CN109970672A - A kind of high-purity thermostabilization replaces the crystal form and preparation method and application of 3- isoxazole alkanone compound - Google Patents

Abstract

The present invention provides crystal forms and preparation method and application that a kind of high-purity thermostabilization replaces 3- isoxazole alkanone compound.The high-purity thermostabilization crystal form is prepared by this technology ad hoc approach, and X- single crystal diffraction is detected as orthorhombic: space group is P21 21 21, and cell parameter is α=90 °, β=90 °, γ=90 °.The orthorhombic crystal can be conveniently used for pesticidal preparations, such as the preparation of suspending agent, water dispersible granules；Its manufactured novel formulation has more superior activity of weeding and safety.

Description

A kind of high-purity thermostabilization replaces crystal form and the preparation side of 3- isoxazole alkanone compound Method and application

Technical field

The invention belongs to agrochemical fields, and in particular to a kind of high-purity thermostabilization 2- (2,4- dichlorophenyl) methyl -4,4- The crystal form and preparation method and application of dimethyl -3- isoxazole alkanone compound

Background technique

2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone is isoxazoline type herbicides The new show risen in front yard, compared to the clomazone herbicide generally used currently on the market, 2- (2,4- dichlorophenyl) methyl- 4,4- dimethyl -3- isoxazole alkanone was drawn attention by many companies in recent years because having weaker volatility.

Clomazone (Formula II) chemical name is 2- (2- chlorphenyl) methyl -4,4- dimethyl -3- isoxazole alkanone, knot Structure formula is expressed as follows:

BCPC report compound II is grease at room temperature, and fusing point is 25.0-34.7 DEG C, and boiling point is 275.4-281.7 DEG C.

2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) and clomazone (formula II it) is substituted by a chlorine atom both compared to four hydrogen of phenyl ring, structural formula is as follows:

Fu Mei reports 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) in room in fact Lower temperature is grease (patent US4405357, embodiment 22).

Fu Meishi discloses 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) in jade Alternatively purposes (the patent of property preemergence herbicide on rice, rice, sorghum, barley, rye and cole crop WO2012148689).The patent reports 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone simultaneously Close object (Formulas I) suspending agent (SC) single dose preparation method, raw medicine used be by grease made from patent US4405357 method, Intermediate steps include raw medicine powdered, but grease raw medicine how pulverizing technology with no specific disclosure of.Grease raw medicine at present The practical technique of powdered is to be made into female powder by the way that oily raw medicine is adsorbed on mixing on solid carrier (such as white carbon black) first, so Mechanical powder afterwards.It is this be first made female powder be mechanically pulverized again powdered processing method not only need additional auxiliary agent, processing Equipment increases preparation cost, while generating a large amount of dust during mechanical powder, is a big safety and environmental protection hidden danger.In addition to this, The formulation products produced so usually unstable quality.

Bayer has applied for 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound in 2016 The patent (WO2017025418) of (Formulas I) as blade face (after bud) herbicide new application.The patent does not disclose preparation used Specific dosage form and preparation method.

Bayer disclosed a kind of active agrochemicals ingredient (a) containing 50 DEG C to 80 DEG C of melting range and 2- in 2018 The preparation method of the compounding SC dosage form of (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) (CN109068631A).The compounding suspending agent preparation method is to melt agrochemicals ingredient (a), then under stiring by the work Property agrochemicals ingredient (a) in the molten state with 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone It closes object (Formulas I) to be added to together in the water containing at least one ionically and/or non-ionically dispersing agent and carrier material, is cooled to and is lower than Active component (a) fusing point is hereinafter, grinding is made.

Resultant force chemistry reports a kind of specific preparation different evil of 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- recently Oxazolidinone compounds (Formulas I) fusing point is the method (CN201910188658.2) of 45 DEG C of monoclinic crystals.Cell parameter is as follows: space Group is P21/c, cell parameter a=10.6368B=11.8019C=20.0931 (4), α=90 °, β =92.825 ° (1), γ=90 °.But the monoclinic crystal is not suitable for directly preparing the farm chemical preparation of green, environmental protection, such as the system of SC It is standby.In general, the condition for preparing SC is: active agrochemicals congruent melting point needs to be less than greater than solubility in 60 DEG C, water 100mg/L, in aqueous solution stable (Xu Yan " liquid pesticide preparation ", Chemical Industry Press: P31).Fusing point is lower than 60 DEG C Active agrochemicals ingredient is easy fusing, softening in preparation SC crushing and sand grinding process, influences the physical stability of preparation, leads Cause flocculation, livering.Secondly, its manufactured suspending agent product is often easy to appear layering during storage, partial size increases, influence to make With.

2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) is used as water dispersion at present Agent (WG) dosage form has not been reported；In addition, 2- (2,4- dichlorophenyl) methyl -4,4- dimethyl -3- isoxazole alkanone compound (formula I) specific report is had no as the use of preemergence herbicide in wheat crop.

This technology personnel in view of the deficiencies of the prior art and defect, have found by a large amount of mental labour and verification experimental verification A kind of higher 2- of thermal stability (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) is new brilliant Body.Moreover, this technology personnel also found that the new crystal of the high-purity can be more convenient, efficiently be used to prepare green ring Pesticidal preparations are protected, such as suspending agent (SC) or water dispersant (WG) preparation.

Summary of the invention

The present invention in view of the deficiencies of the prior art and defect, provide a kind of efficient preparation high-purity thermostabilization 2- (2, 4- dichlorophenyl) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) crystal form and preparation method and application.

