer separately to various possible array mode.
In addition, also can carry out arbitrary combination between various different embodiment of the present invention, as long as it is without prejudice to thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (10)
1. a preparation method for isoxazole humulone, the structure of described isoxazole humulone is such as formula shown in (II), and the method comprises the compound shown in formula (I) and oxidising agent, it is characterized in that, containing peroxide organic acid in described oxygenant; Described peroxide organic acid is the compound shown in formula (III), and in formula (III), X, Y and Z are identical or different, is the one in the substituted or unsubstituted alkyl of hydrogen, halogen, C1-C3 independently of one another,
2. method according to claim 1, wherein, the condition of described contact comprises: the temperature of contact is 0-95 DEG C; The temperature of preferred described contact is 10-80 DEG C.
3. method according to claim 1, wherein, described peroxide organic acid is for being selected from least one in trifluoro Peracetic Acid, difluoro Peracetic Acid, a fluorine Peracetic Acid, difluoro monochloroperacetic acid, a fluorine dichloroperacetic acid, monochloroperacetic acid, dichloroperacetic acid, trichloroperacetic acid, a fluorine monochloroperacetic acid, 2-chlorine Perpropionic Acid, 3-chlorine Perpropionic Acid, 2,2-dichloro Perpropionic Acids, Perpropionic Acid, Perbutyric Acid and Peracetic Acid.
4. according to the method in claim 1-3 described in any one, wherein, described peroxide organic acid is by obtaining the organic acid corresponding to the compound shown in formula (III) and hydrogen peroxide donor exposure; Preferred described hydrogen peroxide donor is at least one in hydrogen peroxide, perborate, percarbonate and Urea Peroxide element.
5. method according to claim 4, wherein, described peroxide organic acid is dichloroperacetic acid and Peracetic Acid, and the consumption mol ratio of dichloro acetic acid and acetic acid is 0.5-4:1, and the condition of described contact comprises: the temperature of contact is 10-30 DEG C.
6. method according to claim 4, wherein, when described peroxide organic acid be Peracetic Acid and/or Perpropionic Acid time, the method comprises carries out in the presence of a mineral acid; The condition of preferred described contact comprises: the temperature of contact is 55-80 DEG C.
7. method according to claim 6, wherein, the consumption mol ratio of described mineral acid and acetic acid is 0.01-10:1; Be preferably 0.03-6:1.
8. the method according to claim 6 or 7, wherein, described mineral acid comprises sulfuric acid, at least one replaced in sulfuric acid, substituted sulfonic acid, hydrochloric acid, hydroiodic acid HI, Hydrogen bromide, nitric acid, phosphoric acid, phosphorous acid, metaphosphoric acid and tetra-sodium; At least one that preferred described mineral acid is sulfuric acid and replaces in sulfuric acid.
9. method according to claim 4, wherein, the consumption mol ratio of the organic acid corresponding to compound shown in described formula (III) and the compound shown in formula I is 1-100:1.
10. method according to claim 1, wherein, the method also comprises carries out in the presence of solvent, and described solvent comprises at least one in water, chloroform, methylene dichloride, chlorobenzene, toluene, toluene(mono)chloride and acetic acid.
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