One of the object of the invention, which is to provide, a kind of prepares 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole The method of alkanone compound (Formulas I) stable crystal crystal seed, includes the following steps:

2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) of the present invention is sub- Thermostabilization monoclinic crystal is by 2- made from patent CN201910188658.2 method (2,4 dichloro benzene base) methyl -4,4- diformazan Base -3- isoxazole alkanone compound (Formulas I) monoclinic crystal (45 DEG C of fusing point).The Formulas I Asia thermostabilization monoclinic crystal is dissolved in organic solvent A, by heating, cooling, the slow solvent flashing A of temperature-rise period, crystallization prepare 2- (2,4- dichlorophenyl) methyl -4,4- diformazan again The orthogonal crystal seed of base -3- isoxazole alkanone compound (Formulas I)；The organic solvent A is one kind or more of alkanes, cycloalkane Kind, 2- (2,4- dichlorophenyl) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) is with organic solvent A weight ratio 1:10-20, first time warming temperature be 40-90 DEG C, cooling temperature be subzero 10 to 10 DEG C, temperature fall time 10-20 hours, second Secondary warming temperature is 15-40 DEG C, and the volatilization time is 3-30 days.Preferred organic solvent A is petroleum ether (60-90 DEG C of boiling range), 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) and organic solvent A weight ratio are 1:15- 20, first time warming temperature is 60-90 DEG C, and cooling temperature is subzero 5 to 5 DEG C, temperature fall time 15-20 hours, is heated up for the second time Temperature is 15-30 DEG C, and the volatilization time is 10-20 days.Invention technician is surprised to find as obtained by the technical program Crystallization has external needle-shaped, interior diamond mixed crystallization body to be formed, and acicular crystal is collected the differential scanning calorimetry (DSC) after and examined Surveying fusing point is 83.8 DEG C.

2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) monoclinic crystal is molten at other Agent/combination solvent, in chloroform, n-hexane, methanol, ethyl acetate, toluene, acetone, DMF/ water, DMSO/ water, above-mentioned similar Under the conditions of, what is obtained is grease or the longer hybrid solid of melting range, without the formation of above-mentioned acicular crystal.

The second object of the present invention is to determining and providing the different evil of above-mentioned 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- The crystal form of the new acicular crystal of oxazolidinone compounds (Formulas I).Above-mentioned new acicular crystal is detected through X- single crystal diffractometer, as a result, it has been found that 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) crystal form is orthorhombic crystal.Specific structure cell Parameter is as described in table 1:

The X- single crystal diffraction crystallographic parameter of 1 orthorhombic crystal of table

The parameter has following meanings:

A, the side length of b, c=structure cell；

α, β, γ=structure cell angle；

The number of molecule in Z=structure cell.

Above-mentioned 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) rhombic form exists X-ray powder diffraction (PXRD) at 25 DEG C as shown in figure 4, feature diffraction parameters (2 θ) as shown in table 2, preferred diffraction parameters (2 θ) is at least three in the following table 2, secondly preferably at least 4, more preferably at least 5, preferably all:

X-ray powder diffraction (PXRD) parameter of 2 orthorhombic crystal of table

In the present invention, term X-ray powder diffraction collection (PXRD) refers to the diffraction pattern or be originated from it that experimental observation arrives Parameter.Powder x-ray diffraction map is characterized by peak position (abscissa) and peak intensity (ordinate).

The object of the invention third is that studying above-mentioned 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone The stability of compound (Formulas I) rhombic form.Above-mentioned compound of formula I orthorhombic crystal is respectively in high temperature (60 ± 2 DEG C) baking oven, 90 It places 10 days under ± 5% damp condition, under 4500 ± 500lux illumination condition, is penetrated in the 5th day, the 10th day separately sampled progress X Line powder diffraction analysis, as a result, it has been found that consistent before 2 angles θ of compound of formula I orthorhombic crystal X- powder diffraction and storage, formula I Compound orthorhombic is stablized under high temperature, high humidity, illumination, belongs to stable crystal form.

The four of the object of the invention are to provide a kind of efficient preparation high-purity 2- (2,4 dichloro benzene base) methyl -4,4- diformazan The method of base -3- isoxazole alkanone (Formulas I) orthorhombic crystal, includes the following steps:

By the 2- prepared by distinct methods (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone chemical combination Object (Formulas I) crude product is dissolved in solvent B, is completely dissolved by being warming up to 40-100 DEG C and is cooled to 10-30 DEG C again, cooled down The rhombic form crystal seed of compound of formula I is put into journey, crystallization filters and high-purity thermostabilization orthorhombic crystal is made.The crude product For oily liquids (content > 80%) or solid (monoclinic crystal that such as fusing point is 45 DEG C).The solvent B is alkanes, cycloalkane Class, alkyl halide hydro carbons, aromatic hydrocarbons, ethers, alcohols, esters, ketone, sulfoxide type, amide solvent, water it is one or more, it is excellent Be selected as alkanes, alkyl halide hydro carbons, aromatic hydrocarbons, alcohols solvent, water it is one or more；More preferably petroleum ether, toluene, chlorine It is imitative, ethyl alcohol, water one or more；2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (formula It I is) 1:0.5-3 with solvent B weight/volume.The prepared different evil of 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- Oxazolidinone compounds (Formulas I) orthorhombic crystal purity is greater than 99%.

The five of the object of the invention are to provide the application on compound of formula I orthorhombic crystal pesticidal preparations.The orthorhombic crystal can be with It is prewired or be applied in combination with inert additwe.Compound of formula I orthorhombic crystal disclosed by the invention can be processed to this field The dosage form known, such as solution, emulsion, suspension, powder agent, foaming agent, paste, granule, aerosol and microcapsules, poly- Close object and be used for seed, and warm atomization preparation in coated composition etc..

Inert additwe includes solid carrier or liquid-carrier, can also include surfactant, such as wetting agent, dispersion Agent, viscosity modifier additive (thickener), defoaming agent, antifreezing agent, pH reagent, stabilizer, preservative etc..

Wetting agent such as alkyl benzene calcium sulfonate/sodium, alkylsurfuric acid calcium/sodium, alcohol ethers etc..

Dispersing agent such as lignin, sulfonate, phosphoric acid ester, carboxylate high molecular polymer, EO-PO block copolymer Deng.

Filler such as moistens soil, kaolin, white carbon black, Attagel, aluminium-magnesium silicate.

Viscosity modifier additive (thickener): polyvinylpyrrolidone, Arabic gum, xanthan gum, sodium cellulose glycolate, Polyvinyl alcohol, sodium alginate, guar gum etc..

The defoaming agent such as fatty alcohol of organosilicon ketone, C8-C10, C10-C20 saturated fat acids and ester ethers etc..

Antifreezing agent such as ethylene glycol, glycerine, polyethylene glycol, urea element, sorbierite etc..

Preservative such as propionic acid and its sodium salt, sorbic acid and its sodium salt or sylvite, benzoic acid and sodium benzoate, P-hydroxybenzoic acid Sodium salt, methyl para hydroxy phenyl ester, Yi Sai oxazoline ketone etc..

Stabilizer such as bentonite, white carbon black, precipitated calcium carbonate etc..

For example, compound of formula I orthorhombic crystal can be convenient, directly be processed to 40% suspending agent.Preparation method includes For by compound of formula I orthorhombic crystal, Borresperse CA (lignosulfonates), (the EOPO block copolymerization of Ethylan 324 Object), SAG1572 (organosilicon), kelzan S-PLUS (xanthan gum), ethylene glycol and water each component mix according to the ratio of formula Uniformly, accordingly 40% suspending agent can be obtained through sand mill grinding.

For another example, compound of formula I orthorhombic crystal can be convenient, directly be processed to 40% water dispersible granules.Preparation method Including by compound of formula I orthorhombic crystal, stepanolDX-165N (lauryl sodium sulfate), Morwet D-425 (poly- naphthalene sulfonic acids Salt), Borresperse CA (lignosulfonates), AGNIQUE Soap-L (tallow fatty acid sodium), TS-1 (kaolin) is through machinery It crushes, mediate, be granulated, obtain corresponding 40% water dispersible granules after drying.

It is worth noting that being made into not appearing in the newspapers in the current technical field of WG dosage form containing compound of formula I orthorhombic crystal Road.

The five of the object of the invention are to provide application of the compound of formula I orthorhombic crystal on control of weeds.

As herbicide in use, compound of formula I orthorhombic crystal can be 0.01~99 weight %.Compound of formula I is orthogonal Crystal can be administered in combination with one or more herbicides (abbreviation compound A), acted synergistically, to expand degrass spectrum, prevented Safety occurs or increases for resistance.When being used in combination with other herbicides, can with compound A prepare or with compound A Sequential application.Compound A is selected from:

A.1 ALS enzyme inhibitor,

A.2 acetylfluoride alcohol A carboxylase (ACC ase) inhibitor,

A.3 proporphyrinogen oxidase PPO inhibitor,

A.4HPPD inhibitor or

A.5 other include carotenoid biosynthesis inhibitor, cell division and growth inhibitor, auxin conveying inhibition Agent, plant growth regulator and herbicide-safener etc..

Specific such as fenoxapropPethyl, clodinafop-propargyl, diclofop-methyl, benthiocarb, triallate, pendimethalin, trefanocide pyrazoles grass Amine, pentyl xanthate, S-metolachlor, terbufos benzthiazuron, diuron, isoproturon, 2,4-D, 2 first, 4 chlorine, fluorine chlorine pyrrole fluoroacetic acid (different monooctyl ester), dicamba, bentazone, azoles humulone, florasulam, tribenuron-methyl, chlorsulfuron, amidosulfuron, cyclopropyl sulphur is grand, fluorine azoles Sulphur is grand, mesosulfuron, diquat dibromide, paraquat, glyphosate (isopropyl amine salt) etc..

As herbicide in use, compound of formula I or its above-mentioned composition can be applied together with safener, to increase crop Safety.The safener includes: naphthoic acid anhydride, dichloroacetyl amine, oxime ethers, heterocyclic, sulfonylureas (amine) class, plant life Long regulator class, fungicide class etc..Specific such as 1,8- naphthalic anhydride, allyl dichloride amine, benoxacor, Furilazole, solution grass Amine, phthalic acid, bromophthalic acid acid anhydride, fenclorim, benoxacor, cyometrinil, R25788, MG191 etc..

2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) orthorhombic crystal can be applied The control of weeds in the crops such as corn, wheat, rape, rice, sorghum, barley or rye.The corn field weed mainly includes Barnyard grass, herba digitariae, herba setariae viridis, herba eleusines indicae, Bermuda grass, reed, cyperus iria, knotweed, Siberian cocklebur, piemarker, purslane, black nightshade, Chenopodiaceae, iron amaranth Dish, ox chickweed, Amaranthus retroflexus, concave head amaranth, Horseweed Herb, elscholtiza, setose thistle, field thistle, sonchus oleraceus, Eclipta prostrata, ivy glorybind, humid euphorbia, duck plantar Grass, wild watermelon, Asiatic plantain, alfalfa, Wild soybean etc..

The wheat weeds mainly include amur foxtail, Alopecurus, Wang grass, herba bromi japonici, annual bluegrass, wild avena sativa (Avena Fatua), caput grass, rye grass, Triticum tauschii, tongue of sparrow grass, clearvers, ox chickweed, herba stellariae mediae, grasswort, Veronica, Hairy Bittercress, garden sorrel Leaf knotweed, common vetch, shepherd's purse, Chinese ixeris herb, lyrate hemistepta herb, creeping oxalis, wartwort, field bindweed, conical silene herb, Chenopodiaceae, small Li, pivot storage, tooth tartaric acid Film, ivy glorybind, penny cress, Herb of Common Nipplewort, benbie, mexicana etc..

Other weeds such as velvetleaf, black nightshade, Radix seu Herba Astilbes rivularis, artemisiifolia, sheep's hay, Itanlian rye, datura, johnson grass (Sorghum Halepense), ipomoea, couchgrass, sunflower, RHIZOMA FAGOPYRI CYMOSI (Polygonum convolvulus), wild mustard (Sinapis Arvensis), setaria glauca, green green bristlegrass, Chenopodium album, bengal dayflower herb, fennelflower, wide leaf Brachiaria Griseb, creeping thistle, Binzhou Siberian cocklebur (Xanthium pensylvanicum), corn poppy, huge herba setariae viridis, hair clover, resist herbicidal black race at field violet Grass, horseweed, big herba digitariae grass, small seed Phalaris grass, Pennsylvania knotweed, depression potato, thorn bur, silk gentle breeze grass, wild orangutan Wood, Huang Shacao (cyperue esculentus Cyperus esculentus) etc..

For example, the suspending agent (SC) of the orthorhombic crystal containing compound of formula I is living to herba stellariae mediae is prevented and kill off in 62.5g a.i./ha dosage Property is up to 100%, to annual bluegrass activity up to 97%.These data prove orthorhombic crystal containing compound of formula I provided by the present invention New suspending agent (SC) activity of weeding (such as far beyond comparison medicament (clomazone, commercially available) and its corresponding homogeneous liquid preparation EC) herbicidal effect.Meanwhile test result shows that the new suspending agent is more excellent to crop such as corn, Safe to wheat: working as active component When dosage is up to 500g ai/ha, only slight growth effect, safety is good.

For another example, the water dispersible granules of orthorhombic crystal containing compound of formula I (WG) are in 62.5g a.i./ha dosage to preventing and kill off herba stellariae mediae Activity is up to 100%, to annual bluegrass activity up to 97%.These data prove orthorhombic containing compound of formula I provided by the present invention New suspending agent (SC) activity of weeding of body far beyond comparison medicament (clomazone, commercially available) and its corresponding homogeneous liquid preparation, Such as missible oil (EC), herbicidal effect.It is worth noting that compared with above-mentioned SC dosage form, when WG remains to keep effective under low dosage Activity of weeding.For example, activity of weeding is still up to 80% or more when WG dosage is reduced to 15.625g a.i./ha.It should WG dosage form is good to crop such as corn, Safe to wheat, suitable with new SC dosage form.

The beneficial effects of the present invention are embodied in the followings:

(1) present invention discover that 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound (formula I) rhombic form that fusing point is 83-85 DEG C is light, wet, thermostabilization crystal form.It can simply, easily store, not generate at room temperature Crystal phenomenon will not influence the further processing and application of product.

(2) 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound provided by the present invention (Formulas I) rhombic form preparation method is convenient, efficient.Compound of formula I grease crude product (content 80%) that distinct methods obtain or Sub- thermostabilization crystal (45 DEG C of fusing point) provided method efficiently can be converted into stable rhombic form through the invention, It is suitable for large-scale industrial production.

(3) compound of formula I orthorhombic crystal provided by the present invention can facilitate, directly be used for farm chemical preparation, especially more The preparation containing solid pharmaceutical preparation such as environmentally protective SC, WG, overcome oily/low melting point Asia thermostabilization raw medicine be not suitable for directly by with In processing the problem of containing solid pharmaceutical preparation.

(4) compound of formula I orthorhombic crystal prepares resulting (such as SC, WG) containing solid pharmaceutical preparation, while weeding through the invention Activity is more excellent.Especially WG can reach ideal herbicidal effect relative to homogeneous liquid preparation (such as EC) with lower dosage, reduce and use It is medicine cost, environmentally friendly.

(5) compound of formula I orthorhombic crystal prepares resulting (such as SC, WG) containing solid pharmaceutical preparation through the invention, as removing Careless agent significantly improves crop (such as corn, wheat) safety.

Detailed description of the invention

Fig. 1: monoclinic crystal crystal form differential scanning calorimetry thermogram；

Fig. 2: the single crystal X-ray crystal structure figure of monoclinic crystal crystal form；

Fig. 3: X-ray powder diffraction (PXRD) diffraction pattern of monoclinic crystal crystal form；

Fig. 4: orthorhombic crystal form differential scanning calorimetry thermogram；

Fig. 5: the single crystal X-ray crystal structure figure of orthorhombic crystal form；

Fig. 6: X-ray powder diffraction (PXRD) diffraction pattern of orthorhombic crystal form.

Specific embodiment

The following examples further illustrate some features of the invention, but the present invention applies for the content of protection It is not limited by following embodiments with range.

It is detected using differential scanning calorimeter (TA (Du Pont) Instruments), acquires information with the speed of 10 DEG C/min Sample temperature is increased to 200 DEG C by 30 DEG C by rate.

It is detected using X-ray single crystal diffractometer (Gemini A Ultra, Agilent company, the U.S.), the CuKa of transmitting is penetrated Line collects single crystal data with the θ scanning mode of ω/2.

It is detected using the X-ray powder diffraction detector (X ' Pert PRO) of Dutch PNAlytical company, it is specific to acquire Information is as follows: Cu anode (40kV, 150mA), 2 0~45 ° of θ scanning ranges, 8 °/min of scanning speed, and 0.02 ° of step-length, DS transmitting 1 ° of slit, 1 ° of SS antiscatter slits, it is 0.15mm that RS, which receives slit,.

Embodiment 1 (patent US4405357 preparation method)

In 1L three-necked bottle, 100g 2 is added under stirring, 4- dichlorobenzaldehyde is dissolved in 500mL ethyl alcohol.At 20 DEG C, in batches Secondary addition 79.4g hydroxylamine hydrochloride, after charging, is warming up to 30 DEG C, and 20% sodium hydroxide solution 230g, time for adding is added dropwise 30 minutes, process temperature is added dropwise and rises to 45 DEG C, after completion of dropwise addition, reaction mixture stirs 1.5 hours, cooling, slowly by feed liquid It is added in 500mL water and stirs 1h, filtering, vacuum drying obtain 2,4- dichloro benzaldoxime solid 103g.

At 20 DEG C, 2, the 4- dichloro benzaldoxime that above-mentioned reaction obtains is dissolved in 1000mL methanol, while being added dropwise and containing 42.2g sodium cyanoborohydride and 1mL colorant 1- ethyl -2- [3- (1-ethylnaphthalene simultaneously [1,2-d] thiazole -2 (1H)-subunit) -2- Methyl-1-propylene -1- base]-naphtho- [1,2-d] thiazolium bromide methanol solution 700mL and 314mL2N hydrochloric acid methanol it is molten Liquid, it is acidity that the process that is added dropwise, which maintains reaction system,.Charging terminates, and 1.5h is stirred at room temperature, and removed under reduced pressure methanol adds water and stirs, warp Alkali cleaning, washing, dries to obtain solid N- (2,4 dichloro benzene methyl) azanol 67.4g at filtering.

Under inert gas shielding, at -10 DEG C, 67.4gN- (2,4- dichlorobenzyl) azanol of above-mentioned experiment preparation 97g pyridine is added in 600mL dichloromethane solution, under stirring, 42g trim,ethylchlorosilane, charging are slowly added in batches After, -10 DEG C are stirred 30 minutes, are warming up to 0 DEG C, and chloro- 2, the 2- dimethylpropionic acid chloride of 35.6g3- and 30mL methylene chloride is added dropwise Time for adding 20 minutes, 18h was stirred at room temperature in mixed liquor, after reaction, by washing, pickling, saturated common salt water washing point Layer, the dry precipitation of organic layer obtain the chloro- N- of 3- (2,4- dichlorophenyl) methyl-N-hydroxy -2,2- dimethylpropionamide 24.5g.

The chloro- N- of the 3- of above-mentioned preparation (2,4 dichloro benzene base) methyl-N-hydroxy -2,2- dimethylpropionamide 24.5g is molten In 500mL methanol, the potassium hydroxide solution of 5.26g85% is added, 18h is stirred at room temperature, filters.Removed under reduced pressure solvent adds water-soluble Solution, aqueous layer extracted, merging organic layer, the dry organic layer of anhydrous sodium sulfate, filtering, organic layer subtract 300mL methylene chloride in two times Pressure is concentrated to give grease 2- (2,4- dichlorophenyl) methyl -4,4 dimethyl -3- isoxazole alkanone (Formulas I) 17.5g, GC detection master Content is 75%.

Embodiment 2 (patent CN201910188658.2 method)

By 23g 4,4- dimethyl -3- isoxazole alkanone is dissolved in 200mL DMF solvent, and sodium carbonate 25g, heating 75 is added DEG C, vacuum distillation band water, when system moisture is lower than 0.1%, band water terminates.At 75 DEG C, 2,4- dichloro benzyl chloride 39g, drop is added dropwise After adding, 2h is kept the temperature, solvent is sloughed in decompression, and methylene chloride and water, layering is added, and organic phase precipitation obtains 2- (2,4- dichloro-benzenes Base) methyl -4,4- dimethyl -3- isoxazole alkanone compound grease crude product 55g, GC, which is detected, removes target principal product (92%) Outside, 2,4- dichloro benzyl chloride accounts for about 2%.

By above-mentioned crude product 55g, is dissolved with 95mL isopropanol, be cooled to -15 DEG C, 5mL water is slowly added dropwise.Crystal is precipitated, mistake 50g white solid product is filtered to obtain, GC testing product content is 99.1%, and 2,4- dichloro benzyl chlorides are lower than detection limit, and fusing point is 45 DEG C (DSC data attached drawing 1).¹H NMR(500MHz,CDCl₃) δ 7.40 (d, J=2.0Hz, 1H), 7.28 (d, J=8.3Hz, 1H), 7.24 (dd, J=8.3,2.0Hz, 1H), 4.79 (s, 2H), 4.01 (s, 2H), 1.26 (s, 6H).

X-ray powder diffraction proves that 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone (Formulas I) is Crystalline compounds (attached drawing 3).X-ray monocrystalline ray experimental further proves monoclinic structure (attached drawing 2).

Embodiment 3

Embodiment 2 is prepared into resulting 500mg 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone Compound (Formulas I) monoclinic crystal (45 DEG C of fusing point) is mixed with 10mL petroleum ether (60-90 DEG C of boiling range), is warming up to reflux, is cooled to 0 DEG C place 18h, room temperature continue place 20 days, slowly volatilization crystallization.It was found that there is external needle-shaped, interior diamond crystal form mixed crystallization Body generates, and external acicular crystal is collected, 300mg crystal is obtained.GC testing product content is 99.8%, 83.8 DEG C of (DSC numbers of fusing point According to attached drawing 4).

X-ray powder diffraction proves that 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone (Formulas I) is Crystalline compounds (attached drawing 6).X-ray monocrystalline ray experimental further proves orthogonal crystal structure (attached drawing 5), cell parameter It is shown in Table 1.

Embodiment 4

Embodiment 2 is prepared into gained 20g 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkane (Formulas I) Monoclinic crystal is dissolved in 10mL volume ratio 10:1 petroleum ether and toluene Mixed Solvent, is warming up to 60 DEG C of reflux, keeps the temperature 3 hours, drop Warm to room temperature 25 DEG C.After removing about 1/3 volume of solvent of filtrate, it is down to room temperature, 10mg is added in temperature-fall period and is prepared by embodiment 3 Crystal seed, stirring, precipitate crystal again, filter white solid 17g, GC testing product content be 99.3%, 84.5 DEG C of fusing point. X-ray powder diffraction data and embodiment 3 are coincide.

Embodiment 5

Gained 15g 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone is prepared according to embodiment 1 (Formulas I) grease is dissolved in 15ml ethyl alcohol, is warming up to 78 DEG C, and 10mg is added to 10 DEG C, in temperature-fall period by embodiment 3 for slow cooling The crystal seed of preparation, stirring, precipitate crystal, filter white solid 12.1g, GC testing product content be 98.5%, 83 DEG C of fusing point. X-ray powder diffraction data and embodiment 3 are coincide.

Embodiment 6

Gained 10g 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone is prepared according to embodiment 1 (Formulas I) grease is dissolved in 25ml chloroform, is warming up to 60 DEG C, slow cooling to room temperature, and 10mg embodiment 3 is added in temperature-fall period and makes Standby crystal seed, stir 30min, precipitate crystal, filter white solid 8g, GC testing product content be 99%, 83.5 DEG C of fusing point. X-ray powder diffraction data and embodiment 3 are coincide.

Embodiment 7

Gained 10g 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone is prepared according to embodiment 1 (Formulas I) grease is dissolved in 25ml ethyl alcohol, is warming up to reflux, keeps the temperature 1h, slow cooling to room temperature, be added in temperature-fall period 10mg by Crystal seed prepared by embodiment 3,30min is stirred, no crystal is precipitated.

8 2- of embodiment (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone (Formulas I) orthorhombic stability Experiment

2- obtained by embodiment 3,4,5,6 (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone (formula I) crystal is placed in high temperature (60 ± 2 DEG C) baking oven, under 90 ± 5% damp conditions, under 4500 ± 500lux illumination condition respectively 10 days, in the 5th day, the 10th day separately sampled carry out powder x-ray diffraction analysis.

As a result formula is surveyed through X-ray powder diffraction, 2 angles θ of orthorhombic crystal X- powder diffraction and storage are preceding consistent, illustrate orthogonal Jingjing body is stablized under high temperature, high humidity, illumination, belongs to stable crystal form.

9 2- of embodiment (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone (Formulas I) 40% suspending agent Preparation

Effective component as shown in the following chart, dispersing agent, wetting agent, defoaming agent, thickener, antifreeze and water each component are pressed It is uniformly mixed according to the ratio of formula, obtains 2- (2,4- dichlorophenyl) methyl -4,4- dimethyl -3- isoxazole alkanone through sand mill 40% suspending agent.

Experimenter has surprisingly found that, gained suspending agent can satisfy the requirement of aqueous suspension agent routine physicochemical property, and The phenomenon that becoming larger during storage without discovery degradation, partial size.

Detection project	Testing result
		Content, %	39.13%
Content, (54 DEG C, 14 days)	39.10%
		Suspensibility, %	95.46
PH(MT75.2)	8.51
		Persistently blistering mL, 1min	0
Partial size, D90, μm	5.1
		Partial size, D90, μm (54 DEG C, 14 days)	5.3

10 2- of embodiment (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone (Formulas I) 40% water dispersion The preparation of granula

The ratio being formulated as shown in the following chart is uniformly mixed, obtains 2- (2,4- after mechanical crushing, kneading, granulation, drying Dichlorophenyl) 40% water dispersible granules of methyl -4,4- dimethyl -3- isoxazole alkanone.

Component	The trade mark	Percentage
			2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole		40%
Lauryl sodium sulfate	stepanolDX-165N	3%
			Poly naphthalene sulfonate	Morwet D-425	4%
Lignosulfonates	Borresperse CA	4%
			Tallow fatty acid sodium	AGNIQUE Soap-L	0.5%
Kaolin	TS-1	It supplies

Through detecting, gained water dispersible granules meet the requirement of conventional physicochemical property.

11 2- of embodiment (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone (Formulas I) 25% missible oil Preparation

It takes 25g to be added in reaction flask orthorhombic crystal body obtained in embodiment 3, auxiliary agent shown in following table is added, at 30 DEG C Under be uniformly mixed, transparent uniform liquid.2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone contains Amount 25%.2h, 2mL foam, without free oil, without emulsifiable paste.For 24 hours, non-foam, without free oil, without emulsifiable paste.Heat storage, content at 54 DEG C It is unchanged.

Component	The trade mark	Percentage
			2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole		25%
Styryl ethoxy compound	TS160	8%
			Calcium dodecyl benzene sulfonate	CAL	5%
Mineral oil	Solvesso 150	62%

The examination of 12 2- of embodiment (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone (Formulas I) bioactivity It tests

Test target: activity of weeding evaluation test target is broadleaf weeds herba stellariae mediae (Stellaria media), grass family is miscellaneous Careless annual bluegrass (Poa annua L), weed seed are field acquisition, are saved in seed chamber.Safety evaluatio experiment target is denoted as Object is wheat (Triticum aestirum) and corn (Zea mays), and seed is bought from seeds company.

Medical fluid configuration: it is accurate to claim certain mass medicament, the clear water dilution containing 0.1% Tween 80 emulsifier is added and is configured to Certain concentration solution processing, preparation are directly handled with distilled water dilution.

Using greenhouse pot culture facture, quantitative soil is filled in plastic tub, will be broadcasted sowing for trying target weed seed 15~20 Yu Tubiao covers 0.5~1cm of fine earth and is placed on culture in greenhouse, soil spraying treatment is carried out after 24 hours.Embodiment 9,10,11 SC, WG, EC preparation of preparation are with 15.625,31.25,62.5,250,375,500 grams/ha of (g a.i./ha) effective doses pair Crop and weeds carry out soil spraying treatment before bud, and each processing is repeated 3 times.The blank control processing and control of non-medication are set Medicament 360g/L clomazone SC (clomazone, commercially available) processing, blank control group clear water are spraying.Processing, which is placed in greenhouse, trains It supports, the growing state of routine observation target plant, range estimation in 30 days or so integrates growth inhibition ratio after processing.With hazard of plant symptom (inhibition, deformity, yellow, albefaction) shows the growth inhibition ratio of degree range estimation medicament, and 0 indicates no growth effect, and 100% indicates Completely inhibit plant growth.Activity of weeding and crop safety ocular estimate evaluation criterion are as follows:

Test 1: comparison medicament (clomazone), embodiment 11EC dosage form, embodiment 9SC dosage form, embodiment 10WG dosage form are removed Careless activity test.

By test result: 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone (Formulas I) WG Dosage form is 82-100%, 60-97%, activity of weeding highest to the activity of weeding of herba stellariae mediae, annual bluegrass；It secondly is SC dosage form, weeding Activity is 53-100%, 50-97%；EC dosage form again, activity of weeding 50-100%, 43-87%；Comparison medicament activity is most It is low, activity of weeding 50-100%, 10-60%.

Test 2: comparison medicament (clomazone), embodiment 11EC dosage form, embodiment 9SC dosage form, embodiment 10WG dosage form are made Object safety testing.

By test result: 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone (Formulas I) EC Safety highest, be 0-7% and 0% to the growth inhibition ratio of wheat and corn, almost without growth effect, safety is very It is good；SC, WG dosage form are secondly, be 0-13%, 0-11% and 0-15%, 0-13% to the growth inhibition ratio of wheat, corn, only gently Micro- growth effect, safety are preferable；Comparison medicament is 93-100% and 0-5% to the growth inhibition ratio of wheat and corn, to jade Rice safety is preferable but very heavy to wheat phytotoxicity, dangerous.As it can be seen that 2- (2,4- dichlorophenyl) methyl -4,4- dimethyl -3- Isoxazole alkanone (Formulas I) shows preferable safety, safety of EC, SC, WG difference preparation to crop wheat to wheat, corn Property is significantly higher than comparison medicament.

Integration test 1,2, it is believed that 2- (2,4- dichlorophenyl) methyl -4,4- dimethyl -3- isoxazole alkanone orthorhombic crystal Each agent activity being prepared into is significantly better than comparison medicament, and SC containing solid pharmaceutical preparation made from the crystal form, WG activity of weeding are better than EC preparation；The crystal form EC, SC, WG preparation are preferable to the crop safety of wheat and corn, and the especially safety of wheat is aobvious It writes and is better than comparison medicament.As it can be seen that the crystal form is more excellent to the crop safety performance for test compared with comparison medicament, and to miscellaneous for trying The herbicidal effect of grass is higher, will have better application and development prospect.

The preferred embodiment of the present invention has been described above in detail, but the tool that present invention is not limited to the embodiments described above Body details within the scope of the technical concept of the present invention can be with various simple variants of the technical solution of the present invention are made, these letters Monotropic type all belongs to the scope of protection of the present invention.

Claims (12)

1. a kind of crystal of 2- (2,4- dichlorophenyl) methyl -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I), special Sign is that the crystal is orthorhombic, and space group is P21 21 21, and cell parameter is α=90 °, β=90 °, γ=90 °；

2. 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound according to claim 1 The crystal of (Formulas I), it is characterised in that radiated using Cu-K α, with the X-ray powder diffraction position that 2 θ angles indicate, it is described just Crystal is handed at least to show following 3 ranked:

(1) 2 θ=10.53 ± 0.2 °

(2) 2 θ=14.20 ± 0.2 °

(3) 2 θ=15.92 ± 0.2 °

(4) 2 θ=18.54 ± 0.2 °

(5) 2 θ=19.80 ± 0.2 °

(6) 2 θ=21.10 ± 0.2 °

(7) 2 θ=24.92 ± 0.2 °

(8) 2 θ=27.73 ± 0.2 °.

3. 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone chemical combination according to claim 1 or 2 The crystal of object (Formulas I), it is characterised in that the crystalline melting point is 83-85 DEG C.

4. a kind of 2- of any of claims 1 or 2 (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone chemical combination The crystal seed preparation method of the crystal of object (Formulas I), it is characterised in that 2- (2,4- dichlorophenyl) methyl -4,4- dimethyl -3- is different Oxazolidinone compound (Formulas I) Asia thermostabilization monoclinic crystal is dissolved in organic solvent A, and by heating, cooling, temperature-rise period is slowly waved again Send out solvent A, crystallization preparation；The organic solvent A be alkane, cycloalkane it is one or more.

5. 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone compound according to claim 4 The crystal seed preparation method of the crystal of (Formulas I), it is characterised in that the organic solvent A is petroleum ether, and the petroleum ether boiling range is 60- 90℃。

6. a kind of efficiently preparation high-purity thermostabilization 2- described in claim 1 (2,4 dichloro benzene base) methyl -4,4- dimethyl - The method of 3- isoxazole alkanone compound (Formulas I) crystal, it is characterised in that 2- (2,4- dichlorophenyl) methyl -4,4- dimethyl - 3- isoxazole alkanone compound (Formulas I) crude product is dissolved in solvent B, by being warming up to 40-100 DEG C of dissolution, then through being cooled to 10-30 DEG C, temperature-fall period puts into 2- (2,4- dichlorophenyl) methyl -4,4- dimethyl-that method as claimed in claim 4 is prepared The orthogonal crystal seed of 3- isoxazole alkanone compound (Formulas I), crystallization filter and high-purity thermostabilization orthorhombic crystal are made；The crude product is Oily liquids or solid；The solvent B is alkanes, cycloalkane, alkyl halide hydro carbons, aromatic hydrocarbons, ethers, alcohols, esters, ketone Class, sulfoxide type, amide solvent, water it is one or more.

7. efficient preparation high-purity thermostabilization 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl-according to claim 6 The method of 3- isoxazole alkanone compound (Formulas I) crystal, it is characterised in that 2- (2,4- dichlorophenyl) methyl -4 in the crude product, The content of 4- dimethyl -3- isoxazole alkanone compound (Formulas I) is not less than 80%；The solvent B is alkanes, halogenated alkane Class, aromatic hydrocarbons, alcohols solvent, water it is one or more；The different evil of 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- Oxazolidinone compounds (Formulas I) and solvent B weight/volume are 1:0.5-3.

8. according to any efficient preparation high-purity thermostabilization 2- (2,4 dichloro benzene base) methyl -4,4- of claim 6-7 The method of dimethyl -3- isoxazole alkanone compound (Formulas I) crystal, it is characterised in that the solvent B is petroleum ether, toluene, chlorine It is imitative, ethyl alcohol, water one or more.

9. according to any efficient preparation high-purity thermostabilization 2- (2,4 dichloro benzene base) methyl -4,4- two of claim 6-7 The method of methyl -3- isoxazole alkanone compound (Formulas I) crystal, it is characterised in that prepared 2- (2,4- dichlorophenyl) first Base -4,4- dimethyl -3- isoxazole alkanone compound (Formulas I) content is greater than 99%.

10. any 2- (2,4 dichloro benzene base) methyl -4,4- dimethyl -3- isoxazole alkanone chemical combination of claim 1-3 The crystal of object (Formulas I) is in farm chemical preparation preparation, the application of crop control of weeds.

11. application according to claim 10, it is characterised in that the farm chemical preparation is water dispersible granules, suspending agent；Institute Stating crop includes corn, wheat, rape, rice, sorghum, barley or rye；The weeds are barnyard grass, herba digitariae, herba setariae viridis, Cowhells Grass, Bermuda grass, reed, cyperus iria, knotweed, Siberian cocklebur, piemarker, purslane, black nightshade, Chenopodiaceae, acalypha copperleaf, ox chickweed, Amaranthus retroflexus, dent Amaranth, concave head amaranth, Horseweed Herb, elscholtiza, setose thistle, field thistle, sonchus oleraceus, Eclipta prostrata, ivy glorybind, humid euphorbia, dayflower, wild watermelon, Chinese herbaceous peony Grass, alfalfa, Wild soybean, amur foxtail, Alopecurus, Wang grass, herba bromi japonici, annual bluegrass, wild avena sativa (Avena fatua), stick Head grass, rye grass, Triticum tauschii, tongue of sparrow grass, clearvers, herba stellariae mediae, grasswort, Veronica, Hairy Bittercress, pale persicaria, common vetch, shepherd's purse Dish, Chinese ixeris herb, lyrate hemistepta herb, creeping oxalis, wartwort, field bindweed, conical silene herb, small Li, pivot storage, tooth tartaric acid film, penny cress, Herb of Common Nipplewort, Benbie, mexicana, velvetleaf, Radix seu Herba Astilbes rivularis, artemisiifolia, sheep's hay, Itanlian rye, datura, johnson grass (Sorghum Halepense), ipomoea, couchgrass, sunflower, RHIZOMA FAGOPYRI CYMOSI (Polygonum convolvulus), wild mustard (Sinapis Arvensis), setaria glauca, green green bristlegrass, Chenopodium album, bengal dayflower herb, fennelflower, wide leaf Brachiaria Griseb, creeping thistle, Binzhou Siberian cocklebur (Xanthium pensylvanicum), corn poppy, huge herba setariae viridis, hair clover, resistance fennelflower, add field violet It puts on airs first fluffy, big herba digitariae grass, small seed Phalaris grass, Pennsylvania knotweed, depression potato, thorn bur, silk gentle breeze grass, open country poinsettia, Huang Nutgrass flatsedge (cyperue esculentus Cyperus esculentus).

12. application according to claim 11, it is characterised in that farm chemical preparation is water dispersible granules, and the crop is jade Rice, wheat；The weeds are herba stellariae mediae, annual bluegrass.